Rivastigmine

Additional information

Swedish patients diagnosed with dementia by a specialist (and not by a general practitioner), are diagnosed with Alzheimer’s disease (AD) in 2/3 of the cases. The prevalence of dementia is higher in women, especially among the oldest patients [1]. The incidence of AD in Europe is significantly higher in women than in men (13.25 vs 7.02  per 1000 person-years); these rates increased with age [2].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 [3]. Another review identified 48 RCTs of which two had taken patient’s sex into account when evaluating AD treatment efficacy [4].

Pharmacokinetics and dosing

No studies with a clinically 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 [5]. In a randomized placebo-controlled trial (486 men, 532 women), the InDDEx trial [6], 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 [7]. With so few men included in the study and thus a low statistical power it is hard to draw any conclusions regarding sex differences and treatment outcome. A Japanese cohort study, the Okayama Late Dementia Study OLDS included patients with AD treated with rivastigmine (20 men, 43 women) [8] 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 [6], evaluated the effect of patient's sex on treatment response of rivastigmine 3- to 12 mg/day capsules in patients with mild cognitive impairment (MCI) [9]. 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 [9].

Adverse effects

In the post hoc analysis of the RCT InDDEx trial mentioned above (486 men, 532 women), the prevalence of serious adverse events in the rivastigmine groups were 27.0% in women and 29.0% in men [9].

Reproductive health issues

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

Other information

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 [10]. 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 [11].

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 [12]. 

A German study (4883 men, 8027 women) found that younger men (45-60 years) and patients with private health insurance had a lower risk of discontinuation of AD treatment with memantine, donepezil, galantamine, and rivastigmine [13].