Although several studies have demonstrated that tolterodine ER is generally well tolerated in subjects with different demographical characteristics (23
), none have investigated the tolerability of tolterodine ER in subjects aged ≥ 75 years relative to younger age groups. The current retrospective evaluation of pooled data from five studies provides further evidence that tolterodine ER is well tolerated in younger (aged < 65 years) and in older subjects (aged 65–74 or ≥ 75 years) with OAB. Importantly, the ratio of discontinuations because of AEs between tolterodine ER vs. placebo groups was similar among subjects aged < 65 years and subjects aged 65–74 or ≥ 75 years. However, it was found that AE-related discontinuation rates tended to be slightly higher in older subjects in both treatment groups. This finding is consistent with the notion that the older subjects may be more prone to tolerability and safety issues compared with their younger counterparts (32
). Possible factors contributing to this finding may include changes in pharmacokinetics of antimuscarinics with age and polypharmacy in older patients (33
). However, because the slight elevation in discontinuation rates was of similar magnitude among subjects ≥ 75 years in both placebo and tolterodine ER treatment groups, it is likely that this finding is primarily attributable to other factors, perhaps including comorbidities that lead to study discontinuation.
Not surprisingly, dry mouth, the most commonly reported AE associated with antimuscarinic agents (29
), was consistently higher in subjects treated with tolterodine ER compared with placebo. Notably, neither the frequency nor the severity of dry mouth associated with tolterodine ER treatment was greater among subjects aged 65–74 or ≥ 75 years than among subjects aged < 65 years. Headache and constipation were also reported slightly more often by subjects receiving tolterodine ER compared with placebo. The occurrence of the other AEs investigated, including nausea, UTI, blurred vision, dry eye, dizziness and micturition disorder, was relatively low (< 3%), and none appeared to be associated with or attributed to tolterodine ER treatment. Moreover, none of these AEs was higher in older subjects, and no AEs occurred more frequently in subjects aged 65–74 or ≥ 75 years than among subjects aged < 65 years who were treated with tolterodine ER.
These data should be viewed within the context of their inherent limitations. For example, the analyses did not take into account the potential differences in medical comorbidities among the three age cohorts. Furthermore, because these studies were not designed for the purpose of comparing tolerability across age groups, outcomes for which older people may be particularly vulnerable were not assessed. The risk of cognitive impairment, from mild confusion to delirium and dementia, is of particular concern in older patients with a variety of pharmacological agents, including anticholinergic medications. Such concern is based on age- and health-related changes in neuropharmacological response and pharmacokinetics, as well as increased total anticholinergic burden related to greater likelihood of polypharmacy in the elderly (34
). One published study found that anticholinergic use was associated with a greater risk for mild cognitive impairment (MCI) among elderly individuals (36
); MCI was not evaluated in any of the five studies included in the current analysis. There is evidence that oxybutynin alters quantitative electroencephalogram (qEEG) activity in healthy volunteers (37
) and may compromise cognitive activity in older patients (38
). Tolterodine does not readily cross the blood–brain barrier (40
) and exerts little impact on qEEG activity (37
), although there have been isolated case reports of cognitive impairment (41
). This issue deserves further investigation through large well-controlled clinical trials powered to assess this outcome.
The data presented in this report are consistent with the most recent Beers criteria (30
), which provide guidance for appropriate prescribing practices in older adults. The Beers criteria do not list tolterodine as a medication to be avoided in older individuals except in those with clinically significant bladder outlet obstruction (BOO). This is based on a theoretic concern about increased risk of urinary retention (30
). As stated in the prescribing information for tolterodine ER and other antimuscarinics (44
), such agents must be used with caution in individuals of any age with clinically significant BOO. Thus, this appears to be a class effect rather than an age-related effect. Although not listed in the Beers criteria, antimuscarinic agents are also contraindicated in individuals with a history of unstable or untreated narrow-angle glaucoma (44
), the prevalence of which is increased in older individuals.
These data are also consistent with previous studies in which tolterodine immediate release (IR) was shown to have a favourable tolerability profile in older subjects. In a double-blind placebo-controlled study with subjects aged ≥ 65 years, no differences were found in the occurrence of serious AEs between subjects taking placebo vs. tolterodine IR (1 or 2 mg bid) (26
). Similarly, a logistic regression analysis of data from a large, open-label, observational study did not find any significant effect of age on the tolerability of tolterodine IR treatment (27
). The results of a nursing home urinary incontinence management programme also suggest that tolterodine IR (1 or 2 mg bid) is well tolerated in this older population (28
). The results of the current analysis suggest that tolterodine ER, which has better efficacy and tolerability than tolterodine IR (22
), is also well tolerated in older individuals. This finding, combined with the observations that tolterodine ER is an effective and safe treatment for OAB, is important because the prevalence of OAB increases with age. Thus, the potential for differential susceptibility to these common AEs, as well as others, needs to continue to be explored (3