Mirabegron

Additional information

The selective beta-3 adrenoreceptor agonist mirabegron induce relaxation of the bladder detrusor muscle and is used to treat urgency incontinence and symptoms of overactive bladder. Due to differences in  etiology of these symptoms in men and women, mirabegron’s place in therapy is  different. Therefore, treatment guidelines for LUTS (lower tract urinary symptoms) differ in men and women. In women, mirabegron treatment is used as an alternative to anticholinergics when non-pharmacological treatments such as bladder training are insufficient [1]. In men, benign prostate hyperplasia is a possible cause of urgency symptoms. Other drugs, primarily alpha-1 blockers, are therefore common as first-line treatments. However, mirabegron can be used in addition to drugs for benign prostate hyperplasia or as monotherapy as an alternative to anticholinergic drugs [2,3].The baseline symptoms described in studies differ between men and women regarding prevalence of incontinence episodes and frequency of urgency episodes [4, 5]. Treatment effects on these parameters are common outcomes in clinical studies and differences in treatment effect between men and women need to be interpreted in relation to differences at baseline.The placebo effect seen in clinical studies of overactive bladder treatment is relatively high. According to a meta-analysis, 41% of the patients in placebo groups report cure or symptom improvement [6]. Two other meta-analyses report that changes from baseline with placebo treatment are significant for mean micturitions, mean incontinence episodes and mean voided volume [7, 8]. Most studies include more women than men, and the low number of men included can affect the ability to detect statistically significant differences [9].

Pharmacokinetics and dosing

According to the manufacturer’s documentation to FDA, clinical studies showed that Cmax and AUC are 40-50% higher in women. After adjusting for body weight the difference was 20-30% [10]. Data from two pharmacokinetic studies (65 men, 38 women) showed that after a single dose mirabegron AUC was 27% and 64% higher in women, for IV and PO administration respectively. These differences were largely due to differences in body weight and in the case of oral treatment also absolute bioavailability. Similarly, clearance was lower in women than in men mostly due to differences in weight and bioavailability [11].Another study on healthy individuals (32 young men, 32 young women, 16 elderly men, 16 elderly women) given multiple doses, 50-300 mg, of an oral controlled absorption mirabegron tablet. Both Cmax and AUC was about 40% higher in women. After adjustment for body weight the difference was 20% [12]. A study on healthy East Asian subjects showed similar sex differences regarding pharmacokinetic parameters [13].The exposure of mirabegron is decreased by food intake and this effect has been shown to be similar in men and women [14].

No sex differentiation in dosing has been recommended by the manufacturer [10]. The dosing recommendation differs between EU and the US. The recommended starting dose in both men and women with normal kidney and liver function and without concurrent use of CYP3A inhibitors is 50 mg in EU [15]. In the US the recommended starting dose is 25 mg, with possible increase to 50 mg after 8 weeks based on efficacy [16]. In general women have higher CYP3A4 activity [15].

Effects

No difference in effect between men and women was found in a cohort study with patients on low dose mirabegron [17] while larger effects in women, have been found in pooled analyses of clinical trials [10, 18]. The sex differences in effect may at least partly be related to differences in clinical presentation of the condition itself. The studies are described below.

Based on data from three phase 3-studies, the mean reduction from baseline regarding incontinence episodes was larger in women, although men were less likely than women to have incontinence episodes at baseline. Mirabegron has been reported to reduce incontinence episodes and micturations in both men and women [10].In a pooled data analysis from 10 phase 2-4 studies, double-blind, 12-week mirabegron monotherapy studies in adults with overactive bladder (1287 men, 3948 women), the magnitude of changes from baseline in the mean number of incontinence episodes/24 h versus placebo was, in general, numerically higher in women [18].In patients (101 men, 76 women) with overactive bladder treated with low dose mirabegron (25 mg), symptom improvement (Overactive Bladder Symptom Score, Urgency Severity Score, urge urinary incontinence, International Prostate Symptom Score) and drug persistence rate did not differ between men and women [17].

Adverse effects

No sex differences in safety of mirabegron were found in pooled analyses of clinical trials [18, 19]. Similar results were also found in observational studies exploring correlations with a patient’s sex and QT-interval in mirabegron users [20], or associations of incident dementia [21] or cancer risk with mirabegron use compared with antimuscarinics among men and women [22]. Only one small observational study showed prolonged QTc in women but not in men, in healthy subjects with supratherapeutic doses of mirabegron [23]. The studies are described below.

In a cross-over safety study including healthy subjects (22 men, 22 women) supratherapeutic doses of 200 mg mirabegron caused prolonged QTc in women but not in men. At therapeutic doses of 50 mg and supratherapeutic doses of 100 mg, no QTc-prolongation was found in either sex [23]. No correlations with a patient’s sex and QT-interval or heart rate were found in patients with overactive bladder and concomitant cardiovascular disease treated with mirabegron (25 mg or 50 mg), in a Japanese post-marketing observational study (146 men, 90 women) [20].In a Canadian population-based case-control study (13534 men, 27739 women), no association between receipt of mirabegron and incident dementia was found among men or women [21]. However, in a Canadian population-based cohort study, a patient’s sex was found to be an effect modifier to the increased risk of dementia among anticholinergic users (21058 men, 26266 women) compared to beta-3 agonist users (10529 men, 13133 women)  [24].A cohort study with Swedish and Danish register data of cancer occurrence in users of mirabegron (80637, 66% women) and antimuscarinic treatment (169885, 66% women) for overactive bladder showed no association between mirabegron use and risk of cancer, compared with antimuscarinic medications, in either men or women [22].The major clinical studies of mirabegron treatment include mostly women (between 69 and 89%).  In a pooled analysis of data from four phase III studies, three 12-week and one 12-month study, sex differences regarding safety and tolerability were evaluated (total 1932 men, 5123 women, mirabegron 1208 men, 3160 women). The overall frequency of  adverse reactions in the 12-week studies was higher in women, however the difference compared to placebo was similar between sexes. Most adverse reactions were also more common in women, with the notable exception of hypertension. No significant difference between men and women regarding overall adverse reactions was seen in the 12-month study [19].The frequencies of dry mouth, constipation, tachycardia, urinary retention, and of adverse effects leading to discontinuation were similar for men and women. Urinary tract infection occurred at a higher frequency in women compared to men (2.3% vs <1%) [18].

Reproductive health issues

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