Drug products: Betmiga
ATC code: G04BD12
Exposure is higher in women but dose adjustment due to only sex is not recommended.
The majority of participants in the clinical studies were women and analysis of differences between men and women in effect and adverse events are based on pooled data. Sex differences in effect of mirabegron may at least partly be related to differences in clinical presentation of the condition itself.
A small study showed supratherapeutic doses of mirabegron to induce QT prolongation in women but not in men.
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 possible etiology of these symptoms in men and women mirabegron’s place in therapy is slightly different. In women, mirabegron treatment is used as an alternative to anticholinergics when non-pharmacological treatments such as bladder training are insufficient. 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 .The baseline symptoms described in studies differ between men and women regarding prevalence of incontinence episodes and frequency of urgency episodes [2, 3]. 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 . Two other meta-analysis report that changes from baseline with placebo treatment are significant for mean micturitions, mean incontinence episodes and mean voided volume [5, 6]. Most studies include more women than men, and the low number of men included can affect the ability to make statistically significant analysis.
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% . 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 . Another study on healthy individuals (32 young men, 32 young women, 16 elderly men, 16 elderly women) given multiple doses, 50 to 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% . A study on healthy East Asian subjects showed similar sex differences regarding pharmacokinetic parameters .
The exposure of mirabegron is decreased by food intake and this effect has been shown to be similar in men and women .
No sex differentiation in dosing has been recommended by the manufacturer . 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. In the US the recommended starting dose is 25 mg, with possible increase to 50 mg after 8 weeks based on efficacy. In general women have higher CYP3A4 activity .
Based on data from three phase 3 studies the mean reduction from baseline regarding incontinence episodes was larger in women, men were less likely than women to have incontinence episodes at baseline though. Mirabegron has been reported to reduce incontinence episodes and micturations in both men and women .
In a cross over safety study including healthy subjects (22 men and 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 .
The major clinical studies of mirabegron treatment include mostly women (between 69-89%). In a pooled analysis of data from four phase 3 studies, three 12 week and one 12 month study, sex differences regarding safety and tolerability was evaluated. The overall frequency of treatment emergent adverse effects in the 12 week studies was higher in women, however the difference compared to placebo was similar between sexes. Most adverse effects were also more common in women, with the notable exception of hypertension. No significant difference between men and women regarding overall adverse effects was seen in the 12 month study .
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Patient satisfaction with anticholinergic treatment was evaluated in a survey study in Japanese patients with overactive bladder syndrome (in total 514 men, 455 women). In the entire study one third of all patients were satisfied and one third dissatisfied with their treatment, men were overall less satisfied than women. Dissatisfaction was commonly influenced by poor efficacy or adverse effects, mainly constipation .
Date of litterature search: 2015-03-12
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson