Mirabegron

Mirabegron, at therapeutic doses, has not demonstrated clinically relevant QT prolongation in clinical studies. However, since patients with a known history of QT prolongation or patients who are taking medicinal products known to prolong the QT interval were not included in these studies, the effects of mirabegron in these patients is unknown. Caution should be exercised when administering mirabegron in these patients.

In healthy volunteers, the inhibitory potency of mirabegron towards CYP2D6 is moderate and the CYP2D6 activity recovers within 15 days after discontinuation of mirabegron. Multiple once daily dosing of mirabegron IR resulted in a 90% increase in C_max and a 229% increase in AUC of a single dose of metoprolol. Multiple once daily dosing of mirabegron resulted in a 79% increase in C_max and a 241% increase in AUC of a single dose of desipramine.

Caution is advised if mirabegron is co-administered with medicinal products with a narrow therapeutic index and significantly metabolised by CYP2D6, such as thioridazine, Type 1C antiarrhythmics (e.g., flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Caution is also advised if mirabegron is co-administered with CYP2D6 substrates that are individually dose titrated.

Mirabegron has not been studied in patients with end stage renal disease (ESRD) (estimated glomerular filtration rate (eGFR) <15 ml/min/1.73 m²), patients requiring haemodialysis, or patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, it is not recommended for use in these patient populations.

The following table provides the daily dosing recommendations for adult overactive bladder (OAB) syndrome patients with renal or hepatic impairment.

Table 1. Daily dosing recommendations for adult OAB patients with renal or hepatic impairment:

¹ Mild/Moderate: eGFR 30 to 89 ml/min/1.73 m²; Severe: eGFR 15 to 29 ml/min/1.73 m²; ESRD: eGFR <15 ml/min/1.73 m².
² Mild: Child-Pugh Class A; Moderate: Child-Pugh Class B; Severe: Child-Pugh Class C.
^* In patients with mild to moderate renal impairment or mild hepatic impairment concomitantly
receiving strong CYP3A inhibitors, the recommended dose is no more than 25 mg.
^** Not recommended for use in patients with severe renal impairment or moderate hepatic impairment concomitantly receiving strong CYP3A inhibitors.

The following table provides the daily dosing recommendations for paediatric neurogenic detrusor overactivity (NDO) patients aged 3 to less than 18 years with renal or hepatic impairment weighing 35 kg or more.

Table 2. Daily dosing recommendations for paediatric NDO patients aged 3 to less than 18 years with renal or hepatic impairment weighing 35 kg or more:

¹ Mild/Moderate: eGFR 30 to 89 ml/min/1.73 m²; Severe: eGFR 15 to 29 ml/min/1.73 m²; ESRD: eGFR <15 ml/min/1.73 m². No dose adjustment is necessary for patients with mild to moderate renal impairment.
² Mild: Child-Pugh Class A; Moderate: Child-Pugh Class B; Severe: Child-Pugh Class C.
^* In patients with mild to moderate renal impairment or mild hepatic impairment concomitantly receiving strong CYP3A inhibitors, the recommended dose is no more than the starting dose.
^** Not recommended for use in patients with severe renal impairment or moderate hepatic impairment concomitantly receiving strong CYP3A inhibitors.

Mirabegron is a weak inhibitor of P-gp. Mirabegron increased C_max and AUC by 29% and 27%, respectively, of the P-gp substrate digoxin in healthy volunteers. For patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should be prescribed initially. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. The potential for inhibition of P-gp by mirabegron should be considered when digoxin is combined with sensitive P-gp substrates e.g. dabigatran.

Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medicinal products for the treatment of OAB has been reported in post-marketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in patients treated with mirabegron; however, mirabegron should be administered with caution to patients with clinically significant BOO. Mirabegron should also be administered with caution to patients taking antimuscarinic medicinal products for the treatment of OAB.

Data are limited in patients with stage 2 hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg).

There are no or limited amount of data from the use of mirabegron in pregnant women. Studies in animals have shown reproductive toxicity. Mirabegron is not recommended during pregnancy.

Mirabegron is excreted in the milk of rodents and therefore is predicted to be present in human milk. No studies have been conducted to assess the impact of mirabegron on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child.

Mirabegron should not be used during breast-feeding.

Woman of childbearing potential

Mirabegron is not recommended in women of childbearing potential not using contraception.

Fertility

There were no treatment-related effects of mirabegron on fertility in animals. The effect of mirabegron on human fertility has not been established.

Mirabegron has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The safety of mirabegron was evaluated in 8 433 adult patients with OAB, of which 5 648 received at least one dose of mirabegron in the phase ⅔ clinical program, and 622 patients received mirabegron for at least 1 year (365 days). In the three 12-week phase 3 double blind, placebo-controlled studies, 88% of the patients completed treatment with this medicinal product, and 4% of the patients discontinued due to adverse events. Most adverse reactions were mild to moderate in severity.

The most common adverse reactions reported for adult patients treated with mirabegron 50 mg during the three 12-week phase 3 double blind, placebo-controlled studies are tachycardia and urinary tract infections. The frequency of tachycardia was 1.2% in patients receiving mirabegron 50 mg. Tachycardia led to discontinuation in 0.1% patients receiving mirabegron 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving mirabegron 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving mirabegron 50 mg. Serious adverse reactions included atrial fibrillation (0.2%).

Adverse reactions observed during the 1-year (long term) active controlled (muscarinic antagonist) study were similar in type and severity to those observed in the three 12-week phase 3 double blind, placebo-controlled studies.

Tabulated list of adverse reactions

The table below reflects the adverse reactions observed with mirabegron in adults with OAB in the three 12-week phase 3 double blind, placebo-controlled studies.

The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000) and not known (cannot be established from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

^* observed during post-marketing experience

Paediatric population

The safety of mirabegron tablets and oral suspension was evaluated in 86 paediatric patients aged 3 to less than 18 years with NDO in a 52-week, open-label, baseline-controlled, multicentre, dose titration study. The most commonly reported adverse reactions observed in the paediatric population were urinary tract infection, constipation, and nausea.

In the paediatric patients with NDO, no severe adverse reactions were reported.

Overall, the safety profile in children and adolescents is similar to that observed in adults.