In vitro data: Mirabegron is transported and metabolised through multiple pathways. Mirabegron is a substrate for cytochrome P450 (CYP) 3A4, CYP2D6, butyrylcholinesterase, uridine diphospho‑glucuronosyltransferases (UGT), the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1, OCT2 and OCT3. Studies of mirabegron using human liver microsomes and recombinant human CYP enzymes showed that mirabegron is a moderate and time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. Mirabegron inhibited P‑gp‑mediated drug transport at high concentrations.
In vivo data: CYP2D6 polymorphism: CYP2D6 genetic polymorphism has minimal impact on the mean plasma exposure to mirabegron (see Pharmacology: Pharmacokinetics under Actions). Interaction of mirabegron with a known CYP2D6 inhibitor is not expected and was not studied. No dose adjustment is needed for mirabegron when administered with CYP2D6 inhibitors or in patients who are CYP2D6 poor metabolisers.
Drug-drug interactions: The effect of co-administered medicinal products on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of other medicinal products was studied in single- and multiple-dose studies. Most drug‑drug interactions were studied using a dose of 100 mg mirabegron given as oral controlled absorption system (OCAS) tablets. Interaction studies of mirabegron with metoprolol and with metformin used mirabegron immediate-release (IR) 160 mg.
Clinically relevant drug interactions between mirabegron and medicinal products that inhibit, induce or are a substrate for one of the CYP isozymes or transporters are not expected except for the inhibitory effect of mirabegron on the metabolism of CYP2D6 substrates.
Effect of enzyme inhibitors: Mirabegron exposure (AUC) was increased 1.8-fold in the presence of the strong inhibitor of CYP3A/P-gp ketoconazole in healthy volunteers. No dose adjustment is needed when Betmiga is combined with inhibitors of CYP3A and/or P-gp. However, in patients with mild to moderate renal impairment (GFR 30-89 mL/min/1.73 m2) or mild hepatic impairment (Child‑Pugh Class A) concomitantly receiving strong CYP3A inhibitors, such as itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended dose is 25 mg once daily with or without food (see Dosage & Administration). Betmiga is not recommended in patients with severe renal impairment (GFR 15-29 mL/min/1.73 m2) or patients with moderate hepatic impairment (Child‑Pugh Class B) concomitantly receiving strong CYP3A inhibitors (see Dosage & Administration and Precautions).
Effect of enzyme inducers: Substances that are inducers of CYP3A or P-gp decrease the plasma concentrations of mirabegron. No dose adjustment is needed for mirabegron when administered with therapeutic doses of rifampicin or other CYP3A or P-gp inducers.
Effect of mirabegron on CYP2D6 substrates: 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 Cmax and a 229% increase in AUC of a single dose of metoprolol. Multiple once daily dosing of mirabegron resulted in a 79% increase in Cmax 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.
Effect of mirabegron on transporters: Mirabegron is a weak inhibitor of P-gp. Mirabegron increased Cmax and AUC by 29% and 27%, respectively, of the P-gp substrate digoxin in healthy volunteers. For patients who are initiating a combination of Betmiga 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 Betmiga is combined with sensitive P-gp substrates e.g. dabigatran.
Other interactions: No clinically relevant interactions have been observed when mirabegron was co-administered with therapeutic doses of solifenacin, tamsulosin, warfarin, metformin or a combined oral contraceptive medicinal product containing ethinylestradiol and levonorgestrel. Dose adjustment is not recommended.
Increases in mirabegron exposure due to drug-drug interactions may be associated with increases in pulse rate.