— hypersensitivity to the active substance or to any of the excipients;
— children's age (the lack of data on efficacy and safety);
— pregnancy and breastfeeding;
— end-stage renal disease (eGFR<15 1="" 73="" sup="">2 or patients who have shown the kidney dialysis);
— heavy stage renal disease (eGFR 15-29 ml/min/1.73 m2) while the use of strong inhibitors of CYP3A isozyme;
— heavy stage liver failure (class C on a scale child-Pugh);
— moderate stage liver failure (class b on a scale child-Pugh) while the use of strong inhibitors of CYP3A isozyme.
With caution:
Patients with renal and hepatic insufficiency
Patients with severe-stage renal disease should be treated with caution and dose for them should not exceed 25 mg/day.
Patients with mild to moderate-stage renal disease, at the same time receiving strong inhibitors of isoenzyme CYP3A, should be treated with caution and dose for them should not exceed 25 mg/day.
Patients with moderate-stage liver failure should be treated with caution and dose for them should not exceed 25 mg/day.
Patients with mild stage of hepatic insufficiency (Class And on a scale child-Pugh), at the same time receiving strong inhibitors of isoenzyme CYP3A, should be treated with caution and dose for them should not exceed 25 mg/day.
Patients with uncontrolled severe arterial generasie
Since studies with the drug ATmega in patients with uncontrolled severe arterial hypertension (systolic BP>180 mm Hg.St. and/or diastolic blood pressure >110 mm Hg.St.), was conducted, so the drug is not recommended for use in this category of patients.
There are only limited data regarding this drug ATmega in patients with stage 2 hypertension (systolic BP>160 mm Hg. article and/or diastolic blood pressure>100 mm Hg.St.).
Patients with congenital or acquired QT prolongation
Mirabegron at therapeutic doses, has not demonstrated clinically significant QT interval prolongation in the framework of the conducted research. However, since the patients taking drugs that may cause QT prolongation, have not participated in these studies with application of mirabehn, and the impact on such category of patients is not known. This category of patients should receive marabahan with caution.
Should be cautious appoint mirabehn in combination with drugs having a narrow therapeutic index and drugs that are largely metabolized by CYP2D6 isoenzyme, for example, thioridazine, drugs for the treatment of arrhythmia Type 1C (for example, flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Mirabegron should be taken with caution when co-administered with drugs that are metabolized by CYP2D6 isoenzyme and the dose of which is subject to individual definition.
Application of pregnancy and breastfeeding
Pregnancy
There are limited data on the use of mirabehn during pregnancy. The results of reproductive toxicity studies in animals do not indicate direct or indirect negative impacts of marabahan. To prevent possible negative effects on the fetus should be avoided Betmiga of the drug in pregnant women and women in childbearing age and not using contraception.
Lactation
In rodents, Mirabegron is excreted in breast milk, therefore, in humans there is also the risk of the drug in breast milk. Studies on the influence of Mirabegron for the production of breast milk, discharge of Mirabegron breast milk and the impact on the child missing. Mirabehn should not be used in women during breast-feeding.
Fertility
In animal studies the influence of marabahan on fertility at non-lethal doses were not revealed.
Not installed, does mirabehn on fertility in humans.
Application for violations of liver function
Patients with moderate-stage liver failure should be treated with caution and dose for them should not exceed 25 mg/day.
Patients with mild stage of hepatic insufficiency (Class And on a scale child-Pugh), at the same time receiving strong inhibitors of isoenzyme CYP3A, should be treated with caution and dose for them should not exceed 25 mg/day.
Application for violations of renal function
Patients with severe-stage renal disease should be treated with caution and dose for them should not exceed 25 mg/day.
Patients with mild to moderate-stage renal disease, at the same time receiving strong inhibitors of isoenzyme CYP3A, should be treated with caution and dose for them should not exceed 25 mg/day.
The children
Prohibited use of the drug in children since no data on efficacy and safety.
Special instructions
Effects on ability to drive vehicles and operate machinery
Betmiga the drug has no clinically significant effect on the ability to drive vehicles and mechanisms.
Overdose
A single appointment of Mirabegron healthy volunteers used doses up to 400 mg At this dose level recorded adverse events in the form of palpitations (1 of 6 volunteers) and increase heart rate over 100 BPM (3 of 6 volunteers). In case of repeated (within 10 days) use of the drug in daily doses up to 300 mg in healthy volunteers reported an increase in heart rate and increase in systolic blood pressure.
In case of overdose symptomatic and supportive therapy. It is necessary to control heart rate, blood pressure and ECG.
Drug interactions
Data of in vitro studies
Mirabegron is a moderate inhibitor with the time dependence of the isoenzyme CYP2D6 and a weak inhibitor of isoenzyme CYP3A. At high concentrations of Mirabello inhibited the transport of drugs by P-glycoprotein.
These studies in vivo
Polymorphism of the isoenzyme CYP2D6
Genetic polymorphism of the CYP2D6 isoenzyme has a minimal effect on the average concentration of Mirabegron in blood plasma. Although the interaction of marabahan with inhibitors of CYP2D6 isoenzyme has not been studied, theoretically, it is expected. In patients receiving inhibitors of the CYP2D6 isoenzyme, as well as in patients with a slow metabolism substrates CYP2D6 isoenzyme of the need for dose adjustment of Mirabegron no.
Drug-drug interactions
Most drug-drug interactions were studied using 100 mg of marabahan in the form of controlled release tablets (OKAS). In the study of the interactions of Mirabegron metoprolol and metforminom used Mirabegron immediate-release (IR) dose of 160 mg. Clinically significant interactions between miramiguoa and drugs that inhibit, activate, or are a substrate for one of the CYP isozymes or transporters, are not expected, except for inhibitory effect of marabahan on the metabolism of substrates of CYP2D6 isoenzyme.
Effect on enzyme inhibitors
The concentration of Mirabegron (AUC) increased by 1.8 times under the influence of a strong inhibitor of the isoenzyme CYP3A/P-gp ketoconazole in healthy volunteers. Dose adjustment of Mirabegron not required when co-administered with inhibitors of isoenzyme CYP3A or P-gp. However, in patients with mild or moderate renal insufficiency (eGFR 30-89 ml/min/1.73 m2) or mild hepatic insufficiency (class And on a scale child-Pugh), which takes such strong inhibitors of isoenzyme CYP3A like Itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended daily dose of mirabehn is 25 mg regardless of the meal.
Effect on enzyme inducers
Substances that induce isoenzyme CYP3A or P-gp, reduce the concentration of Mirabegron in plasma. Dose adjustment is not required when applying marabahan along with therapeutic doses of rifampicin or other inducers of isoenzyme CYP3A or P-gp.
The influence of marabahan on drugs, metaboliziruemah the isoenzyme CYP2D6
In healthy volunteers Mirabegron moderately ingibiruet isoenzyme CYP2D6, whose activity is restored after 15 days after discontinuation of marabahan. Daily intake of Mirabegron led to increase in Cmax 90% and ACC by 229% for a single dose of metoprolol. Daily intake of mirabehn has led to an increase in Cmax by 79% and ACC 241% for one dose desipramine. Should be cautious appoint mirabehn in combination with drugs having a narrow therapeutic index and drugs that are largely metabolized by CYP2D6 isoenzyme, for example, thioridazine, drugs for the treatment of arrhythmia type 1C (for example, flecainide, propafenone) and tricycline antidepressants (e.g., imipramine, desipramine). Mirabegron should be taken with caution when co-administered with drugs that are metabolized by CYP2D6 isoenzyme and the dose of which is subject to individual definition.
The influence of Mirabegron of drugs transported by the protein Transporter (P-gp)
Mirabegron is a weak inhibitor of the protein P-gp. Mirabello contributed to an increase in Cmax and ACC 29% and 27% respectively when taken with digoxin in healthy volunteers. For patients who start taking mirabehn and digoxin at the same time, be receiving digoxin at low dose. In this case it is necessary to monitor digoxin concentrations in plasma and recruitment of further effective doses of digoxin on the results of control tests. Potential inhibiting protein P-gp miramiguoa should be taken into account in the appointment of Mirabegron together with drugs that are transported by proteins P-gp, e.g. dabigatran.
Other forms of interaction
Clinically significant interactions when co-administered of marabahan with solifenacin, tamsulosin, warfarin, Metformin or combined oral contraceptives containing ethinyl estradiol and levonorgestrel, have been identified. Dose adjustment is not required.
The growing influence of Mirabegron when co-administered with other drugs has been reflected in increased heart rate.
