Description of the drug BETMIGA
Mirabegron is a moderate, time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. At high concentrations, mirabegron inhibited drug transport via P-glycoprotein.
Clinically significant interactions between mirabegron and medicinal products that inhibit, activate or are a substrate of one of the CYP isoenzymes or transporters are not expected, with the exception of the inhibitory effect of mirabegron on the metabolism of CYP2D6 isoenzyme substrates.
Mirabegron concentration (AUC) increased 1.8-fold under the influence of the strong CYP3A/P-gp inhibitor ketoconazole in healthy volunteers. Dose adjustment of mirabegron is not required when taken together with inhibitors of the CYP3A or P-gp isoenzyme. However, in patients with mild to moderate renal impairment (eGFR 30-89 ml/min/1.73 m2) or mild hepatic impairment (Child-Pugh class A) taking strong CYP3A inhibitors such as itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended daily dose of mirabegron is 25 mg, regardless of meals.
Substances that induce CYP3A or P-gp isoenzymes reduce the plasma concentration of mirabegron.
In healthy volunteers, mirabegron moderately inhibits the CYP2D6 isoenzyme, the activity of which is restored 15 days after discontinuation of mirabegron. Daily dosing of mirabegron resulted in a 90% increase in Cmax and 229% increase in AUC for a single dose of metoprolol. Daily dosing of mirabegron resulted in a 79% increase in Cmax and 241% increase in AUC for a single dose of desipramine. Mirabegron should be used with caution in combination with drugs that have a narrow therapeutic index and drugs that are significantly metabolized by CYP2D6, such as thioridazine, drugs for the treatment of class I C arrhythmias (for example, flecainide, propafenone) and tricyclic antidepressants (for example, imipramine, desipramine). Mirabegron should also be taken with caution when co-administered with drugs that are metabolized by the CYP2D6 isoenzyme and the dose of which must be individually determined.
Mirabegron is a weak inhibitor of the P-gp protein. Mirabegron increased Cmax and AUC by 29% and 27%, respectively, when administered with digoxin to healthy volunteers. For patients starting to take mirabegron and digoxin at the same time, digoxin should be taken at the lowest dose. In this case, it is necessary to monitor the concentrations of digoxin in the blood plasma and select a further effective dose of digoxin based on the results of control tests. The potential for P-gp inhibition by mirabegron should be taken into account when mirabegron is administered concomitantly with drugs transported by P-gp proteins, such as dabigatran.
The increased effect of mirabegron when taken together with other drugs is expressed in an increase in heart rate.
Betmiga, 50 mg, extended-release film-coated tablets, 30 pcs.
Pharmaceutical group: Drugs for the treatment of urological diseases / Pharmaceutical action: Mirabegron is a powerful selective beta3-adrenergic receptor agonist. Studies with mirabegron have demonstrated relaxation of bladder smooth muscle in rats and in isolated human tissue, as well as an increase in cAMP concentrations in bladder tissue in rats. Thus, mirabegron improves the reservoir function of the bladder by stimulating beta3-adrenergic receptors located in its wall. Studies have demonstrated the effectiveness of mirabegron both in patients who have previously received M-anticholinergics for the treatment of overactive bladder (OAB), and in patients without a history of previous therapy with M-anticholinergics. Mirabegron was also effective in patients with OAB who discontinued M-anticholinergic treatment due to lack of effect. Urodynamics. A 12-week study in men with lower urinary tract symptoms (LUTS) and bladder outlet obstruction (IVO) demonstrated the safety and good tolerability of mirabegron at doses of 50 and 100 mg once daily, and no effect of mirabegron on cystometric parameters. Effect on QT interval. At doses of 50 mg and 100 mg, mirabegron had no effect on the heart rate-corrected QT interval (QTcI value), which was recorded in the analysis for groups by gender and for the entire group of patients. The effect of repeated oral administration of mirabegron at a therapeutic dose (50 mg once daily) and supratherapeutic doses (100 and 200 mg once daily) on QTcI was studied in a separate study (TQT study) (n = 164 healthy male volunteers and n = 153 healthy female volunteers). In both men and women receiving mirabegron 50 and 100 mg, the upper limit of the one-sided 95% confidence interval for the largest time-matched difference from placebo in QTcI did not exceed 10 ms at any time point. Effect on pulse rate and blood pressure in patients with OAB. In a 12-week, double-blind, placebo-controlled, phase 3 study in patients with OAB (mean age 59 years) receiving mirabegron 50 mg once daily, there was an increase in baseline mean difference from placebo in heart rate (by 1 bpm) ) and systolic blood pressure/diastolic blood pressure (SBP/DBP) (by about 1 mmHg or less). Changes in heart rate and blood pressure during treatment are reversible and disappear after discontinuation of the drug. Effect on intraocular pressure (IOP). 56 days after starting treatment with mirabegron at a dose of 100 mg once daily, no increase in IOP was observed in healthy volunteers. A phase I study (n = 310) assessed the effect of mirabegron on IOP using Goldmann applanation tonometry: mirabegron 100 mg did not differ from placebo in the effect size with respect to the mean change in baseline mean individual IOP values at day 56. Pharmacokinetics: Absorption. Following oral administration, mirabegron is absorbed into the bloodstream and reaches its maximum plasma concentration (Cmax) between three and four hours after administration. Studies have shown an increase in absolute bioavailability from 29% to 35% after increasing the dose from 25 mg to 50 mg. In this case, the average Cmax value and the AUC value increased more than in proportion to the dose. Equilibrium concentrations are achieved after 7 days of taking mirabegron once a day. After repeated once-daily administration, plasma concentrations of mirabegron at steady state are approximately twice as high as those after a single dose of the drug. The effect of food intake on drug absorption. Phase 3 studies demonstrated the same effectiveness and safety of treatment when taking mirabegron during and outside meals. Thus, the recommended dose of mirabegron can be taken both during and outside meals. Distribution. Mirabegron is intensively distributed in the body. The volume of distribution under stable conditions (Vss) is approximately 1670 l. Mirabegron is approximately 71% protein bound in plasma and also exhibits moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron is distributed to red blood cells. Concentrations of 14C-labeled mirabegron in erythrocytes were 2 times higher than in plasma (as shown in in vitro studies). Metabolism. There are many pathways for mirabegron metabolism in the body, including dealkylation, oxidation, (direct) glucuronidation and amide hydrolysis. After a single administration of 14C-mirabegron, the main circulating component is mirabegron. Two main metabolites of mirabegron were found in human plasma: both are glucuronides (phase II metabolites) and constitute, respectively, 16% and 11% of the total drug concentration. These metabolites do not have pharmacological activity. Despite the participation of the enzymes CYP2D6 and CYP3A4 in the oxidative pathway of mirabegron metabolism in vitro, in vivo the role of these isoenzymes in the overall elimination is small. Excretion. The total clearance (Cltotal) of the drug is approximately 57 l/hour. The terminal half-life (t1/2) is approximately 50 hours. Renal clearance (Clren) is approximately 13 l/hour, which corresponds to almost 25% of the Cltot value. The main mechanisms of excretion by the kidneys are active tubular secretion and glomerular filtration. The amount of unchanged mirabegron excreted in the urine is dose-dependent and varies from 6.0% after taking the drug at a daily dose of 25 mg to 12.2% after taking a daily dose of 100 mg. After administration of 160 mg of 14C-mirabegron to healthy volunteers, approximately 55% of the tracer was detected in urine and 34% in feces. The unchanged mirabegron fraction accounted for approximately 45% of the total isotopically labeled drug in urine, indicating the presence of metabolites. Most of the isotopically labeled drug in the feces was represented by unchanged mirabegron. Features of pharmacokinetics in certain categories of patients: Age. In elderly patients, there is no need for dose adjustment. In studies, Cmax and AUC values for mirabegron and its metabolites were similar in older (≥ 65 years) and younger volunteers (18-45 years). Floor. No dose adjustment is required depending on the gender of the patient. Race. No dose adjustment is required depending on the patient's race. Race does not affect the pharmacokinetics of the drug.
Betmiga tablets ppo prolong 50 mg No. 30
Compound
Active substance: mirabegron 50 mg.
Excipients: macrogol 2,000,000 - 70 mg, macrogol 8000 - 119.6 mg, hyprolose - 7.5 mg, butylated hydroxytoluene - 0.4 mg, magnesium stearate - 2.5 mg. Film shell composition: opadry 03F42192 (hypromellose 2910 6 mPa sec - 69.536%, macrogol 8000 - 13.024%, yellow iron oxide dye - 17.44%) - 7.5 mg.
Pharmacokinetics
Following oral administration, mirabegron is absorbed into the bloodstream and reaches Cmax in plasma between three and four hours after administration. Studies have shown an increase in absolute bioavailability from 29% to 35% after increasing the dose from 25 to 50 mg. In this case, the average Cmax value and AUC value increased more than proportionally to the dose. Css is achieved after 7 days of taking mirabegron once a day. After repeated use once a day, the Css of mirabegron in the blood plasma are approximately 2 times higher than those after a single dose of the drug.
Mirabegron is intensively distributed in the body. Vd in stable conditions (Vss) is approximately 1670 l. Mirabegron is approximately 71% protein bound in plasma and also exhibits moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron is distributed to red blood cells. Concentrations of 14C-mirabegron in erythrocytes were 2 times higher than in plasma (as shown by in vitro studies).
There are many ways mirabegron is metabolized in the body, incl. dealkylation, oxidation, (direct) glucuronidation and amide hydrolysis. After a single administration of C-mirabegron, the main circulating component is mirabegron. Two main metabolites of mirabegron were found in human plasma: both are glucuronides (phase II metabolites) and constitute, respectively, 16% and 11% of the total drug concentration. These metabolites do not have pharmacological activity.
Despite the participation of the CYP2D6 and CYP3A4 isoenzymes in the oxidative pathway of mirabegron metabolism in vitro, in in vivo conditions the role of these isoenzymes in the overall elimination is small.
The total plasma clearance is about 57 l/h. The final T1/2 is approximately 50 hours. Renal clearance is approximately 13 l/h, which corresponds to almost 25% of the total clearance. The main mechanisms of excretion by the kidneys are active tubular secretion and glomerular filtration. The amount of unchanged mirabegron excreted in the urine is dose-dependent and varies from 6.0% after taking the drug at a daily dose of 25 mg to 12.2% after taking a daily dose of 100 mg. After administration of 160 mg of C-mirabegron to healthy volunteers, approximately 55% of the radiolabel was detected in urine and 34% in feces. The unchanged mirabegron fraction accounted for approximately 45% of the total isotopically labeled drug in urine, indicating the presence of metabolites. Most of the isotopically labeled drug in the feces was represented by unchanged mirabegron.
Indications for use
Overactive bladder (OAB) with symptoms of urinary incontinence, frequent urination and urinary urgency.
Contraindications
- End-stage renal failure (eGFR<15 ml/min/1.73 m2 or patients for whom hemodialysis is indicated);
- severe renal failure (eGFR 15-29 ml/min/1.73 m2) with simultaneous use of strong inhibitors of the CYP3A isoenzyme;
- severe stage of liver failure (class C on the Child-Pugh scale); severe uncontrolled hypertension, defined as systolic blood pressure ≥180 mm Hg. and/or diastolic blood pressure ≥110 mm Hg;
- moderate stage of liver failure (class B on the Child-Pugh scale) with simultaneous use of strong inhibitors of the CYP3A isoenzyme;
- children's age (lack of data on effectiveness and safety);
- pregnancy and breastfeeding;
- hypersensitivity to the active substance.
Directions for use and doses
Adults (≥18 years), incl. elderly: 50 mg once a day orally with liquid, regardless of meal time. The Betmiga tablet should be taken whole and should not be chewed, as this may affect the prolonged release of the active substance.
special instructions
Mirabegron at therapeutic doses did not demonstrate clinically significant prolongation of the QT interval in the studies conducted. However, since patients taking drugs that may cause QT prolongation did not participate in these studies with mirabegron, the effect on these patients is not known. This category of patients should take mirabegron with caution.
Mirabegron should be used with caution in combination with drugs that have a narrow therapeutic index and drugs that are significantly metabolized by CYP2D6, such as thioridazine, drugs for the treatment of class 1 C arrhythmias (for example, flecainide, propafenone) and tricyclic antidepressants (for example, imipramine, desipramine). Mirabegron should also be taken with caution when co-administered with drugs that are metabolized by the CYP2D6 isoenzyme and the dose of which must be individually determined.
During post-marketing surveillance of the use of mirabegron in patients with bladder outlet obstruction (VFO) and in patients already taking anticholinergic drugs for the treatment of OAB, cases of urinary retention were observed. A controlled clinical safety study in patients with IFO did not find an increase in urinary retention in patients receiving mirabegron; however, mirabegron should be used with caution in patients with clinically significant IFO.
Mirabegron should also be used with caution in patients already taking anticholinergic drugs for the treatment of OAB.
Mirabegron may increase blood pressure. It is recommended to measure blood pressure before starting treatment and periodically during treatment with mirabegron, especially in patients with arterial hypertension.
Conditions for dispensing from pharmacies
On prescription.
Dosage form
Long-acting, film-coated tablets.
Use in children
The use of the drug in children is prohibited, because There are no data on effectiveness and safety.
Pharmacodynamics
Selective agonist of β3-adrenergic receptors. Studies with mirabegron have demonstrated relaxation of bladder smooth muscle in rats and in isolated human tissue, as well as an increase in cAMP concentrations in bladder tissue in rats. Thus, mirabegron improves the reservoir function of the bladder by stimulating β3-adrenergic receptors located in its wall.
Studies have demonstrated the effectiveness of mirabegron both in patients who have previously received anticholinergic drugs for the treatment of overactive bladder (OAB), and in patients without a history of previous anticholinergic therapy.
Mirabegron was also effective in patients with OAB who discontinued treatment with anticholinergic drugs due to lack of effect.
A 12-week study in men with lower urinary tract symptoms (LUTS) and bladder outlet obstruction (IBO) demonstrated the safety and good tolerability of mirabegron in doses of 50 and 100 mg once a day, as well as the absence of mirabegron’s effect on cystometric parameters.
Changes in heart rate and blood pressure during treatment are reversible and disappear after treatment is discontinued.
Side effects
Infections and infestations: often - urinary tract infection; uncommon - vaginal infection, cystitis.
From the organ of vision: rarely - swelling of the eyelids.
From the cardiovascular system: often - tachycardia; infrequently - rapid heartbeat, atrial fibrillation, increased blood pressure
From the digestive system: often - nausea; infrequently - dyspepsia, gastritis, increased activity of GGT, AST, ALT; rarely - swelling of the lips.
From the skin and subcutaneous tissue: uncommon - urticaria, rash, macular rash, papular rash, itching; rarely - leukocystoclastic vasculitis, purpura, angioedema.
From the musculoskeletal system: infrequently - swelling of the joints.
From the reproductive system: infrequently - vulvovaginal itching.
*Detected during post-marketing use.
Use during pregnancy and breastfeeding
Pregnancy There is limited data on the use of mirabegron in pregnant women. Animal studies have shown reproductive toxicity. Mirabegron is not recommended during pregnancy or in women of childbearing age who are not using contraception.
Breastfeeding period In rodents, mirabegron is excreted in breast milk, therefore, in humans there is also a risk of the drug getting into breast milk. There are no studies examining the effect of mirabegron on breast milk production, the excretion of mirabegron in breast milk and the effect on the child. Mirabegron should not be used in women during breastfeeding.
Fertility: Animal studies have not shown any effect of mirabegron on fertility at non-lethal doses. It has not been established whether mirabegron affects fertility in humans.
Interaction
Data from in vitro studies: Mirabegron is a moderate time-dependent inhibitor of the CYP2D6 isoenzyme and a weak inhibitor of the CYP3A isoenzyme. At high concentrations, mirabegron inhibited drug transport via P-glycoprotein.
Data from in vivo studies: CYP2D6 polymorphism. Genetic polymorphism of CYP2D6 has a minimal effect on the mean plasma concentration of mirabegron. Although the interaction of mirabegron with inhibitors of the CYP2D6 isoenzyme has not been studied, theoretically it is not expected. In patients taking inhibitors of the CYP2D6 isoenzyme, as well as in patients with slow metabolism of CYP2D6 isoenzyme substrates, there is no need to adjust the dose of mirabegron.
Drug-Drug Interactions: Most drug-drug interactions have been studied with 100 mg mirabegron controlled-release tablets (CRTAs). In an interaction study of mirabegron with metoprolol and metformin, immediate-release (IR) mirabegron was used at a dose of 160 mg. Clinically significant interactions between mirabegron and drugs that inhibit, activate or are a substrate of one of the CYP enzymes or transporters are not expected, with the exception of the inhibitory effect of mirabegron on the metabolism of CYP2D6 substrates.
Effect on enzyme inhibitors. The concentration of mirabegron (area under the concentration-time curve - AUC) increased 1.8-fold under the influence of the strong CYP3A/P-gp inhibitor ketoconazole in healthy volunteers. Dose adjustment of Betmiga is not required when taken together with CYP3A or P-gp inhibitors. However, in patients with mild to moderate renal impairment (eGFR 30 89 ml/min/1.73 m2) or mild hepatic impairment (Child-Pugh Class A) taking strong CYP3A inhibitors such as itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended daily dose of mirabegron is 25 mg, regardless of meals.
Effect on enzyme inducers. Substances that induce CYP3A or P-gp isoenzymes reduce the plasma concentration of mirabegron. No dose adjustment is required when mirabegron is taken with therapeutic doses of rifampicin or other inducers of CYP3A or P-gp isoenzymes.
The effect of mirabegron on drugs metabolized by the CYP2D6 isoenzyme. In healthy volunteers, mirabegron moderately inhibits CYP2D6, the activity of which is restored 15 days after discontinuation of mirabegron. Daily dosing of mirabegron resulted in a 90% increase in Cmax and a 229% increase in AUC for a single dose of metoprolol. Daily dosing of mirabegron resulted in a 79% increase in Cmax and 241% increase in AUC for a single dose of desipramine. Mirabegron should be used with caution in combination with drugs that have a narrow therapeutic index and drugs that are significantly metabolized by CYP2D6, such as thioridazine, drugs for the treatment of Type 1C arrhythmias (for example, flecainide, propafenone) and tricyclic antidepressants (for example, imipramine). , desipramine). Mirabegron should also be taken with caution when co-administered with drugs that are metabolized by the CYP2D6 isoenzyme and the dose of which must be individually determined. Effect of mirabegron on drugs transported by transporter protein (P-gp).
Mirabegron is a weak inhibitor of the P-gp protein. Mirabegron increased Cmax and AUC by 29% and 27%, respectively, when administered with digoxin to healthy volunteers. For patients who start taking Betmiga and digoxin at the same time, digoxin should be taken at the lowest dose. In this case, it is necessary to monitor the concentrations of digoxin in the blood plasma and select a further effective dose of digoxin based on the results of control tests. The potential for P-gp inhibition by mirabegron should be taken into account when prescribing Betmiga with drugs transported by P-gp proteins, such as dabigatran.
Other forms of interaction: No clinically significant interactions were identified when mirabegron was co-administered with solifenacin, tamsulosin, warfarin, metformin or combined oral contraceptives containing ethinyl estradiol and levonogestrel. No dose adjustment is required. The increased effect of mirabegron when taken together with other drugs is expressed in an increase in heart rate.
Overdose
Symptoms: Doses up to 400 mg have been used in single doses of mirabegron to healthy volunteers. When using this dose level, adverse events were recorded in the form of rapid heartbeat (in 1 out of 6 volunteers) and an increase in heart rate of more than 100 beats/min (in 3 out of 6 volunteers). With repeated (over 10 days) use of the drug in daily doses of up to 300 mg, an increase in heart rate and an increase in systolic blood pressure were recorded in healthy volunteers. Treatment Symptomatic and supportive therapy. Monitoring of pulse rate, blood pressure and ECG is necessary.
