Betmig film-coated pills with prolonged action 50mg N10
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Active ingredients
Mirabegron
Release form
Pills
Composition
Mirabegron 50 mg per tablet. Excipients: macrogol 2,000,000 - 70 mg, macrogol 8000 - 119.6 mg, hyprolosis - 7.5 mg, butylhydroxytoluene - 0.4 mg, magnesium stearate - 2.5 mg. The composition of the film shell: opadry 03F42192 (hypromellose 2910 6 MPa · s - 69.536%, macrogol 8000 - 13.024%, iron dye yellow oxide - 17.44%) - 7.5 mg.
Pharmacological effect
Pharmaceutical group: Preparations for the treatment of urological diseases / Pharmacological action: Mirabegron is a powerful selective beta3-adrenoreceptor agonist. In studies with mirabagron, relaxation of the bladder smooth muscles in rats and in an isolated human tissue preparation, as well as an increase in cAMP concentrations in bladder tissues in rats, was demonstrated. Thus, Mirabagron improves the reservoir function of the bladder by stimulating beta3-adrenoreceptors located in its wall. Studies have demonstrated the effectiveness of Mirabagron in patients who have previously received M-anticholinergics for the treatment of overactive bladder (GMF), and in patients without a history of previous M-anticholinergic therapy. Mirabegron was also effective in patients with GMF who stopped treatment with M-holinoblokatorami due to lack of effect. Urodynamics. A 12-week study in men with lower urinary tract symptoms (LUTS) and infravesical obstruction (IVO) demonstrated 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. The effect on the QT interval. At doses of 50 mg and 100 mg, Mirabagron had no effect on the QT interval corrected by pulse rate (QTcI value), which was recorded during the analysis for groups based on sex and for the entire group of patients. The effect of repeated oral intake of Mirabegron in a therapeutic dose (50 mg once a day) and supertherapeutic doses (100 and 200 mg once a day) on the QTcI value was studied in a separate study (TQT study) (n = 164 healthy male volunteers and n = 153 healthy female volunteers). In both men and women who received Mirabegron in doses of 50 and 100 mg, the upper limit of the one-sided 95% confidence interval for the greatest time-coordinated difference from placebo in QTcI at any time did not exceed 10 msec. Effect on pulse rate and blood pressure in patients with GMF.During the 12-week double-blind, placebo-controlled studies of phase 3 in patients with GMF (mean age 59 years) who received 50 mg of Mirabegron once a day, there was an increase in baseline mean values of the difference with placebo in pulse rate (by 1 beats / min ) and systolic blood pressure / diastolic blood pressure (SBP / DBP) (approximately 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 the start of receiving Mirabegron at a dose of 100 mg once a day, healthy volunteers did not observe an increase in IOP. In the Phase I study (n = 310), the effect of Mirabegron on IOP was estimated using Goldmann applanation tonometry: Mirabegron at a dose of 100 mg did not differ from placebo in terms of the magnitude of the effect on the mean value of the change in initial average individual IOP values at 56 days.
Pharmacokinetics
Suction. After oral administration, Mirabagron is absorbed into the bloodstream and reaches a 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. At the same time, the average value of Cmax and the value of CPD increased more than proportionally to the dose. Equilibrium concentrations are achieved after 7 days of taking Mirabegron once a day. After repeated use once a day, the concentration of mirabegron in the blood plasma in the equilibrium state is approximately two times higher than those after a single dose of the drug. The effect of food intake on the drug. During the Phase 3 studies, the same efficacy and safety of treatment was demonstrated when taking Mirabegron during and outside the meal. Thus, the recommended dose of mirabegron can be taken both during and outside the meal. Distribution. Mirabegron is intensively distributed in the body. The volume of distribution in stable conditions (Vss) is approximately 1,670 l. Mirabegron binds (approximately 71%) to plasma proteins 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 red blood cells were 2 times higher than in plasma (as shown by in vitro studies). Metabolism. There are many metabolic pathways of mirabagron in the body, including dealkylation, oxidation, (direct) glucuronidation and amide hydrolysis. After a single injection of 14C-Mirabegron, the main circulating component is Mirabegron. Two main metabolites of mirabegron were found in human blood plasma: both are glucuronides (phase II metabolites) and constitute, respectively, 16% and 11% of the total concentration of the drug. These metabolites do not possess pharmacological activity. Despite the participation of CYP2D6 and CYP3A4 enzymes in the oxidative metabolic pathway of Mirabogron in in vitro conditions, in in vivo conditions the role of these isoenzymes in total elimination is small. Inference. The total clearance (Clobshch) of the drug - about 57 l / h. The final half-life (t1 / 2) is approximately 50 hours. Renal clearance (Clpoch) is approximately 13 l / h, which corresponds to almost 25% of Cl total. The main mechanisms of kidney removal are active tubular secretion and glomerular filtration. The amount of unchanged Mirabegron excreted in urine is dose-dependent in nature and varies from 6.0% after taking the drug in a daily dose of 25 mg to 12.2% after taking a daily dose of 100 mg. After ingestion of 160 mg of 14C-mirabegron by healthy volunteers, approximately 55% of the radiolabel is found in the urine and 34% in the feces. The fraction of unchanged mirabagron was approximately 45% of the total isotope-labeled drug in the urine, indicating the presence of metabolites. Most of the isotope-labeled drug in feces was represented by unchanged mirabegron. Features of pharmacokinetics in certain categories of patients: Age. Elderly patients do not need a dose adjustment. In studies, Cmax and AUC values for Mirabegron and its metabolites were similar in the elderly (≥ 65 years) and younger volunteers (18–45 years). Floor. Dose adjustment depending on the gender of the patient is not required. Race. Dose adjustment depending on the race of the patient is not required. Race does not affect the pharmacokinetics of the drug.
Indications
treatment of urge to urinate, frequent urination and / or urgent urinary incontinence in patients with overactive bladder syndrome (OAB)
Contraindications
- hypersensitivity to the active component of the drug Betmiga or to excipients - children and adolescents under 18 years of age - pregnancy and lactation
Precautionary measures
Patients with renal and hepatic impairment Patients with severe renal insufficiency should be treated with caution and the dose for them should not exceed 25 mg / day. Patients with mild and moderate renal insufficiency, while taking strong inhibitors of the CYP3A isoenzyme, should be treated with caution and the dose for they should not exceed 25 mg / day. Patients with a moderate stage of liver failure should be treated with caution and the dose for them should not exceed 25 mg / day. Patients with a mild peche stage night failure (Class A on the Child-Pugh scale), while taking strong inhibitors of the CYP3A isoenzyme, should be treated with caution and the dose should not exceed 25 mg / day. Patients with uncontrolled severe arterial hypertension Since there have been studies with Betmig in patients with uncontrolled arterial hypertension (systolic blood pressure> 180 mm Hg and / or diastolic blood pressure> 110 mm Hg) was not performed, so the drug is not recommended for use in this category of patients. There are only limited nnye Betmiga data regarding the use of the drug in patients with stage 2 hypertension (systolic blood pressure> 160 mm Hg. st. and / or diastolic blood pressure> 100 mmHg.) Patients with congenital or acquired lengthening of the QT interval Mirabegron in therapeutic doses did not demonstrate a clinically significant lengthening of the QT interval in the framework of the conducted studies. However, since patients taking drugs that may provoke prolongation of the QT interval did not participate in these studies using Mirabegron, the effect on such categories of patients is not known. This category of patients should be taken with Mirabagron with caution. It is necessary to prescribe Mirabagron in combination with drugs with a narrow therapeutic index, and drugs that are largely metabolized by a CYP2D6 isoenzyme, for example, thioridazine, drugs for the treatment of arrhythmia Type 1C (for example, flecainide, propafenone) and tricyclic antidepressants (for example, imipramine, desipramine).Mirabegron should also be taken with caution when taken together with drugs that are metabolized by the isoenzyme CYP2D6 and the dose of which is subject to individual determination.
Use during pregnancy and lactation
Pregnancy There are limited data on the use of Mirabegron during pregnancy. The results of animal reproductive toxicity studies do not indicate a direct or indirect negative effect of Miragegron. To prevent possible negative effects on the fetus, the use of Betmiga should be avoided in pregnant women and in women of childbearing age and not using contraceptives. Lactation period In rodents, mirabegron is excreted in breast milk, therefore, in humans there is also a risk of the drug getting into breast milk. Studies on the effect of mirabegron on the production of breast milk, the allocation of miragegrone with breast milk and effects on the child are absent Mirabegron should not be used in women during lactation. Fertility In animal studies, the effect of miragegron on fertility in non-lethal doses was not detected. It is not established whether Mirabagron affects fertility in humans.
Dosage and administration
Adults (over 18 years old), incl. elderly 50 mg once a day inside, with a liquid, regardless of the time of meals. The tablet must be taken whole, it can not be chewed, because This may affect the prolonged release of the active substance.
Side effects
The most frequent adverse reactions reported during the 12-week double-blind, placebo-controlled trials of phase 3 in patients receiving Mirabegron at a dose of 50 mg are tachycardia and urinary tract infections. In patients receiving Mirabagron in a dose of 50 mg, the frequency of tachycardia reached 1.2%. In 0.1% of patients receiving Mirabegron in a dose of 50 mg, the development of tachycardia caused the early termination of participation in the study. In patients receiving Mirabagron 50 mg, the incidence of urinary tract infections was 2.9%. The development of urinary tract infections did not cause an early termination of participation in the study in any of the patients receiving Mirabegron at a dose of 50 mg.Serious adverse reactions included atrial fibrillation (0.2%). In the course of a long-term (1 year) study with active control (control drug-m-holinoblokator), adverse reactions were recorded, similar in appearance and frequency to those recorded during 12-week double-blind, placebo-controlled studies of phase 3. Within each group, the reactions are listed as the degree of severity decreases. Infections and invasions: often - urinary tract infection, infrequently - vaginal infection, cystitis. Disorders of the organ of vision: rarely - eyelid edema Disorders of the cardiovascular system: often - tachycardia; infrequently - rapid heart beat, atrial fibrillation. Violations of the gastrointestinal tract: infrequently - dyspepsia, gastritis; rarely - swelling of the lips. Violations of the skin and subcutaneous tissue: infrequently - urticaria, macular rash, papular rash, rash, itching; rarely - leukocytoclastic vasculitis, purpura. Disorders of the musculoskeletal system and connective tissue: infrequently - inflammation of the joints. Disorders of the reproductive system and the breast: infrequently - vulvovaginal itching. Abnormalities identified in laboratory studies: infrequently - increased blood pressure, increased GGT activity, increased AST activity, increased ALT activity.
Overdose
In the case of a single prescription of Mirabegron, healthy volunteers used doses up to 400 mg. When using such a dose level, adverse events were recorded in the form of rapid heartbeat (in 1 of 6 volunteers) and an increase in the pulse rate of more than 100 beats / min (in 3 of 6 volunteers). With repeated (within 10 days) use of the drug in daily doses up to 300 mg in healthy volunteers, an increase in the pulse rate and an increase in systolic blood pressure were recorded. In case of overdose, symptomatic and supportive therapy is indicated. Need to control heart rate, blood pressure and ECG.
Interaction with other drugs
Data from in vitro studies Mirabegron is a moderate inhibitor with a time-dependent CYP2D6 isoenzyme and a weak inhibitor of the CYP3A isoenzyme. In high concentrations, Mirabagron inhibited the transport of drugs through P-glycoprotein.Research data in vivo CYP2D6 isoenzyme polymorphism The genetic polymorphism of CYP2D6 isoenzyme has a minimal effect on the average concentration of miragegron in blood plasma. Although the interaction of miragegron with inhibitors of the CYP2D6 isoenzyme has not been studied, in theory it is not expected. In patients taking CYP2D6 isoenzyme inhibitors, as well as in patients with a slower metabolism of substrates of CYP2D6 isoenzyme, there is no need for dose adjustment of mirabegron. Inter-Drug Interactions Most inter-drug interactions have been studied using 100 mg of Miragegron in the form of controlled-release pills (OKAS). In the study of the interactions of Mirabegron with metoprolol and mstformin, Mirabegron was used with an immediate release (IR) in a dose of 160 mg. Clinically significant interactions between mirabagron and drugs that inhibit, activate or are the substrate of one of the CYP isoenzymes or carriers are not expected, except for the inhibitory effect of Mirabagron on the metabolism of the substrates of the CYP2D6 isoenzyme. Effect on enzyme inhibitors Mirabegron concentration (AUC) increased 1.8 times under the influence of a strong inhibitor of CYP3A / P-gp isoenzymes ketoconazole in healthy volunteers. Dose adjustment of Mirabegron is not required when taken together with CYP3A or P-gp isoenzyme inhibitors. However, in patients suffering from mild or moderate renal insufficiency (eGFR 30–89 ml / min / 1.73 m2) or mild hepatic insufficiency (Child-Pugh class A), taking such strong inhibitors of CYP3A isoenzymes as itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended daily dose of Mirabegron is 25 mg, regardless of the meal. Effects on enzyme inducers Substances inducing CYP3A or P-gp isoenzymes reduce plasma miragegron concentration. Dose adjustment is not required when taking Mirabegron along 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 the isoenzyme CYP2D6, whose activity is restored 15 days after the cessation of receiving Mirabegron.Daily use of Mirabegron led to an increase in Cmax by 90% and PEP by 229% for a single dose of metoprolol. Daily intake of Mirabegron led to an increase in Cmax by 79% and PEP by 241% for a single dose of desipramine. It should be carefully prescribed Mirabagron in combination with drugs with a narrow therapeutic index, and drugs that are largely metabolized by the CYP2D6 isoenzyme, for example, thioridazine, drugs for the treatment of arrhythmias type 1C (for example, flecineide, propafenone) and tricyclic antidepressants (for example, imipramine , desipramine). Mirabegron should also be taken with caution when taken together with drugs that are metabolized by the isoenzyme CYP2D6 and the dose of which is subject to individual determination. The effect of Mirabegron on drugs transported by the carrier protein (P-gp) Mirabegron is a weak inhibitor of the P-gp protein. Mirabegron contributed to an increase in Cmax and CPD by 29% and 27%, respectively, when taken with digoxin by healthy volunteers. For patients who are starting to take Mirabagron and Digoxin at the same time, Digoxin should be taken at the lowest dose. At the same time, it is necessary to monitor concentrations of digoxin in the blood plasma and to select a further effective dose of digoxin according to the results of control tests. The inhibition potential of P-gp protein by mirabegron should be taken into account when prescribing mirabegron in conjunction with preparations transported by P-gp proteins, for example, dabigatran. Other Forms of Interaction No clinically significant interactions were observed when mirabagron was taken together with solifenacin, tamsulosin, warfarin, metformin or combined oral contraceptives containing ethinyl estradiol and levonogestrel. Dose adjustment is not required. Strengthening the effect of mirabegron when combined with other drugs is reflected in an increase in the pulse rate.
special instructions
Influence on the ability to drive and work with mechanisms The Betmig drug does not have a clinically significant effect on the ability to drive vehicles and mechanisms.