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Pharmaceuticals: Preparations for the treatment of urological diseases /
Pharmaceutical 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-anticholinegic due to lack of effect.
A 12-week study in men with lower urinary tract symptoms (LUTS) and infrasing 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 influence of Mirabegron on cystometric parameters.
Effect on QT interval.
At doses of 50 mg and 100 mg, Mirabagron had no effect on the QT interval corrected for 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 administration of Mirabegron at 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 largest time-consistent difference from placebo in QTcI at any given 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 trials of phase 3 in patients with GMF (mean age of 59 years) who received 50 mg of Mirabegron once a day, 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 mirabagron in a dose of 100 mg once a day in healthy volunteers no increase in IOP was recorded. The study of Phase I (n = 310) estimated the effect of Mirabegron on IOP using Goldmann's 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.
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 Cmax value and the AUC value 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.
In the course of studies of phase 3, the same efficacy and safety of treatment were demonstrated when taking mirabegron during and outside meals.Thus, the recommended dose of mirabegron can be taken both during and outside the meal.
Mirabegron is intensively distributed in the body. The volume of distribution in stable conditions (Vss) is approximately 1670 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 miragegron in red blood cells were 2 times higher than in plasma (as shown by in vitro studies).
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 involvement 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.
The total clearance (Cl.C.) of the drug is approximately 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 excretion 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 mirabegron 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 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.
- treatment of urgent urge to urinate, frequent urination and / or urgent urinary incontinence in patients with overactive bladder syndrome (GMF)
1 tab .:
- Mirabegron 50 mg
excipients: macrogol 2000000, macrogol 8000, hydroxypropylcellulose, butylhydroxytoluene, purified water, magnesium stearate
The composition of the shell of the tablet:
Opadry 03F43159 (hypromellose 2910 6 MPa-s, macrogol 8000, iron yellow oxide (E172), iron red oxide (E172)),
Opadray 03F42192 (hypromellose 2910 6 mPa-s, macrogol 8000, iron oxide yellow (E172)).
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Dosage and Administration
Adults (≥18 years), incl. elderly:
At 50 mg once a day inside, with a liquid, regardless of the time of meals.
Betmig tablet must be taken whole, it can not be chewed, as this may affect the prolonged release of the active substance.
Often (≤1 / 100 and - urinary tract infection
Infrequently (≤1 / 1000 and - vaginal infection, vulvovaginal itching, cystitis
- high blood pressure, heart palpitations, atrial fibrillation
- dyspepsia, gastritis
- urticaria, macular and papular rash, itching
- inflammation of the joints
- elevated levels of GGT, AST, ALT
Rarely (≤1 / 10,000 and - eyelid edema
- lip swelling
- leukocytostatic vasculitis
- hypersensitivity to the active component of the drug Betmig or excipients
- children's and teenage age up to 18 years
- pregnancy and lactation
In vitro research data:
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.
These in vivo studies:
The genetic polymorphism of CYP2D6 has a minimal effect on the average concentration of Miragegron in the blood plasma. Although the interaction of miragegron with inhibitors of the CYP2D6 isoenzyme has not been studied, it is theoretically 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.
Most of the drug-free interactions have been studied using 100 mg of mirabegron in the form of controlled-release pills (OKAS). In the study of the interactions of Mirabegron with metoprolol and metformin, 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 enzymes or carriers are not expected, except for the inhibitory effect of Miragegron on the metabolism of CYP2D6 substrates.
Effect on enzyme inhibitors.
The concentration of Mirabagron (the area under the “concentration-time” curve - CPD) increased 1.8 times under the influence of a strong inhibitor of the isoenzymes CYP3A / P-gp ketoconazole in healthy volunteers. Dose adjustment of the drug Betmig is not required when taken together with inhibitors of CYP3A or P-gp. However, in patients suffering from mild or moderate renal insufficiency (eGFR 30–89 ml / min / 1.73 m2) or mild hepatic insufficiency (Class A on the Child-Pugh scale) taking such strong inhibitors of CYP3A isoenzymes as itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended daily dose of Mirabogron is 25 mg, regardless of the meal.
Effect on enzyme inducers.
Substances that induce 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.
Effect of Mirabegron on drugs metabolized by the CYP2D6 isoenzyme.
In healthy volunteers, Mirabegron moderately inhibits CYP2D6, whose activity is restored 15 days after stopping Mirabegron's administration. Daily use of Mirabegron led to an increase in Cmax by 90% and PEP by 229% for a single dose of metoprolol. Daily use of Mirabegron led to an increase in Cmax by 79% and PEP by 241% for a single dose of desipramine.
Mirabagron should be used with caution in combination with drugs with a narrow therapeutic index and drugs that are largely metabolized by the CYP2D6 isoenzyme, for example, thioridazine, Type 1C drugs for treating arrhythmias , 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 Mirabagron on drugs transported by the carrier protein (P-gp).
Mirabegron is a weak inhibitor of the protein P-gp. Mirabegron contributed to an increase in Cmax and CPD by 29% and 27%, respectively, when taken with digoxin by healthy volunteers. For patients who begin taking the drug Betmiga and digoxin at the same time, digoxin should be taken in 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 potential for inhibition of the P-gp protein by mirabegron should be taken into account when prescribing the Betmig drug in conjunction with drugs transported by P-gp proteins, for example, dabigatran.
Other forms of interaction:
There were no clinically significant interactions when co-administering Mirabegron 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.
In the case of a single mirabagron administration, healthy volunteers used doses up to 400 mg. When using this 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.
Treatment: symptomatic and supportive therapy. It is necessary to control the pulse rate, blood pressure and ECG.
- Modulation of non-voiding activity by the muscarinergic antagonist tolterodine and the β3-adrenoceptor agonist mirabegron in conscious rats with partial outflow obstruction
- Development and validation of LC–MS/MS methods for the determination of mirabegron and its metabolites in human plasma and their application to a clinical pharmacokinetic study
- Effect of Renal or Hepatic Impairment on the Pharmacokinetics of Mirabegron
- Effects of Mirabegron, a Novel β3-Adrenoceptor Agonist, on Primary Bladder Afferent Activity and Bladder Microcontractions in Rats Compared With the Effects of Oxybutynin
- Efficacy and Tolerability of Mirabegron, a β3-Adrenoceptor Agonist, in Patients with Overactive Bladder: Results from a Randomised European–Australian Phase 3 Trial
- Randomized Double-blind, Active-controlled Phase 3 Study to Assess 12-Month Safety and Efficacy of Mirabegron, a β3-Adrenoceptor Agonist, in Overactive Bladder
- Mirabegron as a New Class of Oral Drug for Overactive Bladder Syndrome: Many Positive Perspectives, Some Concerns
- Mirabegron use in the treatment of overactive bladder symptoms
- Use of mirabegron in treating overactive bladder
- Effect of mirabegron, a novel β3-adrenoceptor agonist, on bladder function during storage phase in rats
- Pharmacokinetic Properties of Mirabegron, a β3-Adrenoceptor Agonist: Results From Two Phase I, Randomized, Multiple-Dose Studies in Healthy Young and Elderly Men and Women
- PUK23 Understanding the Effects on HR-QoL of Treatment for Overactive Bladder: a Detailed Analysis of EQ-5D Clinical Trial Data for Mirabegron
- PUK14 Cost-Effectiveness Analysis of Mirabegron Versus Tolterodine Extended Release in the Treatment of Patients With Overactive Bladder in the United States
- Results of a Randomized Phase III Trial of Mirabegron in Patients with Overactive Bladder
- Proarrhythmic Safety of Repeat Doses of Mirabegron in Healthy Subjects: A Randomized, Double-Blind, Placebo-, and Active-Controlled Thorough QT Study
- A proof-of-concept study: Mirabegron, a new therapy for overactive bladder