Betmiga tablets coated. prolong. 50 mg 10 pcs. pack (Miraberon)

Pharmacological action of

Pharmaceutical group:

Drugs for the treatment of urological diseases /

Pharmaceutical action:

Mirabegron is a potent selective beta3-adrenergic receptor agonist. In studies with exposure to mirabegron, relaxation of the smooth muscles of the bladder in rats and in an isolated preparation of human tissues was demonstrated, as well as an increase in cAMP concentrations in rat bladder tissues. Thus, mirabegron improves the reservoir function of the bladder by stimulating beta3-adrenergic receptors located in its wall.

Studies have shown the efficacy of mirabegron as in patients previously treated with M-anticholinergics for the treatment of overactive bladder (GMF), and in patients without a history of previous therapy with M-anticholinergics. Mirabegron was also effective in patients with GMF who discontinued treatment with M-anticholinergics due to lack of effect.

Urodynamics.

A 12-week study in men with lower urinary tract symptoms (LUTS) and infravesical obstruction (IVO) demonstrated the safety and good tolerance of mirabegron at doses of 50 and 100 mg once a day, as well as the absence of the effect of mirabegron on cystometric indices .

Effect on QT interval.

At doses of 50 mg and 100 mg, mirabegron had no effect on the pulse rate-adjusted QT interval (QTcI value), which was recorded during 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 a day) and super-therapeutic doses (100 and 200 mg once a day) on the QTcI value was studied in a separate study (TQT study) (n = 164 healthy male and n volunteers = 153 healthy female volunteers). In both men and women who received mirabegron in doses of 50 and 100 mg, the upper limit of the unilateral 95% confidence interval for the largest time-consistent difference with placebo in terms of QTcI at any time did not exceed 10 ms.

Effect on heart rate and blood pressure in patients with hypertension.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 taking mirabegron at a dose of 100 mg once a day in healthy volunteers, there was no increase in IOP. In a Phase I study (n = 310), the effect of mirabegron on IOP was evaluated using Goldman applanation tonometry: mirabegron at a dose of 100 mg did not differ from placebo in terms of effect in relation to the average value of the change in the initial average individual IOP on day 56.

Pharmacokinetics:

Absorption.

Following oral administration, mirabegron is absorbed into the bloodstream and reaches a maximum plasma concentration (Cmax) between three and four hours after ingestion. 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 value of Cmax and the value of PPC increased more than in proportion to the dose. Equilibrium concentrations are reached after 7 days of taking mirabegron once a day. After repeated use once a day, the concentrations of mirabegron in plasma in equilibrium are approximately two times higher than those after a single dose.

Effect of food intake on drug absorption.

Phase 3 studies demonstrated the same efficacy 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 distribution volume under stable conditions (Vss) is approximately 1670 liters. Mirabegron binds (approximately 71%) to plasma proteins and also demonstrates 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 by in vitro studies).

Metabolism.

There are many ways to metabolize mirabegron 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 blood plasma: both are glucuronides (phase II metabolites) and comprise, respectively, 16% and 11% of the total concentration of the drug. 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.

Withdrawal.

The total clearance (Cltotal) of the drug is approximately 57 l / h. The final half-life (t1 / 2) is approximately 50 hours. Renal clearance (Clpoch) - approximately 13 l / h, which corresponds to almost 25% of the value of Cltotal. 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 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 taking 160 mg of 14C-mirabegron by healthy volunteers, approximately 55% of the RFID tag was found in urine and 34% in feces. The unchanged mirabegron fraction accounted for 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.

Pharmacokinetics in selected patient categories:

Age. In elderly patients, there is no need for dose adjustment. In the studies, the values ​​of Cmax and AUC for mirabegron and its metabolites were similar in the elderly (≥65 years) and younger volunteers (18-45 years old).

Paul Dose adjustment depending on the patient’s gender 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 urgent urination, rapid urination and / or urgent urinary incontinence in patients with hyperactive bladder syndrome (GMF)

Contraindications

- hypersensitivity to the active component of the Betmiga drug or excipients

- children and adolescents under 18 years old

- pregnancy and lactation

Composition of

1 tab: - mirabegron 25 mg, 50 mg

excipients:

macrogol 2,000,000,

macrogol 8000,

hydroxypropyl cellulose,

butylhydroxitol water, srdlprldgld 2910 6 mPa-s, macrogol 8000, iron oxide yellow (E172), iron oxide red (E172)),

Opadry 03F42192 (hypromellose 2910 6 mPa-s, macrogol 8000, iron oxide yellow (E172)).

Dosage and administration of

Adults ( 18 years of age), including elderly:

50 mg once daily orally, washed down with liquid, regardless of the meal time.

Betmig tablet must be taken as a whole, it can not be chewed, as this can affect the prolonged release of the active substance.

Side effects of

Often ( 1/100 and - urinary tract infection

- tachycardia

Uncommon ( 1/1000 and - vaginal infection, vulvovaginal itching, cystitis

- high blood pressure, heart disease, heart disease gastritis

- urticaria, macular and papular rash, pruritus

- inflammation of the joints

- elevated levels of GGT, AST, ALT

Rarely

Often ( 1/100 and <1/10)

- inf urinary tract projection

- tachycardia

Infrequently ( 1/1000 and < 1/100)

- vaginal infection, vulvovaginal pruritus, cystitis

- high blood pressure, palpitations, atrial fibrillation

- dyspepsia, gastritis

- urticaria, macular and papular rash, acute sr , ALT

Rarely ( 1/10000 and <1/1000)

- edema of the eyelids

- swelling of the lips

- leukocystoclastic vasculitis

- purpura

Drug Interactions

In vitro Research Data:

Mirabegron is a mild inhibitor with time-dependent isoenzyme CYP2D6 and a weak inhibitor of isoenzyme CYP3A. In high concentrations, mirabegron inhibited drug transport via P-glycoprotein.

In vivo research data:

CYP2D6 polymorphism.

Genetic polymorphism of CYP2D6 has minimal effect on the average plasma concentration of mirabegron. Although the interaction of mirabegron with inhibitors of the CYP2D6 isoenzyme has not been studied, it is theoretically not expected. In patients taking inhibitors of the CYP2D6 isoenzyme, as well as in patients with a slowed metabolism of substrates of the CYP2D6 isoenzyme, there is no need to adjust the dose of mirabegron.

Drug Interactions:

Most drug interactions have been studied using 100 mg of mirabegron in the form of controlled release tablets (OKAS). In a study of the interactions of mirabegron with metoprolol and metformin, an immediate release (IR) mirabegron at a dose of 160 mg was used.

Clinically significant interactions between mirabegron and drugs that inhibit, activate or are a substrate of one of the CYP enzymes or carriers 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 (the area under the concentration-time curve - PPC) increased by 1.8 times under the influence of a strong inhibitor of the isocenets CYP3A / P-gp ketoconazole in healthy volunteers. Betmiga dose adjustment is not required when taken with CYP3A or P-gp inhibitors. However, in patients suffering from mild or moderate renal failure (eGFR 30 - 89 ml / min / 1.73 m2) or mild hepatic insufficiency (Child-Pugh Class A) taking strong CYP3A isoenzyme inhibitors such as itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended daily dose of mirabegron is 25 mg, regardless of food intake.

Effect on enzyme inducers.

Substances inducing CYP3A or P-gp isoenzymes reduce the plasma concentration of mirabegron. 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 CYP2D6, the activity of which is restored 15 days after discontinuation of mirabegron. Daily intake of mirabegron led to an increase in Cmax by 90% and PPC by 229% for a single dose of metoprolol. Daily intake of mirabegron led to an increase in Cmax by 79% and PPC by 241% for one dose of desipramine.

Mirabegron should be used with caution in combination with drugs that have a narrow therapeutic index and drugs that are largely metabolized by the CYP2D6 isoenzyme, e.g. imipramine, desipramine). Mirabegron should also be taken with caution when taken together with drugs, which are metabolized by the isoenzyme of CYP2D6 and the dose of which is individually determined.

Influence 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 AUC by 29% and 27%, respectively, when taken with digoxin by healthy volunteers. For patients who begin to take Betmiga and digoxin at the same time, digoxin should be taken at the lowest dose. In this case, monitoring of plasma digoxin concentrations and the selection of a further effective dose of digoxin according to the results of control analyzes are necessary. The potential for inhibition of the P-gp protein by mirabegron should be taken into account when prescribing Betmig in conjunction with drugs transported by P-gp proteins, for example, dabigatran.

Other forms of interaction:

Clinically significant interactions with the combined use of mirabegron with solifenacin, tamsulosin, warfarin, metformin, or combined oral contraceptives containing ethinyl estradiol and levonogestrel have not been identified. Dose adjustment is not required.

The increased effect of mirabegron when taken together with other drugs is expressed in an increase in heart rate.

Overdose of

Symptoms:

With a single dose of mirabegron to healthy volunteers, doses up to 400 mg have been used. Using this dose level, adverse events were recorded in the form of a rapid heartbeat (in 1 of 6 volunteers) and an increase in heart rate of more than 100 beats / min (in 3 of 6 volunteers).

With multiple (within 10 days) use of the drug in daily doses up to 300 mg in healthy volunteers, an increase in heart rate and an increase in systolic blood pressure were recorded.

Treatment:

symptomatic and supportive therapy. It is necessary to control heart rate, blood pressure and ECG.

Active ingredient

Mirabegron

Terms of delivery from

pharmacies Prescription

Dosage form

tablets prolong.

Appointment

Adult prescription



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