Betmiga 50mg Astellas drugs treat urine symptoms (3 blisters x 10 tablets)

Mechanism of action

Mirabegron is a strong and selective copper of the beta-3 sympathetic receptor.

Mirabegron relaxes the bladder smooth muscle in the mouse and the isolated tissue in humans, increases the concentration of AMP in the mouse bladder tissue and shows the effect of dilating the bladder in mouse bladder function models.

Mirabegron increases the average urine volume each time urinating and reducing the frequency of bladder contractions with no urination, without affecting urinating pressure or urine to save in mouse models

Increase bladder activity. In the monkey model, Mirabegron reduces the number of urination.

These results show that Mirabegron increases the function of urine by stimulating the beta-3 sympathetic receptor in the bladder.

In the period of urine, when urine accumulates in the bladder, stimulating sympathetic nerves is the mainstream. Noradrenaline is released from the ends of the nerves, leading to the activation of the beta sympathetic receptor in the bladder muscle layer, and thus relaxing the bladder smooth muscles. During urination, the bladder is mainly dominated by sympathetic nervous system. Acetylcholine, released from the nerves of the pot, stimulates the Cholinergic M2 and M3 receptors, creates bladder spasms. Activating the M2 path also inhibits the Camp through the beta-3 sympathetic receptor. Therefore, stimulating the beta-3 sympathetic receptor will not interfere with urination. This is confirmed in the mouse, which is deadlocked, in which Mirabegron reduces the frequency of bladder contractions without urination without affecting the volume of urine every time urinating, urinating or volume of urine.

Pharmacological impact

Dynamic urology

Betmiga at a dose of 50 mg and 100 mg once a day for 12 weeks in men suffer from lower urinary tract symptoms (Luts) and clogged the lower urinary tract (BOO) does not affect the pressure parameters of the bladder, safety and well -tolerated. The impact of Mirabegron on the maximum urinary flow rate and the tip pressure at the maximum urine rate are evaluated in the study of this diuretic, including 200 male patients with symptoms of the lower urinary tract (Luts) and the lower ureter blockage (BOO). Use Mirabegron at a dose of 50 mg and 100 mg once a day for 12 weeks does not adversely affect the maximum urine speed or the tip pressure at the maximum urine speed. In this study, in men with LUSS/BOO, the average change (SE) from the beginning to the end of treatment for the volume of residual after urination (ml) is 0.55 (10.702), 17.89 (10.190), 30.77 (10,598) for the placebo group, Mirabegron 50 mg and Mirabegron 100 mg corresponding.

Impact on the QT range

Betmiga at the dose of 50 mg or 100 mg does not affect the QT interval, which is corrected separately according to the heart rate (QTCL Interval) when assessed or by gender or the entire research group.

A study of a complete QT range (TQT) (n = 164 healthy male volunteers and n = 153 healthy female volunteers with an average age of 33 years old) assessing the impact of the oral doses of Mirabegron at the designated dose (50 mg once daily) and at two doses on the dose of treatment (100 mg and 200 mg once daily) on QT interval is corrected (QtcinterValVal). Doses on the treatment dose have higher Mirabegron exposure levels about 2.6 and 6.5 times the contact at the treatment dose, respectively. The single dose of 400 mg moxifloxacin is used as a positive control. Each level of Mirabegron and Moxifloxacin is assessed in individual treatment groups, each group includes placebo - control (parallel cross -designed design). In both men and women using Mirabegron 50 mg and 100 mg, the upper limit of 95% trust interval does not exceed 10 msec at any time for the maximum average difference in time compared to the placebo compared to the QTCL range. In women, Mirabegron is at a dose of 50 mg, the average difference from the placebo on the interval of QTCL at 5 hours after the drug is 3.67 msec (the upper limit of 95% KTC is 5.72 msec). In men, the difference is 2.89 msec (the upper limit of KTC 95% on one side is 4.90 msec). At the dose of Mirabegron 200 mg, the QTCL is not exceeding 10 msec at any time in men, while in women, the upper limit of 95% trust intervals exceeds 10 msec between 0.5 and 6 hours, with a maximum difference compared to the placebo at 5 hours where the average impact is 10.42 msec (the upper limit of KTC 95% is 13.44 MSEC). The results for QTCF and QTCLF are also consistent with QTCL.

In this TQT study, Mirabegron increases the heart rate on the electrocardiogram in the way of the dose depends in the amplitude of survey dose from 50 mg to 200 mg.

Maximum average difference from placebo in the heart rate ranges from 6.7 times/minute with Mirabegron 50 mg up to 17.3 times/minute with Mirabegron 200 mg in healthy research objects.

Impact on vascular frequency and blood pressure in patients with bladder activity

In patients with increased bladder (59 years old) in three blind studies, placebo control, phase 3, lasting 12 weeks, using Betmiga 50 mg once a day, there is an average increase in the placeboards about 1 time/minute for vascular frequency and about 1 mmHg or less in centralized blood pressure/diastolic blood pressure. Changes in vascular frequency and blood pressure can recover when discontinued.

Impact on internal pressure

Mirabegron 100 mg once daily does not increase internal pressure in healthy research subjects after 56 days of treatment. In a phase 1 study, Betmiga's impact assessment on intraocular pressure by Goldmann contact labeling technique in 310 healthy research subjects, the dose of Mirabegron 100 mg is no less than placebo for research objectives is the difference in medium change from the beginning to the 56th average internal pressure; The upper limit of 95% confidence interval on the two sides is different for treatment between Mirabegron 100 mg and placebo is 0.3 mm Hg.

Clinical efficiency and safety

The effect of Betmiga is assessed in three randomly blind studies, placebo control, phase 3, lasting 12 weeks, in the treatment of bladder activity with urinary and urination symptoms with many times or without controlled urine. Female patients (72%) and male (28%) with an average age of 59 years old (amplitude 18 - 95 years old) were put into research. The research complex consists of about 48% of patients who have never treated Muscarinic resistance as well as about 52% of patients who have been previously resistant to Muscarinic. In one study, 495 patients became a positive control group (long -lasting tolterodine.

The main research objective of effective coordination is (1) changes from the beginning to the end of treatment for an average number of urinary incontinence every 24 hours and (2) changes from the beginning to the end of the average treatment of urination every 24 hours based on 3 -day urination. Mirabegron shows more improvement of statistical significance compared to placebo for the main research objectives as well as extra research goals.

Please see more information about the drug in the instruction sheet of the drug attached.

subjective improvement of life quality indicators related to health

In three blind studies, placebo control, phase 3, lasting 12 weeks, treating symptoms of bladder activity with Mirabegron once a day leads to statistical improvement compared to placebo, life quality indicators related to the following health: treatment satisfaction and discomfort due to symptoms.

Effective in patients with or not treating bladder activity with previous Muscarinic anti -drugs

The effect is shown in patients with or not treating bladder activation with previous Muscarinic drugs. In addition, Mirabegron shows the effectiveness in patients with increased bladder, which has stopped treating Muscarinic resistance earlier due to incomplete treatment effect.

Please see more information about drugs in the instructions for the use of drugs attached.

Children

The European Pharmaceutical Agency has allowed to delay the obligation to submit the results of the Betmiga research on one or more children's subgroups in the "idiopathic increased bladder treatment" and "the treatment of hyperplasia due to neurological causes".

Dynamic pharmacokinetics

absorption

After taking oral Mirabegron at a healthy volunteer, Mirabegron was absorbed and reached the peak of plasma (CMAX) between 3rd and 4th hours. Absolutely biological use increased from 29% at 25 mg to 35% at the dose of 50 mg. CMAX and AUC average increases linearly in the amplitude of the dose, more than willow. In the entire research group both men and women, double the Mirabegron dose from 50 mg to 100 mg increases CMAX and Auctau about 2.9 and 2.6 times, respectively, while 4 times the Mirabegron dose from 50 mg to 200 mg increases CMAX and AUCTAU about 8.4 and 6.5 times. Stable concentration is reached within 7 days at Mirabegron doses once a day.

After taking the medication once a day, the stable Mirabegron exposure in plasma is about double the level of exposure after the single dose.

The effect of food on absorption

Use a combination of 50 mg tablets with a fatty meal that reduces CMAX and AUC of Mirabegron by 45% and 17%, respectively. Low -fat meals reduce CMAX and AUC of Mirabegron 75% and 51%, respectively. In phase 3 studies, Mirabegron is used or not accompanied by food and shows both safety and effectiveness. Therefore, Mirabegron can be used or not accompanied by food at the recommended dose.

distribution

Mirabegron is widely distributed in the body. The distribution volume in a stable state (V) is about 1670 L. Mirabegron binds (about 71%) with plasma proteins, and has a medium affinity with albumin and Alpha-1 acid Glycoprotein. Mirabegron is distributed in red blood cells. The concentration of 14C-Mirabegron in red blood cells is about 2 times higher in plasma.

Biological shift

Mirabegron is metabolized by many paths related to alkyl reduction, oxidation, glucuronylation (direct), and amide hydrolysis. Mirabegron is an administrative component in the blood after a single dose of T 14C-Mirabegron.

Two main metabolites are present in human plasma; Both are Glucuronide phase 2, accounting for 16% and 11% of the total contact. These metabolites have no pharmacological activity.

Although experimental studies suggest the role of CYP2D6 and CYP3A4 in Mirabegron oxidation metabolism, research results on living objects show that these global piercings play a limited role in eliminating drugs in general. Experimental studies and studies on live tissue shows the relationship of butyrylcholinesterase, UGT and maybe both alcohol dehydrogenase (ADH) in Mirabegron's metabolism, besides CYP3A4 and CYP2D6.

polymorphism CYP2D6

In healthy research subjects are poor metabolic people with CYP2D6 genetic (used instead of CYP2D6 inhibitors), CMAX and AUCINF average at the single dose of 60 mg of Mirabegron IR (instant release) are 14% and 19% higher than strong metabolic people, showing the polymorphic CYP2D6 gene has very low influence on the medium MirabRRRRO. The interaction between Mirabegron and a CYP2D6 inhibitor is thought to be non -occurring and not studied. No need to adjust the dose of mirabegron when used with CYP2D6 inhibitors or in patients with poor metabolism CYP2D6.

Elimination

Total clearance (cltot) from plasma is about 57 l/hour. The half -life (T1/2) is about 50 hours. Kidney clearance (CLR) is about 13 l/hour, equivalent to nearly 25% Cltot. Eliminating Mirabegron through the kidney is mainly due to active excretion in the renal tubules along with glomerular filtration. The issue in urine for unexplained Mirabegron is dependent on the dose and ranges from about 6.0% after the dose per day 25 mg to 12.2% after the daily dose per day 100 mg. After the dose of 160 mg 14C-Mirabegron for healthy volunteers, about 55% of radioactive activity is detected in urine and 34% in feces.

Mirabegron is not converted, accounting for 45% of the radioactive activity in the urine, showing the presence of metabolites. Mirabegron is not converted to the majority of radioactive activity in feces.

Age

CMAX and AUC of Mirabegron and chemical transformations after many doses repeated by oral in the older volunteer (≥ 65 years) are similar to younger volunteers (18 - 45 years old).

Sex

CMAX and AUC are about 40% to 50% higher than in women. The difference and AUC by gender are due to the difference in weight and bioavailability.

race

pharmacokinetics are not affected by races.

Renal impairment

After using a single dose of 100 mg of Betmiga in volunteers with mild renal function (EGFR-MDRD 60 to 89 ml/min/1.73 m2), Mirabegron's average CMAX and AUC increased by 6% and 31% compared to normal kidney function. Volunteers are impaired on average renal function (EGFR-MDRD 30 to 59 ml/min/1.73 m2), CMAX and AUC increased by 23% and 66%, respectively. In volunteers with severe impaired renal function (EGFR-MDRD 15 to 29 ml/min/1.73 m2), the average CMAX AUC value is higher than 92% and 118%. Mirabegron has not been studied in patients with end -stage kidney disease (GFR

impaired liver function

After using a single dose of 100 mg of Betmiga in volunteers with a mild liver impairment (group A), Mirabegron's average CMAX and AUC increased by 9% and 19% compared to the volunteer with normal liver function. In volunteers with average liver function reduction (group B), the average CMAX and AUC values ​​are higher than 175% and 65%. Mirabegron has not been studied in patients with severe liver function (group C).

Be cautious when using

need to be very careful when taking the drug for patients in the following cases:

Renal impairment

Betmiga has not been studied in patients with end -stage renal disease (GFR impaired liver function

Betmiga has not been studied in patients with severe liver function (group C) and therefore, has not been recommended to use in these rings. Betmiga has not been recommended in patients with medium liver function impairment (group B) is using combination of strong CYP3A inhibitors.

Hypertension

Betmigac can increase blood pressure. It is recommended to measure blood pressure periodically, especially in hypertension patients.

It is not recommended to use Betmiga in unprovered hypertension patients, defined as systolic blood pressure ≥ 180 mmHg and/or diastolic blood pressure ≥ 110 mmHg.

Patients with prolonged or congenital QT or suffered

Betmiga at the dose of treatment, does not extend the QT clinical significance in clinical studies. However, because patients with a clear history of QT or patients who are taking drugs are known to extend the QT interval not to be included in these studies, the effects of Mirabegron on these patients are not known. Caution should be used when using Mirabegron in these patients.

Patients with lower urinary tract congestion and patients taking antacentants because bladder activity

Urinary retention in patients with lower urinary tract clogs and patients taking antacarinic drugs to treat increased bladder bladder were recorded in after -sales reports in patients using Mirabegron. Clinical control research on safety in patients with lower urinary tract congestion does not see an increase in the risk of urinary retention in patients treated with Betmiga; However, Betmiga should be used carefully in patients with clinical clinical clinical clogged. Betmiga should also be used cautiously in patients who are taking Muscarinic anti -anti -bladder drugs to treat increased bladder.

The effect of drugs on driving and operating machinery

Betmiga does not affect or affect the ability to drive and operate machinery.

Use drugs for women during pregnancy and lactation

Pregnancy

There are not many research data on the use of Betmiga in pregnant women. Animal studies show reproductive toxicity.

Betmiga has not been recommended during pregnancy and in women may not use birth control pills.

Breastfeeding period

Mirabegron is output in rodents, and therefore, predicted will be present in human milk. No research has been conducted to assess the effects of Mirabegron on human milk production, the presence of Mirabegron in human milk, or the effects of Mirabegron on breastfed babies. Betmiga should not be used during breastfeeding.

fertility

There is no effect on Mirabegron's treatment on animal fertility. The impact of Mirabegron on the fertility in humans has not been determined.

Drug interaction

Experimental data

Mirabegron is transported and transformed through many roads.

Mirabegron is a substrate for Cytochrome P450 (CYP) 3A4, CYP2D6, Butyrylcholininology, Uridine Diphosphoro-glucuronosyltransferases (UGT), P-GP (P-Glycoprotein, Export Pumps), OCT1 (Organic Cation Transporters, OCT2 and OCT2, OCT2) Oct3. Mirabegron studies use microsomes from human liver and recombinant CYP enzymes show that Mirabegron is an average, time -dependent CYP2D6 inhibitor, and a weak CYP3A inhibitor. Mirabegron inhibits drug transportation through high concentrations of P-GP.

Data on living objects

polymorphism of CYP2D6

The polymorphism of the CYP2D6 gene has a very small impact that the average Mirabegron contact in plasma. The interaction between Mirabegron and 1 CYP2D6 inhibitor is thought to be non -occurring and not studied. No need to adjust the Mirabegron dose when used in combination with CYP2D6 inhibitors or in inferior metabolic patients CYP2D6.

Interaction between drugs

The impact of combining multiple drugs on Mirabegron's pharmacokinetics and the effects of Mirabegron on the pharmacokinetics of other drugs surveyed in single and multi -dose studies. Most drug interactions are studied using 100 mg of Mirabegron in the form of OCAS (Oral ControlLed Absorption System, controlled oral absorption system). Interactive studies between Mirabegron and Metoprolol and with Metformin use Mirabegron instant release 160 mg.

Clinically significant drug interactions between Mirabegron and inhibitors, induction or substrates for one of the CYP enzymes or transportation are thought to be no except for the inhibitory effect of Mirabegron on the metabolism of CYP2D6 substrates.

The impact of enzyme inhibitors

Mirabegron exposure (AUC) increased by 1.8 times when there was a appearance when there was the presence of a strong CYP3A/P-GP inhibitor as ketoconazole in healthy volunteers. No dose adjustment when Betmiga is in combination with CYP3A and or P-GP inhibitors. However, in patients with mild to medium-sized renal function (GFR 30 to 89 ml/min/1.73 m2) or mild liver function impairment (group A) is simultaneously using strong CYP3A inhibitors, such as Itraconazole, Ketoconazole, Ritonavir and Clarithromycin, the dose is 25 mg daily, with no food. Betmiga has not been recommended in patients with severe impaired renal function (GFR 15 to 29 ml/min/1.73 m2) or patients with average liver function impairment (group B) are simultaneously using strong CYP3A inhibitors.

The impact of enzymes

CYP3A or P-GP induction substances reduce mirabegron levels in plasma. There is no need to adjust the dose of mirabegron when used with rifampicin or other CYP3A or P-GP induction substances at the treatment dose.

Mirabegron's impact on CYP2D6 substrates

In healthy volunteers, Mirabegron's inhibitory ability for CYP2D6 is the average and active CYP2D6 recovery within 15 days after the mirabegron stops. Take the dose once a day a day Mirabegron instant release increases CMAX and AUC of Metoprolol single dose to 90% and 229%, respectively. Take the dose once a day a day Mirabegron increases CMAX and AUC of Desipramine single dose to 79% and 241%, respectively.

Should be cautious if Mirabegron is used in combination with drugs with narrow treatment index and significantly metabolized thanks to CYP2D6, such as thioridazine, 1C anti -arrhythmic drugs (such as Flecainide, Propafenone) and three -ring anti -depression drugs (such as imipramine, desipramine). It is also necessary to be cautious if Mirabegron is used in combination with CYP2D6 substrates that the dose needs to be individualized.

Mirabegron's impact on shipping substances

Mirabegron is a weak inhibitor of P-GP. Mirabegron increases CMAX and AUC of Digoxin, which is the substrate for P-GP, up to 29% and 27%, respectively, in healthy volunteers. In patients using Betmiga and Digoxin combination, starting should prescribe digoxin at the lowest dose. Digoxin serum levels should be monitored to adjust the digoxin dose to achieve the desired clinical effect. Mirabegron's P-GP inhibitory ability should be considered when Betmiga is in combination with sensitive P-GP substrates, such as Dabigatran.

Other interactions

There is no clinical interaction that is observed when Mirabegron is used with solifenacin, tamsulosin, warfarin and metformin at the dose of treatment or with oral contraceptives in combination with ethinyylestradiol and levonorgestrel. Do not recommend adjusting the dose.

Increased mirabegron exposure due to drug interaction may come with vascular frequency increase.