Active ingredients: Mirabegron
Betmiga 25 mg prolonged-release tablets
Betmiga 50 mg prolonged-release tablets
Why is Betmiga used? What is it for?
Betmiga contains the active ingredient mirabegron. It is a bladder muscle relaxant (a so-called beta 3 adrenergic receptor agonist), which reduces the activity of an overactive bladder and treats its symptoms.
Betmiga is used to treat symptoms of overactive bladder syndrome in adults, such as:
- sudden need to empty the bladder (so-called urgency)
- the need to empty the bladder more frequently than normal (so-called increased urinary frequency)
- inability to control bladder emptying (so-called urge incontinence).
Contraindications When Betmiga should not be used
Do not take Betmiga:
- if you are allergic to mirabegron or any of the other ingredients of this medicine (listed in section 6).
- if you have uncontrolled very high blood pressure.
Precautions for use What you need to know before taking Betmiga
Talk to your doctor or pharmacist before using Betmiga:
- if you have trouble emptying your bladder or if you have a weak urine stream or if you take other medicines for overactive bladder, such as antimuscarinic medicines
- if you have kidney or liver problems. Your doctor may need to reduce your dose or may tell you not to use Betmiga, especially if you are taking other medications such as itraconazole, ketoconazole, ritonavir or clarithromycin. Tell your doctor if you are taking any other medicines.
- if you have very high uncontrolled blood pressure.
- if you have an "ECG abnormality" (tracing of heart activity) known as QT prolongation or if you are taking a drug known to cause this abnormality such as: drugs used to treat heart rhythm disorders, such as quinidine, sotalol, procainamide, ibutilide, flecainide, dofetilide and amiodarone; drugs used to treat allergic rhinitis; antipsychotic drugs (medicines used to treat mental illness), such as thioridazine, mesoridazine, haloperidol and chlorpromazine; anti-infective drugs, such as pentamidine, moxifloxacin, erythromycin.
If you experience high blood pressure, mirabegron can increase or worsen your blood pressure. It is recommended that your doctor check your blood pressure while you are taking mirabegron.
Children and adolescents
Do not give this drug to children and adolescents under the age of 18 as the safety and efficacy of Betmiga in this age group has not yet been demonstrated.
Interactions Which drugs or foods can change the effect of Betmiga
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.
Betmiga can affect the way some other medicines work, and some other medicines can affect the way Betmiga works.
- Tell your doctor if you are taking thioridazine (a medicine used to treat mental illness), propafenone or flecainide (medicines used to treat heart rhythm disorders), imipramine or desipramine (medicines used to treat depression). These specific medicines may require your doctor to adjust your dose.
- Tell your doctor if you are taking digoxin, a medicine used to treat heart failure or heart rhythm disturbances. The blood levels of this medicine are measured by your doctor.If blood levels are abnormal, your doctor may want to adjust your digoxin dose.
- Tell your doctor if you are taking dabigatran etexilate (a medicine that is used to reduce the risk of blockage of blood vessels in the brain or body caused by clot formation in adult patients with abnormal heart rhythms (atrial fibrillation) and with other factors risk). This drug may require a dose adjustment by your doctor.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant or are planning to become pregnant you should not use Betmiga.
If you are breast-feeding, ask your doctor or pharmacist for advice before using this medicine. This medicine is likely to pass into breast milk. Together with your doctor, you will have to decide whether to take Betmiga or breastfeed. It is not possible to do both.
Driving and using machines
There are no data available indicating that this drug impairs the ability to drive or use machines.
Dose, Method and Time of Administration How to use Betmiga: Posology
Always use this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The recommended dose is one 50 mg tablet taken orally once a day. If you have kidney or liver problems, your doctor may need to reduce your dose to one 25 mg tablet taken orally once a day. Take this medication with liquid and swallow the tablet whole. Do not break or chew the tablet. Betmiga can be taken before, during or after meals.
Overdose What to do if you have taken too much Betmiga
If you take more Betmiga than you should
If you have taken more tablets than prescribed, or if someone else has accidentally taken your tablets, contact your doctor, pharmacist or hospital immediately.
Symptoms of overdose may include a rapid heartbeat, an increase in pulse, or an increase in blood pressure.
If you forget to take Betmiga
If you forget to take a dose, take it as soon as you remember, unless there is 6 hours or less until your next dose. Then continue taking the medicine at the usual time.
Do not take a double dose to make up for a forgotten dose. If you forget to take more doses, contact your doctor and follow his advice.
If you stop taking Betmiga
Do not stop taking Betmiga prematurely if you do not see an immediate effect. Your bladder may need some time to adjust. Keep taking your tablets.
Do not stop treatment when your bladder condition improves. Stopping treatment may result in the symptoms of overactive bladder syndrome returning. Do not stop taking Betmiga without first talking to your doctor, as your overactive bladder syndrome symptoms may return.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Betmiga
Like all medicines, this medicine can cause side effects, although not everybody gets them.
The most serious side effects may include an irregular heartbeat (atrial fibrillation). This is an uncommon side effect (may affect up to 1 in 100 people), but if this side effect occurs, stop taking the medicine and consult a doctor immediately.
Other side effects include:
Common side effects (may affect up to 1 in 10 people)
- Faster heart rate (tachycardia)
- Infection of the channels that carry urine (urinary tract infections) - Nausea
Uncommon side effects (may affect up to 1 in 100 people)
- Bladder infection (cystitis)
- Awareness of heartbeat (palpitations)
- Vaginal infection
- Indigestion (dyspepsia)
- Stomach infection (gastritis)
- Swelling of the joints
- Itching of the vulva or vagina (vulvovaginal itching)
- Increased blood pressure
- Increased liver enzymes (GGT, AST and ALT)
- Itching, rash or rash (hives, rash, macular rash, papular rash, pruritus)
Rare side effects (may affect up to 1 in 1,000 people)
- Swelling of the eyelid (eyelid edema)
- Swelling of the lips (lip edema)
- Swelling of the deeper layers of the skin, caused by an increase in fluids which can affect any part of the body including the face, tongue or throat and can cause difficulty in breathing.
- Small purplish skin rash (purpura)
- Inflammation of small blood vessels mostly in the skin (leukocytoclastic vasculitis)
- Inability to completely empty the bladder (urinary retention)
Not known (frequency cannot be estimated from the available data)
- Insomnia
Betmiga may make it more difficult for you to empty your bladder if you have a bladder obstruction or if you are taking other medicines to treat overactive bladder. Call your doctor right away if you are unable to empty your bladder.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton, blister or bottle after EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
After first opening the bottle, the tablets should be used within 6 months.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Betmiga contains
- The active ingredient is mirabegron. Each tablet contains 25 mg or 50 mg of mirabegron.
- The other ingredients are: Tablet core: Macrogol, hydroxypropylcellulose, butylhydroxytoluene, magnesium stearate. Coating: hypromellose, macrogol, yellow iron oxide (E172), red iron oxide (E172) (25 mg tablets only).
Description of the appearance of Betmiga and contents of the pack
Betmiga 25 mg prolonged-release film-coated tablets are brown and oval-shaped tablets, engraved with the company logo and "325" on the same side. Betmiga 50 mg prolonged-release film-coated tablets are yellow and oval-shaped tablets, engraved with the company logo and "355" on the same side.
Betmiga is available in alu-alu blisters containing 10, 20, 30, 50, 60, 90, 100 or 200 tablets and in high-density polyethylene (HDPE) bottles with silica gel desiccant and child resistant closure, containing 90 tablets.
Not all pack sizes may be marketed. The bottles may not be available in your country.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
BETMIGA 25 MG EXTENDED RELEASE TABLETS
▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 25 mg of mirabegron.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Prolonged-release tablet.
Brown, oval tablet, engraved with the company logo and "325" on the same side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Symptomatic treatment of urgency, increased frequency of urination and / or urge incontinence which may occur in adult patients with overactive bladder (OAB) syndrome.
04.2 Posology and method of administration
Dosage
Adults (including elderly patients)
The recommended dose is 50 mg once daily taken with or without food.
Special populations
Renal and hepatic impairment
Betmiga has not been studied in patients with end stage renal disease (GFR 2 or patients requiring hemodialysis) or severe hepatic impairment (Child-Pugh Class C) and is therefore not recommended for use in these patient populations (see paragraphs 4.4 and 5.2).
The following table provides recommendations for daily dosing in patients with hepatic or renal impairment in the presence or absence of potent CYP3A inhibitors (see sections 4.4, 4.5 and 5.2).
1. Mild: glomerular filtartion rate (GFR) from 60 to 89 mL / min / 1.73m2; moderate: GFR 30 to 59 mL / min / 1.73m2; severe: GFR 15 to 29 mL / min / 1.73m2.
2. Mild: Child-Pugh Class A; Moderate: Child-Pugh Class B.
3. For potent CYP3A inhibitors see section 4.5.
Sex
No dose adjustment is necessary based on gender.
Pediatric population
The safety and efficacy of mirabegron in children under the age of 18 have not yet been established.
No data are available.
Method of administration
The tablet should be taken once daily, with liquid, swallowed whole and should not be chewed, divided or broken.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Renal impairment
Betmiga has not been studied in patients with end-stage renal disease (GFR 2 or in patients requiring hemodialysis) and is therefore not recommended for use in this patient population. Data in patients with severe renal impairment (GFR 15 to 29 mL / min / 1.73 m2) are limited; based on pharmacokinetic studies (see section 5.2) in this population a dose reduction to 25 mg is recommended. The use of Betmiga is not recommended in patients with severe renal impairment (GFR 15 to 29 mL / min / 1.73 m2) who are concomitantly receiving potent CYP3A inhibitors (see section 4.5).
Hepatic impairment
Betmiga has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and is therefore not recommended for use in this patient population. The use of Betmiga is not recommended in patients with moderate renal impairment (Class B of Child-Pugh) who are concomitantly receiving potent CYP3A inhibitors (see section 4.5).
Hypertension
Betmiga has not been evaluated in patients with severe uncontrolled hypertension (systolic blood pressure ≥ 180 mmHg and / or diastolic blood pressure ≥ 110 mmHg); therefore, use in these patients is not recommended. In patients with stage 2 hypertension (systolic blood pressure ≥ 160 mmHg and / or diastolic blood pressure ≥ 100 mmHg) there are limited data.
Patients with congenital or acquired QT interval prolongation
In clinical trials, administration of Betmiga at therapeutic doses did not cause a clinically relevant QT interval prolongation (see section 5.1). patients who are taking medicines known to prolong the QT interval, therefore the effect of mirabegron in these patients is not known. Caution should be used when administering mirabegron to these patients.
Patients with cervical urethral obstruction taking antimuscarinic drugs for OAB
In postmarketing, cases of urinary retention have been reported in patients taking mirabegron in subjects with bladder outlet obstruction (BOO) and in subjects taking antimuscarinic drugs for the treatment of OAB. A controlled clinical study of safety in patients with BOO did not demonstrate increased urinary retention in patients treated with Betmiga; on the other hand, however, Betmiga should be administered with caution in patients with clinically significant BOO. Betmiga should also be administered with caution in patients taking antimuscarinic drugs for the treatment of OAB.
04.5 Interactions with other medicinal products and other forms of interaction
Data in vitro
Mirabegron is transported and metabolized through multiple pathways. Mirabegron is a substrate for cytochrome P450 CYP3A4, CYP2D6, butyrylcholinesterase, uridine diphosphate glucuronosyltransferase (UGT), the extra-cellular membrane transporter P-glycoprotein (P-gp) and the intra-cellular organic cation transporter (OCT) OCT1, OCT2 and OCT3. Studies with mirabegron in human liver microsomes and recombinant human CYPs have shown that mirabegron is a moderate, time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. At high concentrations mirabegron inhibited P-gp mediated drug transport.
Data in vivo
CYP2D6 polymorphism
The CYP2D6 genetic polymorphism has minimal impact on the mean plasma exposure to mirabegron (see section 5.2). The interaction of mirabegron with a known CYP2D6 inhibitor is not expected and has not been studied. No dose adjustments of mirabegron are required when administered with CYP2D6 inhibitors or in patients who are poor metabolisers of CYP2D6.
Interaction between drugs
The effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs were evaluated in single-dose and repeat-dose studies. Most drug interactions have been studied by administering mirabegron at a dose of 100 mg as a controlled oral absorption system (OCAS) tablet.
Interaction studies of mirabegron with metoprolol and metformin used mirabegron immediate release (IR) 160 mg.
Clinically relevant interactions between mirabegron and medicinal products that inhibit, induce or are substrates for any of the CYP isoenzymes or transporters are not expected, except for the inhibitory effect of mirabegron on the metabolism of CYP2D6 substrates.
Effect of enzyme inhibitors
Mirabegron exposure (AUC) was increased 1.8-fold in the presence of potent CYP3A / P-gp ketoconazole inhibitors in healthy volunteers. When Betmiga is given in combination with CYP3A and / or P-gp inhibitors it is not required. a dose adjustment. D "the other hand in patients with mild to moderate renal impairment (GFR 30 to 89 mL / min / 1.73 m2) or moderate hepatic impairment (Child-Pough Class A) concurrently receiving potent inhibitors of CYP3A, such as itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended daily dose is 25 mg once daily with or without food (see section 4.2). Betmiga is not recommended in patients with severe renal impairment (GFR 15 to 29 mL / min / 1.73 m2) or in patients with moderate hepatic impairment (Child-Pough Class B) concurrently receiving CYP3A inhibitors (see sections 4.2 and 4.4).
Effect of enzyme inducers
Substances that are inducers of CYP3A or P-gp reduce the plasma concentration of mirabegron.No dose adjustments are required when mirabegron is administered with rifampicin or other inducers of CYP3A or P-gp at therapeutic doses.
Effect of mirabegron on CYP2D6 substrates
In healthy volunteers, the inhibitory potency of mirabegron against CYP2D6 is moderate and CYP2D6 activity is recovered within 15 days after discontinuation of mirabegron. Repeated administrations of the daily dose of mirabegron IR cause a 90% increase in Cmax and 229 % of the AUC of a single dose of metoprolol. Repeated administration of the daily dose of mirabegron results in a 79% increase in Cmax and 241% in AUC in a single dose of desipramine.
Caution should be used if mirabegron is co-administered with medicinal products with a narrow therapeutic index and significantly metabolised by CYP2D6, such as thioridazine, Type C1 antiarrhythmics (e.g. flecainide, propafenone) and tricyclic antidepressants (e.g. imipramine, desipramine). Caution should also be used if mirabegron is co-administered with CYP2D6 substrates whose dose is to be individually titrated.
Effect of mirabegron on transporters
Mirabegron is a weak P-gp inhibitor. In healthy volunteers, mirabegron increases Cmax and AUC by 29% and 27% of the P-gp substrate digoxin. In patients starting to take the combination of Betmiga and digoxin, the lower dose of digoxin should initially be prescribed. .
Serum digoxin concentration should be monitored and used for dose titration of digoxin to achieve the desired clinical effect. The inhibitory potential of mirabgron against P-gp when Betmiga is combined with substart sensitive to P-gp should be considered. P-gp, e.g. dabigatran.
Other interactions
No clinically relevant interactions were observed when mirabegron was co-administered with therapeutic doses of solifenacin, tamsulosin, warfarin, metformin or combined oral contraceptive medicinal products containing ethinylestradiol and levonorgestrel. Dose adjustment is not recommended.
Increased exposure to mirabegron caused by drug-drug interaction may be associated with increased pulse rate.
04.6 Pregnancy and lactation
Pregnancy
There are limited data from the use of Betmiga in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Betmiga is not recommended during pregnancy and in women of childbearing potential not using contraceptive measures. .
Feeding time
Mirabegron is excreted in the milk of rodents and is therefore expected to be present in human milk (see section 5.3). No studies have been conducted to investigate the impact of mirabegron on breast milk production in humans, its presence in breast milk or its effect on breastfed infants. Betmiga should not be administered during breastfeeding.
Fertility
No mirabegron treatment-related effects on fertility were observed in animals (see section 5.3). The effect of mirabegron on human fertility has not been established.
04.7 Effects on ability to drive and use machines
Betmiga has no or negligible influence on the ability to drive or use machines.
04.8 Undesirable effects
Summary of the safety profile
The safety of Betmiga was evaluated in 8,433 patients with OAB, of whom 5,648 had received at least one dose of mirabegron during phases 2/3 of the clinical program, and 622 patients had received Betmiga for at least 1 year (365 days). In the three Phase 3, double-blind, placebo-controlled, 12-week studies, 88% of patients had completed treatment with Betmiga and 4% had discontinued it due to adverse events. Most reactions were of mild to moderate entity.
The most common adverse reactions reported in patients treated with Betmiga 50 mg during the three Phase 3, double-blind, placebo-controlled, 12-week studies were tachycardia and urinary tract infections. The frequency of tachycardia was 1.2% in patients who received Betmiga 50 mg. Tachycardia caused treatment discontinuation in 0.1% of patients who received Betmiga 50 mg. The frequency of urinary tract infections was 2.9% in patients who received Betmiga 50 mg. Urinary tract infections did not cause treatment discontinuation in any of the patients who received Betmiga 50 mg. Serious adverse reactions included atrial fibrillation (0.2%).
Adverse reactions observed during a 1-year (long-term) active substance (muscarinic antagonist) study were similar in type and severity to those observed in the three 12-week double-blind placebo-controlled phase 3 studies.
Table of adverse reactions
The table below lists the adverse reactions observed during the three 12-week, double-blind, placebo-controlled phase 3 studies.
The frequency of adverse reactions is defined as follows: very common (≥1 / 10); common (≥1 / 100,
Within the same frequency group, adverse reactions are listed in order of descending severity.
* observed during post-marketing experience
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
04.9 Overdose
Mirabegron has been administered to healthy volunteers in single doses up to 400 mg. At this dose, adverse events recorded included palpitations (1 of 6 subjects) and increased pulse above 100 beats per minute (bpm) (3 of 6 subjects). Multiple doses of mirabegron up to 300 mg per day for 10 days showed an increase in pulse and systolic blood pressure when administered to healthy volunteers.
Treatment of overdose should be symptomatic and supportive. In the event of an overdose, monitoring of pulse, blood pressure and ECG is recommended.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Urologicals, urinary spasmolytics. ATC code: G04BD12.
Mechanism of action
Mirabegron is a potent and selective agonist of beta 3 adrenergic receptors. Mirabegron resulted in relaxation of bladder smooth muscle in isolated rat and human tissue, increased concentrations of cyclic adenosine monophosphate (cAMP) in rat bladder tissue, and showed a relaxing effect on the bladder in rat urinary bladder models.
Mirabegron increased the mean voiding volume per urination and reduced the frequency of contractions that do not lead to voiding, without affecting voiding pressure or residual urine in rat overactive bladder models. In a monkey model, mirabegron demonstrated reduced voiding frequency These results indicate that mirabegron improves urine storage function by stimulating beta 3 adrenergic receptors in the bladder.
During the accumulation phase, ie when urine accumulates in the bladder, stimulation of the sympathetic nerves is prevalent. Noradrenaline is released from the nerve endings, determining mostly the activation of the beta-adrenergic receptors of the bladder muscles, and hence the relaxation of the smooth muscle of the bladder. During the emptying phase, the bladder is mainly controlled by the parasympathetic nervous system. Acetylcholine, released from the pelvic nerve endings, stimulates the cholinergic receptors M & SUP2; and M & SUP3 ;, inducing contraction of the bladder. Activation of the M & SUP2; it also inhibits cAMP increases induced by beta 3 adrenergic receptors. Therefore, stimulation of beta 3 adrenergic receptors should not interfere with the emptying process, as confirmed in the rat with partial urethral obstruction, where mirabegron reduced the frequency of contractions. not inducing voiding, without affecting the voiding volume per urination, voiding pressure or residual urine volume.
Pharmacodynamic effects
Urodynamics
Betmiga at doses of 50 mg and 100 mg administered once daily for 12 weeks in male subjects with lower urinary tract symptoms (LUTS) and cervical urethral obstruction (BOO) showed no effect on cystometric parameters and was safe and well tolerated. . The effects of mirabegron on maximum flow rate and detrusor pressure at maximum flow rate were evaluated in a urodynamic study in 200 male patients with LUTS and BOO. Administration of mirabegron at doses of 50 mg and 100 mg once daily for 12 weeks did not adversely affect maximum flow rate or detrusor pressure at maximum flow rate. In this study in male patients with LUTS / BOO, the adjusted mean change (SE) from baseline to end of treatment in residual volume after voiding (mL) was 0.55, 17.89, 30.77 for the placebo groups. , mirabegron 50 mg and mirabegron 100 mg.
Effect on the QT interval
Betmiga at doses of 50 mg and 100 mg had no effect on the individually corrected QT interval for heart rate (QTcI interval) assessed for either gender or the whole group.
A thorough QT (TQT) study (n = 164 healthy male volunteers and n = 153 healthy female volunteers with a mean age of 33 years) evaluated the effect of repeated oral doses of mirabegron at the indicated dose. (50 mg once daily) and two supratherapeutic doses (100 mg and 200 mg once daily) over the QTcI interval. Supratherapeutic doses are approximately 2.6 and 6.5 times the therapeutic dose exposure, respectively. . A single 400 mg dose of moxifloxacin was used as a positive control. Each dose level of mirabegron and moxifloxacin was evaluated in separate treatment arms, both with placebo control (parallel cross-over design). For male and female subjects who received mirabegron at doses of 50 mg and 100 mg, the upper limit of the 95% confidence interval, one-sided test, did not exceed 10 msec at any time for the associated maximum mean difference. time versus placebo in the QTcI interval. In female subjects who received mirabegron at a dose of 50 mg, the mean difference from placebo in the QTcI interval at 5 hours post dose was 3.67 msec (upper bound of the 95% confidence interval one-sided test , 5.72 msec). In male subjects the difference was 2.89 msec (upper limit of the 95% confidence interval, one-sided test, 4.90 msec). At a dose of 200 mg of mirabegron, the QTcI interval did not exceed 10 msec at any time in male subjects, while in female subjects the upper limit of the one-sided 95% confidence interval exceeded 10 msec between 0.5 and 6 hours, with a maximum difference versus placebo at 5 hours where the mean effect was 10.42 msec (upper limit of the 95% confidence interval, one-sided test, 13.44 msec). The results for QTcF and QTcIf were consistent with the QTcI interval.
In this TQT study, mirabegron resulted in a dose-dependent increase in heart rate on ECG in the examined dose range of 50 mg to 200 mg. The maximum mean difference versus placebo in heart rate ranged from 6.7 bpm with mirabegron 50. mg at 17.3 bpm with mirabegron 200 mg in healthy subjects.
Effects on pulse and blood pressure in patients with OAB
In the three Phase 3, double-blind, placebo-controlled, 12-week studies in patients with OAB (mean age: 59 years) who received Betmiga 50 mg once daily, an increase in the mean difference versus was observed. placebo of approximately 1 bpm for pulse and approximately 1 mmHg or less for systolic blood pressure / diastolic blood pressure (SBP / DBP). The changes in pulse and blood pressure are reversible upon discontinuation of treatment.
Effect on intraocular pressure (IOP)
Mirabegron 100 mg administered once daily showed no increase in IOP in healthy subjects after 56 days of treatment. In a Phase 1 study evaluating the effect of Betmiga on IOP by Goldmann applanation tonometry in 310 healthy subjects, a 100 mg dose of mirabegron was non-inferior to placebo for the primary endpoint of treatment difference in terms of mean change from baseline to day 56 in mean / subject IOP; the upper limit of the 95% confidence interval, two-sided test of the treatment difference between mirabegron 100 mg and placebo was 0.3 mmHg.
Clinical efficacy and safety
The efficacy of Betmiga was evaluated in three randomized, double-blind, placebo-controlled, 12-week Phase 3 studies for the treatment of overactive bladder syndrome associated with symptoms of urgency and frequency with or without incontinence. including female (72%) and male (28%) patients with a mean age of 59 years (age range: 18-95 years). The study population consisted of approximately 48% of patients not previously undergoing antimuscarinic therapy and approximately 52% of patients previously treated with antimuscarinics. In one study, 495 patients received an active control drug (tolterodine extended-release formulation).
The co-primary efficacy endpoints consisted of: change from baseline in the mean number of incontinence episodes for 24 hours at the end of treatment; change from baseline to end of treatment in mean number of micturitions per 24 hours based on a completed micturition diary over 3 days. Mirabegron showed statistically significant improvements versus placebo for both co-primary endpoints as well as secondary endpoints (see Tables 1 and 2).
Table 1: Co-primary and secondary efficacy endpoints selected at the end of treatment for the unified studies
The unified studies consisted of studies 046 (EU / Australia), 047 (North America [NA]) and 074 (EU / NA).
† Least squares mean adjusted for baseline, gender, and study.
* Significantly higher statistically than placebo at the 0.05 level without multiplicity correction.
# Statistically significantly higher than placebo at the 0.05 multiplicity corrected level.
FAS: Full analysis set, all randomized patients who received at least 1 dose of study drug in double blind and with a micturition measure in the baseline diary and at least 1 post-baseline visit diary with micturition measure.
FAS-I: Subgroup of FAS with at least 1 episode of incontinence in the diary at baseline.
CI: Confidence Interval
Table 2: Co-primary and secondary efficacy endpoints selected at end of treatment for studies 046, 047 and 074
† Least squares mean adjusted for baseline, gender, and geographic region.
* Significantly higher statistically than placebo at the 0.05 level without multiplicity correction.
# Statistically significantly higher than placebo at the 0.05 multiplicity corrected level.
‡ From a statistical point of view, nonsignificant superiority over placebo at the 0.05 multiplicity corrected level.
FAS: Full analysis set, all randomized patients who received at least 1 dose of study drug in double-blind and micturition diary at baseline and at least 1 post-baseline visit diary with micturition computation.
FAS-I: Subgroup of FAS with at least 1 episode of incontinence in the diary at baseline.
Betmiga 50 mg administered once daily was effective at first detection at week 4, and efficacy was maintained throughout the 12-week treatment period. A long-term, randomized, active-controlled study demonstrated that efficacy was maintained throughout the 1-year treatment period.
Subjective improvement of the parameters of the quality of life in reference to health
In the three Phase 3, double-blind, placebo-controlled, 12-week studies, treatment of OAB symptoms with mirabegron administered once daily resulted in a statistically significant improvement versus placebo in the following health-related quality of life parameters : satisfaction with the treatment and annoyance of the symptoms.
Efficacy in patients who have or have not previously undergone antimuscarinic therapies for the treatment of OAB
Efficacy has been demonstrated in patients who have either undergone or have not previously undergone antimuscarinic therapy for the treatment of OAB. Mirabegron has also been shown to be effective in patients who had previously discontinued treatment with antimuscarinic therapy for the treatment of OAB due to insufficient efficacy ( see Table 3).
Table 3: Co-primary efficacy endpoints for patients previously receiving antimuscarinic therapy for the treatment of OAB
The unified studies consisted of studies 046 (EU / Australia), 047 (North America [NA]) and 074 (EU / NA).
† Least squares mean adjusted for baseline, gender, study, subgroup, treatment interaction subgroup for the Pooled Studies and least squares mean corrected for baseline, gender and geographic region, subgroup, treatment interaction subgroup for study 046.
FAS: Full analysis set, all randomized patients who received at least 1 dose of study drug in double-blind and micturition diary at baseline and at least 1 post-baseline visit diary with micturition measurement.
FAS-I: Subgroup of FAS with at least 1 episode of incontinence in the diary at baseline.
Pediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with Betmiga in one or more subsets of the pediatric population in the indications "Treatment of idiopathic overactive bladder syndrome" and "Treatment of" neurogenic detrusor overactivity "(see section 4.2 for information on pediatric use).
05.2 Pharmacokinetic properties
Absorption
Following oral administration in healthy volunteers, mirabegron is absorbed to reach peak plasma concentrations (Cmax) between 3 and 4 hours. Absolute bioavailability increased from 29% at a 25 mg dose to 35% at a 50 mg dose. Mean Cmax and AUC increased more than dose proportionally over the dose range. In the total male and female population, a 2-fold increase in the dose of mirabegron, from 50 mg to 100 mg, resulted in an increase Cmax and AUCtau of approximately 2.9 and 2.6-fold, respectively, while a 4-fold increase in the dose of mirabegron, from 50 mg to 200 mg, resulted in an increase in Cmax and AUCtau of approximately 8.4 and 6.5 times. The concentrations at steady state are achieved within 7 days of once daily administration of mirabegron. Following once daily dosing, the plasma exposure of mirabegron at steady state is approximately double that observed following single dose administration.
Effect of food on absorption
Co-administration of a 50 mg tablet and a high-fat meal resulted in a reduction of mirabegron Cmax and AUC by 45% and 17%, respectively. A low-fat meal resulted in a reduction in mirabegron Cmax and AUC by 75% and 51%, respectively. In phase 3 studies, mirabegron was administered with or without food, proving to be safe and effective. Mirabegron can therefore be taken with or without food at the recommended dose.
Distribution
Mirabegron is widely distributed. The volume of distribution at steady state (Vss) is approximately 1670 L. Mirabegron is bound (approximately 71%) to human plasma proteins and exhibits a moderate "affinity for albumin and alpha-1 acid glycoprotein. Mirabegron is distributed in erythrocytes. Concentrations. erythrocytes in vitro of 14C-mirabegron were approximately 2 times higher than those in plasma.
Biotransformation
Mirabegron is metabolised through multiple pathways involving dealkylation, oxidation, (direct) glucuronidation and amide hydrolysis. Mirabegron is the major circulating component following administration of a single dose of 14C-mirabegron. Two major metabolites have been observed in human plasma; both are phase 2 glucuronides representing respectively 16% and 11% of the total exposure. These metabolites are not pharmacologically active.
Based on studies in vitro, it appears that mirabegron does not inhibit the metabolism of medicinal products co-administered by cytochrome P450 enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1 since mirabegron does not inhibit the activity of these enzymes at clinically undetectable concentrations. o CYP3A Mirabegron is not expected to cause clinically significant inhibition of OCT-mediated drug transporters.
Although the studies in vitro suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, the results in vivo indicate that these isoenzymes play a limited role in overall elimination. Studies in vitro and ex vivo showed the involvement of butyrylcholinesterase, UGT and possibly alcohol dehydrogenase (ADH) in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6.
CYP2D6 polymorphism
In healthy subjects who are genetically poor metabolisers of CYP2D6 substrates (used as a substitute for inhibition of CYP2D6), the mean Cmax and AUCinf of a single 160 mg dose of the mirabegron IR formulation were 14% and 19% higher than in strong metabolisers, indicating that the CYP2D6 genetic polymorphism has minimal impact on the mean plasma exposure to mirabegron. The interaction of mirabegron with a known CYP2D6 inhibitor is not predictable and has not been studied. No dose adjustment is required for mirabegron when administered with CYP2D6 inhibitors or in patients poor metabolisers of CYP2D6.
Elimination
Total body clearance (CLtot) of plasma is approximately 57 L / h. The terminal elimination half-life (t½) is approximately 50 hours. Renal clearance (CLR) is approximately 13 L / h, which corresponds to almost 25% of CLtot. Renal elimination of mirabegron occurs mainly through active tubular secretion together with glomerular filtration. Urinary excretion of unchanged mirabegron is dose-dependent and ranges from approximately 6.0% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. Following administration of 160 mg of 14C-mirabegron in healthy volunteers, approximately 55% of the radiolabeller was recovered in urine and 34% in faeces. Unchanged Mirabegron accounted for approximately 45% of urinary radioactivity, indicating the presence of metabolites. Unchanged Mirabegron accounted for the majority of fecal radioactivity.
Age
The Cmax and AUC of mirabegron and its metabolites following multiple oral doses in elderly volunteers (age ≥ 65 years) were similar to those of younger volunteers (age 18-45 years).
Sex
Cmax and AUC are approximately 40-50% higher in females than in males, respectively. Differences in Cmax and AUC by gender are attributed to differences in body weight and bioavailability.
Race
The pharmacokinetics of mirabegron are not affected by race.
Renal impairment
Following administration of a single 100 mg dose of Betmiga to volunteers with mild renal impairment (eGFR 60 to 89 mL / min / 1.73 m2 as estimated in the Modification of Diet in Renal Disease (MDRD) study) , the mean Cmax and AUC of mirabegron are
increased by 6% and 31% respectively compared to volunteers with normal renal function. In volunteers with moderate renal impairment (eGFR-MDRD 30 to 59 mL / min / 1.73 m2), Cmax and AUC increased by 23% and 66%, respectively. In volunteers with severe renal impairment (eGFR-MDRD 15 to 29 mL / min / 1.73 m2), mean Cmax and AUC were 92% and 118% higher, respectively. Mirabegron has not been studied in patients with end-stage renal disease (GFR 2 or patients requiring hemodialysis).
Hepatic impairment
Following administration of a single 100 mg dose of Betmiga in volunteers with mild hepatic impairment (Child-Pugh Class A), the mean Cmax and AUC of mirabegron increased by 9% and 19%, respectively, compared to volunteers with normal hepatic function In volunteers with moderate hepatic impairment (Child-Pugh Class B), mean Cmax and AUC were 175% and 65% higher, respectively. Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).
05.3 Preclinical safety data
Preclinical studies have identified toxicity target organs compatible with clinical observations. In the rat, transient increases in liver enzymes and hepatocyte alterations (necrosis and reduction of glycogen particles) were observed. An increase in heart rate was observed in rats as well as rabbits, dogs and monkeys. Genotoxicity and carcinogenicity studies did not reveal a genotoxic or carcinogenic potential in vivo.
At sublethal doses (19 times the maximum recommended human equivalent dose, maximum human recommended dose MHRD), no impairment of fertility was observed. cardiomegaly) at systemic exposures 36 times higher than those observed in MHRD. Furthermore, lung malformations (absence of the accessory lung lobe) and increased implantation losses were observed in rabbits at systemic exposures 14 times higher than in "MHRD, while reversible effects on ossification (wavy ribs, delayed ossification, reduced number of ossified segments in the sternum, metacarpus or metatarsus) were noted in the rat at 22 times higher systemic exposures than in MHRD. Embryo-fetal toxicity was detected at doses associated with maternal toxicity. The cardiovascular malformations observed in the rabbit have been shown to be mediated by the activation of the beta 1 adrenergic receptor.
Pharmacokinetic studies with radiolabelled mirabegron have shown that the parent compound and / or its metabolites are excreted in rat milk at levels approximately 1.7 times the plasma levels at 4 hours post dose (see section 4.6).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablets
Macrogol
Hydroxypropylcellulose
Butylhydroxytoluene
Magnesium stearate
Coating
Hypromellose
Macrogol
Yellow iron oxide (E172)
Red iron oxide (E172)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years
Shelf life after first opening the bottle: 6 months
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Alu-alu blisters in cartons containing 10, 20, 30, 50, 60, 90, 100 or 200 tablets.
HDPE bottles with child resistant polypropylene (PP) caps and silica gel desiccant containing 90 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Astellas Pharma Europe B.V.
Sylviusweg 62
2333 BE Leiden
Netherlands
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/12/809/001 - 007
042647014
042647026
042647038
042647040
042647053
042647065
042647077
EU / 1/12/809/015
042647154
EU / 1/12/809/016
042647166
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 20 December 2012
10.0 DATE OF REVISION OF THE TEXT
D.CCE November 2014
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