Consumer medicine information

Betmiga

Mirabegron

BRAND INFORMATION

Brand name

Betmiga

Active ingredient

Mirabegron

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Betmiga.

What is in this leaflet

This leaflet answers some common questions about BETMIGA.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking BETMIGA against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What BETMIGA is used for

BETMIGA contains mirabegron, a beta 3-adrenoceptor agonist, which is used to treat symptoms of an overactive bladder.

Overactive bladder occurs when you cannot control your bladder contractions. When these muscle contractions happen too often or cannot be controlled, you can get symptoms such as:

  • suddenly needing to empty your bladder (urgency)
  • having to empty your bladder more than usual (increased urinary frequency)
  • not being able to control when you empty your bladder (urgency incontinence).

BETMIGA works by reducing the activity of an overactive bladder and treats the related symptoms.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is only available with a doctor's prescription.

The safety and effectiveness of BETMIGA in children and adolescents under the age of 18 years have not been established.

There is no information to suggest that BETMIGA affects your ability to drive or use machinery. Be careful driving or operating machinery until you know how BETMIGA affects you. It may cause dizziness in some people. If this occurs, do not drive or use machinery.

Before you take BETMIGA

When you must not take it

Do not take BETMIGA if you have an allergy to:

  • any medicine containing mirabegron
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take BETMIGA if you have very high blood pressure (systolic greater than or equal to 180mmHg and /or diastolic greater than or equal to 110mmHg).

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • kidney problems
  • liver problems
  • high blood pressure
  • heart disorders, including an irregular heartbeat, an abnormal electrical signal in the heart that can cause an irregular heart rhythm called "prolongation of the QT interval", or if you are taking any medicine known to cause irregular heart rhythm (see 'Taking other medicines')
  • trouble emptying your bladder or you have a weak urine stream

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell him/her before you start taking BETMIGA.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and BETMIGA may interfere with each other. These include:

  • thioridazine (a medicine for mental illness), propafenone or flecainide (medicines for abnormal heart rhythm), metoprolol (a medicine for high blood pressure or heart problems), imipramine or desipramine (medicines used for depression). These specific medicines may require dose adjustment by your doctor.
  • some anti-fungal medicines (e.g. itraconazole, ketoconazole)
  • ritonavir (a medicine used to treat HIV/AIDS)
  • digoxin (a medicine for heart failure or abnormal heart rhythm). Blood levels of digoxin are measured by your doctor. If the blood level is out of range, your doctor may adjust the dose of digoxin
  • medicines used for the management of overactive bladder (e.g. solifenacin, tolterodine, oxybutynin, darifenacin, trospium, fesoterodine) and medicines used for the management of enlarged prostate (e.g. tamsulosin)
  • some medicines that are known to prolong QT interval, such as quinidine, sotalol, amiodarone (medicines used for abnormal heart rhythm), mesoridazine, haloperidol (medicines for mental illness), or erythromycin, clarithromycin (anti-infectives)

These medicines may be affected by BETMIGA or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take BETMIGA

Follow directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

The usual dose is 25 mg tablet once a day. Based upon your response and tolerability, your doctor may increase your dose to 50 mg once daily. The maximum dose for BETMIGA is 50 mg once daily.

How to take it

Swallow the tablet whole with a full glass of water. Do not crush or chew the tablet.

You can take the tablet with or without food.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will help you remember when to take it.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

Do not stop treatment with BETMIGA early if you do not see an immediate effect. Your bladder might need some time to adapt.

Do not stop taking BETMIGA when your bladder condition improves.

This medicine helps to control your condition, but does not cure it. Stopping treatment may result in a recurrence of symptoms of an overactive bladder.

If you forget to take it

If it is 6 hours or less before your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much BETMIGA. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much BETMIGA, you may feel a fast heart rate.

While you are using BETMIGA

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking BETMIGA.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

Do not take BETMIGA to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or alter the dosage without checking with your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking BETMIGA.

This medicine helps most people with overactive bladder but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not.

You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • indigestion (dyspepsia)
  • common cold symptoms (nasopharyngitis)
  • headache
  • dizziness
  • nausea (feeling sick) or vomiting
  • fatigue
  • constipation
  • stomach, back or joint pain
  • urinary tract infection, including signs such as burning or pain when passing urine, or an urge to pass urine frequently. Urine may have a strong smell, looks cloudy or contains blood
  • vaginal discharge, itching or burning
  • increased blood pressure
  • increase in liver enzymes

Tell your doctor as soon as possible if you notice any of the following:

  • fast or irregular heartbeats
  • swelling of the face, eyelid, lips, tongue, throat, airways or joints
  • rash, itchiness or hives

The above list includes serious side effects that may require medical attention.

If swelling involves the tongue, throat or airways seek medical attention immediately.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Some of these side effects (for example, changes in blood test results, blood pressure or liver enzymes) can only be found when your doctor does tests from time to time to check your progress.

After using BETMIGA

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Do not store BETMIGA or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

BETMIGA is available in 25 mg or 50 mg strengths:

25 mg tablet is an oval, brown film-coated tablet, debossed with the (Astellas logo) and "325"

50 mg tablet is an oval, yellow film-coated tablet, debossed with the (Astellas logo) and "355"

Both strengths are available in packs of 30 tablets.

Ingredients

BETMIGA contains 25 mg or 50 mg of mirabegron as the active ingredient.

The tablets also contain:

  • macrogol 8000
  • macrogol 2000000
  • hyprolose
  • purified water
  • butylated hydroxytoluene
  • magnesium stearate
  • OPADRY complete film coating system 03F43159 ORANGE (25 mg tablet only)
  • OPADRY complete film coating system 03F42192 YELLOW (50 mg tablet only).

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

BETMIGA is supplied in Australia by:

Astellas Pharma Australia Pty Ltd
6 Eden Park Drive
Macquarie Park, NSW 2113

Medical Information:
1800 751 755

® = Registered Trademark

Australian Registration Numbers

  • 25 mg tablet: AUST R 199664
  • 50 mg tablet: AUST R 199668

This leaflet was prepared in May 2020

Published by MIMS July 2020

BRAND INFORMATION

Brand name

Betmiga

Active ingredient

Mirabegron

Schedule

S4

 

1 Name of Medicine

Mirabegron.

6.7 Physicochemical Properties

Mirabegron is white to off-white crystals or powder. It is freely soluble in dimethyl sulfoxide, soluble in methanol and insoluble in water.
The dissociation constant (pKa) is 4.5 and 8.0.

Chemical structure.


Chemical name: 2-(2-amino-1,3-thiazol-4-yl)- N-[4-(2-{[(2R)- 2-hydroxy-2-phenylethyl]amino} ethyl)phenyl]acetamide.
Molecular formula: C21H24N4O2S.

CAS number.

223673-61-8.

2 Qualitative and Quantitative Composition

Betmiga contains mirabegron 25 mg or 50 mg as the active ingredient.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Prolonged-release film-coated tablets.

25 mg.

An oval, brown film-coated tablet, debossed with the (Astellas logo) and "325".

50 mg.

An oval, yellow film-coated tablet, debossed with the (Astellas logo) and "355".

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Mirabegron is an agonist of the human beta 3-adrenoceptor (AR) as demonstrated by in vitro laboratory experiments using the cloned human beta 3-AR. Although mirabegron showed very low intrinsic activity for cloned human beta 1 and beta 2-AR, results in humans indicate that some beta 1-AR stimulation occurs at mirabegron doses of 50 to 200 mg. Mirabegron showed relaxation of bladder smooth muscle in rat and human isolated tissue, increased cAMP concentrations in rat bladder tissue and showed a bladder relaxant effect in rat urinary bladder function models. Mirabegron increased mean voided volume per micturition and decreased the frequency of nonvoiding contractions, without affecting voiding pressure, or residual urine in rat models of bladder overactivity. In a monkey model, mirabegron showed decreased voiding frequency. These results indicate that mirabegron enhances urine storage function by stimulating beta 3-AR in the bladder.
During the urine storage phase, when urine accumulates in the bladder, sympathetic nerve stimulation predominates. Noradrenaline is released from nerve terminals, leading predominantly to beta adrenoceptor activation in the bladder musculature, and hence bladder smooth muscle relaxation. During the urine voiding phase, the bladder is predominantly under parasympathetic nervous system control. Acetylcholine, released from pelvic nerve terminals, stimulates cholinergic M2 and M3 receptors, inducing bladder contraction. The activation of the M2 pathway also inhibits beta 3-AR induced increases in cAMP. Therefore beta 3-AR stimulation should not interfere with the voiding process. This was confirmed in rats with partial urethral obstruction, where mirabegron decreased the frequency of nonvoiding contractions without affecting the voided volume per micturition, voiding pressure, or residual urine volume.

Pharmacodynamic effects.

Urodynamics.

Mirabegron at doses of 50 mg and 100 mg once daily for 12 weeks in men with lower urinary tract symptoms (LUTS) and bladder outlet obstruction (BOO) showed no effect on cystometry parameters and was safe and well tolerated. The effects of mirabegron on maximum flow rate and detrusor pressure at maximum flow rate were assessed in an urodynamic study consisting of 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 the maximum flow rate or detrusor pressure at maximum flow rate.

Effect on QT interval.

Mirabegron at doses of 50 mg or 100 mg had no effect on the QT interval individually corrected for heart rate (QTcI interval) when evaluated either by sex or by the overall group.
A thorough QT (TQT) study (n = 164 healthy male and n = 153 healthy female volunteers with a mean age of 33 years) evaluated the effect of repeat oral dosing of mirabegron at the indicated dose (50 mg once daily) and two supra-therapeutic doses (100 and 200 mg once daily) on the QTcI interval. The supra-therapeutic doses represent approximately 2.6 and 6.5-fold the exposure of the therapeutic dose, 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 each including placebo control (parallel cross over design). For both males and females administered mirabegron at 50 mg and 100 mg, the upper bound of the one sided 95% confidence interval (CI) did not exceed 10 ms at any time point for the largest time matched mean difference from placebo in the QTcI interval. In females administered mirabegron at the 50 mg dose, the mean difference from placebo on QTcI interval at 5 hours postdose was 3.67 ms (upper bound of the one sided 95% CI 5.72 ms). In males, the difference was 2.89 ms (upper bound of the one sided 95% CI 4.90 ms). At a mirabegron dose of 200 mg, the QTcI interval did not exceed 10 ms at any time point in males, while in females the upper bound of the one sided 95% CI did exceed 10 ms between 0.5-6 h, with a maximum difference from placebo at 5 hours where the mean effect was 10.42 ms (upper bound of the one sided 95% CI 13.44 ms). Results for QTcF and QTcIf were consistent with QTcI.
In this TQT study, mirabegron increased heart rate on ECG in a dose dependent manner across the 50 mg to 200 mg dose range examined. The maximum mean difference from placebo in heart rate ranged from 6.7 bpm with mirabegron 50 mg up to 17.3 bpm with mirabegron 200 mg in healthy subjects.

Effects on pulse rate and blood pressure in patients with overactive bladder (OAB).

In OAB patients (mean age of 59 years) across three 12 week phase 3 double blind, placebo controlled studies receiving mirabegron 50 mg once daily, an increase in mean difference from placebo of approximately 1 bpm for pulse rate and approximately 1 mmHg or less in systolic blood pressure/diastolic blood pressure was observed. Changes in pulse rate and blood pressure are reversible upon discontinuation of treatment.

Effect on intraocular pressure (IOP).

Mirabegron 100 mg once daily did not increase IOP in healthy subjects after 56 days of treatment. In a phase 1 study assessing the effect of mirabegron on IOP using Goldmann applanation tonometry in 310 healthy subjects, a dose of mirabegron 100 mg was noninferior to placebo for the primary endpoint of the treatment difference in mean change from baseline to day 56 in subject average IOP; the upper bound of the two sided 95% CI of the treatment difference between mirabegron 100 mg and placebo was 0.3 mmHg.

Clinical trials.

Efficacy of mirabegron was evaluated in three phase 3 randomized, double blind, placebo controlled, 12 week studies for the treatment of overactive bladder with symptoms of urgency and frequency with or without incontinence. Female (72%) and male (28%) patients with a mean age of 59 years (range 18-95 years) were included. The study population consisted of approximately 48% antimuscarinic treatment naive patients as well as approximately 52% patients previously treated with antimuscarinic medication. In one study, 495 patients received an active control (tolterodine prolonged release formulation), but this study did not directly compare mirabegron to tolterodine.
The coprimary efficacy endpoints were (1) change from baseline to end of treatment in mean number of incontinence episodes per 24 hours and (2) change from baseline to end of treatment in mean number of micturitions per 24 hours based on a 3 day micturition diary. Mirabegron demonstrated statistically significant larger improvements compared to placebo for both coprimary endpoints as well as secondary endpoints (see Tables 3 and 4).
Mirabegron 50 mg once daily was effective at the first measured time point of week 4, and efficacy was maintained throughout the 12 week treatment period. A randomized, active controlled, long-term study (1 year) illustrated that response to mirabegron therapy was sustained throughout the treatment period.

Subjective improvement in health related quality of life measurements.

In the three 12 week phase 3 double blind, placebo controlled studies, treatment of the symptoms of OAB with mirabegron once daily resulted in a statistically significant improvement over placebo on the following health related quality of life measures: treatment satisfaction and symptom bother.

Efficacy in patients with or without prior OAB antimuscarinic therapy.

Efficacy was demonstrated in patients with and without prior OAB antimuscarinic therapy. In addition mirabegron showed efficacy in patients who previously discontinued OAB antimuscarinic therapy due to insufficient effect (see Table 5).

5.2 Pharmacokinetic Properties

Absorption.

After oral administration of mirabegron in healthy volunteers mirabegron is absorbed to reach peak plasma concentrations (Cmax) between 3 and 4 hours. The absolute bioavailability increased from 29% at a dose of 25 mg to 35% at a dose of 50 mg. Mean Cmax and AUC increased more than dose proportionally over the dose range. In the overall population of males and females, a 2-fold increase in dose from 50 mg to 100 mg mirabegron increased Cmax and AUCtau by approximately 2.9 and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 mg to 200 mg mirabegron increased Cmax and AUCtau by approximately 8.5 and 6.5-fold. Steady-state concentrations are achieved within 7 days of once daily dosing with mirabegron. After once daily administration, plasma exposure of mirabegron at steady state is approximately double that seen after a single dose.
Co-administration of a 50 mg tablet with a high fat meal reduced mirabegron Cmax and AUC by 45% and 17%, respectively. A low fat meal decreased mirabegron Cmax and AUC by 75% and 51%, respectively. In the phase 3 studies, mirabegron was administered with or without food and demonstrated both safety and efficacy. Therefore, mirabegron can be taken with or without food at the recommended dose.

Distribution.

Mirabegron is extensively distributed. The volume of distribution at steady state (Vss) is approximately 1670 L. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron distributes to erythrocytes. In vitro erythrocyte concentrations of 14C-mirabegron were about 2-fold higher than in plasma.

Metabolism.

Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component following a single dose of 14C-mirabegron. Two major metabolites were observed in human plasma; both are phase 2 glucuronides representing 16% and 11% of total exposure. These metabolites are not pharmacologically active. Although in vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, in vivo results indicate that these isozymes play a limited role in the overall elimination. In vitro and ex vivo studies have shown the involvement from butyrylcholinesterase and UGT in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6.

Excretion.

Total body clearance (CLtot) from plasma is approximately 57 L/h. The terminal elimination half-life (t1/2) is approximately 50 hours. Renal clearance (CLR) is approximately 13 L/h, which corresponds to nearly 25% of CLtot. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular filtration. The urinary excretion of unchanged mirabegron is dose dependent and ranges from approximately 6% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. Following the administration of 160 mg 14C-mirabegron to healthy volunteers, approximately 55% of the radiolabel was recovered in the urine and 34% in the faeces. Unchanged mirabegron accounted for 45% of the urinary radioactivity, indicating the presence of metabolites. Unchanged mirabegron accounted for the majority of the faecal radioactivity.

Pharmacokinetic characteristics in special populations.

Age/ gender/ race.

No dose adjustment is necessary for the elderly. The Cmax and AUC of mirabegron and its metabolites following multiple oral doses in elderly volunteers (≥ 65 years) were similar to those in younger volunteers (18-45 years).
No dose adjustment is necessary based on gender or race. The Cmax and AUC are approximately 40% to 50% higher in females than in males. Gender differences in Cmax and AUC are attributed to differences in body weight and bioavailability. The pharmacokinetics of mirabegron are not influenced by race.

Renal impairment.

Following single dose administration of 100 mg mirabegron in volunteers with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2 as estimated by MDRD), mean mirabegron Cmax and AUC were increased by 6% and 31% relative to volunteers with normal renal function. In volunteers with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2), Cmax and AUC were increased by 23% and 66%, respectively. In volunteers with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), mean Cmax and AUC values were 92% and 118% higher. Mirabegron has not been studied in patients with endstage renal disease (eGFR < 15 mL/min/1.73 m2 or patients requiring haemodialysis).

Hepatic impairment.

Following single dose administration of 100 mg mirabegron in volunteers with mild hepatic impairment (Child-Pugh class A), mean mirabegron Cmax and AUC were increased by 9% and 19% relative to volunteers with normal hepatic function. In volunteers with moderate hepatic impairment (Child-Pugh class B), mean Cmax and AUC values were 175% and 65% higher. Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

5.3 Preclinical Safety Data

Genotoxicity.

Mirabegron showed no evidence of genotoxicity in the Ames bacterial reverse mutation assay, did not induce chromosomal aberrations in human peripheral blood lymphocytes in vitro, and was not clastogenic in the rat micronucleus assay.

Carcinogenicity.

Long-term carcinogenicity studies were conducted in rats and mice dosed orally with mirabegron for two years. Mirabegron showed no carcinogenic potential at systemic exposures 25 to 45-fold higher in rats and 23-fold higher in mice than the human systemic exposure at the maximum recommended therapeutic dose.

4 Clinical Particulars

4.1 Therapeutic Indications

Symptomatic treatment of urgency, increased micturition frequency and/or urgency incontinence in patients with overactive bladder (OAB) syndrome.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Patients with severe uncontrolled hypertension (systolic ≥ 180 mmHg and/or diastolic ≥ 110 mmHg).

4.4 Special Warnings and Precautions for Use

Increases in blood pressure and heart rate.

Betmiga can increase blood pressure and heart rate. Blood pressure should be measured at baseline and monitored periodically during Betmiga treatment, especially in hypertensive patients (see Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects, Effects on pulse rate and blood pressure in patients with overactive bladder (OAB)).
Betmiga is contraindicated in patients with severe uncontrolled hypertension (defined as systolic blood pressure greater than or equal to 180 mmHg and/or diastolic blood pressure greater or equal to 110 mmHg) (see Section 4.3 Contraindications). There is limited data in patients with moderate (grade 2) hypertension (systolic blood pressure 160-169 mmHg and/or diastolic 100-109 mmHg) and thus, caution is advised.

Patients with congenital or acquired QT prolongation.

Consider observations from the QT study (see Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects, Effect on QT interval) in clinical decisions to prescribe Betmiga to patients with a known history of QT prolongation or patients who are taking medicinal products known to prolong QT interval (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Other).

Urinary retention in patients with bladder outlet obstruction and in patients taking antimuscarinic medications for OAB.

Urinary retention in patients with BOO and in patients taking antimuscarinic medications for the treatment of OAB has been reported in postmarketing experience in patients taking Betmiga. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Betmiga treated patients; however, Betmiga should be administered with caution to patients with BOO and with caution in patients taking antimuscarinic agents (see Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects, Urodynamics).

Angioedema.

Angioedema of the face, lips, tongue, and/or larynx has been reported with Betmiga. In some cases angioedema occurred after the first dose. Cases of angioedema have been reported to occur hours after the first dose or after multiple doses. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, promptly discontinue Betmiga and initiate appropriate therapy and/or measures necessary to ensure a patent airway.

Patients taking drugs metabolised by CYP2D6.

Mirabegron is a moderate CYP2D6 inhibitor and systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolised by CYP2D6 such as thioridazine, flecainide and propafenone (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in hepatic impairment.

Betmiga has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and, therefore, it is not recommended for use in this patient population.

Use in renal impairment.

Betmiga has not been studied in patients with endstage renal disease (eGFR < 15 mL/min/1.73 m2 or patients requiring haemodialysis) and, therefore, it is not recommended for use in this patient population.

Use in the elderly.

No dose adjustment is necessary for the elderly (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetic characteristics in special populations).

Paediatric use.

The safety and efficacy of Betmiga in patients below 18 years of age have not yet been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro data.

Clinically relevant drug interactions between mirabegron and medicines that inhibit, induce or are a substrate for one of the cytochrome P450 (CYP) isozymes or transporters are not expected except for the inhibitory effect of mirabegron on the metabolism of CYP2D6 substrates. Mirabegron is transported and metabolized through multiple pathways. Mirabegron is a substrate for CYP3A4, CYP2D6, butyrylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT), the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Sulfonylurea hypoglycaemic agents glibenclamide (a CYP3A4 substrate), gliclazide (a CYP2C9 and CYP3A4 substrate) and tolbutamide (a CYP2C9 substrate) did not affect the in vitro metabolism of mirabegron. Mirabegron did not affect the metabolism of glibenclamide or tolbutamide.
Studies of mirabegron using human liver microsomes and recombinant human CYP enzymes showed that mirabegron is a moderate and time dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. Mirabegron is unlikely to inhibit the metabolism of co-administered drugs metabolized by the following cytochrome P450 enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1 because mirabegron did not inhibit the activity of these enzymes at clinically relevant concentrations. Mirabegron did not induce CYP1A2 or CYP3A. Mirabegron inhibited P-gp mediated drug transport at high concentrations. Mirabegron is predicted not to cause clinically relevant inhibition of OCT-mediated drug transport.

In vivo data.

CYP2D6 polymorphism.

In healthy subjects who are genotypically poor metabolizers of CYP2D6 substrates (used as a surrogate for CYP2D6 inhibition), mean Cmax and AUCinf of a single 160 mg dose of a mirabegron immediate release (IR) formulation were 14% and 19% higher than in extensive metabolizers, indicating that CYP2D6 genetic polymorphism has minimal impact on the mean plasma exposure to mirabegron. Interaction of mirabegron with a known CYP2D6 inhibitor is not expected and was not studied. No dose adjustment is needed for mirabegron when administered with CYP2D6 inhibitors or in patients who are CYP2D6 poor metabolizers.

Drug-drug interactions.

Drug interaction studies were conducted to investigate the effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs (e.g. ketoconazole, rifampin, solifenacin, tamsulosin, and oral contraceptives). No dose adjustment is recommended when these drugs are co-administered with mirabegron.
The following are drug interactions for which monitoring is recommended:

Drugs metabolised by CYP2D6.

Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure of drugs metabolized by CYP2D6 enzyme such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary when Betmiga is co-administered with these drugs, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide and propafenone (see Section 4.4 Special Warnings and Precautions for Use, Patients taking drugs metabolised by CYP2D6).

Digoxin.

When given in combination, mirabegron increased mean digoxin Cmax from 1.01 to 1.3 nanogram/mL (29%) and AUC from 16.7 to 19.3 nanogram.h/mL (27%). Therefore, for patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be considered. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.

Warfarin.

The mean Cmax of S and R-warfarin was increased by approximately 4% and AUC by approximately 9% when administered as a single dose of 25 mg after multiple doses of 100 mg mirabegron. Following a single dose administration of 25 mg warfarin, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as international normalized ratio (INR) and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic endpoints such as INR and prothrombin time has not been fully investigated.

Other.

Mirabegron, at therapeutic doses, has not demonstrated clinically relevant QT prolongation in clinical studies (see Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects, Effect on QT interval). However, since patients with a known history of QT prolongation or patients who are taking medicinal products known to prolong the QT interval were not included in these studies, the effects of mirabegron in these patients is unknown. Caution should be exercised when administering mirabegron in these patients (see Section 4.4 Special Warnings and Precautions for Use). Examples of drugs that are known to prolong the QT interval include: quinidine, sotalol, amiodarone, mesoridazine, haloperidol, erythromycin, clarithromycin.
Figures 1 and 2 show the magnitude of these interactions on the pharmacokinetic parameters and the recommendations for dose adjustment, if any.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There were no treatment-related effects of mirabegron on fertility in animals at non-lethal doses (human equivalent dose ≥ 22-fold of maximum recommended human dose).
The effect of mirabegron on human fertility has not been established.
(Category B3)
There are no adequate and well controlled studies using mirabegron in pregnant women. Mirabegron was shown to cross the placenta in pregnant rats, resulting in fetal exposure. Toxicokinetic studies in rabbits, but not in rats, showed an approximately two-fold increase in mirabegron exposure during pregnancy, but this was not observed in rats. The effect of pregnancy on human pharmacokinetics is unknown. Animal studies indicate a low probability of direct or indirect harmful effects with respect to reproductive toxicity at therapeutic doses. Systemic exposure at the embryofetal NOAEL (rabbits and rats) and peri-postnatal NOAEL (rats) was similar to (rabbits) or up to six times higher (rats) than the therapeutic exposure level at the maximum recommended human dose. Reversible adverse developmental findings consisting of delayed ossification and wavy ribs in rats and decreased fetal body weights in rabbits occurred at exposures greater than or equal to 22 and 14 times, respectively, the maximum recommended therapeutic dose. At maternally toxic exposures decreased fetal weights were observed in rats and rabbits, and additional findings in rabbits included fetal death, dilated aorta, and cardiomegaly. Increased postnatal mortality and reduced pup weight were observed in rats whose dams were exposed to mirabegron levels 22 times higher than therapeutic levels during pregnancy and lactation, but there were no adverse behavioural or developmental effects. As a precautionary measure, it is preferable to avoid the use of mirabegron during pregnancy.
Mirabegron is excreted in the milk of rodents and therefore is predicted to be present in human milk. Pharmacokinetic studies performed with radio-labelled mirabegron have shown that the parent compound and/or its metabolites are excreted in the milk of rats at levels that were approximately 1.7-fold higher than plasma levels at 4 hours post-administration. No studies have been conducted to assess the impact of mirabegron on milk production in humans, its presence in human breast milk, or its effects on the breastfed child. Mirabegron should not be administered during breastfeeding.

4.8 Adverse Effects (Undesirable Effects)

The safety of Betmiga was evaluated in 8433 patients with OAB, of which 5648 received at least one dose of mirabegron in the phase 2/3 clinical program, and 622 patients received mirabegron for at least 1 year (365 days). In the three 12-week phase 3 double blind, placebo controlled studies, 88% of the patients completed treatment with mirabegron, and 4% of the patients discontinued due to adverse effects. Most adverse drug reactions were mild to moderate in severity.
Table 1 lists adverse events that were reported in studies 046, 047 and 074 at an incidence greater than placebo and in 1% or more of patients treated with Betmiga 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of Betmiga patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection and headache.
Other adverse reactions reported by less than 1% of patients treated with Betmiga in studies 046, 047, 074 included:

Cardiac disorders.

Palpitations, blood pressure increased (see Section 5.1 Pharmacodynamic Properties, Pharmacodynamic Effects, Effects on pulse rate and blood pressure in patients with overactive bladder (OAB)).

Eye disorders.

Glaucoma (see Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects, Effect on intraocular pressure (IOP)).

Gastrointestinal disorders.

Dyspepsia, gastritis, abdominal distension.

Infections and infestations.

Sinusitis, rhinitis.

Investigations.

GGT increased, AST increased, ALT increased, LDH increased.

Renal and urinary disorders.

Nephrolithiasis, bladder pain.

Reproductive system and breast disorders.

Vulvovaginal pruritus, vaginal infection.

Skin and subcutaneous tissue disorders.

Urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip oedema.
Table 2 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with Betmiga 50 mg for up to 52 weeks in long-term safety study 049. The most commonly reported adverse reactions (> 3% of Betmiga patients) were hypertension, urinary tract infection, headache, and nasopharyngitis.
The following events have been reported in association with mirabegron use in worldwide postmarketing experience:

Cardiac disorders.

Atrial fibrillation.

Gastrointestinal disorders.

Nausea.

Skin and subcutaneous tissue disorders.

Angioedema.

Urologic.

Urinary retention (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Adults (including elderly patients).

The recommended starting dose of Betmiga is 25 mg once daily. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.
Betmiga can be taken with or without food. The tablet should be taken with liquids, swallowed whole and is not to be chewed, divided, or crushed.

Patients with renal impairment.

No dose adjustment is necessary in patients with mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2 as estimated by MDRD). In patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), the recommended dose is 25 mg once daily with or without food. Betmiga has not been studied in patients with end stage renal disease (eGFR < 15 mL/min/1.73 m2 or patients requiring haemodialysis) (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetic characteristics in special populations).

Patients with hepatic impairment.

No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). In patients with moderate hepatic impairment (Child-Pugh class B) the recommended dose is 25 mg once daily with or without food. Betmiga has not been studied in patients with severe hepatic impairment (Child-Pugh class C) (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetic characteristics in special populations).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machinery have been performed. There is no indication in the preclinical or clinical studies that Betmiga affects the ability to drive or operate machinery, or impairs mental ability. Dizziness, somnolence and blurred vision were infrequently reported adverse events in the clinical studies.

4.9 Overdose

Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations (1 of 6 subjects) and increased pulse rate exceeding 100 bpm (3 of 6 subjects). Multiple doses of mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers.
Treatment for overdose should be symptomatic and supportive. In the event of overdose, pulse rate, blood pressure, and ECG monitoring is recommended.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

6 Pharmaceutical Particulars

6.1 List of Excipients

Betmiga contains the following excipients: macrogol 8000, macrogol 2000000, hyprolose, purified water, butylated hydroxytoluene, magnesium stearate, Opadry complete film coating system 03F43159 orange (25 mg tablet only), Opadry complete film coating system 03F42192 yellow (50 mg tablet only).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

The tablets are packed in PA/Al/PVC/Al blisters in cartons containing 10, 20, 30, 60, 90 or 200 tablets.
(Note: Not all pack sizes may be marketed.)

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes