Betmiga 25mg and 50mg prolonged-release tablets

error on date of renewal and revision of text- should be 19 Sept 2017

error on date of renewal and revision of text- should be 19 Sept 2017

1. Removal of Black Triangle
Section 4.2
The statement regarding ‘with or without food’ is moved from posology to method of administration and once daily removed from method of administration.
Section 4.4
The term Betmiga is replaced by medicinal product and/or mirabegron.
Section 4.5
The paragraph on ‘Effect of CYP2D6 polymorphism’ is moved from 1st to 4th paragraph
Section 4.6
New header stating ‘Woman of childbearing potential’ and sentence stating ‘not recommended in women of childbearing potential not using contraception’ move to header
Section 4.8 Nervous system disorders Headache*: - Common: Dizziness* moved up in table
Renal and urinary disorders - Rare: Urinary retention* moved up in table
Section 6.1
Name change for following excipients: Macrogol 8,000 and 2,000,000, Hypromellose 2910, 6 mPa and Macrogol 8,000
Section 6.5
HDPE bottles with child resistant closure of polypropylene (PP) and a silica gel desiccant containing 90 tablets. Each carton contains one bottle.
Section 9
Date of latest renewal: 19 September 2017
Section 10
19 September 2017

1. Removal of Black Triangle
Section 4.2
The statement regarding ‘with or without food’ is moved from posology to method of administration and once daily removed from method of administration.
Section 4.4
The term Betmiga is replaced by medicinal product and/or mirabegron.
Section 4.5
The paragraph on ‘Effect of CYP2D6 polymorphism’ is moved from 1st to 4th paragraph
Section 4.6
New header stating ‘Woman of childbearing potential’ and sentence stating ‘not recommended in women of childbearing potential not using contraception’ move to header
Section 4.8 Nervous system disorders Headache*: - Common: Dizziness* moved up in table
Renal and urinary disorders - Rare: Urinary retention* moved up in table
Section 6.1
Name change for following excipients: Macrogol 8,000 and 2,000,000, Hypromellose 2910, 6 mPa and Macrogol 8,000
Section 6.5
HDPE bottles with child resistant closure of polypropylene (PP) and a silica gel desiccant containing 90 tablets. Each carton contains one bottle.
Section 9
Date of latest renewal: 19 September 2017
Section 10
19 September 2017

Joint SPC now covering Betmiga 25mg and Betmiga 50mg.

Section 4.8
The following have been added to the table of adverse drug reactions:

Vascular disorders: Hypertensive crisis* (very rare frequency)
Gastrointestinal disorders: Constipation*, Diarrhoea* (common frequency)
Nervous system disorders: Headache*, Dizziness* (common frequency)


*observed during post-marketing experience

Section 10
Date of revision amended to 31 March 2016

Joint SPC now covering Betmiga 25mg and Betmiga 50mg.

Section 4.8
The following have been added to the table of adverse drug reactions:

Vascular disorders: Hypertensive crisis* (very rare frequency)
Gastrointestinal disorders: Constipation*, Diarrhoea* (common frequency)
Nervous system disorders: Headache*, Dizziness* (common frequency)


*observed during post-marketing experience

Section 10
Date of revision amended to 31 March 2016

Section 4.3, the following contraindication has been added (previously present as a warning in section 4.4) :

- Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg.

 

Section 4.4, the following has been added:

Hypertension

Mirabegron can increase blood pressure. Blood pressure should be measured at baseline and periodically during treatment with Betmiga, especially in hypertensive patients

Section 4.8, the following have been added based on post marketing experience;

Insomnia, frequency: not known (cannot be estimated from the available data)

Urinary retention, frequency: rare

Section 10, the date of revision has been updated to 14 September 2015

Section 4.3, the following contraindication has been added (previously present as a warning in section 4.4) :

- Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg.

 

Section 4.4, the following has been added:

Hypertension

Mirabegron can increase blood pressure. Blood pressure should be measured at baseline and periodically during treatment with Betmiga, especially in hypertensive patients

Section 4.8, the following have been added based on post marketing experience;

Insomnia, frequency: not known (cannot be estimated from the available data)

Urinary retention, frequency: rare

Section 10, the date of revision has been updated to 14 September 2015

Section 4.8
Addition of nausea to the tabulated list of adverse reactions under "common"
Section 10
Date of revision of text revised to March 2015

Section 4.8
Addition of nausea to the tabulated list of adverse reactions under "common"
Section 10
Date of revision of text revised to March 2015

Section 4.8 (undesirable effects), Addition of “angioedema*” (asterisk refers to post marketing data)
Section 4.8, change to reporting of side effects to reflect HPRA wording & name change
Section 10, date of revision of text changed to "November 2014"

Section 4.8 (undesirable effects), Addition of “angioedema*” (asterisk refers to post marketing data)
Section 4.8, change to reporting of side effects to reflect HPRA wording & name change
Section 10, date of revision of text changed to "November 2014"

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

 

4.4     Special warnings and precautions for use

 

Patients with congenital or acquired QT prolongation

 

Mirabegron Betmiga, at therapeutic doses, has not demonstrated clinically relevant QT prolongation in clinical studies (see section 5.1). 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.

 

Patients with bladder outlet obstruction and patients taking antimuscarinics medications for OAB

 

Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in patients treated with Betmiga; however, Betmiga should be administered with caution to patients with clinically significant BOO. Betmiga should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.

 

4.6     Fertility, pregnancy and lactation

 

Pregnancy

 

There are limited amount of data from the use of mirabegron Betmiga in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

 

Breast‑feeding

 

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 breast-fed child.

mirabegron Betmiga should not be administered during breast‑feeding.

 

4.8         Undesirable effects

 

Summary of the safety profile

 

The safety of Mirabegron 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 Betmiga 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 Betmiga, and 4% of the patients discontinued due to adverse events. Most adverse reactions were mild to moderate in severity.

 

The most common adverse reactions reported for patients treated with Mirabegron Betmiga 50 mg during the three 12-week phase 3 double blind, placebo controlled studies are tachycardia and urinary tract infections. The frequency of tachycardia was 1.2% in patients receiving Mirabegron Betmiga 50 mg. Tachycardia led to discontinuation in 0.1% patients receiving Mirabegron Betmiga 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving Mirabegron Betmiga 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving Mirabegron Betmiga 50 mg. Serious adverse reactions included atrial fibrillation (0.2%).

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1         Pharmacodynamic properties

 

Pharmacodynamic effects

 

Urodynamics

Mirabegron Betmiga 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.

 

Effect on QT interval

Mirabegron Betmiga 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.

 

Effects on pulse rate and blood pressure in patients with OAB

In OAB patients (mean age of 59 years) across three 12-week phase 3 double blind, placebo controlled studies receiving Mirabegron Betmiga 50 mg once daily, an increase in mean difference from placebo of approximately 1 bpm for pulse rate and approximately 1 mm Hg or less in systolic blood pressure/ diastolic blood pressure (SBP/DBP) 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 Betmiga on IOP using Goldmann applanation tonometry in 310 healthy subjects, a dose of mirabegron 100 mg was non-inferior 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 mm Hg.

 

Clinical efficacy and safety

 

Efficacy of Mirabegron Betmiga 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.

...

Mirabegron Betmiga 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 demonstrated that efficacy was maintained throughout a 1-year treatment period.

 

5.2     Pharmacokinetic properties

 

Renal impairment

 

Following single dose administration of 100 mg Mirabegron Betmiga in volunteers with mild renal impairment (eGFR-MDRD 60 to 89 mL/min/1.73 m²), mean mirabegron C_max and AUC were increased by 6% and 31% relative to volunteers with normal renal function.

Hepatic impairment

 

Following single dose administration of 100 mg Mirabegron Betmiga in volunteers with mild hepatic impairment (Child-Pugh Class A), mean mirabegron C_max and AUC were increased by 9% and 19% relative to volunteers with normal hepatic function.

 

10.     DATE OF REVISION OF THE TEXT

 

January 2014 April 2014

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

 

4.4     Special warnings and precautions for use

 

Patients with congenital or acquired QT prolongation

 

Mirabegron Betmiga, at therapeutic doses, has not demonstrated clinically relevant QT prolongation in clinical studies (see section 5.1). 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.

 

Patients with bladder outlet obstruction and patients taking antimuscarinics medications for OAB

 

Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in patients treated with Betmiga; however, Betmiga should be administered with caution to patients with clinically significant BOO. Betmiga should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.

 

4.6     Fertility, pregnancy and lactation

 

Pregnancy

 

There are limited amount of data from the use of mirabegron Betmiga in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

 

Breast‑feeding

 

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 breast-fed child.

mirabegron Betmiga should not be administered during breast‑feeding.

 

4.8         Undesirable effects

 

Summary of the safety profile

 

The safety of Mirabegron 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 Betmiga 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 Betmiga, and 4% of the patients discontinued due to adverse events. Most adverse reactions were mild to moderate in severity.

 

The most common adverse reactions reported for patients treated with Mirabegron Betmiga 50 mg during the three 12-week phase 3 double blind, placebo controlled studies are tachycardia and urinary tract infections. The frequency of tachycardia was 1.2% in patients receiving Mirabegron Betmiga 50 mg. Tachycardia led to discontinuation in 0.1% patients receiving Mirabegron Betmiga 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving Mirabegron Betmiga 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving Mirabegron Betmiga 50 mg. Serious adverse reactions included atrial fibrillation (0.2%).

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1         Pharmacodynamic properties

 

Pharmacodynamic effects

 

Urodynamics

Mirabegron Betmiga 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.

 

Effect on QT interval

Mirabegron Betmiga 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.

 

Effects on pulse rate and blood pressure in patients with OAB

In OAB patients (mean age of 59 years) across three 12-week phase 3 double blind, placebo controlled studies receiving Mirabegron Betmiga 50 mg once daily, an increase in mean difference from placebo of approximately 1 bpm for pulse rate and approximately 1 mm Hg or less in systolic blood pressure/ diastolic blood pressure (SBP/DBP) 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 Betmiga on IOP using Goldmann applanation tonometry in 310 healthy subjects, a dose of mirabegron 100 mg was non-inferior 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 mm Hg.

 

Clinical efficacy and safety

 

Efficacy of Mirabegron Betmiga 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.

...

Mirabegron Betmiga 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 demonstrated that efficacy was maintained throughout a 1-year treatment period.

 

5.2     Pharmacokinetic properties

 

Renal impairment

 

Following single dose administration of 100 mg Mirabegron Betmiga in volunteers with mild renal impairment (eGFR-MDRD 60 to 89 mL/min/1.73 m²), mean mirabegron C_max and AUC were increased by 6% and 31% relative to volunteers with normal renal function.

Hepatic impairment

 

Following single dose administration of 100 mg Mirabegron Betmiga in volunteers with mild hepatic impairment (Child-Pugh Class A), mean mirabegron C_max and AUC were increased by 9% and 19% relative to volunteers with normal hepatic function.

 

10.     DATE OF REVISION OF THE TEXT

 

January 2014 April 2014

4.8 Undesirable effects

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via:

IMB Pharmacovigilance

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

 

6.5          Nature and contents of container

 

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 a silica gel desiccant containing 90 tablets.

 

8.         MARKETING AUTHORISATION NUMBER(S)

 

EU/1/12/809/008 - 014

EU/1/12/809/017

EU/1/12/809/018

 

10.       DATE OF REVISION OF THE TEXT

 

December 2012 January 2014

 

4.8 Undesirable effects

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via:

IMB Pharmacovigilance

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

 

6.5          Nature and contents of container

 

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 a silica gel desiccant containing 90 tablets.

 

8.         MARKETING AUTHORISATION NUMBER(S)

 

EU/1/12/809/008 - 014

EU/1/12/809/017

EU/1/12/809/018

 

10.       DATE OF REVISION OF THE TEXT

 

December 2012 January 2014

 

None provided

None provided