Mirabegron

Registered South African indications:

• Overactive bladder (OAB) syndrome
  - Urinary urgency
  - Increased micturition frequency
  - Urgency incontinence

Contraindications
South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• End-stage renal impairment (eGFR<15ml/min/1.73m²)
• Severe hepatic impairment (Child-Pugh class C)
• Severe uncontrolled hypertension (systolic blood pressure ≥180mmHg and/or diastolic blood pressure ≥110mmHg)

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Severe uncontrolled hypertension (systolic blood pressure ≥180mmHg and/or diastolic blood pressure ≥110mmHg)

Cautions
South African manufacturer recommendations

• Pregnancy
• Women of childbearing potential not using contraception
• Breastfeeding
• Severe renal impairment (eGFR>15-29ml/min/1.73m²)
• Moderate hepatic impairment (Child-Pugh class B)
• Hypertension
• Congenital or acquired QT prolongation
• Clinically significant bladder outlet obstruction (BOO)
• Coadministration with agents known to prolong QT interval 
• Coadministration with antimuscarinic agents for the treatment of overactive bladder (OAB)
• Coadministration with agents with a narrow therapeutic index and significantly metabolised by CYP2D6 (e.g. thioridazine)
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Severe to end-stage renal impairment (eGFR<29ml/min/1.73m²) (without strong CYP3A inhibitor)
  - Requiring haemodialysis
• Renal impairment (coadministered with strong CYP3A inhibitor)
• Moderate to severe hepatic impairment (without strong CYP3A inhibitor)
• Hepatic impairment (coadministered with strong CYP3A inhibitor)
• Hypertension
• Known history of QT prolongation
• Clinically significant bladder outlet obstruction (BOO)
• Coadministration with agents known to prolong QT interval
• Coadministration with antimuscarinic agents for the treatment of overactive bladder (OAB)
• Coadministration with agents with a narrow therapeutic index and significantly metabolised by CYP2D6 (e.g. thioridazine)

Forms avail. in SA and covered in this monograph: tab

Symptomatic treatment of overactive bladder (OAB) syndrome 
- Urinary urgency
- Increased micturition frequency 
- Urgency incontinence 

• Oral (tab): 50mg, dly

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To be administered with liquids, swallowed whole and is not to be chewed, divided, or crushed

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Mirabegron may be taken with or without food

Not established for use in children below 18 years

Pregnancy
South African manufacturer recommendations

• Caution; not recommended
• Safety in pregnancy has not been established. It is recommended that mirabegron be avoided during pregnancy
• Mirabegron is not recommended in women of childbearing potential not using contraception

International manufacturer recommendations

• Caution; not recommended
• There are limited amount of data from the use of mirabegron in pregnant women. Studies in animals have shown reproductive toxicity. Mirabegron is not recommended during pregnancy

Breastfeeding
South African manufacturer recommendations

• Caution; not recommended
• Mirabegron may be present in human milk. Mirabegron should not be administered to mothers who are breastfeeding their infants

International manufacturer recommendations

• Caution; not recommended
• Mirabegron is excreted in the milk of rodents and therefore is predicted to be present in human milk. 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

Fertility
South African manufacturer recommendations

• No information available

International manufacturer recommendations

• There were no treatment related effects of mirabegron on fertility in animals. The effect of mirabegron on human fertility has not been established

Renal Impairment
South African manufacturer recommendations

• Mild to moderate (eGFR≥30-89ml/min/1.73m²): No dose adjustment recommended 
• Severe (eGFR≥15-29ml/min/1.73m²): Caution; dose adjustment recommended 
  Oral (tab): 25mg, dly
• End-stage renal disease (eGFR<15ml/min/1.73m²): Contraindicated 
  Mirabegron has not been studied in patients requiring haemodialysis and, therefore, it is not recommended for use
  Mirabegron is not recommended for use in patients concomitantly receiving strong CYP3A inhibitors

International manufacturer recommendations
Without strong CYP3A inhibitor

• Mild to moderate (eGFR≥30-89ml/min/1.73m²): No dose adjustment recommended 
• Severe (eGFR≥15-29ml/min/1.73 m²): Caution; dose adjustment recommended 
• End-stage renal disease (eGFR<15ml/min/1.73 m²): Caution; no information available 
  Mirabegron has not been studied in patients with end-stage renal disease or patients requiring haemodialysis and, therefore, it is not recommended for use in this patient population

Coadministered with strong CYP3A inhibitor

• Mild to severe (eGFR≥15-89ml/min/1.73m²): Caution; dose adjustment recommended 
• End-stage renal disease (eGFR<15ml/min/1.73m²): Caution; no information available 
  Mirabegron has not been studied in patients with end-stage renal disease or patients requiring haemodialysis and, therefore, it is not recommended for use in this patient population

GFR (ml/min/1.73m2)	Strong CYP3A inhibitors*
	Without inhibitor	With inhibitor
60-89	50 mg	25mg
30-59	50 mg	25mg
15-29	25mg	Not recommended

*Examples of strong CYP3A inhibitors: itraconazole, ketoconazole, ritonavir and clarithromycin

Hepatic Impairment
South African manufacturer recommendations

• Mild (Child-Pugh class A): No dose adjustment recommended 
• Moderate (Child-Pugh class B): Caution; dose adjustment recommended 
  Oral (tab): 25mg, dly
  Mirabegron is not recommended for use in patients with moderate hepatic impairment concomitantly receiving strong CYP3A inhibitors
• Severe (Child-Pugh class C): Contraindicated 

International manufacturer recommendations

Without strong CYP3A inhibitor

• Mild (Child-Pugh class A): No dose adjustment recommended 
• Moderate (Child-Pugh class B): Caution; dose adjustment recommended 
• Severe (Child-Pugh class C): Caution; no information available 

Coadministered with strong CYP3A inhibitor

• Mild to moderate (Child-Pugh class A and B): Caution; dose adjustment recommended
• Severe (Child-Pugh class C): Caution; no information available 

	Strong CYP3A inhibitors*
Child-Pugh Class	Without inhibitor	With inhibitor
A	50mg	25mg
B	25mg	Not recommended

*Examples of strong CYP3A inhibitors: itraconazole, ketoconazole, ritonavir and clarithromycin

Elderly

• No dose adjustment recommended

Gender

South African manufacturer recommendations

• Caution; dose adjustment recommended
  Dose adjustment may be necessary based on gender. The C_max and AUC are approximately 40% to 50% higher in females than in males
  Gender differences in C_max and AUC are attributed to differences in body weight and bioavailability

International manufacturer recommendations

• No dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Dizziness
• Insomnia
• Confusional state

Cardiovascular Disorders

• Tachycardia
• Palpitation
• Atrial fibrillation
• Hypertensive crisis
• Increased blood pressure

Gastrointestinal Disorders

• Nausea
• Constipation
• Diarrhoea
• Dyspepsia
• Gastritis
• Lip oedema

Hepatobiliary Disorders

• Increased gamma-glutamyl transferase
• Increased aspartate aminotransferase 
• Increased alanine transaminase

Genitourinary Disorders

• Urinary tract infection
• Vaginal infection
• Cystitis
• Vulvovaginal pruritus
• Urinary retention

Musculoskeletal Disorders

• Joint swelling

Skin and Subcutaneous Tissue Disorders

• Urticaria
• Rash
• Macular rash 
• Papular rash 
• Pruritus
• Leukocytoclastic vasculitis
• Purpura
• Angioedema

Sensory Disorders

• Eyelid oedema

• CYP2D6 substrates
• CYP3A inhibitors
• Itraconazole
• Ketoconazole 
• Ritonavir
• Clarithromycin
• Thioridazine
• Type 1C antiarrhythmics
• Flecainide
• Propafenone
• Tricyclic antidepressants
• Imipramine
• Desipramine
• P-glycoprotein substrates
• Dabigatran
• Digoxin

• Blood pressure
• Postvoid residual urine volume

Specific cases may require

• Digoxin levels

Additional observations

• Signs and symptoms of urinary retention

Mirabegron is a potent and selective beta 3-adrenoceptor agonist. Mirabegron showed relaxation of bladder smooth muscle in rat and human isolated tissue, increased cyclic adenosine monophosphate (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 non-voiding 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-adrenoceptors 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-adrenoceptor induced increases in cAMP. Therefore beta 3-adrenoceptor stimulation should not interfere with the voiding process. This was confirmed in rats with partial urethral obstruction, where mirabegron decreased the frequency of non-voiding contractions without affecting the voided volume per micturition, voiding pressure, or residual urine volume.

Tablet 25mg

• Betmiga (Astellas Pharma) originator

Tablet 50mg

• Betmiga (Astellas Pharma) originator