Betmira ER50 mg

Betmira ER 50 mg is indicated for the symptomatic treatment of urgency, increased micturition frequency and urgency incontinence as may occur in adult patients with overactive bladder (OAB) syndrome.

BPH/ Urinary retention/ Urinary incontinence

Betmira ER 50 mg is a potent and selective beta 3-adrenoceptor agonist. Betmira ER 50 mg 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. Betmira ER 50 mg 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, Betmira ER 50 mg showed decreased voiding frequency. These results indicate that Betmira ER 50 mg 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 Betmira ER 50 mg decreased the frequency of non-voiding contractions without affecting the voided volume per micturition, voiding pressure or residual urine volume.

Recommended starting dose: 25 mg once daily, alone or in combination with solifenacin succinate 5 mg, once daily. Based on individual efficacy and tolerability, may increase dose to 50 mg once daily, alone or in combination with solifenacin succinate 5 mg, once daily. Swallow whole with water, with or without food, do not chew, divide or crushPatients with Severe Renal Impairment or Patients with Moderate Hepatic Impairment: Maximum dose is 25 mg Betmira ER 50 mg once daily Patients with End Stage Renal Disease (ESRD) or Patients with Severe Hepatic Impairment: Not recommended

Adults including elderly: The recommended starting dose is Betmira ER 50 mg 25 mg tablet once daily with or without food. Based on individual patient efficacy and tolerability the dose may be increased to Betmira ER 50 mg 50 mg tablet once daily. Renal or hepatic impairment: Patients with severe renal impairment (ClCr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2) or moderate hepatic impairment (Child-Pugh Class B), the daily dose of Betmira ER 50 mg should not exceed 25 mg tablet once daily. Betmira ER 50 mg has not been studied in patients with end stage renal disease (GFR <15 mL/min/1.73 m2 or patients requiring haemodialysis) or severe hepatic impairment (Child Pugh Class C) and it is therefore not recommended for use in these patient populations. Gender: No dose adjustment is necessary according to gender.Paediatric population: The safety and efficacy of Betmira ER 50 mg in children below 18 years of age have not yet been established.

Betmira ER 50 mg tablet is to be taken once daily, with liquids, swallowed whole and is not to be chewed, divided, or crushed.

Effect of enzyme inhibitors: Betmira ER 50 mg exposure (AUC) was increased 1.8-fold in the presence of the strong inhibitor of CYP3A/P-gp ketoconazole in healthy volunteers. No dose adjustment is needed when Betmira ER 50 mg is combined with inhibitors of CYP3A and/or P-gp. However, in patients with mild to moderate renal impairment or mild hepatic impairment concomitantly receiving strong CYP3A inhibitors, such as itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended dose is 25 mg once daily with or without food. Betmira ER 50 mg is not recommended in patients with severe renal impairment or patients with moderate hepatic impairment concomitantly receiving strong CYP3A inhibitors. Effect of enzyme inducers: Substances that are inducers of CYP3A or P-gp decrease the plasma concentrations of Betmira ER 50 mg. No dose adjustment is needed for Betmira ER 50 mg when administered with therapeutic doses of rifampicin or other CYP3A or P-gp inducers. Effect of Betmira ER 50 mg on CYP2D6 substrates: In healthy volunteers, the inhibitory potency of Betmira ER 50 mg towards CYP2D6 is moderate and the CYP2D6 activity recovers within 15 days after discontinuation of Betmira ER 50 mg. Multiple once daily dosing of Betmira ER 50 mg IR resulted in a 90% increase in Cmax and a 229% increase in AUC of a single dose of metoprolol. Multiple once daily dosing of Betmira ER 50 mg resulted in a 79% increase in Cmax and a 241% increase in AUC of a single dose of desipramine. Caution is advised if Betmira ER 50 mg is co-administered with medicinal products with a narrow therapeutic index and significantly metabolised by CYP2D6, such as thioridazine, Type 1 C antiarrhythmics (e.g., flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Caution is also advised if Betmira ER 50 mg is co-administered with CYP2D6 substrates that are individually dose titrated. Effect of Betmira ER 50 mg on transporters: Betmira ER 50 mg is a weak inhibitor of P-gp. Betmira ER 50 mg increased Cmax and AUC by 29% and 27%, respectively, of the P-gp substrate digoxin in healthy volunteers. For patients who are initiating a combination of Betmira ER 50 mg and digoxin, the lowest dose for digoxin should be prescribed initially. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.Other interactions: No clinically relevant interactions have been observed when Betmira ER 50 mg was co-administered with therapeutic doses of solifenacin, tamsulosin, warfarin, metformin or a combined oral contraceptive medicinal product containing ethinylestradiol and levonorgestrel. Dose-adjustment is not recommended.

Betmira ER 50 mg is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients and severe uncontrolled hypertension defined as systolic blood pressure 180 mm Hg and/or diastolic blood pressure 110 mm Hg.

The most common side effects reported for patients treated with Betmira ER 50 mg 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 Betmira ER 50 mg 50 mg. Tachycardia led to discontinuation in 0.1% patients receiving Betmira ER 50 mg 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving Betmira ER 50 mg 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving Betmira ER 50 mg 50 mg. Serious adverse reactions included atrial fibrillation (0.2%).

Use in Pregnancy: There are limited amount of data from the use of Betmira ER 50 mg in pregnant women. Studies in animals have shown reproductive toxicity. Betmira ER 50 mg is not recommended during pregnancy and in women of childbearing potential not using contraception.Use in Lactation: Betmira ER 50 mg 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 Betmira ER 50 mg on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Betmira ER 50 mg should not be administered during breast-feeding

Renal impairment: Betmira ER 50 mg has not been studied in patients with end stage renal disease (GFR <15 mL/min/1.73 m2 or patients requiring haemodialysis) and therefore, it is not recommended for use in this patient population. Data are limited in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2); based on a pharmacokinetic study a dose reduction to 25 mg is recommended in this population. Betmira ER 50 mg is not recommended for use in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2) concomitantly receiving strong CYP3A inhibitors. Hepatic impairment: Betmira ER 50 mg 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. Betmira ER 50 mg is not recommended for use in patients with moderate hepatic impairment (Child-Pugh Class B) concomitantly receiving strong CYP3A inhibitors. Hypertension: Betmira ER 50 mg can increase blood pressure. Blood pressure should be measured at baseline and periodically during treatment with Betmira ER 50 mg, especially in hypertensive patients. Data are limited in patients with stage 2 hypertension (systolic blood pressure 160 mm Hg or diastolic blood pressure 100 mm Hg). Patients with congenital or acquired QT prolongation: Caution should be exercised when administering Betmira ER 50 mg in patients with congenital or acquired QT prolongation. Patients with bladder outlet obstruction and patients taking antimuscarinics medications for OAB: A controlled clinical safety study in patients with bladder outlet obstruction (BOO) did not demonstrate increased urinary retention in patients treated with Betmira ER 50 mg; however, Betmira ER 50 mg should be administered with caution to patients with clinically significant bladder outlet obstruction. Betmira ER 50 mg should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.

Betmira ER 50 mg has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations and increased pulse rate exceeding 100 beats per minute (bpm). Multiple doses of Betmira ER 50 mg 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.

Store in a cool and dry place, protected from light.

Renal and Hepatic Impairment: Betmira ER 50 mg has not been studied in patients with end stage renal diseaseGender: No dose adjustment is necessary according to gender.Children: The safety and efficacy of Betmira ER 50 mg in children below 18 years of age have not yet been established. No data are available.

BPH/ Urinary retention/ Urinary incontinence

Betmira ER 50 mg is the first beta-3 adrenoceptor agonist. Betmira ER 50 mg exerts its effect via a dual mechanism, both directly acts on the bladder smooth muscle and also via the sensory nervous system, it increases the levels of cyclic adenosine monophosphate (cyclic AMP) and leads to relaxation of the detrusor smooth muscle during storage phase of urinary bladder fill-void cycle by activation of beta-3 adrenoceptor which increase bladder capacity.

There are limited amount of data from the use of Betmira ER 50 mg in pregnant women. Studies in animals have shown reproductive toxicity. Betmira ER 50 mg is not recommended during pregnancy and in women is planning to be pregnant. Betmira ER 50 mg 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 Betmira ER 50 mg on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Betmira ER 50 mg should not be administered during breast-feeding. There were no treatment-related effects of Betmira ER 50 mg on fertility in animals. The effect of Betmira ER 50 mg on human fertility has not been established.