Mirasol XR Tablet (Extended Release) 25 mg

Uses

Mirasol XR Tablet (Extended Release) 25 mg is a beta-3 adrenergic agonist used for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.

Mirasol XR Tablet (Extended Release) 25 mg, in combination with the muscarinic antagonist solifenacin succinate, is used for the treatment of OAB with symptoms of urge urinary incontinence, urgency, and urinary frequency

Mirasol XR Tablet (Extended Release) 25 mg is also used to associated treatment for these conditions: Neurogenic Detrusor Overactivity, Urinary Bladder, Overactive

How Mirasol XR Tablet (Extended Release) 25 mg works

Mirasol XR Tablet (Extended Release) 25 mg is a potent and selective agonist of beta-3 adrenergic receptors. The activation of beta-3 receptors relaxes detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle, which increases the bladder's storage capacity thereby alleviating feelings of urgency and frequency.

Dosage

Mirasol XR Tablet (Extended Release) 25 mg dosage

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 crush

Patients with Severe Renal Impairment or Patients with Moderate HepaticImpairment: Maximum dose is 25 mg Mirasol XR Tablet (Extended Release) 25 mg once daily

Patients with End Stage Renal Disease (ESRD) or Patients with SevereHepatic Impairment: Not recommended

Side Effects

The most common adverse reactions reported for patients treated with Mirasol XR Tablet (Extended Release) 25 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 Mirasol XR Tablet (Extended Release) 25 mg 50 mg. Tachycardia led to discontinuation in 0.1% patients receiving Mirasol XR Tablet (Extended Release) 25 mg 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving Mirasol XR Tablet (Extended Release) 25 mg 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving Mirasol XR Tablet (Extended Release) 25 mg 50 mg. Serious adverse reactions included atrial fibrillation (0.2%).

Toxicity

At doses of up to 400mg in healthy volunteers (~8x the recommended maximum), reported symptoms of overdose included palpitations and increased heart rate. Symptoms of chronic overdosage are similar in presentation and may also include a rise in systolic blood pressure. In cases of overdosage, employ standard symptomatic and supportive measures in addition to ECG monitoring.

Interaction

The effect of co-administered medicinal products on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of other medicinal products was studied in single- and multiple-dose studies. Most drug-drug interactions were studied using a dose of mirabegron 100 mg given as oral controlled absorption system (OCAS) tablets. Interaction studies of mirabegron with metoprolol and with metformin used mirabegron immediate-release (IR) 160 mg.

Clinically relevant drug interactions between mirabegron and medicinal products that inhibit, induce or are a substrate for one of the CYP isozymes or transporters are not expected, except for the inhibitory effect of mirabegron on the metabolism of CYP2D6 substrates.

Food Interaction

• Take with food. While adults may take mirabegron with or without food, prescribing information recommends that children always co-administer mirabegron with food.

[Minor] Food reduces the oral absorption and bioavailability of mirabegron.

According to the product labeling, administration of a 50 mg tablet with a high-fat meal decreased mirabegron peak plasma concentration (Cmax) and systemic exposure (AUC) by 45% and 17%, respectively, whereas administration with a low-fat meal decreased mirabegron Cmax and AUC by 75% and 51%, respectively.

In phase 3 clinical studies demonstrating both safety and efficacy, mirabegron was administered without regards to food content and intake.

Therefore, mirabegron can be taken with or without food at the recommended dosage.

Mirasol XR Tablet (Extended Release) 25 mg Hypertension interaction

[Moderate] Mirasol XR Tablet (Extended Release) 25 mg can increase blood pressure.

In clinical studies, the use of mirabegron was associated with dose-related increases in supine blood pressure.

At the maximum recommended dose of 50 mg, the mean maximum increase in systolic

Worsening of preexisting hypertension was reported infrequently in patients receiving mirabegron.

Therapy with mirabegron should be administered cautiously in patients with hypertension.

Periodic blood pressure determinations are recommended.

Mirasol XR Tablet (Extended Release) 25 mg is not recommended for use in patients with severe, uncontrolled hypertension, defined as systolic blood pressure >=180 mm Hg and

Mirasol XR Tablet (Extended Release) 25 mg Drug Interaction

Moderate: diphenhydramine, tamsulosin, metoprolol, metoprolol, solifenacinUnknown: aspirin, aspirin, rosuvastatin, apixaban, fluticasone nasal, pregabalin, polyethylene glycol 3350, acetaminophen / hydrocodone, acetaminophen, bifidobacterium infantis / lactobacillus acidophilus, levothyroxine, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol

Mirasol XR Tablet (Extended Release) 25 mg Disease Interaction

Moderate: urinary retention, hypertension, liver disease, renal dysfunction

Volume of Distribution

Following intravenous administration, mirabegron has an apparent steady-state volume of distribution (Vd) of 1670 L indicating extensive distribution.

Elimination Route

The absolute bioavailability of orally administered mirabegron ranges from 29% at a dose of 25 mg to 35% at a dose of 50 mg. The T_max for the extended-release tablet and suspension formulations are approximately 3.5 hours, while the T_max for the granule formulation is 4-5 hours. Both C_max and AUC increase more than dose proportionally - an increase in dose from 50mg to 100mg results in a 2.9- and 2.6-fold increase in C_max and AUC, respectively, whereas an increase from 50mg to 200mg results in a 8.4- and 6.5-fold increase in C_max and AUC, respectively.

Steady-state concentrations of mirabegron are achieved after approximately 7 days of once-daily administration.

Half Life

The mean terminal elimination half-life of mirabegron in adults being treated for overactive bladder is approximately 50 hours. In pediatric patients receiving the granule formulation for the treatment of neurogenic detrusor overactivity, the mean terminal elimination half-life is approximately 26-31 hours.

Clearance

Total plasma clearance following intravenous administration is approximately 57 L/h, with renal clearance accounting for roughly 25% at approximately 13 L/h.

Elimination Route

Of a 160mg radiolabeled dose administered to healthy volunteers, approximately 55% of the radioactivity was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in the urine while 0% was recovered in the feces.

Renal elimination is achieved primarily via active tubular secretion with some contribution by glomerular filtration.

Pregnancy & Breastfeeding use

Use in Pregnancy: There are limited amount of data from the use of Mirasol XR Tablet (Extended Release) 25 mg in pregnant women. Studies in animals have shown reproductive toxicity. Mirasol XR Tablet (Extended Release) 25 mg is not recommended during pregnancy and in women of childbearing potential not using contraception.

Use in Lactation: Mirasol XR Tablet (Extended Release) 25 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 mirabegron on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Mirasol XR Tablet (Extended Release) 25 mg should not be administered during breast-feeding

Contraindication

Mirasol XR Tablet (Extended Release) 25 mg is contraindicated in patients with: Hypersensitivity to the active substance or to any of the excipients. Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg.

Special Warning

Renal and Hepatic Impairment: Mirasol XR Tablet (Extended Release) 25 mg has not been studied in patients with end stage renal disease

Gender: No dose adjustment is necessary according to gender.

Children: The safety and efficacy of mirabegron in children below 18 years of age have not yet been established. No data are available.

Acute Overdose

Mirasol XR Tablet (Extended Release) 25 mg 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 beats per minute (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 an overdosage, pulse rate, blood pressure and ECG monitoring is recommended.

Storage Condition

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

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