Overview
Mirabegron is commercially available as Myrbetriq. It is an extended-release tablet administered orally. It was approved by the United States (US) government in 2012. Mirabegron is a beta-3 adrenergic agonist. It is used for the treatment of overactive bladder. The advancement of drug combination is the use of Mirabegron with a muscarinic antagonist since April 2018. Also, the US government has given precautionary measures for treating patients with urinary retention due to bladder obstruction. Now, there is a major change in the dosage of Mirabegron with a muscarinic antagonist for treating the overactive bladder.
How Does Mirabegron Work?
Mirabegron is a white powder and is insoluble in water. The solubility increases in methanol and dimethyl sulfoxide. Recent research shows that cloning human cells shows a beta-3 adrenergic receptor for Mirabegron. The activation of beta-3 adrenergic receptors relaxes the detrusor smooth muscle. It gets activated during the storage phase of the urinary bladder. These receptors increase the bladder capacity. Though Mirabegron shows less intrinsic activity for cloned receptors like human beta-1 adrenergic receptor and beta-2 adrenergic receptor, stimulation of beta-1 receptors occurred at a 200 mg dosage.
What Are the Uses of Mirabegron?
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Adult Overactive Bladder - Mirabegron monotherapy is indicated in patients with increased urinary frequency and urgency.
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Mirabegron Combination Therapy With Solifenacin Succinate - Mirabegron is used in combination with Solifenacin succinate to treat adult patients with overactive bladder with the symptoms of urinary incontinence and urgency.
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Pediatric Neurogenic Detrusor Overactivity - Mirabegron granules are used to treat children three years of age and above with pediatric neurogenic detrusor overactivity. Mirabegron tablets are indicated for the treatment of neurogenic detrusor overactivity for children weighing above 35 kgs.
For Patients
What Should You Know About Overactive Bladder?
Adult patients with overactive bladder pass urine out frequently. They show symptoms like wanting to urinate more than eight times a day and two to three times at night. These patients have a sudden urge to urinate. If not, there is a leakage of urine immediately.
What Are the Causes of An Overactive Bladder?
When the healthy bladder has urinary waste, the brain sends signals to the bladder. The bladder helps in passing the urinary waste through the urethra, following which the bladder relaxes. But in an overactive bladder, the brain passes signals to the empty bladder. The muscles present in the bladder are excessively active.
Nervous disorders, too much fluid intake, excess caffeine intake, pre-existing diseases like diabetes, and post-menopause in women may cause an overactive bladder. It is commonly present in patients above 35 years of age.
What Happens In An Overactive Bladder?
The overactive bladder affects occupation, social life, and sleep. The patient passes urine in drips before reaching the bathroom. It affects the relationship and sex life with the partner. Constant leakage of urine gives rise to infection and skin problems in the private parts.
What is Neurogenic Detrusor Overactivity (NDO) in Pediatric Patients?
The frequent contraction of the detrusor muscle in children leads to uncontrolled urinary discharge. It is due to the neurological abnormality, which in turn inhibits the signals of the central nervous system and urinary bladder. This causes involuntary urination. The symptoms and retention of the urinary bladder can be improved using Mirabegron.
Dosage
The oral dosage of Mirabegron extended-release tablets contains 25 mg or 50 mg. It has inactive ingredients like polyethylene oxide, glycol, hydroxypropyl cellulose, magnesium, and ferric oxide.
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Mirabegron Monotherapy - The recommended oral dosage of Mirabegron is 25 mg once daily. The oral dosage can be increased up to 50 mg after the administration for four to eight weeks.
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Mirabegron Combination Therapy with Solifenacin Succinate - The combination therapy of Mirabegron and Solifenacin succinate should be administered orally at a starting dosage of 25 mg and 5 mg, respectively. The oral dosage can be increased up to 50 mg of Mirabegron once daily after four to eight weeks.
Recommended Dose for Pediatric Patients Above 3 Years of Age:
The appropriate product is selected depending on the weight of the pediatric patient.
For the pediatric patient weighing 11 kgs to 22 kgs, 24 mg is the starting dose and can be increased to 48 mg. For pediatric patients weighing 22 kgs to 35 kgs, the starting dose should be 32 mg and can be increased to 64 mg.
Recommended Dosage for Pediatric Patients Weighing More Than 35 kgs:
Mirabegron granules (extended-release) are administered once daily as an oral suspension. The starting oral dose should be 48 mg once daily. It can be increased to 80 mg once daily after four to eight weeks.
Contraindications
It is contraindicated for patients who are sensitive to drugs and experience symptoms like nausea, headache, hypertension, diarrhea, and tachycardia.
For Doctors
Indication
Mirabegron is the first line of treatment for overactive bladder.
Pharmacodynamics
Urinary Bladder - Research was conducted to assess the maximum urinary flow rate and pressure in the detrusor muscle during maximum flow rate. After administering Mirabegron to the patient once daily for three months, it was observed that the mean flow rate did not correlate with the detrusor pressure. But it should be administered with caution.
Heart - A study was conducted on four types of subjects by administering multiple doses of Mirabegron (50 mg, 100 mg, and 200 mg) once daily. The QT interval was determined in the electrocardiography. High dosage results in a mean difference of 3.5 seconds from placebo in the QT interval after five hours of drug administration. The patients administered 200 mg showed a substantial increase in the blood level of 50 mg. The QT interval in such cases is 6.1 msec after four to five hours of administering the drugs. In females, the interval goes up to 13.4 sec. Thus the heart rate depends on the dosage. The heart rates are 6.7, 11, and 17 beats per minute for 50 mg, 100 mg, and 200 mg doses respectively. The change in pulse rate from baseline was found to be 1 bpm.
Effects on Blood Pressure - After administering the dosage of 50 mg, there is a mean increase of 4.0/1.6 mm Hg in the systolic and diastolic blood pressure. Continuous administration for ten days shows an increase in systolic blood pressure. The mean increase of systolic blood pressure for 50 mg, 100 mg, 200 mg, and 300 mg are 2.5 mm Hg, 4.5 mm Hg, 5.5 mm Hg, and 6.5 mm Hg respectively. The alteration in systolic and diastolic blood pressure can be reversed after the withdrawal of Mirabegron. When Mirabegron was administered with 5 mg Solifenacin succinate, no difference was found in systolic and diastolic blood pressure. It is detected after 24 hours using ambulatory blood pressure monitoring (ABPM).
Effects on Intraocular Pressure - Administering Mirabegron one dose daily did not increase the intraocular pressure. It was given after treating the patients for two months. When 100 mg Mirabegron was administered, there was a mean difference of 0.3 mm Hg from the baseline.
Pharmacokinetics
Absorption
The study was conducted on healthy volunteers. Mirabegron was found to reach the plasma after 3.5 hrs. The dosage of Mirabegron 25 mg and 50 mg show a bioavailability of 29 % and 35 % respectively. In females, there was a two-fold increase of 2.9 and 2.6-fold when the dosage was increased from 50 mg to 100 mg. There was an increase in Cmax and AUCtau. When the Mirabegron dosage was increased from 50 mg to 200 mg, there was a four-fold increase by 8.4 and 6.5 fold. It also had an increase in Cmax and AUCtau. On administering a single daily dose, the concentrations were maintained at a steady state.
Mirabegron for Overactive Neurogenic Detrusor in Children:
In pediatric patients, a single dose of Mirabegron extended-release was administered in the fasting state for up to four to five hours. After that, an analysis was made to predict the median Tmax. It continued for three to four hours. This analysis gave an effective result of Mirabegron for the management of overactive neurogenic detrusor muscles in kids. There was a 120 % AUC increase in the kids who are in the fed state. There was an increase of 170 % and 80 % in Cmax and AUC for the kids in a starved state.
What Is the Effect of Food on Mirabegron?
In adults, Mirabegron monotherapy did not produce any significant changes in adults with or without food.
Distribution
The monotherapy of Mirabegron in adults distributes the drug widely inside the body. After an intravenous administration, there is a steady-state volume of 1670 L. 71 % of Mirabegron is bound to human plasma proteins and has a greater affinity to albumin. It has a moderate affinity to alpha-1 glycoprotein. In addition, it adheres to RBC (red blood cells). There was a 2-fold increase of Mirabegron in the erythrocyte steady-state to plasma.
Distribution in Pediatric Patients With Overactive Detrusor Muscle:
In children, the Mirabegron distribution is relatively large compared to adults. The ratio of V2/F in children in the fed state shows a distribution range of 4895 L to 13726 L. The drug distribution increases with weight.
Elimination of Mirabegron in Adults:
The half-life of Mirabegron is 50 hours. It is the terminal elimination of the drug in adults with overactive detrusor muscle.
Elimination of Mirabegron in Pediatric Patients:
The half-life of Mirabegron in children is approximately 26 to 31 hours.
Metabolism
The multiple metabolic processes like dealkylation, hydrolysis, oxidation, and glucuronidation are involved in the metabolism of Mirabegron. The major circulating component is Mirabegron. The metabolites present in plasma and phase 2 glucuronides represent 16 % and 11 % respectively. They are inactive to the beta-3 adrenergic receptor. The isoenzymes CYP2D6 and CYP3A4 play an important role in eliminating the drug. The healthy volunteers with poor metabolism of CYP2D6 due to the genotype had Cmax and AUCtau of 16 % and 17 % which were higher than the patients with extensive metabolizers. The butylcholinesterase, glucuronosyltransferase, and alcohol dehydrogenase are also involved in the metabolism of Mirabegron.
Excretion
Mirabegron is excreted completely at 57 L/h from the body after an intravenous administration. The half-life elimination of Mirabegron is 50 hours. The renal clearance of Mirabegron is 13 L/h. It involves 25 % of the total clearance. It occurs in glomerular filtration. The unchanged Mirabegron has been eliminated as 6 % and 12.2 % for the dosage of 25 mg and 100 mg, respectively. Administering 160 mg to adults gives a radioactive dose of 55 % in urine and 34 % in faeces. 25 % of unchanged Mirabegron was present in urine, but there was nothing in the feces.
Specific Population
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Age- In patients above 65 years, the Cmax and AUC of Mirabegron after multiple doses are similar to the individuals aged 18 to 45 years.
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Gender - The pharmacokinetics of Mirabegron had no specific impact on the gender of patients aged 3 to 18 years.
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Race - The exposure of Mirabegron to Japanese was proved to be higher than in North Americans. However, there was a minimal difference if the Cmax and AUC were modified depending on the weight.
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Mirabegron Study in Renal Impairment Patients - In adults with mild renal impairment, after the administration of 100 mg Mirabegron, the glomerular filtration rate was estimated as 60 to 89 mL/min, and there was an increase by 6 % and 31 % of Cmax and AUC respectively. In patients with moderate renal impairment with a glomerular filtration rate of 30 to 58 mL/min, the Cmax and AUC have an increase up to 23 % and 66 %, respectively. In severe renal impairment conditions, with a glomerular filtration rate of 15 mL/min, the value of Cmax and AUC were found to be 92 % and 118 % higher than healthy individuals who had a normal renal function. Patients with a glomerular filtration rate of less than 15 mL/min are considered end stage renal disease and require dialysis for management. The Mirabegron study was not made in such cases.
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Mirabegron Study in Hepatic Impairment Patients - After 100 mg Mirabegron administration in adult patients with mild hepatic illness, the Cmax and AUC increased by 9 % and 19 % compared to adult patients. The individuals with moderate hepatic illness had Cmax and AUC values of 175 % and 65 % respectively. It is not studied in adults with severe hepatic disease.
Clinical Trials
The adverse drug reactions vary from clinical practice. In a double-blind study in more than 2000 patients, the safety and efficacy of Mirabegron was evaluated. Atrial fibrillation and prostate cancer were the two potential adverse effects reported in a few patients.
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Cardiac Disorders - The adult patients had palpitations associated with increased blood pressure.
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Eye Disorders - Glaucoma is observed in elderly patients.
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Gastrointestinal Disorders - There is abdominal distension with inflammatory bowel and dyspepsia.
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Infections - Sinusitis and rhinitis.
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Renal and Urinary Disorders - Pain in the bladder due to nephrolithiasis.
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Reproductive System - Inflammation in the urethra and vaginal infection called vulvovaginal pruritus.
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Skin and Subcutaneous Tissue Disorders - Itching in the urethra, lip edema, vasculitis, and purpura.
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On investigation using serum ALT (alanine transaminase) and AST (aspartate transaminase) the markers of osteoarthritis increased 10-fold from baseline.
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Neoplasms like breast cancer, lung cancer, and prostate cancer were reported in patients who were administered 100 mg Mirabegron.
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One patient administered with 100 mg Mirabegron reported Stevens-Johnson syndrome with elevated alanine transaminase (ALT), aspartate transaminase (AST), and bilirubin.
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The commonly seen adverse effects of combination therapy with Mirabegron and Solifenacin succinate are blurred vision, squamous cell carcinoma, and basal cell carcinoma.
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In pediatric patients with neurogenic detrusor overactivity the clinical trial study duration was 52 weeks. The common adverse reactions like nasopharyngitis and urinary tract infection due to the intake of Mirabegron granules.
Drug Interaction Studies
What Are The Effects of Other Drugs on Mirabegron?
There are various metabolic activities involved in the metabolism of Mirabegron. It is the substrate of enzymes like CYP3A4 and CYP2D6, receptors like butyrylcholinesterase, and transporters like glycoprotein. It also involves the organic transporters OCT1, OCT2, and OCT3. The Glibenclamide, Gliclazide, and Tolbutamide agents did not affect the Mirabegron metabolism.
What Are The Effects of Mirabegron on Other Drugs?
Recent research has proved that Mirabegron is a moderate and time-dependent inhibitor of the enzyme-like CYP2D6 and a weak inhibitor of the CYP3A enzyme. Mirabegron does not affect the drug metabolized by the P450 enzymes. It inhibits only at a very low concentration. There is no action on CYP1A2 and CYP3A enzymes. It reduced the action of P-gp-mediated drug transport. The study stated that the Mirabegron is no longer effective in the OCT medicated drugs. It also did not affect the glibenclamide and tolbutamide metabolism.
What is The Effect of Alcohol on Mirabegron?
Alcohol increases the dissolution of Mirabegron at pH 6.8. But there was no dissolution at a pH of 1.
Interaction of Mirabegron Extended-Release Tablets with Other Drugs
The study was conducted on a 23-year-old male and a few female subjects to analyze the effect of Mirabegron in patients when co-administered Metoprolol, Metformin, and Ketoconazole. Ketoconazole has increased drug exposure (the Cmax and AUC were 45 % and 80 % after the administration of 400 mg). It was given a week before the administration of 100 mg Mirabegron.
The Cmax and AUC of Metoprolol increased by 90 % and 230 % after administering 160 mg of Mirabegron continuously for a week.
The Cmax and AUC of Desipramine increased by 79 % and 241 % after administering 100 mg of Mirabegron continuously for two weeks.
The Cmax and AUC of Digoxin increased by 14 % and 10 % respectively.
The Cmax and AUC of Tamsulosin increased by 47 % and 55 % respectively. It is correlated to the inhibition of cytochrome P450.
Carcinogenesis
The study conducted about the carcinogens showed no carcinogenic effect at a 50 mg Mirabegron dosage with an AUC of 38 to 45 fold.
Mutagenesis
There were no significant chromosomal abnormalities in the peripheral blood lymphocytes of the healthy individuals.
Fertility
The Mirabegron 100 mg dosage did not affect fertility in men and women.
Patient Counseling Information
Ensure that the patient reads the US Food and Drug Administration (FDA) guidelines before taking the medications.
Blood Pressure
Give prior information that the Mirabegron granules increase the blood pressure. So they should monitor their blood pressure periodically and consult a medical professional if necessary.
Urinary Retention
Inform the patients about urinary retention due to bladder obstruction and muscarinic antagonist medications. Ask the patient to consult an urologist if they experience any of the symptoms.
Angioedema
The Mirabegron granules cause angioedema. In severe cases it leads to swelling of the upper respiratory tract and causes life threatening conditions. The patient should discontinue the drug and seek medical help immediately.
Drug Interaction
The patients should inform their physician about the use of prescribed and over the counter medications and supplements, because this can interfere with Mirabegron granules. Sometimes the patient requires a dose adjustment and frequent monitoring of the vital signs.
Mirabegron Administration
Ask the adult patient to swallow the Mirabegron with water and avoid chewing. Most importantly, the tablets should not be crushed or divided while swallowing. Advise the adult patients to take Mirabegron before or after eating food.
In the case of pediatric patients, ask the caretaker to provide Mirabegron tablets for children to swallow using water. It should not be chewed, crushed or divided and should be taken only after eating the food.
Advise the caretakers of pediatric patients to measure the Mirabegron granules and read the instructions before giving the oral suspension with extended release. It should be consumed within an hour after preparation. Also, it should not be stored for the next day. It should be taken once daily after food.
Ask the caretaker to shake the bottle for a minute before use if it is not used for more than 2 days. It should be shaken vigorously for a minute so that there is a foam accumulation on the top of the suspension. It will go off after one to two minutes.
Missed Dose
In case of missed dose, advise the caretakers or patients to take the medication as soon as they remember or most probably within 12 hours of the missed dose. If it is more than 12 hours, then the drug can be skipped and advised to take the next dose as usual.
For Patients
Adults
Mirabegron is prescribed by the physician and can be used alone or co-administered with Solifenacin succinate to the adults. It is usually preferred for patients with symptoms due to overactive bladder. The symptoms include:
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The adult patients have an urge to urinate due to incontinence. They have an increased urge during leakage or accidents due to wetting.
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There is a strong need to urinate at the same moment.
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Frequency - Adult patients want to urinate often.
Children
Mirabegron is prescribed only for children 3 years of age and above with a medical condition called neurogenic detrusor overactivity.
It is prescribed only for children weighing above 77 pounds or 35 kgs.
It is not safe and effective for children under 3 years of age.
Who Should Avoid Mirabegron Tablets or Mirabegron Granules?
The adult patients who are allergic to Mirabegron or any of the ingredients present in Mirabegron granules or Mirabegron tablets should avoid taking it. The patient should read the information present on the leaflet to know about the ingredients present in Mirabegron tablets and Mirabegron granules.
What Should Be Informed to Your Physician Before Taking Mirabegron?
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Liver problems as the hepatic impairment may influence the metabolism of Mirabegron.
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Kidney problems because renal impairment may influence the metabolism of Mirabegron.
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The patients with high blood pressure because Mirabegron further increases the blood pressure.
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The adults having trouble in passing urine or weak urine streams.
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Adult women who are pregnant or planning for pregnancy. Though studies are going on about the effects of Mirabegron tablets and Mirabegron granules on the fetus, it is important to inform the doctor about the present situation.
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Women who are breastfeeding or planning to breastfeed in future because there is a chance of transmission of Mirabegron tablets or Mirabegron granules through the breast milk. It is better to ask your physician about the timings to feed the baby after the administration of Mirabegron.
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Keep the doctor informed about the medications and vitamin supplements taken because they may interact with the Mirabegron granules. The particular medications include:
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Thioridazine.
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Digoxin.
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Solifenacin succinate.
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Propafenone.
How to Take Mirabegron Tablets?
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Take one dose of Mirabegron daily.
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If it is co-administered with Solifenacin succinate, then take each tablet once daily.
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Adults can swallow the tablet using water before or after eating food. Avoid taking the tablets in fragments.
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Children should take Mirabegron after eating food.
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The missed dose can be taken any time in the 12 hours before the succeeding dose. If 12 hours is exceeded, take the next dose.
How to Take Mirabegron Granules?
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Adults and children should consume Mirabegron granules orally once daily with food.
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Use the preparation within 12 hours.
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If the dose of Mirabegron granules is missed, then take it within 12 hours.
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Skip the dose if it is more than 12 hours and take the next dose.
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Shake the bottle for a minute vigorously before using it.
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Allow it to stand for two to three minutes and take it once the foam is gone.
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Use the oral dosing device to take the suspension.
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Wash it with detergent after every use and keep it dry.
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If the drug is consumed in overdosage, visit the nearest hospital for an emergency.
What Are the Side Effects of Mirabegron in Adults?
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Hypertension - Mirabegron may increase the blood pressure and make the condition worse if the patient has hypertension. The doctor will check the blood pressure before prescribing Mirabegron tablets or Mirabegron granules.
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Urinary Retention - Mirabegron increases the chances of inability to empty the bladder. It may also be due to other medications taken for overactive bladder. Inform your doctor if there is an uncomfortable feeling while passing urine.
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Angioedema - Some adult patients may be allergic to Mirabegron and get swelling in the lips, face, tongue, and throat. In such situations stop taking Mirabegron.
The common side effects of Mirabegron include:
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Flu or cold.
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Dry mouth.
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Urinary tract infection or inflammation.
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Back pain.
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Dizziness.
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Headache.
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Bodyache or joint pain.
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Constipation.
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Sinus infection.
The common side effects when Mirabegron is administered with Solifenacin succinate:
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Constipation.
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Rapid heart beat.
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Urinary infection.
How to Store Mirabegron?
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Mirabegron should be stored between 60°F to 86°F.
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Always close the bottle after use.
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Keep the Mirabegron tablets and Mirabegron granules out of the reach of children.
General Information About the Safety and Effective Use of Mirabegron:
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Mirabegron may be prescribed by the doctors for other purposes apart from the conditions mentioned in the leaflet.
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Avoid using the Mirabegron for the conditions which are not prescribed for.
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Avoid giving to other people with the same symptoms. It is harmful.
What Are the Ingredients of Mirabegron Tablets or Granules?
The active ingredient is Mirabegron.
The inactive ingredients are
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Polyethylene oxide.
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Polyethylene glycol.
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Hydroxypropyl cellulose.
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Butylated Hydroxytoluene.
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Magnesium Stearate.
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Hypromellose.
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Yellow and red ferric oxide.