Mirabegron


Article Author:
Omar Dawood


Article Editor:
Ahmed El-Zawahry


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Karim Hamawy


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Phillip Hynes
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Sandeep Sekhon


Updated:
6/28/2019 11:52:46 AM

Indications

The International Continence Society definition of overactive bladder (OAB) is, “urinary urgency, usually accompanied by frequency, nocturia, with or without urge urinary incontinence.”[1] It is important to understand that OAB isn't an exact disease, but rather, a symptom complex with multiple, distinct etiologies. It is an incredibly embarrassing condition, and many patients are uncomfortable discussing it with their providers. The treatment of OAB includes a three-step algorithm starting with lifestyle modification, then, medication, and lastly, minimally invasive intervention. Lifestyle and behavioral modification including paying close attention to fluid consumption and bladder irritants, bladder training, and pelvic muscle floor therapy. The second line includes using anticholinergics or beta-3 adrenoceptor agonist. The third line consists of the injection of onabotulinum-toxin A, sacral neuromodulation, and percutaneous posterior tibial nerve stimulation.

The medications used in OAB typically are the antimuscarinics. However, given their broad side-effect profile, they have to be used cautiously, especially in patients with acute angle-closed glaucoma, older patients, and chronic constipation. Mirabegron, a beta-3 adrenoceptor agonist, has been shown to have high safety and efficacy profile by large random placebo-controlled clinical trials. Mirabegron is used for the treatment of urgency, urge urinary incontinence, and increased urinary frequency found in the overactive bladder.[2] It received approval from the US Food and Drug Administration (FDA) in June 2012 for the treatment of this condition.[3] Mirabegron has been reported to have better tolerance and compliance by patients as compared to the antimuscarinics. In this article, we will cover the use of mirabegron. We will pay close attention to the mechanism of action, routes of administration/combination therapy, adverse effects, contraindications, monitoring, and coordination between health team providers.

Mechanism of Action

The human bladder expresses various sympathetic and parasympathetic receptors to help regulate micturition. Activation of the parasympathetic system will result in bladder contraction. Receptors positively affecting bladder contraction and micturition include the M2 and M3 receptor subtypes, which function via the parasympathetic nervous system.[4] These receptors work to increase intracellular calcium and down-regulate cyclic-adenosine respectively, which will increase muscle contraction. Negatively affecting micturition predominantly includes the sympathetic beta-3 adrenergic receptors.[5] Mirabegron is a beta-3 receptor agonist which will cause detrusor muscle relaxation. Animal studies have shown that beta-3 receptor agonists exhibit a dose-dependent detrusor relaxation (mediated via up-regulation of cyclic-adenosine) during the storage phase of micturition.[3] In this way, mirabegron can aid in the symptomatic relief of OAB.

Administration

Mirabegron is a once daily orally administered drug.[3] It is available in 25 mg or 50 mg strengths. The lower strength tablet is recommended as a starting dose and for patients with severe renal or moderate hepatic impairment, and the higher dose tablet is recommended for patients to take with or without food if they tolerate the lower dose.[3] Other therapeutic routes of administration (intravenous, rectal, enteral, epidural, intracerebral, etc.,) for mirabegron are not FDA approved in the treatment of OAB. Mirabegron may take 4 to 8 weeks before patients see improvements in their symptoms.

In addition to monotherapy, combination therapy with low dose mirabegron (25 mg) and a low dose of solifenacin (5 mg), an anti-muscarinic, has been shown to have significant improvement of urinary urgency and urgency incontinence when compared to monotherapy. Three large double-blind, randomized controlled trials (Symphony, Beside, and Synergy) have shown the safety and efficacy of combination therapy. Recently, the FDA has approved combination therapy for patients with urinary urgency.

Adverse Effects

Side effects of mirabegron are generally mild and tolerable. One study showed that the adverse effects of mirabegron include hypertension (most commonly), nasopharyngitis, and urinary tract infection.[6]  Dry mouth (a common side effect of the anti-muscarinics) is six-fold less in mirabegron[6] which is because mirabegron does not affect the muscarinic receptors in the salivary glands. Other side effects include tachycardia, constipation, headache, back pain, dizziness, palpitations, atrial fibrillation, urticarial reaction, joint pain, and joint swelling.[7] Mirabegron is considered a very safe and effective drug. Mirabegron may also be more useful in the elderly population as the neurocognitive concerns of anti-muscarinic therapy may not be as much of a problem; however, this requires further investigation.

Contraindications

If patients are currently on mirabegron therapy, it is essential to monitor their blood pressure. Mirabegron use correlates with hypertension, and its contraindication includes severe uncontrolled hypertension and pregnancy.[8] Analysis of hypertension should depend on the discretion of the clinician. Resistant hypertension is defined as blood pressure that that remains elevated above 140/90 despite the use of three different anti-hypertensive drugs at the most tolerated doses, one of which being a diuretic.[9] In this light, the optimization of blood pressure should be a consideration before initiating mirabegron therapy.

Monitoring

Mirabegron is absorbed fairly quickly after oral administration with maximum plasma concentration achieved in roughly 3 hours. The liver’s CYP450 system predominantly metabolizes mirabegron. Monitoring and dose adjustment should take place with patients on other medications that have a narrow therapeutic index, and that also undergo metabolism via CYP2D6.[7] According to American Family Physicians (AAFP), potent inhibitors of the CYP2D6 system are amiodarone, cimetidine, diphenhydramine, fluoxetine, paroxetine, quinidine, ritonavir, and terbinafine. Substrates of the CYP2D6 system are amitriptyline, carvedilol, codeine, donepezil, haloperidol, metoprolol, paroxetine, risperidone, and tramadol. There are no significant inducers. In this light, it is vital to consider all comorbidities and drugs that patients are on to prevent undesirable drug-drug interactions. It is recommended to take a thorough history, with consideration of past medical history and review of medications before staring mirabegron therapy.

Toxicity

Mirabegron has been shown to have a very broad safety level in humans. Caution is advisable with drugs that exert effects on or are metabolized by the liver, as mirabegron is also hepatically metabolized. Though safe in humans, studies have shown toxicity in dogs in the form of tachycardia and erythema.[10]

Enhancing Healthcare Team Outcomes

According to one study, the rate of serious adverse effects of mirabegron was low and not directly related to the drug itself (Level of evidence 1a, Grade A).[8] Pooled safety date from SCORPIO, ARIES, and CAPRICORN (three large randomized, controlled clinical trials) have shown that there is no dose-response relationship among treatment groups for rates of treatment-emergent adverse effects (TEAE) with mirabegron (level 1).[11] Recommendations for management of patients on mirabegron include periodic measurement of blood pressure and symptomatic investigation of urinary retention tract infection; accomplishing this goal is best with a healthcare team approach including prescribing clinicians, nursing, and pharmacists.


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Mirabegron - Questions

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Which beta 3-receptor agonist has been approved by the FDA for treat treatment of overactive bladder?



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Biochemically, cyclic-AMP is a regulator that works to impact glycolysis negatively. Nerves many times, release chemicals that result in alterations of levels of intracellular cyclic-AMP to modulate the effect of the sympathetic nervous system. In a similar light, some medications work to increase the levels of cyclic-AMP. Which of the following medications used in the treatment of overactive bladder work to increase the levels of this biochemical regulator?



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A 65-year-old woman presents to with urinary frequency and urgency incontinence. She has medical problems with asthma, diabetes, narrow-angle glaucoma, and high blood pressure. She also complains of nocturia about 3 to 4 times. She has a good stream and can empty her bladder well. Urinalysis is negative for infection. Her blood pressure in the clinic during the visit is 175/110 mm Hg while on antihypertensives. She has failed behavioral therapy and biofeedback in the past. She is in the clinic seeking help. What is a contraindication to the use of mirabegron in this patient?



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Mirabegron - References

References

Willis-Gray MG,Dieter AA,Geller EJ, Evaluation and management of overactive bladder: strategies for optimizing care. Research and reports in urology. 2016;     [PubMed]
Goulooze SC,Cohen AF,Rissmann R, Mirabegron. British journal of clinical pharmacology. 2015 Oct;     [PubMed]
Sacco E,Bientinesi R, Mirabegron: a review of recent data and its prospects in the management of overactive bladder. Therapeutic advances in urology. 2012 Dec;     [PubMed]
Abrams P,Andersson KE,Buccafusco JJ,Chapple C,de Groat WC,Fryer AD,Kay G,Laties A,Nathanson NM,Pasricha PJ,Wein AJ, Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. British journal of pharmacology. 2006 Jul;     [PubMed]
Andersson KE, On the Site and Mechanism of Action of β{sub}3{/sub}-Adrenoceptor Agonists in the Bladder. International neurourology journal. 2017 Mar 24;     [PubMed]
Wolff GF,Kuchel GA,Smith PP, Overactive bladder in the vulnerable elderly. Research and reports in urology. 2014;     [PubMed]
Sharaf A,Hashim H, Profile of mirabegron in the treatment of overactive bladder: place in therapy. Drug design, development and therapy. 2017;     [PubMed]
Corcos J,Przydacz M,Campeau L,Gray G,Hickling D,Honeine C,Radomski SB,Stothers L,Wagg A,Lond F, CUA guideline on adult overactive bladder. Canadian Urological Association journal = Journal de l'Association des urologues du Canada. 2017 May;     [PubMed]
Yaxley JP,Thambar SV, Resistant hypertension: an approach to management in primary care. Journal of family medicine and primary care. 2015 Apr-Jun;     [PubMed]
Schmid RD,Hovda LR, Mirabegron Toxicosis in Dogs: a Retrospective Study. Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2018 Jun;     [PubMed]
Vij M,Drake MJ, Clinical use of the β3 adrenoceptor agonist mirabegron in patients with overactive bladder syndrome. Therapeutic advances in urology. 2015 Oct;     [PubMed]

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