Mirabegron Associated Angioedema: A Case Report

Abstract

Purpose: To review a case of angioedema associated with mirabegron. Summary: A 77-year-old woman presented to the emergency department with swelling of the left anterior side of the tongue beginning 90 minutes prior to arrival. She noticed tingling on her tongue while eating a hamburger, chips, and ice cream. The patient had no history of medication-related allergies. Home medications include acetaminophen, aspirin, biotin, black cohosh, Co-enzyme Q-10, cranberry, fish oil, multivitamin, alendronate, and mirabegron all taken orally. The patient reports being on mirabegron for 3 to 4 years but recently decided to self-taper off the medication. Her initial laboratory test results were unremarkable. The patient was diagnosed with left tongue angioedema, and she received methylprednisolone, epinephrine, famotidine, and 2 units of plasma. After medication administration, the patient underwent a flexible nasopharyngeal laryngoscopy resulting in no significant angioedema in the pharynx and hypopharynx with a small area of possible edema noted on the right base of tongue/lingual tonsil. Patient’s symptoms improved with medication treatment and discontinuation of mirabegron. The use of Naranjo et al. adverse-event probability scale revealed that mirabegron was the possible (score of 4) cause of the patient’s left tongue angioedema. Conclusion: A 77-year-old woman developed drug induced tongue angioedema associated with mirabegron after being compliant on this medication for 3 to 4 years. Patient was self-tapering her dose of mirabegron. This patient responded well to medication treatment and discontinuation of drug. To our knowledge, this is the second case report of mirabegron induced angioedema.

Key points:

• This is a rare case report of tongue angioedema caused by miragebron.

• The initial mirabegron package insert in 6/2012 did not have angioedema listed as a possible ADR. Due to post marking information reported, the package insert was updated in 8/2015 to list angioedema as a rare but serious ADR.

• To date there is only 1 case report of mirabegron associated angioedema.

Angioedema is defined by nonpitting edema of the dermis and subcutaneous layers lasting from hours to 3 days. Commonly, angioedema occurs in the lips, tongue, face, and throat. Uncommonly, it can occur in the extremities, genitalia, and viscera. ¹ Angioedema is a medical emergency, as it can lead to life-threating airway swelling. The pathophysiology behind angioedema is believed to be caused by either mast cell degranulation (with a rapid release of histamine) or activation of the kallikrein-kinin cascade (with a rapid release of bradykinin). Mast cell degranulation is a process when mast cells are stimulated and release histamine. ² In angioedema caused by mast cell degranulation, there is a rapid release of histamine from the cells. Drug-induced, allergic angioedema is a type I hypersensitivity reaction and is mediated by histamine release. This type of angioedema has a rapid onset of action and may present with an urticarial rash and often resolves with medication treatment such as antihistamines. Kallikrein-kinin cascade is an endogenous metabolic cascade in which vasoactive kinins are released, specifically bradykinin-related peptides. ³ Overproduction of bradykinin can stimulate an angioedema reaction. Drug-induced, non-allergic angioedema is mediated by bradykinin. Urticarial rash is not typically present in this type of angioedema. This reaction has a gradual onset, unlike allergic angioedema. Symptoms will subside after discontinuing the offending agent.^4,5 Mirabegron, a beta-3-agonist, is indicated for overactive bladder and urinary incontinence. ⁶ We describe a case of drug-induced tongue angioedema related to use of mirabegron. A MEDLINE search, without date limits, using the terms mirabegron and angioedema or drug-induced angioedema identified 1 case report. ⁷

Case Report

A 77-year-old female with a body mass index of 19.01 kg/m² arrived at the emergency department with complaints of left-sided tongue swelling and tingling, tightness in the back of her throat and difficulty speaking because of a lisp. Her symptoms began after consuming a cheeseburger, potato chips, and ice cream. Due to symptom progression, she presented to the emergency room 1.5 hours later. She has no previous history of allergies, angioedema, or anaphylaxis. Her past medical history was significant for osteoporosis and overactive bladder, both of which are not chronic degenerative diseases. Vitals on admission include blood pressure: 182/95 mmHg, pulse: 98 BPM, respiratory rate: 18 breaths/minute, SpO2: 98% on room air. Body temperature was 36.3°C. Given the patient was hemodynamically stable anaphylaxis was ruled out. On physical examination, patient’s anterior tongue was significantly swollen concerning for angioedema versus allergic reaction. The remainder of her physical exam was unremarkable. Complete blood count and differential, osmolality, and international normalized ratio were all unremarkable. The basic metabolic panel was unremarkable except for slightly elevated calcium at 10.8 mg/dL and bicarbonate 31 mmol/L. COVID-19 and respiratory pathogen were both unremarkable. Electrocardiogram showed normal sinus rhythm without ST elevation or other obvious signs of ischemia or arrhythmia. Patient received intravenous methylprednisolone 125 mg, intravenous famotidine 20 mg, and intramuscular epinephrine 0.3 mg shortly after admission to the emergency department. Patient also received 2 units of plasma 2 minutes after receiving the medications listed. After medications and plasma were administered otolaryngology preformed a bedside flexible pharyngo-laryngoscopy procedure with the following results: no significant angioedema in pharynx/hypopharynx, small area possible edema noted on the right base of the tongue/lingual tonsil. Patient’s symptoms began to improve about 90 minutes after medications were administered and the patient was discharged, with a total length of stay being 1 day, without any changes to her home medications. Her home medications included the following: acetaminophen 500 mg twice daily, aspirin 81 mg daily, biotin 1000 μg daily, black cohosh compound 1 tablet daily, Co-enzyme Q-10 1000 mg daily, cranberry 300 mg daily, fish oil 1000 mg daily, multivitamin 1 tablet daily, alendronate 70 mg every Friday, mirabegron 50 mg twice weekly on Monday and Friday, all taken orally. She also used polyvinyl alcohol 1.4% liquiform tear eye drops, 1 drop into both eyes as needed. Of these medications, acetaminophen, ⁸ alendronate, ⁹ aspirin ¹⁰ have been rarely associated with angioedema. This case report will focus on mirabegron as possible cause. The patient reports taking mirabegron for about 3 or 4 years and up until recently she has been taking it as prescribed, once daily. She has recently decided to self-taper off this medication and started to take it twice weekly. Due to the rapid onset of her angioedema and her positive response to methylprednisolone, famotidine, and epinephrine the patient was advised to discontinue mirabegron on discharge. The patient was scheduled to follow up with her primary care provider in 1 week post discharge to discuss whether to continue mirabegron considering this occurrence. It was decided to discontinue mirabegron. The Naranjo et al adverse-event probability scale indicated a score of 4 which indicates possible causality of adverse drug reaction (ADR). ¹¹

Discussion

Mirabegron is indicated for overactive bladder and urinary incontinence. It works by activating beta-3 adrenergic receptors in the bladder resulting in relaxation of the detrusor smooth muscle during the urine storage phase and increasing bladder capacity. Data have shown that beta-adrenoceptors, predominately the beta-3, mediate detrusor smooth muscle tone, and promote the storage function of the human bladder. Mirabegron is generally well tolerated with the most common side effects being increased blood pressure, dry mouth, urinary tract infection, dizziness, headache, and constipation. Serious, but rare, ADRs include hypersensitivity reactions and head and neck angioedema (occurring in <1% of patients). ⁶ The initial mirabegron package insert in 6/2012 ¹² did not have angioedema listed as a possible ADR. Due to post marking information reported, the package insert was updated in 8/2015 ¹³ to list angioedema as a rare but serious ADR. To date there is only 1 case report of mirabegron associated angioedema. This case study examines a 53-year-old female who experienced dyspnea, dysphagia, and throat tightness for 3 to 4 weeks. Through careful history taking the team was able to reveal that she had increased her dose of mirabegron from 25 to 50 mg 1 day prior to symptoms onset. Three days after discontinuing mirabegron she reported symptom resolution. ⁷ Similarly, we report a patient who recently changed her mirabegron dose who experienced tongue angioedema. She was taking mirabegron 50 mg daily for 3 to 4 years and recently cut back to 50 mg on Monday and Fridays. She presented Friday evening and had received her dose for the day. Based on the rapid onset of her tongue swelling and response to treatment we propose the patient experienced drug-induced allergic angioedema. We propose the mechanism causing her angioedema was a type I hypersensitivity mediated by mast cell degranulation and a rapid release of histamine. This is supported by the rapid onset and response to antihistamines and corticosteroids.

Conclusion

A 77-year-old female developed tongue angioedema after self-tapering her mirabegron. Drug-induced allergic angioedema is a rare but is a medical emergency. This case report shows the importance of obtaining an accurate medication history.