The FAERS is a spontaneous reporting system for AEs, providing a public database for the real-world assessment of the post-marketing safety profile of mirabegron. It enables the identification of AEs not yet documented in the drug instructions. To ensure the reliability of reporting sources, our analysis exclusively included reports provided by healthcare professionals and reports specifically documenting mirabegron as the PS drug. The incidence of AEs related to mirabegron was higher in females (60.10%) than in males (34.80%), excluding cases with unknown gender. This may be related to the higher prevalence of OAB in females compared to males [14]. Furthermore, with increasing age, the prevalence of OAB gradually increased [15]. This phenomenon also explained the higher incidence of AEs among individuals aged 65 and older in this study. With the continuous expansion of mirabegron's clinical application, clinicians should be vigilant about AEs associated with mirabegron, especially in elderly patients. Early identification of AEs is essential because these AEs may not only increase the likelihood of patient hospitalization but also pose potential life-threatening risks.
Based on the disproportional analysis, the most frequent and significant signals at the SOC level was renal and urinary disorders, showing positive reactions in both the ROR and IC methods. The related AEs included dysuria, pollakiuria, bladder pain, bladder spasm, neurogenic bladder, etc., but they were often considered as indications of mirabegron (Fig. 2). Therefore, these AEs are considered to be associated with the progression of the underlying medical condition rather than being AEs caused by the medication itself. It is noteworthy that there were 128 reports of urinary retention, with significant signals observed in both the ROR and IC analyses. According to previous research, mirabegron did not have AEs on urinary urodynamic parameters, including maximum urinary flow rate and detrusor pressure at maximum flow, and did not increase the risk of urinary retention [7, 9, 10, 16]. Furthermore, the mechanism of mirabegron involves promoting relaxation of the detrusor muscle and increasing urinary storage capacity without altering voiding pressure or contraction [10]. Mirabegron appeared to exhibit good safety in the AE of urinary retention. Therefore, a reasonable interpretation of the study results was that disease progression, such as benign prostatic hyperplasia or neurogenic bladder, might have been a contributing factor to urinary retention. However, according to a Japanese study, 19 OAB patients with concomitant benign prostatic hyperplasia experienced urinary retention after using mirabegron, with resolution or recovery observed upon discontinuation [17]. Therefore, we believe that the correlation between mirabegron and the AE of urinary retention remains controversial. For patients with evident bladder outlet obstruction in clinical practice, the use of mirabegron should be approached with caution [17]. Additionally, we recommend regular follow-up during mirabegron treatment, where clinicians should monitor patients' voiding patterns, residual urine volume, and urinary flow rates.
Furthermore, significant signals were observed in the ROR method within the SOC categories of cardiac disorders, investigations, and vascular disorders. Based on findings from clinical studies, the predominant cardiovascular AEs linked to mirabegron include hypertension, tachycardia, palpitations, and atrial fibrillation [18–21]. Approximately 9–10% of patients undergoing mirabegron treatment may experience hypertension [22]. Furthermore, there have been reports of an increase in the QTc interval [23]. In accordance with the results of this study, the ROR for blood pressure increased as 14.72 (12.61–17.18), with an IC of 3.84 (2.17). The ROR for hypertension as 5.93 (4.96–7.11), with an IC of 2.54 (0.88). For electrocardiogram QT prolonged, the ROR was 4.26 (2.94–6.18) with an IC of 2.08 (0.42). The ROR for atrial fibrillation was 7.44 (6.04–9.15) with an IC of 2.87 (1.21). Arrhythmia had an ROR of 16.23 (13.06–20.17) with an IC of 3.99 (2.33). The ROR for palpitations was 6.74 (5.29–8.6) with an IC of 2.74 (1.07), and for tachycardia, the ROR was 4.19 (3.2–5.5) with an IC of 2.06 (0.39). As mirabegron is a β3-adrenergic receptor agonist, and β3-adrenergic receptors are also expressed in cardiovascular tissues, the use of mirabegron may have "off-target" effects on the regulation of the cardiovascular system [21]. This could be the potential pharmacological mechanism by which mirabegron induces cardiovascular-related AEs. β3-adrenergic receptors can increase the occurrence of arrhythmias and the risk of atrial fibrillation by activating the cAMP-dependent protein kinase pathway and inducing Ca2 + imbalance [20]. Additionally, the β1-adrenergic receptors expressed in cardiovascular tissues were also target sites for the action of mirabegron [24]. An animal study found that the heart rate effects of mirabegron in dogs were attributed to cross-reactivity with β1-adrenergic receptors [25]. This was further confirmed by a clinical study [24]. Regardless of whether it involved the stimulation of β1-adrenergic receptors in cardiovascular tissues or β3-adrenergic receptors, the administration of supratherapeutic dosages that led to significant multiples of peak plasma concentrations was more prone to causing increases in heart rate, elevated blood pressure, and prolonged QT intervals [24, 26]. Although a treatment dose of 50 mg mirabegron could lead to an increase in baseline pulse rate by one beat per minute [27], the impact was not significant. Furthermore, mirabegron is extensively metabolized by the liver and excreted in urine, either as the parent drug or its metabolites [28]. Therefore, in clinical practice, it is not only important to pay attention to the safe dosage of mirabegron but also to monitor the liver and kidney functions of patients, avoiding excessively high blood drug concentrations that may lead to cardiovascular-related AEs. For patients experiencing cardiovascular-related AEs after using mirabegron, it is recommended to undergo blood drug concentration monitoring. Furthermore, this study also identified some unexpected yet clinically significant safety signals, such as angina pectoris, extrasystoles, and cardiac fibrillation. Although the reported cases of these cardiovascular AEs are limited, they should not be overlooked, as they may have potentially life-threatening implications for patients.
Evidence indicated that mirabegron could cause the AE of headache [29]. In our study, we also identified head discomfort as a significant AE associated with mirabegron, with a signal strength of ROR 3.41 (1.28–9.08) and IC 1.77 (0.1). Additionally, in our results, dementia, transient ischemic attack, Parkinson's Disease, and myasthenia gravis emerged as new significant AEs associated with mirabegron. In a previous clinical study, 23,662 patients with OAB using mirabegron were found to have 603 new cases of dementia [30]. While the reported case numbers are limited, healthcare professionals should not overlook these findings, as mirabegron may potentially cause central nervous system side effects. In the striatum of both rats and humans, the presence of β-3 adrenergic receptor mRNA has been confirmed [31]. Activation of these receptors by mirabegron decreases acetylcholine release from striatal neurons [32]. Acetylcholine deficiency in the brain is linked not only to Alzheimer's disease, vascular dementia, and Lewy body dementia but also to movement disorders [32–35]. Furthermore, β3-adrenergic receptor agonists promote the synthesis and release of serotonin (5-HT) in the striatum of the brain, which may also be an important mechanism [32]. In this study, we identified transient ischemic attack as an AE with significant signal strength, which was not previously listed in the drug label or observed in earlier clinical studies. As of now, the mechanism by which mirabegron induces transient ischemic attack remains unclear. Transient ischemic attack can be caused by various factors, including atherosclerosis, cardiac-related factors, arterial inflammation, and others. Atrial fibrillation was a known risk factor for transient ischemic attack [36]. Therefore, transient ischemic attack may also be associated with mirabegron-related AEs such as atrial fibrillation. The neurologic adverse events caused by mirabegron were unexpected for clinicians, and if not promptly identified, they could potentially result in irreversible damage to the nervous system.
Some other new and unexpected adverse events, including lip swelling, swollen tongue, mouth swelling, peptic ulcer, ischemic colitis, eyelid edema, glaucoma, and retinal vein occlusion, were also identified in this study. Matthew et al [6] reported a case of a patient who experienced tongue swelling, accompanied by difficulty breathing and swallowing, after using mirabegron. In this report, swelling was also observed in areas such as the lips, oral cavity, and eyelids. The mechanism of mirabegron-induced edema is believed to be a type I hypersensitivity reaction mediated by mast cell degranulation [6].
It is noteworthy that both "anti-neutrophil cytoplasmic antibody increased" and "anti-neutrophil cytoplasmic antibody positive vasculitis" exhibited strong positive signals in both the ROR and IC methods. Anti-neutrophil cytoplasmic antibody positive vasculitis is a group of potentially life-threatening autoimmune diseases [37, 38]. Although the exact etiology remains incompletely understood, research indicated that drugs are significant contributors to the development of this condition [39]. Based on previous research findings, the drugs that induced anti-neutrophil cytoplasmic antibody positive vasculitis belonged to various pharmacological categories [39]. These primarily included anti-thyroid drugs, tumor necrosis factor inhibitors, anti-tuberculosis drugs, psychoactive agents, and others [39]. To the best of our knowledge, this study was the first to report the potential induction of anti-neutrophil cytoplasmic antibody positive vasculitis by mirabegron. The finding of this study warrant careful attention from clinicians. Close monitoring of ANCA levels in patients undergoing mirabegron treatment is essential, as it serves as an effective tool for the early diagnosis of drug-induced anti-neutrophil cytoplasmic antibody positive vasculitis. Upon confirmation, immediate discontinuation of the drug is imperative, as most patients experience relief after ceasing the use of this harmful medication [39].
The study findings revealed a median onset time of 25 days, with most AEs happening within the initial 30 days following exposure to mirabegron (n = 358, 55.68%). However, AEs could still occur even a year later. Therefore, clinicians needed to closely follow up with patients using mirabegron, especially within the first 30 days. In future clinical studies, longer follow-up periods were necessary to observe mirabegron-related AEs.
Several limitations in this study need to be addressed. Firstly, the FAERs database is a spontaneous reporting database, and the quality is not rigorously controlled. Although our analysis included reports provided only by healthcare professionals to ensure the reliability of the reporting sources, it inevitably reduced the sample size. Additionally, the occurrence rates of each AE related to mirabegron could not be estimated. Secondly, the presence of reports in the FAERS database does not establish a causal relationship, requiring further well-designed clinical trials to investigate causation. Ultimately, certain confounding factors not measured in the study, such as possible interactions between medications, existing medical conditions, and combinations of drugs, were excluded from the analysis. Despite these limitations, FAERs remains valuable for post-marketing safety surveillance.