Health Sciences Authority (HSA) informs healthcare professionals about a small increased risk of heart valve regurgitation associated with the use of systemic fluoroquinolones. Fluoroquinolones are known to increase the risk of collagen-related disorders such as tendonitis, tendon rupture, and aortic aneurysm and dissection. Recently, these antibiotics have been found to be associated with regurgitation of the heart valves, another collagen-associated adverse event.
Heart valve regurgitation occurs when there is backflow of blood through the valve as the leaflets are closing or when there is leakage of blood through the leaflets that do not close completely. This subjects the heart to higher levels of stress and may lead to other morbidities or mortality if the condition is left untreated. Severe forms of aortic and mitral regurgitation can be life-threatening and may require surgical intervention. Causes of valvular regurgitation include degeneration, calcification, fibrosis or infection of the valve, or alteration of the valvular support structure.
Fluoroquinolones have been associated with collagen-related disorders such as tendonitis, tendon rupture, and aortic aneurysm and dissection. While the mechanism behind these disorders has not been fully elucidated, in vitro studies have showed that fluoroquinolones exert various effects on different cell types, including reduced expression of extracellular matrix (ECM) proteins, upregulation of matrix metalloproteinase (MMP) expression, and inhibition of tendon cell proliferation. It has been hypothesised that fluoroquinolone-induced collagen-related disorders may be due to increased MMP expression, resulting in damage to the collagen fibrils that are found in the Achilles tendon, aorta and heart valves.
In a recently published in vitro study, human aortic myofibroblasts were exposed to ciprofloxacin to assess the capacity for ECM dysregulation. The authors found that fluoroquinolone (ciprofloxacin) exposure resulted in decreased tissue inhibitors of matrix metalloproteinase (TIMP) expression and an increase in the MMP/TIMP ratio, as well as an attenuation of collagen-1 expression. These findings suggested that fluoroquinolone exposure induces human aortic myofibroblast-mediated ECM dysregulation through increased collagen degradation and impaired compensatory collagen deposition, which is in agreement with data from earlier studies.
Etminan et al. investigated the potential risk of heart valve regurgitation with fluoroquinolones, drawing from two sources of data to conduct a disproportionality analysis and case-control study. The disproportionality analysis, which used data from the United States Food and Drug Administration (FDA) adverse event reporting system (FAERS) database between 2004 and 2018, found an increased risk of valvular regurgitation with fluoroquinolone exposure (102 cases) compared to all other drugs in the database (6,099 cases), with a reported odds ratio (ROR) of 1.45 (95% CI: 1.20 – 1.77). Although a reduced risk was observed for moxifloxacin, the confidence interval was too wide to allow a meaningful interpretation of the data. To further confirm the findings from their disproportionality analysis, the authors conducted a matched nested case-control study that included 12,502 cases of valvular regurgitation and 125,020 controls from a United States health claims database between 2006 to 2016. The study found that current users of fluoroquinolones had a 2.4-fold and 1.75-fold increase in risk of combined aortic and mitral valve regurgitation compared to current amoxicillin and azithromycin users, respectively. This risk remained elevated (albeit of a lower magnitude) for recent and past fluoroquinolone users. The authors added that their choice of comparator antibiotics was due to their overlapping indications (e.g. urinary tract infections and respiratory infections), which served to control for confounding by indication.
To date, HSA has not received any local reports of heart valve-related disorders associated with fluoroquinolone use.
HSA has reviewed the available information, taking into account the scientific literature, the biological plausibility of collagen-related disorders with fluoroquinolones, and the regulatory actions taken by European Medicines Agency (EMA) and the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA). HSA’s assessment is that the existing warnings on aortic aneurysm and dissection should be expanded to include heart valve regurgitation as these safety issues are likely related, and is working with the pharmaceutical companies to strengthen the local package inserts for all systemic fluoroquinolones to reflect this risk.
Healthcare professionals are advised to take into consideration the above safety information when prescribing systemic fluoroquinolones and the availability of other therapeutic options for patients with pre-existing risk factors such as heart valve diseases, or predisposing conditions such as connective tissue disorders (e.g., Marfan syndrome, Ehlers-Danlos syndrome), Turner syndrome, Behçet´s disease, hypertension, rheumatoid arthritis, and infective endocarditis. Healthcare professionals are also encouraged to advise patients to seek medical attention if they experience acute dyspnoea, new onset of heart palpitations, or development of oedema, especially if they have started the fluoroquinolone therapy recently.
Please refer to the following website in HSA for details:
http://www.hsa.gov.sg/announcements/safety-alert/risk-of-heart-valve-regurgitation-with-fluoroquinolones
In Hong Kong, there are registered pharmaceutical products containing systemic fluoroquinolones for use in human, including ciprofloxacin (67 products), levofloxacin (53 products), moxifloxacin (7 products), norfloxacin (3 products), ofloxacin (21 products) and prulifloxacin (1 product). All products are prescription-only medicines. So far, the Department of Health (DH) has received 9 cases of adverse drug reaction related to levofloxacin and 1 case related to moxifloxacin, but these cases are not related to heart valve regurgitation.
Related news was previously issued by Taiwan Food and Drug Administration (TFDA) and the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA), and was posted on the Drug Office website on 4 Dec 2020 and 18 Dec 2020. Letters to inform local healthcare professionals were issued by the DH on 4 Dec 2020. As previously reported, the matter will be discussed by the Registration Committee of the Pharmacy and Poisons Board.
Ends/Thursday, May 13, 2021
Issued at HKT 17:00
|
