Erythromycin: caution required due to cardiac risks (QT interval prolongation); drug interaction with rivaroxaban
Erythromycin has been associated with events secondary to QT interval prolongation such as cardiac arrest and ventricular fibrillation. Erythromycin should not be given to patients with a history of QT interval prolongation or ventricular cardiac arrhythmia, including torsades de pointes, or patients with electrolyte disturbances. A potential drug interaction between rivaroxaban and erythromycin resulting in increased risk of bleeding has also been identified.
Post-publication note: March 2022
In February 2022, we published advice on the increased risk of cardiovascular events when systemic macrolide antibiotics are used concurrently with hydroxychloroquine or chloroquine. See Drug Safety Update February 2022 for more information.
Advice for healthcare professionals:
- be aware of reports of cardiotoxicity (QT interval prolongation) with macrolide antibiotics, in particular with erythromycin and clarithromycin
- erythromycin should not be given to patients with:
- a history of QT interval prolongation (congenital or documented acquired QT interval prolongation) or ventricular cardiac arrhythmia, including torsades de pointes
- electrolyte disturbances (hypokalaemia or hypomagnesaemia due to the risk of arrhythmia associated with QT interval prolongation)
- consider the potential benefit of treatment against the cardiac risks when prescribing in patients at increased risk of a cardiac event; patients in whom caution is needed are those with:
- cardiac disease or heart failure
- conduction disturbances or clinically relevant bradycardia
- those concomitantly taking other medicines associated with QT interval prolongation
- direct patients to the patient information leaflet and remind at-risk patients of the importance of seeking medical attention if they develop signs or symptoms of a cardiac event
- erythromycin is widely used in children, some of whom may have QT interval prolongation; therefore, consider the child’s medical history and balance the treatment benefits against the potential risks
- erythromycin may interact with rivaroxaban and increase the risk of bleeding – consider this interaction when prescribing antibiotics and follow precautions in the product information if concomitant use is necessary
- report suspected adverse drug reactions (ADRs) associated with erythromycin to the Yellow Card scheme
Strengthened warnings for cardiac risks
A European review of safety data has highlighted an increased risk of cardiotoxicity with macrolide antibiotics, particularly erythromycin. Both adverse drug reaction data and the published literature report increased short-term risks of adverse cardiac outcomes associated with erythromycin. On the basis of these data, the product information for erythromycin will be updated in line with that for clarithromycin to include warnings regarding the risk of QT interval prolongation and fatal arrhythmia.
A new contraindication has been added for those with risk factors for QT interval prolongation and arrhythmia, including for patients with a history of QT interval prolongation or ventricular arrhythmia and patients with electrolyte disturbances. Warnings have also been strengthened on the risk of cardiac events and risk factors. Cardiac arrest and ventricular fibrillation have been added as potential reactions of unknown frequency; however, given the widespread usage they appear to have been reported very infrequently.
Cardiotoxic effects are recognised with other macrolide antibiotics. Clinicians should be aware of the increased short-term risk of adverse cardiac outcomes, so that the benefits and risks of treatment can be fully evaluated at the time of treatment initiation in each patient, particularly those at high risk of cardiac events.
This balance of treatment benefits versus the potential risks should be especially considered in patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances, or clinically relevant bradycardia. Caution should be exercised in patients concomitantly taking other medicinal products associated with QT interval prolongation, and in patients who are elderly since these groups may be more susceptible to drug-associated effects on the QT interval.
Erythromycin is widely used in children, some of who may have QT interval prolongation. We advise healthcare professionals to consider the child’s medical history to identify those at risk and to consider the possible risks against the treatment benefits when prescribing erythromycin.
Patients should be informed of the signs and symptoms of cardiac events and be advised to seek medical advice should they occur. Warnings on the signs and symptoms of cardiac events have been added to the patient information leaflet.
Rivaroxaban drug interaction
The European review also concluded that rivaroxaban should be included as an example of a potential interaction between erythromycin and oral anticoagulants in the product information since this interaction could lead to increased risk of bleeding. This interaction is already included in the product information for rivaroxaban (Xarelto).
Erythromycin and clarithromycin inhibit CYP3A4 and P-gp and can lead to an increase in the maximum blood concentration of rivaroxaban. The product information for rivaroxaban advises that the interaction with erythromycin can lead to potential increased bleeding risk in high-risk patients, especially in those with mild or moderate renal impairment.
Rivaroxaban is not the only direct-acting oral anticoagulant (DOAC) to interact with macrolides such as erythromycin. For edoxaban, the product information recommends a reduced dose of 30mg a day for patients on concomitant erythromycin. For dabigatran and apixaban the product information states that concomitant administration of P-gp inhibitors (and for apixaban, also CYP3A4 inhibitors) is expected to result in increased plasma concentrations and that blood concentrations were raised when used concomitantly with another macrolide, clarithromycin.
All patients prescribed DOACs, including those also on macrolides, should be informed of the signs and symptoms of bleeding and be advised to seek medical advice should they occur (see Drug Safety Update from June 2020). Follow guidance on dosing of DOACs in patients with renal impairment and monitor renal function during treatment to ensure dose remains appropriate.
About erythromycin
Erythromycin is a macrolide antibiotic that is active against gram-positive cocci and gram-positive bacilli, some gram-negative cocci, and some gram-negative bacilli. It is widely used to treat chest infections such as pneumonia, skin problems, and sexually transmitted diseases. It is used in children, often to treat ear or chest infections. Erythromycin is licensed for use in both adults and children (including infants and babies).
As for all antibiotic medicines, consideration should be given to official guidance on the appropriate use of antimicrobial agents.
Report suspected reactions on a Yellow Card
Please continue to report suspected adverse drug reactions (ADRs) to the Yellow Card Scheme. Reporting suspected ADRs, even those known to occur, adds to knowledge about the frequency and severity of these reactions and can be used to identify patients who are most at risk. Your report helps the safer use of medicines.
Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:
- the Yellow Card website
- the Yellow Card app; download from the Apple App Store or Google Play Store
- some clinical IT systems for healthcare professionals (EMIS, SystmOne, Vision, MiDatabank, and Ulysses)
When reporting please provide as much information as possible, including information about medical history, any concomitant medication, onset, treatment dates, and product brand name.
Article citation: Drug Safety Update volume 14, issue 5: December 2020: 2.