Advice for healthcare professionals:
- an observational study has shown that co-administration of azithromycin with hydroxychloroquine in patients with rheumatoid arthritis is associated with an increased risk of cardiovascular events (including angina or chest pain and heart failure) and cardiovascular mortality
- carefully consider the benefits and risks before prescribing systemic azithromycin or other systemic macrolide antibiotics (erythromycin or clarithromycin) to patients treated with hydroxychloroquine or chloroquine
- if there is a clinical need to prescribe systemic macrolide antibiotics with hydroxychloroquine or chloroquine, use caution in patients with risk factors for cardiac events and follow guidance in the product information for each drug
- be vigilant for psychiatric reactions linked to hydroxychloroquine or chloroquine, especially during the first month of treatment; events have been reported in patients with no history of psychiatric disorders
- report suspected adverse drug reactions to a yellow card
Advice for healthcare professionals to give to patients and carers:
- certain antibiotics (called macrolides) taken by mouth or given by injection at the same time as hydroxychloroquine or chloroquine have been linked to an increased risk of side effects affecting the heart
- seek emergency medical help if you have signs of heart problems (for example, palpitations, fainting, chest pain, or unexplained shortness of breath)
- some patients have also reported mental health symptoms when they started treatment with hydroxychloroquine or chloroquine
- tell your doctor as soon as possible if you or your family members or caregivers notice new or worsening mental health symptoms
- read the patient information leaflet that comes with your medicine (hydroxychloroquine Where chloroquine) and keep it handy in case you need to read it again
Indications for Hydroxychloroquine and Chloroquine
Hydroxychloroquine is indicated for the treatment of rheumatoid arthritis, systemic lupus erythematosus, and sun-aggravated skin conditions. Chloroquine is indicated for the prophylaxis or treatment of malaria, with some products also having indications for the treatment of hepatitis and amoebic abscesses, rheumatoid arthritis and discoid or systemic lupus erythematosus.
Review of cardiovascular safety after observational trial
A observational retrospective study published in August 2020 compared adverse event records in patients initiated on hydroxychloroquine alone with those of patients initiated on sulfasalazine alone for rheumatoid arthritis. The same study compared serious adverse events associated with the use of hydroxychloroquine plus azithromycin with those associated with the use of hydroxychloroquine plus amoxicillin.
The study showed that in the short term (up to 30 days) after the first use of treatment with hydroxychloroquine in combination with azithromycin, there was an increased risk of angina or chest pain, heart failure and cardiovascular mortality compared to the combination of hydroxychloroquine and amoxicillin.
No excess risk of serious adverse events has been identified in the short-term period of hydroxychloroquine alone (compared to sulfasalazine), but longer-term use beyond 30 days has been associated with increased cardiovascular mortality.
Although the mechanism of the observed effects was not examined in detail by the study, it was proposed that the events could be caused by cumulative effects of hydroxychloroquine and azithromycin on the QT interval, potentiating arrhythmias and cardiac death, or by other additive cardiotoxic effects more generally.
A national review of safety data by the Pharmacovigilance Expert Advisory Group of the Commission for Medicinal Products for Human Use examined these data. We have published a public evaluation report of this evaluation.
The review recommended that the product information for hydroxychloroquine and systemic azithromycin medicines be amended to include new warnings and advice about these risks. Due to similar safety profiles, the risks observed with the concomitant use of hydroxychloroquine and azithromycin are considered to apply to the concomitant use of hydroxychloroquine and other systemic macrolide antibiotics (clarithromycin or erythromycin) and the use of chloroquine with systemic macrolide antibiotics. As such, the review recommended that similar warnings also be added to the product information for chloroquine and for systemic clarithromycin or erythromycin.
These warnings are not introduced for topical macrolide products (which are indicated for conjunctivitis or acne), as these products are used at lower doses and with very limited potential for systemic exposure, and do not list the cardiovascular events as potential adverse effects associated with their use.
Reminder of existing cardiac warnings
Product information for hydroxychloroquine and chloroquine already contains warnings about cases of cardiomyopathy leading to heart failure, sometimes fatal. Clinical monitoring for signs and symptoms of cardiomyopathy is advised for patients taking hydroxychloroquine or chloroquine long-term. If signs and symptoms of cardiomyopathy appear during treatment with hydroxychloroquine or chloroquine, treatment should be discontinued.
Evidence suggests that hydroxychloroquine and chloroquine can prolong the QT interval, particularly in overdose or when used in combination with other drugs that can induce cardiac arrhythmias. Warnings are also in place in the product information for azithromycin, clarithromycinand erythromycin to be used with caution in patients with a history of QT prolongation or in patients receiving a drug known to cause QT prolongation.
Characteristics of psychiatric reactions
Hydroxychloroquine and chloroquine have been linked to psychiatric reactions in the past, including cases of depression, anxiety, hallucinations and psychosis.
In November 2020, a European Safety Review recommended updates to warnings for hydroxychloroquine and chloroquine drugs to include a range of reported psychiatric reactions, including rare cases of suicidal behavior. The review noted that when psychiatric events did occur, they generally occurred within the first month of treatment. Events have been reported in patients with no history of psychiatric disorders.
Information on these reactions has been added to the summary of product characteristics and patient information leaflets for hydroxychloroquine and chloroquine.
Advise patients taking hydroxychloroquine or chloroquine medications to contact a doctor immediately if they experience new or worsening mental health problems (such as irrational thoughts, anxiety, hallucinations and feeling confused or depressed, including thoughts of harming or killing yourself). Family members or caregivers may also be advised to be alert to these reactions and the need to seek medical attention if they occur.
Context of clinical studies
This article concerns the regulatory measures taken on the basis of the safety data of the use of these medicinal products in their authorized indications. Other safety studies of hydroxychloroquine alone or combined with azithromycin have been conducted in the treatment of COVID-19. Hydroxychloroquine and chloroquine are not authorized to treat symptoms related to COVID-19 or to prevent infection. MHRA advice since March 2020 is that these products should only be used for COVID-19 in a clinical trial. However, there are currently no ongoing clinical trials in this indication, as enrollment in the hydroxychloroquine arm of the RECOVERY trial was suspended after results showed no benefit of hydroxychloroquine in hospitalized patients. for COVID-19.
Report suspicious reactions on a yellow card
Please continue to report suspected adverse drug reactions to Yellow card scheme.
Healthcare professionals, patients and carers are encouraged to submit reports using the yellow card system electronically using:
When reporting, please provide as much information as possible, including information on lot numbers, medical history, any concurrent medications, onset, dates of treatment, and product brand name.
Report suspected adverse reactions to drugs, vaccines, medical devices and test kits used in the testing and treatment of coronavirus (COVID-19) using the website dedicated to reporting Coronavirus Yellow Cards or the Yellow Card app. Check the MHRA website for the latest information on COVID-19 medicines and vaccines.
Article citation: Drug Safety Update Volume 15, Issue 7: February 2022: 2.