Hydroxychloroquine, chloroquine: increased risk of cardiovascular events when used with macrolide antibiotics; reminder of psychiatric reactions
Carefully consider the benefits and risks before prescribing systemic azithromycin or other systemic macrolide antibiotics (erythromycin or clarithromycin) to patients being treated with hydroxychloroquine or chloroquine. An observational study in patients with rheumatoid arthritis has shown that co-administration of azithromycin with hydroxychloroquine is associated with an increased risk of cardiovascular events and cardiovascular mortality.
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 being 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 advice in the product information for each medicine
- be vigilant for psychiatric reactions associated with hydroxychloroquine or chloroquine, especially in the first month of treatment; events have been reported in patients with no prior history of psychiatric disorders
- report suspected adverse drug reactions on a Yellow Card
Advice for healthcare professionals to give to patients and carers:
- some antibiotics (known as macrolides) taken by mouth or given as an injection at the same time as hydroxychloroquine or chloroquine have been associated with an increased risk of side effects that affect the heart
- seek urgent medical help if you have any signs of problems with your heart (for example, palpitations, fainting, chest pain, or unexplained breathlessness)
- some patients have also reported mental health symptoms when they started treatment with hydroxychloroquine or chloroquine
- speak to your doctor as soon as possible if you or your family members or caregivers notice any new or worsening mental health symptoms
- read the patient information leaflet that comes with your medicine (hydroxychloroquine or chloroquine) and keep it handy in case you need to read it again
Hydroxychloroquine and chloroquine indications
Hydroxychloroquine is indicated for treatment of rheumatoid arthritis, systemic lupus erythematosus, and dermatological conditions aggravated by sunlight. Chloroquine is indicated for malaria prophylaxis or treatment, with some products also having indications for treatment of amoebic hepatitis and abscess, rheumatoid arthritis, and discoid or systemic lupus erythematosus.
Review of cardiovascular safety after observational trial
An observational retrospective study[footnote 1] published in August 2020 compared records of adverse events in patients initiated on hydroxychloroquine alone with those in patients initiated on sulfasalazine alone for rheumatoid arthritis. The same study compared severe adverse events associated with use of hydroxychloroquine plus azithromycin with those associated with use of hydroxychloroquine plus amoxicillin.
The study showed that in a short-term period (up to 30 days) after first use of hydroxychloroquine treatment in combination with azithromycin there was an increased risk of angina or chest pain, heart failure, and cardiovascular mortality compared with the combination of hydroxychloroquine and amoxicillin.
No excess risk of severe adverse events was identified in the short-term period of hydroxychloroquine alone (compared with sulfasalazine), but longer-term use past 30 days was associated with increased cardiovascular mortality.
Although the mechanism of the observed effects was not examined in detail by the study, it has been proposed that events could be caused by cumulative effects of hydroxychloroquine and azithromycin on the QT interval, potentiating arrhythmias and cardiac death, or through other additive cardiotoxic effects more generally.
A national review of safety data by the Pharmacovigilance Expert Advisory Group of the Commission on Human Medicines considered these data. We have published a Public Assessment Report of this assessment.
The review recommended that the product information for hydroxychloroquine and systemic azithromycin medicines should be amended to include new warnings and advice on these risks. Due to the similar safety profiles, the risks seen with concurrent use of hydroxychloroquine and azithromycin are considered to apply to concurrent use of hydroxychloroquine and other systemic macrolide antibiotics (clarithromycin or erythromycin) and to use of chloroquine with systemic macrolide antibiotics. As such, the review recommended that similar warnings should also be added to the product information for chloroquine and for systemic clarithromycin or erythromycin.
These warnings are not being 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 cardiovascular events as potential adverse effects associated with their use.
Reminder of existing cardiac warnings
The product information for hydroxychloroquine and chloroquine already contains warnings about cases of cardiomyopathy resulting in cardiac failure, in some cases with fatal outcome. Clinical monitoring for signs and symptoms of cardiomyopathy is advised for patients taking hydroxychloroquine or long-term chloroquine. If signs and symptoms of cardiomyopathy occur during treatment with either hydroxychloroquine or chloroquine, then treatment should be stopped.
Evidence suggests both hydroxychloroquine and chloroquine can prolong the QT interval, especially in overdose or when used in combination with other medicines with the potential to induce cardiac arrhythmias. Warnings are also in place across the product information for azithromycin, clarithromycin, and erythromycin to use caution in patients with a history of QT interval prolongation or in patients receiving a medicine known to cause QT prolongation.
Characteristics of psychiatric reactions
Hydroxychloroquine and chloroquine have been previously associated with psychiatric reactions, including reports of depression, anxiety, hallucinations, and psychosis.
In November 2020, a European safety review recommended updates to the warnings for hydroxychloroquine and chloroquine medicines to include a range of reported psychiatric reactions, including rare cases of suicidal behaviour. The review noted that when psychiatric events occurred, they were typically within the first month of treatment. Events have been reported in patients with no previous history of psychiatric disorders.
Information about these reactions have been added to the Summary of Product Characteristics and Patient Information Leaflets for hydroxychloroquine and chloroquine.
Advise patients taking hydroxychloroquine or chloroquine medicines to contact a doctor immediately if they experience new or worsening mental health problems (such as irrational thoughts, anxiety, hallucinations, and feeling confused or feeling depressed, including thoughts of self-harm or suicide). Family members or caregivers may also be advised to be vigilant for these reactions and the need to seek medical advice if they occur.
Context of clinical studies
This article concerns regulatory action taken based on safety data from the use of these medicines in their authorised indications. Other safety studies on hydroxychloroquine alone or with azithromycin have been conducted in the context of COVID-19 treatment. Hydroxychloroquine and chloroquine are not authorised 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 within a clinical trial. However, there are currently no ongoing clinical trials in this indication, since recruitment to the hydroxychloroquine arm of the RECOVERY trial was suspended after results showed no benefit of hydroxychloroquine in patients hospitalised with COVID-19.
Report suspected reactions on a Yellow Card
Please continue to report suspected adverse drug reactions to the Yellow Card scheme.
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 batch numbers, medical history, any concomitant medication, onset, treatment dates, and product brand name.
Report suspected side effects to medicines, vaccines, medical device and test kit incidents used in coronavirus (COVID-19) testing and treatment using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app. See the MHRA website for the latest information on medicines and vaccines for COVID-19.
Article citation: Drug Safety Update volume 15, issue 7: February 2022: 2.
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Lane JCE and others. Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study. Lancet Rheumatol 2020: volume 2, pages e698-e711. ↩