Adverse Effects of Hydroxychloroquine, Chloroquine, and Azithromycin

David Juurlink, MD

Physicians and patients must be aware of the potentially serious adverse events related to chloroquine, hydroxychloroquine, and azithromycin for those with coronavirus disease 2019 (COVID-19), according to a recent review.

David Juurlink, MD, and a team of investigators provided an overview of potential harms associated with the drugs being used for COVID-19 patients, as well as their management based on the best available evidence. The team found that potential adverse effects included cardiac arrhythmias, hypoglycemia, and neuropsychiatric effects.

Juurlink, from the Division of Clinical Pharmacology and Toxicology at Sunnybrook Health Sciences Center, and colleagues determined that additional risks of treatment included the prolongation of the QTc interval—especially in patients with preexisting cardiac disease or if co-prescribed with azithromycin—interactions with other drugs, metabolic variability, overdose, and drug shortages.

“Despite optimism (in some, even enthusiasm) for the potential of chloroquine or hydroxychloroquine in the treatment of COVID-19, little consideration has been given to the possibility that the drugs might negatively influence the course of disease,” Juurlink said in a statement. “This is why we need a better evidence base before routinely using these drugs to treat patients with COVID-19.”

Chloroquine and hydroxychloroquine interfere with ventricular repolarization, which could lead to prolongation of the QTc interval and an increased risk of torsades de pointes. The effect is dependent on dose, but the effect varies among individuals and can be pronounced. Although azithromycin itself does not usually cause clinically significant prolongation of the interval, its use in combination with chloroquine or hydroxychloroquine could increase the risk of torsades de pointes.

The drugs also cause a wide spectrum of neuropsychiatric manifestations, including agitation, insomnia, confusion, mania, hallucinations, paranoia, depression, catatonia, psychosis, and suicidal ideation. Stopping the drug could lead to resolution, but symptoms may not quickly resolve.

Hydroxychloroquine and chloroquine are also substrates for CYP2D6 and also inhibit its activity. That could influence the fate of other drugs reliant on CYP2D6 for metabolism. The investigators suggested it was reasonable to assume that despite limited data, chloroquine and hydroxychloroquine potentiate other substrates and undermine the effectiveness of prodrugs reliant on CYP2D6 for activation, like codeine and tramadol.

What’s more, it is possible that chloroquine and hydroxychloroquine could precipitate opioid withdrawal in patients who take the drugs regularly.

The use of chloroquine or hydroxychloroquine and azithromycin to treat or prevent COVID-198 is supported primarily by weak human studies. Because of that, physicians and patients must be aware of uncommon and potentially life-threatening adverse effects of the drugs.

The possibility that the drugs could adversely influence outcomes leads to an urgent need for high-quality randomized controlled trials, the investigators suggested. Better-designed trials can help determine the benefit, if any, in treating or preventing coronavirus.

The review, “Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection,” was published online in Canadian Medical Association Journal.