key: cord-256402-b5fel2d3
authors: Gevers, S.; Kwa, M.S.G.; Wijnans, E.; van Nieuwkoop, C.
title: Safety considerations of chloroquine and hydroxychloroquine in treatment of COVID-19
date: 2020-05-16
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2020.05.006
sha: 
doc_id: 256402
cord_uid: b5fel2d3

Chloroquine and hydroxychloroquine are both used to treat COVID-19. Safety data in this specific population is largely unknown. In particular, cardiologic, gastro-intestinal and neuropsychiatric side-effects of (hydroxychloroquine) needs special attention in COVID-19 patients.

To the Editor: Based on a demonstrated in vitro effect on SARS-CoV-2 and its known safety profile, both chloroquine and hydroxychloroquine (CQ/HCQ) are currently being used off label to treat COVID-19 [1] . However, though safety of CQ/HCQ is well established in malaria or auto-immune disease, COVID-19 patients could be more vulnerable to side-effects because of their advanced age, co-morbidities such as diabetes, obesity and cardiovascular disease, and subsequent co-medication [2] . Both agents are metabolized via the liver and the kidney. Critically ill patients may have an altered metabolism due to changes in the hepatic and renal function, which could increase the risk of adverse reactions. Additionally, there may be interactions with co-medication normally not taken together with CQ/HCQ. Both drugs have long half-lives (approximately 1-2 months) and distribute poorly in fat tissue [3] . Therefore, long-term monitoring for adverse reactions is recommended.

Importantly, CQ/HCQ have narrow therapeutic ranges and toxic effects are related closely to the ingested dose. An one-time dose of 20 mg/kg CQ has been described to be toxic and doses of 30 mg/kg CQ have resulted in case fatalities [4] . Apart from the general safety profile of CQ/HCQ, there are adverse reactions that may interfere with the clinical picture of COVID-19 due to the similarity with symptoms of illness. In particular, this holds for cardiovascular, neuropsychiatric and gastrointestinal adverse drug reactions. Table 1 illustrates the five most commonly reported suspected adverse drug reactions in these system organ classes, as reported to the global pharmacovigilance database of the WHO (VigiAccessTM) [5] . This global database provides insight in spontaneous postmarketing case safety reports on suspected adverse reactions. The data should be interpreted with caution as the number of reports may be influenced by many different factors, including patients' baseline characteristics, extent of exposure and nature of adverse reactions. Reported cardiac side effects of CQ/HCQ include conduction disturbances (bundle-branch block, incomplete or complete atrioventricular block, QT-prolongation and subsequent torsade de pointes) and cardiomyopathy (hypertrophy and congestive heart failure). Due to their systemic infection and comorbidities, COVID-19 patients appear to have an higher risk of cardiac arrhythmia, QT-prolongation and myocardial damage a priori [6] . This could result in cardiotoxicity of CQ/HCQ being of particular importance, especially when given in combination with other QT prolonging agents like azithromycin [7] .

Neurologic and psychiatric side effects have also been reported following CQ/HCQ treatment.

Neurologic side effects include muscular weakness, diplopia, dyskinesia, seizures, myasthenic syndrome, and with long-term use neuromyopathy. Psychiatric side effects include sleeplessness, agitation, psychosis, depression, anxiety, aggressiveness and confusion; with psychiatric side effects starting within a few days after beginning of treatment and improving after cessation of treatment.

COVID-19 patients suffer from dyspnea, which may in turn lead to anxiety and sleeplessness, symptoms that may be aggravated by potential psychiatric side effects of CQ/HCQ. Finally, gastrointestinal symptoms (nausea and diarrhoea) have been reported and are the presenting complaint in some. In 393 patients admitted to two hospitals in New York, diarrhoea and nausea or vomiting were reported in 23.7% and 19.1% of patients, respectively. To these patients, treatment with drugs having potential gastrointestinal side effects could be problematic. [2] In conclusion, it is likely that some of the commonly reported adverse effects of CQ/HCQ will hamper successful treatment of patients suffering from COVID-19. Thus, until adequately powered randomized controlled trials (RCTs) provide more information on the efficacy and the safety of CQ/HCQ use in treatment of patients with COVID-19, it is very important that the potential benefits of these agents will be weighed against the potential risks. Furthermore, clinical trials should also evaluate the long-term (e.g. 3-6 months post-therapy) (side)-effects of COVID-19 and the use of CQ/HCQ, such as cardiomyopathy, muscle weakness, anxiety, sleeplessness and gastro-intestinal disorders. Preferably, until data from RCTs will become available, the off-label use of CQ/HCQ should only be reserved for COVID-19 patients treated in context of clinical trials in order to improve our knowledge on safety and efficacy. Funding: No external funding was received.

The text was written by SG, EW and CN. MK collected and added the pharmacovigilance data. All authors reviewed and revised the manuscript.

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