Toxicity of chloroquine and hydroxychloroquine following therapeutic use or overdose

Abstract

Introduction: While chloroquine, a derivative of quinine, has been used as an antimalarial for 70 years, hydroxychloroquine is now used to treat conditions such as rheumatoid arthritis and systemic lupus erythematosus. In 2020, hydroxychloroquine (and to a lesser extent chloroquine) also received attention as a possible treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). During investigation for treating coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, concerns for serious adverse events arose. Objective: We review the toxicity associated with hydroxychloroquine and chloroquine use both short-term and long-term and in overdose. Methods: Medline (via OVID) was searched from its inception through June 7 2020 using the following as either MeSH or keyword terms: ("Chloroquine/" or "Hydroxychloroquine/") AND ("Adverse Drug Event/" or "Toxicities, Drug/" or "Toxic.mp." or "Toxicity.mp." or "Overdose.mp."). We limited resultant articles to those published in English and reporting on Human subjects. This search yielded 330 articles, of which 57 were included. Articles were excluded due to lack of relevance, not reporting desired outcomes, or being duplicative in their content. Twenty-five additional articles were identified through screening references of included articles. To identify toxicities in individuals treated with hydroxychloroquine or chloroquine with COVID-19, we searched PubMed on June 10th, 2020: ("Chloroquine" or "Hydroxychloroquine") AND ("Coronavirus" or "COVID-19" or "SARS-CoV-2"). This search resulted in 638 articles. We reviewed articles for reporting of adverse events or toxicities. Most citations were excluded because they did not include original investigations or extrapolated data from subjects that did not have COVID-19; 34 citations were relevant. For the drug-interactions section, relevant classes and agents were identified through a screen of the https://www.covid19-druginteractions. org/ website. We then conducted targeted searches of PubMed up to June 7th 2020 combining "chloroquine" and "hydroxychloroquine" with terms for specific drug classes and drugs identified from the drug-interaction site as potentially relevant. We found 29 relevant articles. Toxicity with short-term use: Gastrointestinal: Gastrointestinal toxicities are the most common to occur following initiation of chloroquine or hydroxychloroquine. Nausea, vomiting, and diarrhea account for most reported intolerances. Glucose abnormalities: Alterations in blood glucose concentrations may occur with hydroxychloroquine but are rare with standard therapeutic use. Cardiotoxicity: Short-term use can produce conduction abnormalities. Evidence from COVID-19 treatment suggests QT/QTc prolongation is of concern, particularly when used in combination with azithromycin, although disagreement exists across studies. Dermatologic: Drug eruptions or rashes, followed by cutaneous hyperpigmentation, pruritis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, may occur within days to weeks of exposure but ...

Efficacy and Safety of Hydroxychloroquine for Hospitalized COVID-19 Patients: A Systematic Review and Meta-Analysis

“…Hydroxychloroquine (HCQ), an oral drug used for severe forms of rheumatoid arthritis and lupus erythematosus, has in vitro antiviral efficacy against coronaviruses including SARS-CoV-2 and immune modulating effects [ 3 , 4 , 5 , 6 , 7 ] and was among the first COVID-19 treatments investigated in human studies. HCQ, however, has several known adverse events such as QTc prolongation, cardiomyopathy, hypoglycemia and retinal toxicity in the non-COVID-19 environment [ 8 ]. By late Spring 2020, most of the evidence assessing HCQ efficacy and safety in hospitalized patients were from observational studies and showed widely divergent findings [ 9 ].…”

Toxicity of hydroxychloroquine, a potential treatment for COVID-19, on free-living marine nematodes

“…Numerous works started to explore effects of HCQ on humans after it was proposed as an early treatment of COVID-19 patients ( Million et al, 2020 ). Several of them suggested short-term (days to weeks) toxicity at cardiac ( Doyno et al, 2020 ), cardiovascular ( Stevenson et al, 2020 ), and ocular ( Al Adel et al, 2020 ) tissues. According to Doyno et al (2020) , deaths from overdoses of HCQ most often result from cardiovascular collapse.…”

“…Several of them suggested short-term (days to weeks) toxicity at cardiac ( Doyno et al, 2020 ), cardiovascular ( Stevenson et al, 2020 ), and ocular ( Al Adel et al, 2020 ) tissues. According to Doyno et al (2020) , deaths from overdoses of HCQ most often result from cardiovascular collapse. Several other effects have been reported by McChesney (1983) in association with the response of mammals after HCQ exposure.…”

Low-dose oral hydroxychloroquine led to impaired vision in a child with renal failure

“…A study of 2361 patients who had used HCQ for more than 5 years found that when the cumulative dose exceeded 1000 g of HCQ, the risk of ocular toxicity significantly increased. [ 14 ] At a dose of 6.5 mg/kg, the risk of retinal toxicity within 5 and 10 years is less than 1% and 2%, respectively. [ 15 ] In addition, the deposition of HCQ in the cornea could decrease visual acuity.…”