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Chloroquine or Hydroxychloroquine

Last Updated: May 12, 2020

Overall Recommendation:

  • There are insufficient clinical data to recommend either for or against using chloroquine or hydroxychloroquine for the treatment of COVID-19 (AIII).
  • The COVID-19 Treatment Guidelines Panel (the Panel) recommends against using high-dose chloroquine (600 mg twice daily for 10 days) for the treatment of COVID-19 (AI).

Rationale for Recommendation

Chloroquine and hydroxychloroquine have been used in small randomized trials and in some case series and clinical trials with conflicting study reports (as described below). Both drugs are available through the Strategic National Stockpile for hospitalized adults and adolescents weighing ≥50 kg who cannot access these drugs through a clinical trial.1

Reports have documented serious dysrhythmias in patients with COVID-19 treated with chloroquine or hydroxychloroquine, often in combination with azithromycin and other medicines that prolong the QTc interval. Given the risk of dysrhythmias, the Food and Drug Administration (FDA) cautions against the use of chloroquine or hydroxychloroquine for the treatment of COVID-19 outside of the setting of a hospital or clinical trial.2 When chloroquine or hydroxychloroquine is used, clinicians should monitor the patient for adverse effects (AEs), especially prolonged QTc interval (AIII).

High-dose chloroquine (600 mg twice daily for 10 days) has been associated with more severe toxicities than lower-dose chloroquine (450 mg twice daily for 1 day, followed by 450 mg once daily for 4 days). A comparative trial compared high-dose chloroquine versus low-dose chloroquine in patients with COVID-19; in addition, all of the participants received azithromycin and 89% of the participants received oseltamivir. The study was discontinued early when preliminary results showed higher rates of mortality and QTc prolongation in the high-dose chloroquine group.

Background

Chloroquine is an antimalarial drug developed in 1934. Hydroxychloroquine, an analogue of chloroquine, was developed in 1946 and is used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In general, hydroxychloroquine has fewer and less severe toxicities (including less propensity to prolong the QTc interval) and fewer drug-drug interactions than chloroquine.

Proposed Mechanism of Action and Rationale for Use for COVID-19:

  • Both chloroquine and hydroxychloroquine increase the endosomal pH, inhibiting fusion of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the host cell membranes.3
  • Chloroquine inhibits glycosylation of the cellular angiotensin-converting enzyme 2 receptor, which may interfere with binding of SARS-CoV to the cell receptor.4
  • In vitro, both chloroquine and hydroxychloroquine may block the transport of SARS-CoV-2 from early endosomes to endolysosomes, which may be required for release of the viral genome.5
  • Several studies have demonstrated in vitro activity of chloroquine against SARS-CoV.4,6
  • Both chloroquine and hydroxychloroquine have immunomodulatory effects.

Clinical Data for COVID-19

The clinical data available to date on the use of chloroquine and hydroxychloroquine to treat COVID-19 have been mostly from use in patients with mild, and in some cases, moderate disease. Clinical data on use of the drugs in patients with severe and critical COVID-19 are very limited. The clinical data are summarized below.

Chloroquine

High-Dose Versus Low-Dose Chloroquine

randomized, double-blind, Phase 2b study compared two different chloroquine regimens for the treatment of COVID 19: high-dose chloroquine (600 mg twice daily for 10 days) versus low-dose chloroquine (450 mg twice daily for 1 day followed by 450 mg for 4 days). The study participants were hospitalized adults with suspected severe COVID-19 (respiratory rate >24, heart rate >125, oxygen saturation <90%, and/or shock).7 All patients received ceftriaxone plus azithromycin; 89.6% of the patients also received oseltamivir. Of note, both azithromycin and oseltamivir can increase the QTc interval.

The primary outcome measure for this analysis was mortality at 13 days after treatment initiation. The planned study sample size was 440 participants, which was enough to show a reduction in mortality by 50% with high-dose chloroquine. The study was stopped by the data safety and monitoring board after 81 patients were enrolled into the study.

Results

  • 41 and 40 patients were randomized into the high-dose and low-dose arms, respectively.
  • The overall fatality rate was 27.2%.
  • Mortality by Day 13 was higher in the high-dose arm than in the low-dose arm (death in 16 of 41 patients [39%] vs. in 6 of 40 patients [15%]; P = 0.03). This difference was no longer significant when controlled by age (OR 2.8; 95% confidence interval [CI], 0.9–8.5).
  • Overall, QTcF >500 ms occurred more frequently among patients in the high-dose arm (18.9%) than in the low-dose (11.1%) arm. Among those with confirmed COVID-19, QTcF >500 ms was also more frequent in the high-dose arm (24.1%) than in the low-dose arm (3.6%).
  • Two patients in the high-dose arm experienced ventricular tachycardia before death.

Limitations:

  • More older patients and more patients with a history of heart disease were randomized to the high-dose arm than to the low-dose arm.

Interpretation:

Despite the small number of patients enrolled, this study raises concern for increased mortality with high-dose chloroquine (600 mg twice daily) in combination with azithromycin and oseltamivir.

Chloroquine Versus Lopinavir/Ritonavir

In a small randomized, controlled trial in China, 22 hospitalized patients with COVID-19 (none critically ill) were randomized to receive oral chloroquine 500 mg twice daily or lopinavir 400 mg/ritonavir 100 mg twice daily for 10 days.8 Patients with a history of heart disease (chronic disease and history of arrhythmia), or kidney, liver, or hematologic disease were excluded from participation. The primary study outcome was SARS-CoV-2 polymerase chain reaction (PCR) negativity at Days 10 and 14. Secondary outcomes included improvement of lung computed tomography (CT) scan at Days 10 and 14, discharge at Day 14, and clinical recovery at Day 10, as well as safety determined by evaluation of study drug-related AEs.

Results:

  • Ten patients received chloroquine and 12 patients received lopinavir/ritonavir. At baseline, patients had good peripheral capillary oxygen saturation (SpO2) (97% to 98%).
  • Compared to the lopinavir/ritonavir-treated patients, the chloroquine-treated patients had a shorter duration from symptom onset to initiation of treatment (2.5 days vs. 6.5 days, P < 0.001).
  • Though not statistically significant, patients in the chloroquine arm were younger (median age 41.5 years vs. 53.0 years, P = 0.09). Few patients had co-morbidities.
  • At Day 10, 90% of the chloroquine-treated patients and 75% of the lopinavir/ritonavir-treated patients had a negative SARS-CoV-2 PCR test result. At Day 14, the percentages for the chloroquine-treated patients and the lopinavir/ritonavir-treated patients were 100% and 91.2%, respectively.
  • At Day 10, 20% of the chloroquine-treated patients and 8.3% of the lopinavir/ritonavir-treated patients had CT scan improvement. At Day 14, the percentages for the chloroquine-treated patients and the lopinavir/ritonavir-treated patients were 100% and 75%, respectively.
  • At Day 14, 100% of the chloroquine-treated patients and 50% of the lopinavir/ritonavir-treated patients were discharged from the hospital.
  • The risk ratios of these outcome data cross 1, and the results were not statistically significant.
  • Both chloroquine and lopinavir/ritonavir were generally well-tolerated.

Limitations:

  • The trial sample size was very small, and the participants were fairly young.
  • The chloroquine-treated patients were younger and had fewer symptoms prior to treatment initiation, which are variables that could have affected the study protocol-defined outcomes.
  • Patients who had chronic co-morbidities and who were critically ill were excluded from the study.

Interpretation:

In this small randomized, controlled trial, there was no significant clinical benefit seen with chloroquine compared to lopinavir/ritonavir in the treatment of COVID-19.

Hydroxychloroquine

Retrospective Observational Cohort from the United States Veterans Health Administration

This study has not been peer reviewed.

An observational, retrospective cohort study analyzed data from patients hospitalized at the United States Veterans Health Administration medical centers between March 9, 2020, and April 11, 2020, with confirmed COVID-19.9 Patients were categorized as having received either hydroxychloroquine, hydroxychloroquine plus azithromycin, or no hydroxychloroquine. Doses and duration of hydroxychloroquine or azithromycin use were not specified. All patients also received standard supportive management for COVID-19. The primary endpoints were death and the need for mechanical ventilation. Associations between treatment and outcomes were determined using propensity score adjustment including demographic, co-morbid, and clinical data (including predictors of COVID-19 disease severity). Patients were included in the analysis if body mass index, vital signs, and discharge disposition were noted in their medical records.

Results:

  • 368 patients were eligible for analysis. The patients were categorized into three treatment groups: hydroxychloroquine (n = 97; median age of 70 years), hydroxychloroquine plus azithromycin (n = 113; median age of 68 years), or no hydroxychloroquine (n = 158; median age of 69 years). All patients were male.
  • 70 patients died; 35 of those who died (50%) were not receiving mechanical ventilation.
  • No difference was observed between the groups in the risk of mechanical ventilation.
  • Compared to the no hydroxychloroquine group, the risk of death from any cause was higher in the hydroxychloroquine group (adjusted hazard ratio [HR], 2.61; 95% CI, 1.10–6.17; P = 0.03), but not in the hydroxychloroquine plus azithromycin group (adjusted HR, 1.14; 95% CI, 0.56–2.32, P = 0.72).
  • There was no between-group difference in the risk of death after ventilation.

Limitations:

  • The patient population was entirely male.
  • The dose and duration of administration of hydroxychloroquine and azithromycin are not included in the report. Patients were included if they received a single dose of either or both drugs.
  • Propensity score adjustment was used to account for differences between the groups, but the possibility of residual confounding cannot be excluded as patients who were more ill may have been more likely to receive hydroxychloroquine.
  • No imaging data were presented; severity of chest X-ray findings could predict worse outcomes.
  • Use of other antiviral or immune modulatory agents was not reported.
  • The reason for the high mortality in patients who did not receive mechanical ventilation is not clear, especially as most of these patients appear to have had mild/moderate disease on admission.

Interpretation:

This study showed no beneficial effect of hydroxychloroquine plus azithromycin for the treatment of COVID-19 and a possible association of hydroxychloroquine with increased mortality; however, residual confounding may have affected the study results.

Randomized, Controlled Trial of Hydroxychloroquine Versus Standard of Care

This study has not been peer reviewed.

This multicenter, randomized, open-label trial compared hydroxychloroquine 1,200 mg once daily for 3 days followed by hydroxychloroquine 800 mg once daily for the rest of the treatment duration (2 weeks for patients with mild/moderate COVID-19 [99% of the patients] and 3 weeks for one patient with severe disease) versus standard of care (SOC).10

The primary outcome was negative PCR within 28 days. Secondary outcomes were alleviation of symptoms (resolution of fever, SpO2 >94% on room air, resolution of respiratory symptoms), markers of inflammation (including C-reactive protein [CRP]), and chest X-ray within 28 days. Secondary outcomes for severe cases included all-cause mortality, clinical status, days of mechanical ventilation, extracorporeal membrane oxygenation (ECMO), supplemental oxygenation, and hospital stay.

Results:

  • 75 patients were enrolled in each study arm. Patients were randomized at a mean of 16.6 days after symptom onset.
  • No difference was found between the hydroxychloroquine arm and the SOC arm in negative PCR conversion rate within 28 days (85.4% of participants vs. 81.3% of participants, respectively) or in time to negative PCR conversion (median of 8 days vs. 7 days, respectively).
  • There was no difference in negative PCR conversion rate by age, body mass index, co-morbid conditions, days between symptom onset and randomization, or other conditions analyzed.
  • There was no difference in the rate of symptom alleviation between the groups in the intention-to-treat analysis.
  • There was more rapid normalization of CRP and lymphocytopenia in the hydroxychloroquine group.
  • Adverse effects occurred in 30% of the participants in the hydroxychloroquine arm (most commonly diarrhea) versus in 8.8% of the participants in the SOC arm.

Limitations:

  • The definition of SOC and the use of concomitant medications (two patients received azithromycin) were not clearly stated.
  • It is unclear how the overall rate of symptom alleviation was calculated.
  • The duration of hydroxychloroquine use (2 weeks) was longer than in most other observational cohort or clinical trials for the treatment of COVID-19.
  • The authors note that hydroxychloroquine was associated with increased alleviation of symptoms (HR, 8.83; 95% CI, 1.09–71.3), but this was only in a post-hoc subgroup analysis that excluded patients on other antivirals.

Interpretation:

This study demonstrated no difference in viral clearance between hydroxychloroquine and SOC.

Observational Cohort of Hydroxychloroquine Versus No Hydroxychloroquine

This study has not been peer reviewed.

This observational, retrospective cohort study analyzed data for adult patients hospitalized for COVID-19 pneumonia at four French tertiary care centers over a 2-week period (March 17–31, 2020).11 Patients were eligible if they required oxygen by mask or nasal cannula. Patients were excluded if they were immediately admitted to the intensive care unit (ICU) or admitted with acute respiratory distress syndrome (ARDS) (requiring non-invasive ventilation or mechanical ventilation). The treatment arms compared were initiation of hydroxychloroquine at a daily dose of 600 mg within 48 hours of admission and the absence of hydroxychloroquine during the same period. The primary outcome was a composite of transfer to the ICU within 7 days of enrollment and/or death from any cause. An inverse probability of treatment weighting approach was used to “emulate” randomization.

Results:

  • 81 patients were eligible for the analysis; 84 participants received hydroxychloroquine and 97 participants did not.
  • Co-morbidities were less common in the hydroxychloroquine group; overall initial COVID-19 severity was well balanced across the treatment arms.
  • In the hydroxychloroquine group, 20% of the patients received concomitant azithromycin and 76% of the patients received amoxicillin/clavulanic acid.
  • In the inverse probability of treatment weighting analysis there was no difference in the composite outcome between the hydroxychloroquine group (20.5% of participants) and the non-hydroxychloroquine group (22.1% of participants). Similarly, there was no difference between the groups in the secondary outcomes of all-cause mortality and development of ARDS.
  • Among the 84 patients receiving hydroxychloroquine, eight patients (9.5%) experienced electrocardiogram (ECG) changes requiring treatment discontinuation at a median of 4 days from the start of dosing, including seven patients with a QTc that prolonged >60 ms and one patient with new onset, first-degree atrioventricular (AV) block.

Limitations:

  • This was a retrospective, non-randomized study.
  • The number of patients with QTc prolongation who received hydroxychloroquine only versus those who received hydroxychloroquine plus azithromycin was not reported.

Interpretation:

In this retrospective study, there was no difference in clinically important outcomes between patients who received hydroxychloroquine within 48 hours of hospital admission and those who did not.

Randomized Controlled Trial of Hydroxychloroquine plus Standard Treatment Versus Standard Treatment Alone

This study has not been peer reviewed.

In a randomized controlled trial in China, 62 hospitalized patients with mild (SpO2 ratio >93% or PaO2/FIO2 ratio >300 mm Hg) CT-confirmed COVID-19 pneumonia were randomized to hydroxychloroquine 200 mg twice daily for 5 days plus standard treatment or to standard treatment only.12 Standard treatment included oxygen therapy, antiviral and antibacterial therapy, and immunoglobin, with or without corticosteroids.

Results:

  • Compared to the control patients, the hydroxychloroquine-treated patients had a 1 day-shorter mean duration of fever (2.2 days vs. 3.2 days) and cough (2.0 days vs. 3.1 days).
  • Of the control patients, 13% experienced progression of illness; none of the hydroxychloroquine-treated patients experienced progression of illness.
  • 80.6% of the hydroxychloroquine-treated patients and 54.8% of the control patients experienced either moderate or significant improvement in chest CT scan.
  • Adverse events (one rash, one headache) occurred among two (6.4%) of the hydroxychloroquine-treated patients; none of the control patients experienced an adverse event.

Limitations:

  • The trial had a small sample size and short follow-up.
  • The standard treatment is complex and not well defined.
  • The presence and distribution of associated co-morbidities (e.g., hypertension, diabetes, lung disease) was not reported.
  • There was no indication that radiologists were blinded to the treatment status of the patients, which could have biased determination of the chest CT outcome.

Interpretation:

The methodological limitations of this study preclude determination of efficacy for hydroxychloroquine.

A Case Series of Hydroxychloroquine Versus Control

In a case series from France, 26 hospitalized adults with SARS-CoV-2 infection categorized as asymptomatic or with upper or lower respiratory tract infection who received hydroxychloroquine 200 mg three times daily for 10 days were compared to 16 control individuals (i.e., who refused treatment, did not meet eligibility criteria, or were from a different clinic).13

Results:
  • Six patients in the hydroxychloroquine group were excluded from the analysis for the following reasons:
    • One patient died.
    • Three patients were transferred to the ICU.
    • One patient stopped taking the study drug due to nausea.
    • One patient withdrew from the study.
  • Six patients also received azithromycin.
  • By Day 6, nasopharyngeal (NP) PCRs were negative in 14 of 20 (70%) hydroxychloroquine-treated patients and 2 of 16 (12.5%) controls.
  • Among the hydroxychloroquine patients, 8 of 14 (57.1%) patients who received only hydroxychloroquine and 6 of 6 (100%) patients who received hydroxychloroquine and azithromycin had negative NP PCRs by Day 6.
  • Clinical outcomes for all patients were not reported.

Limitations:

  • There are several methodologic concerns with this case series:
    • The sample size of the series is small.
    • The criteria for enrollment of cases and controls is unclear.
    • Asymptomatic individuals were enrolled.
    • Exclusion of six hydroxychloroquine patients includes one death and three ICU transfers.
    • No clinical outcomes were reported; thus, the clinical significance of a negative PCR is unknown.
    • The reason for the addition of azithromycin for some patients is unclear.

Interpretation:

Methodologic problems with this case series limit the ability to draw conclusions regarding the efficacy of hydroxychloroquine with or without azithromycin.

Adverse Effects:

  • Chloroquine and hydroxychloroquine have a similar toxicity profile, although hydroxychloroquine is better tolerated and has a lower incidence of toxicity than chloroquine.
  • Cardiac Adverse Effects:
    • QTc prolongation, Torsade de Pointes, ventricular arrythmia, and cardiac deaths.
    • The risk of QTc prolongation is greater for chloroquine than for hydroxychloroquine.
    • Concomitant medications that pose a moderate to high risk for QTc prolongation (e.g., antiarrhythmics, antipsychotics, antifungals, macrolides [including azithromycin] and fluoroquinolone antibiotics)14 should be used only if necessary. Consider using doxycycline rather than azithromycin as empiric therapy for atypical pneumonia.
    • Baseline and follow-up ECG are recommended when there are potential drug interactions with concomitant medications (e.g., azithromycin) or underlying cardiac diseases.15
    • The risk-benefit ratio should be closely assessed for patients with cardiac disease, history of ventricular arrhythmia, bradycardia (<50 beats per minute), or uncorrected hypokalemia and/or hypomagnesemia.
  • Other Adverse Effects:
    • Hypoglycemia, rash, and nausea (daily divided doses may reduce nausea).
    • Retinopathy, bone marrow suppression with long-term use, but not likely with short-term use.
  • There is no evidence that glucose-6-phosphate dehydrogenase (G6PD) deficiency is relevant for the use of hydroxychloroquine, and G6PD testing is not recommended.
  • With chloroquine use, there is a greater risk for hemolysis in patients with G6PD deficiency. Conduct G6PD testing before initiation of chloroquine. Consider using hydroxychloroquine until G6PD test results are available. If the test results indicate that the patient is G6PD deficient, hydroxychloroquine should be continued.

Drug-Drug Interactions:

  • Chloroquine and hydroxychloroquine are moderate inhibitors of cytochrome P450 (CYP) 2D6 and are also P-glycoprotein (P-gp) inhibitors. Use caution when co-administering the drugs with concomitant medications metabolized by CYP2D6 (e.g., certain antipsychotics, beta-blockers, selective serotonin reuptake inhibitors, and methadone) or transported by P-gp (e.g., certain direct-acting oral anticoagulants or digoxin).16

Considerations in Pregnancy:

  • Anti-rheumatic doses of chloroquine and hydroxychloroquine have been used safely in pregnant women with SLE.
  • Hydroxychloroquine has not been associated with adverse pregnancy outcomes in ≥300 human pregnancies with exposure to the drug.
  • A lower dose of chloroquine (500 mg once a week) is used for malaria prophylaxis in pregnancy.
  • Dosing/pharmacokinetics/pharmacodynamics: No dosing changes in pregnancy.

Considerations in Children:

  • Chloroquine and hydroxychloroquine have been used routinely in pediatric populations for the treatment and prevention of malaria and for rheumatologic conditions.

Drug Availability:

  • Hydroxychloroquine is approved by the FDA for the treatment of malaria, lupus erythematosus, and RA and is available commercially. Hydroxychloroquine is not approved for the treatment of COVID-19.
  • FDA issued an emergency use authorization (EUA) for the use of chloroquine and hydroxychloroquine donated to the Strategic National Stockpile. The EUA authorizes the use of these donated drugs for the treatment of hospitalized adolescent and adult patients with COVID-19 who weigh ≥50 kg and for whom a clinical trial is not available, or participation is not feasible.

References

  1. Food and Drug Administration. Emergency Use Authorization - COVID-19 Therapeutics. 2020. Available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#covidtherapeutics. Accessed: April 8, 2020.
  2. Food and Drug Administration. FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. 2020. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or. Accessed: May 8, 2020.
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  4. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16115318.
  5. Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32194981.
  6. Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun. 2004;323(1):264-268. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15351731.
  7. Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open. 2020;3(4):e208857. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32339248.
  8. Huang M, Tang T, Pang P, et al. Treating COVID-19 with chloroquine. J Mol Cell Biol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32236562.
  9. Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. medRxiv. 2020. [Preprint]. Available at: https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v2.
  10. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. medRxiv. 2020. [Preprint]. Available at: https://www.medrxiv.org/content/10.1101/2020.04.10.20060558v1.
  11. Mahevas M, Tran V, Roumier M, et al. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial. medRxiv. 2020. [Preprint]. Available at: https://www.medrxiv.org/content/10.1101/2020.04.10.20060699v1.
  12. Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. 2020. [Preprint]. Available at: https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v2.
  13. Gautret P, Lagier J, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. 2020. [In press]. Available at: https://www.sciencedirect.com/science/article/pii/S0924857920300996.
  14. CredibleMeds. Combined list of drugs that prolong QT and/or cause Torsades de Pointes (TDP). 2020. Available at: https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf
  15. American College of Cardiology. Ventricular arrhythmia risk due to hydroxychloroquine-azithromycin treatment for COVID-19. 2020. Available at: https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for-covid-19. Accessed April 8, 2020.
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