Chloroquine or Hydroxychloroquine With or Without Azithromycin
Last Updated: October 9, 2020
Chloroquine is an antimalarial drug that was developed in 1934. Hydroxychloroquine, an analogue of chloroquine, was developed in 1946. Hydroxychloroquine is used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, in addition to malaria. In general, hydroxychloroquine has fewer and less severe toxicities (including less propensity to prolong the QTc interval) and fewer drug-drug interactions than chloroquine.
Both chloroquine and hydroxychloroquine increase the endosomal pH, inhibiting fusion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the host cell membranes.1 Chloroquine inhibits glycosylation of the cellular angiotensin-converting enzyme 2 receptor, which may interfere with binding of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) to the cell receptor.2 In vitro studies have suggested that both chloroquine and hydroxychloroquine may block the transport of SARS-CoV-2 from early endosomes to endolysosomes, possibly preventing the release of the viral genome.3 Both chloroquine and hydroxychloroquine also have immunomodulatory effects. It has been hypothesized that these effects are other potential mechanisms of action for the treatment of COVID-19. However, despite demonstrating antiviral activity in some in vitro systems, hydroxychloroquine with or without azithromycin did not reduce upper or lower respiratory tract viral loads or demonstrate clinical efficacy in a rhesus macaque model.4
Chloroquine and hydroxychloroquine, with or without azithromycin, have been studied in multiple clinical trials for the treatment of COVID-19. The recommendations below are based on an assessment of the collective evidence from these studies.
- The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of chloroquine or hydroxychloroquine with or without azithromycin for the treatment of COVID-19 in hospitalized patients (AI).
- In nonhospitalized patients, the Panel recommends against the use of chloroquine or hydroxychloroquine with or without azithromycin for the treatment of COVID-19, except in a clinical trial (AIIa).
- The Panel recommends against the use of high-dose chloroquine (600 mg twice daily for 10 days) for the treatment of COVID-19 (AI).
The safety and efficacy of chloroquine and hydroxychloroquine with or without azithromycin have been evaluated in randomized clinical trials, observational studies, and single-arm studies. Please see Table 2b for more information.
In a large randomized controlled trial of hospitalized patients in the United Kingdom, hydroxychloroquine did not decrease 28-day mortality when compared to the usual standard of care. Participants who were randomized to receive hydroxychloroquine had a longer median hospital stay than those who received the standard of care. In addition, among patients who were not on invasive mechanical ventilation at the time of randomization, those who received hydroxychloroquine were more likely to subsequently require intubation or die during hospitalization than those who received the standard of care.5
In another randomized controlled trial that was conducted in Brazil, neither hydroxychloroquine alone nor hydroxychloroquine plus azithromycin improved clinical outcomes among hospitalized patients with mild to moderate COVID-19. More adverse events occurred among patients who received hydroxychloroquine or hydroxychloroquine plus azithromycin than among those who received the standard of care.6 Data from another randomized study of hospitalized patients with severe COVID-19 do not support using hydroxychloroquine plus azithromycin over hydroxychloroquine alone.7
In addition to these randomized trials, data from large retrospective observational studies do not consistently show evidence of a benefit for hydroxychloroquine with or without azithromycin in hospitalized patients with COVID-19. For example, in a large retrospective observational study of patients who were hospitalized with COVID-19, hydroxychloroquine use was not associated with a reduced risk of death or mechanical ventilation.8 Another multicenter retrospective observational study evaluated the use of hydroxychloroquine with and without azithromycin in a random sample of a large cohort of hospitalized patients with COVID-19.9 Patients who received hydroxychloroquine with or without azithromycin did not have a decreased risk of in-hospital mortality when compared to those who received neither hydroxychloroquine nor azithromycin.
Conversely, a large retrospective cohort study reported a survival benefit among hospitalized patients who received either hydroxychloroquine alone or hydroxychloroquine plus azithromycin, compared to those who received neither drug.10 However, patients who did not receive hydroxychloroquine had a lower rate of admission to the intensive care unit, which suggests that patients in this group may have received less-aggressive care. Furthermore, a substantially higher percentage of patients in the hydroxychloroquine arms also received corticosteroids (77.1% of patients in the hydroxychloroquine arms vs. 36.5% of patients in the control arm). Given that the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial showed that corticosteroids improve the survival rate of patients with COVID-19 (see Corticosteroids), it is possible that the findings in this study were confounded by this imbalance in corticosteroid use.11 These and other observational and single-arm studies are summarized in Table 2b.
Many of the observational studies that have evaluated the use of chloroquine or hydroxychloroquine in patients with COVID-19 have attempted to control for confounding variables. However, study arms may be unbalanced in some of these studies, and some studies may not account for all potential confounding factors. These factors limit the ability to interpret and generalize the results from observational studies; therefore, results from these studies are not as definitive as those from large randomized trials. Given the lack of a benefit seen in the randomized clinical trials and the potential for toxicity, the Panel recommends against using hydroxychloroquine or chloroquine with or without azithromycin to treat COVID-19 in hospitalized patients (AI).
The Panel also recommends against using high-dose chloroquine to treat COVID-19 (AI). 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 randomized clinical trial compared the use of high-dose chloroquine and low-dose chloroquine in hospitalized patients with severe COVID-19. In addition, all 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.12
Several randomized trials have not shown a clinical benefit for hydroxychloroquine in nonhospitalized patients with COVID-19. However, other clinical trials are still ongoing.13,14 In nonhospitalized patients, the Panel recommends against the use of chloroquine or hydroxychloroquine with or without azithromycin for the treatment of COVID-19, except in a clinical trial (AIIa).
The combination of hydroxychloroquine and azithromycin is associated with QTc prolongation in patients with COVID-19. Given the long half-lives of both azithromycin (up to 72 hours) and hydroxychloroquine (up to 40 days), caution is warranted even when the two drugs are used sequentially instead of concomitantly.15
Please see Table 2b for additional details.
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.16 If chloroquine or hydroxychloroquine is used, clinicians should monitor the patient for adverse events, especially prolonged QTc interval (AIII).
- 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],16 fluoroquinolone antibiotics)17 should be used only if necessary. Consider using doxycycline rather than azithromycin as empiric therapy for atypical pneumonia.
- Multiple studies have demonstrated that concomitant use of hydroxychloroquine and azithromycin can prolong the QTc interval;18-20 in an observational study, the use of hydroxychloroquine plus azithromycin was associated with increased odds of cardiac arrest.9 The use of this combination warrants careful monitoring.
- Baseline and follow-up electrocardiograms are recommended when there are potential drug interactions with concomitant medications (e.g., azithromycin) or underlying cardiac diseases.21
- The risk-benefit ratio should be assessed for patients with cardiac disease, a history of ventricular arrhythmia, bradycardia (<50 bpm), or uncorrected hypokalemia and/or hypomagnesemia.
Other Adverse Effects
- Hypoglycemia, rash, and nausea. Divided doses may reduce nausea.
- Retinopathy. Bone marrow suppression may occur with long-term use, but this is not likely with short-term use.
Chloroquine and hydroxychloroquine are moderate inhibitors of cytochrome P450 (CYP) 2D6, and these drugs are also P-glycoprotein (P-gp) inhibitors. Use caution when administering these drugs with medications that are metabolized by CYP2D6 (e.g., certain antipsychotics, beta-blockers, selective serotonin reuptake inhibitors, methadone) or transported by P-gp (e.g., certain direct-acting oral anticoagulants, digoxin).22 Chloroquine and hydroxychloroquine may decrease the antiviral activity of remdesivir; coadministration of these drugs is not recommended.23
Considerations in Pregnancy
- Antirheumatic doses of chloroquine and hydroxychloroquine have been used safely in pregnant women with SLE.
- Hydroxychloroquine exposure has not been associated with adverse pregnancy outcomes in ≥300 human pregnancies.
- A lower dose of chloroquine (500 mg once a week) is used for malaria prophylaxis during pregnancy.
- No dose changes are necessary for chloroquine or hydroxychloroquine during pregnancy.
Considerations in Children
- Chloroquine and hydroxychloroquine have been routinely used in pediatric populations for the treatment and prevention of malaria and for rheumatologic conditions.
- Hydroxychloroquine, chloroquine, and azithromycin are not approved by the Food and Drug Administration (FDA) for the treatment of COVID-19.
- Hydroxychloroquine is approved by the FDA for the treatment of malaria, lupus erythematosus, and rheumatoid arthritis. Chloroquine is approved for the treatment of malaria and extraintestinal amebiasis. Azithromycin is commonly used for the treatment and/or prevention of nontuberculous mycobacterial infection, various sexually transmitted infections, and various bacterial infections.
- Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32020029.
- 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.
- 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.
- Maisonnasse P, Guedj J, Contreras V, et al. Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates. Nature. 2020;585(7826):584-587. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32698191.
- Horby P, Mafham M, Linsell L, et al. Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-centre, randomized, controlled trial. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.07.15.20151852v1.
- Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate COVID-19. N Engl J Med. 2020; Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32706953.
- Furtado RHM, Berwanger O, Fonseca HA, et al. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. Lancet. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32896292.
- Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med. 2020; Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32379955.
- Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state. JAMA. 2020;323(24):2493-2502. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32392282.
- Arshad S, Kilgore P, Chaudhry ZS, et al. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. Int J Infect Dis. 2020;97:396-403. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32623082.
- RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with COVID-19—preliminary report. N Engl J Med. 2020; Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32678530.
- 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://pubmed.ncbi.nlm.nih.gov/32330277/.
- Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial. Ann Intern Med. 2020; Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32673060.
- Mitja O, Corbacho-Monne M, Ubals M, et al. Hydroxychloroquine for early treatment of adults with mild COVID-19: a randomized-controlled trial. Clin Infect Dis. 2020; Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32674126.
- Institute for Safe Medication Practices. Special Edition: Medication Safety Alert! 2020. Available at: https://ismp.org/acute-care/special-edition-medication-safety-alert-april-9-2020/covid-19. Accessed September 24, 2020.
- Nguyen LS, Dolladille C, Drici MD, et al. Cardiovascular toxicities associated with hydroxychloroquine and azithromycin: an analysis of the World Health Organization pharmacovigilance database. Circulation. 2020;142(3):303-305. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32442023.
- CredibleMeds. Combined list of drugs that prolong QT and/or cause torsades de pointes (TDP). 2020. Available at: https://crediblemeds.org/druglist.
- Chorin E, Dai M, Shulman E, et al. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nature Medicine. 2020. Available at: https://doi.org/10.1038/s41591-020-0888-2.
- Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(9):1036-1041. Available at: https://pubmed.ncbi.nlm.nih.gov/32936252/.
- Bessiere F, Roccia H, Deliniere A, et al. Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) Infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit. JAMA Cardiol. 2020;5(9):1067-1069. Available at: https://pubmed.ncbi.nlm.nih.gov/32936266/.
- 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 September 24, 2020.
- University of Liverpool. COVID-19 drug interactions. 2020. Available at: https://www.covid19-druginteractions.org/. Accessed September 24, 2020.
- Food and Drug Administration. Remdesivir by Gilead Sciences: FDA warns of newly discovered potential drug interaction that may reduce effectiveness of treatment. 2020. Available at: https://www.fda.gov/safety/medical-product-safety-information/remdesivir-gilead-sciences-fda-warns-newly-discovered-potential-drug-interaction-may-reduce. Accessed July 2, 2020.