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Hydroxychloroquine for COVID-19

Aminoquinoline; Antimalarial Agent; Antiviral

(Updated May 13, 2020)



  1. Hydroxychloroquine with azithromycin remains off label use for COVID-19
  2. Hydroxychloroquine inhibits the P-glycoprotein drug transporter and CYP2D6 metabolism and may increase levels of P-glycoprotein substrates (e.g. digoxin,loperamide) and CYP2D6 substrates like metoprolol levels by 65-72%.
  3. Hydroxychloroquine prolongs the QT interval therefore monitor patients with prolonged QT, or at risk of QT interval prolongation (age>65 years, female, hypoK, hypoMg, Hypo Ca, concomitant QT prolonging drugs including diuretics, or a cardiac history).
  4. Hydroxychloroquine decreases the seizure threshold and its use is contraindicated among patients with epilepsy
  5. Hydroxychloroquine may cause hypoglycemia therefore monitor glucose levels in patients on other antihyperglycemics.


Mechanism of Action:  
Antiviral: interferes with binding, viral genome integration into cytosol and post-translational modification of viral proteins. Hydroxychloroquine interferes with viral binding to cellular surface receptor. Inhibition of quinone reductase 2 (structurally similar to UDP-N-acetylglucosamine 2-epimerases) which is involved in the synthesis of sialic acids which are recognized by human coronavirus HCoV-O43 and orthomyxoviruses as receptors. With SARS-CoV-1 (COVID-19), in vitro studies of Vero cells found that chloroquine decreased glycosylation of a virus cell surface receptor, the angiotensin-converting enzyme 2 (ACE2). Hydroxychloroquine alkalinizes endoxomes thereby decreasing pH-dependent endosome-mediated viral entry of enveloped viruses (low pH is required for the fusion of viral and endosomal membranes which allows release of the SARS-CoV-1 genome into the cytosol). Hydroxychloroquine affects post-translation modification of viral proteins thereby interfering with maturation of viral protein.


To date, three studies have been conducted examining hydroxychloroquine in the treatment of Covid-19. In a non-randomized study of hydroxychloroquine with or without azithromycin, negative PCR results in nasopharyngeal samples were reported at day 6 of treatment in 8 of 14 (57%), 6 of 6 (100%) and 2 of 16 (12.5%) of hydroxychloroquine treated, hydroxychloroquine/azithromycin treated and untreated patients, respectively. Clinical outcomes were not described, and treated patients who discontinued therapy or were transferred to the ICU were not included in the analysis. In a follow-up study by the same group of 80 patients receiving hydroxychloroquine/azithromycin, clinical improvement using a composite score was observed in 65 of 80 patients (81.3%). In addition, 93% of participants had negative nasopharyngeal PCR by day 8 of the study. This study had no control group. A more recent trial of 62 patients with mild Covid randomized 31 patients to usual care and 31 patients to hydroxychloroquine 200 mg twice per day plus usual care. In the main analysis of time to clinical recovery (normal temperature plus ‘cough relief’, it appears that hydroxychloroquine shortened the duration of fever by one day. In the secondary analysis, 19 (61.3%) of hydroxychloroquine patients had significant improvement in their chest CT (> 50% resolution at day 6 vs. baseline), versus 5 (16.1%) of control patients. Respective figures for radiographic deterioration were 2 (6.5%) and 9 (29.0%). In another randomized trial, 30 patients were randomized to receive either hydroxychloroquine (400 mg daily for 5 days) with conventional treatment or conventional treatment alone. At day seven, negative nasopharyngeal swabs were observed at day 7 were observed in 13 patients (86.7%) treated with hydroxychloroquine and 14 patients (93.3%) in the conventional treatment arm. It Is unclear what happened with the remaining three patients.


In a nonrandomized, retrospective study from New York of 1438 hospitalized patients COVID-19, there were no significant differences in mortality for patients receiving hydroxychloroquine+azithromycin [189/735 (25.7%); hazard ratio (HR) 1.3; 95 % CI, 0.76 to 2.40], hydroxychloroquine alone [54/271 (19.9%) HR 1.08 ;[95% CI 0.63 to 1.85], or azithromycin alone [21/211 (10.0%) HR 0.56; 95% CI 0.26 to 1.21] relative to patients taking neither drug (28/221; 12.7%).. A greater proportion of patients receiving hydroxychloroquine+azithromycin experienced cardiac arrest (15.5%) and abnormal ECG findings (27.1%), as did those in the hydroxychloroquine alone group (13.7% and 27.3, respectively), compared with azithromycin alone (6.2% and 16.1%, respectively) and neither drug (6.8% and 14.0%, respectively). Following multivariable adjustment, cardiac arrest was more likely in patients receiving hydroxychloroquine+azithromycin (adjusted OR 2.13; 95% CI 1.12 to 4.05] relative to patients taking neither drug. No difference was observed in comparisons among patients taking hydroxychloroquine alone or azithromycin alone relative to patients receiving neither drug, but a higher risk was observed in patients taking hydroxychloroquine alone vs azithromycin alone (adjusted OR, 2.97; 95% CI 1.56 to 5.64]; Patient groups were well balanced with respect to median age (hydroxychloroquine+azithromycin, 61.4 years; hydroxychloroquine alone, 65.5 years; azithromycin alone, 62.5 years; and neither drug, 64.0 years), but patients in the treatment groups presented with more severe disease than patients not receiving either drug.


In a study assessing only the rate of death and need for mechanical ventilation (i.e. no effectiveness data) in 368 men with COVID-19 (median age >65 years), the rate of death was 27.8% (27/97) in those treated with hydroxychloroquine, 22.1% (25/113) in those treated with hydroxychloroquine and azithromycin, and 11.4% (18/158) in those not treated with hydroxychloroquine. Respective proportions requiring mechanical ventilation were 13.3%, 6.9%, and 14.1%.


Dosage: COVID (off label; current clinical trial data): Few options-400 mg po q12h for first 2 doses, then 200 mg BID for 4 days; or 200 mg po TID for 10 days +/- azithromycin.

Drug Interactions: Pharmacodynamic: Other agents that result in QT prolongation, hypoglycemia, decreased seizure threshold

Pharmacokinetic: decreased absorption with antacids, decreases Pglycoprotein therefore increases serum digoxin concentrations (2,4); possible CYP2D6 and PgP inhibition increases increasing metoprolol AUC 65% and Cmax 72%.

Adverse effects (short COVID therapy duration): GI symptoms, ataxia, dizziness, headaches, irritability, seizure, weight loss, exacerbation of porphyria, bullous rash, erythema, acute generalized pustulosis, agranulocytosis, aplastic anemia, leukopenia, thrombocytopenia, hemolysis with glucose-6-phosphate deficiency, angioedema, myopathy, ophthalmic disturbances (7.5%) including accommodation changes, corneal changes, photophobia, macular edema, nystagmus, retinal issues lower risk due to shorter duration of therapy for COVID (retinal pigment changes, retinal vascular changes, retinopathy), vision color changes, visual field defect, severe hypoglycemia, hearing loss, suicidal behavior, heart failure (1,2)

Caution: Cardiomyopathies, with fatalities (uncommon); QT prolongation with ventricular arrhythmias; severe hypoglycemia +/-antidiabetic medications; blood dyscrasias, exacerbation of porphyria; seizure disorder


Monitoring: CBC, SCr in older adult; baseline EKG, monitor for heart failure, seizure (2) If on longer duration of therapy, ophthalmic examinations



Absorption: incomplete and variable (~70% [range: 25 to 100%] or 75% [70-80%]); Tmax 2.4-5h (1)(2). Only 6% first pass

Distribution: protein binding ~40-45%; large Vd 5522L (blood), 44 257L (plasma)(1) (2). High affinity for melanin (increased [] in eye).
Metabolism: liver: 30-60%. Bisdesethylhydroxychloroquine, desethylchloroquine, and desethylhydroxychloroquine all active metabolites (1,2); query CYP2D6 inhibition with higher AUC and Cmax with metoprolol (3,5)

Elimination: renal 16-62% unchanged (2)

Half-life: 172.3h to 50 days (2)


  1. ULC M pharmaceuticals. Mylan-Hydroxychloroquine Product monograph [Internet]. Etobicoke; 2017. Available from:
  2. Hydroxychloroquine. In: Lexi-drugs online [database on the internet]. Hudson (OH): Lexicomp, Inc; 2019 [cited 5 Apr 2019]. Available from: Subscription required to view.
  3. Hydroxychloroquine. In: In Depth Answers [database on the internet]. Ann Arbor (MI): Truven Health Analytics; updated 15 Mar 2019 [cited 5 Apr 2019]. Available from: Subscription required to view.
  4. Hydroxychloroquine. In: Drugbank [database on the internet]. Edmonton (AL): Wishart Research Group; 2019 [updated 15 Mar 2019; cited 5 Apr 2019]. Available from:
  5. Hayeshi R, Masimirembwa C, Mukanganyama S, et al, “The Potential Inhibitory Effect of Antiparasitic Drugs and Natural Products on P-glycoprotein Mediated Efflux,”Eur J Pharm Sci, 2006, 29(1):70-81.
  6. Somer M, Kallio J, Pesonen U, Pyykko K, Huupponen R, Scheinin M. Influence of hydroxychloroquine on the bioavailability of oral metoprolol. Br J Clin Pharmcol. 2000 Jun;49(6):549-54.
  7. Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of COVID19: results of an open label non randomized clinical trial. International Journal of Antimicrobial Agents – In Press 17 March 2020 – DOI : 10.1016/j.ijantimicag.2020.105949
  8. Gautret et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study. Available at: Accessed April 2, 2020.
  9. Chen Z et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. Available at: Accessed April 2, 2020. 10. Chen J, Liu D, Li L et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ. 2020; Mar. (DOI 10.3785/j.issn. 1008-9292.2020.03.03
  10. 10. Chen J, Liu D, Li L et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ. 2020; Mar. (DOI 10.3785/j.issn. 1008-9292.2020.03.03
  11. Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, Weinberg P, Kirkwood J, Muse A, DeHovitz J, Blog DS, Hutton B, Holtgrave DR, Zucker HA. Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State. JAMA. 2020 May 11. doi: 10.1001/jama.2020.8630. [Epub ahead of print]
  12. Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. Preprint (not peer reviewed). (https://
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