What information is available regarding the use of chloroquine or hydroxychloroquine for treatment of COVID-19?

Background on COVID-19

The recent outbreak of respiratory illness was originally reported to the World Health Organization (WHO) when a cluster of pneumonia cases occurred in Wuhan, Hubei Province, China in December 2019.1 The causative agent was deemed to be a novel betacoronavirus, designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).2 The consequent respiratory disease following exposure to the virus has been named coronavirus disease 2019, or COVID-19. The full extent of the clinical course is not yet known. The severity of symptom progression ranges from low grade fever, cough, malaise, and rigors to dyspnea, pneumonia, and death.3 Currently, the recommended standard of care is solely supportive care and supportive management for common complications.4 Investigations into the evidence for the safety and efficacy of drug treatment are ongoing.

Chloroquine (Aralen®) and its analogue hydroxychloroquine (Plaquenil®) are aminoquinolines classified as antimalarial agents.5 Their Food and Drug Administration (FDA)-approved indication is for prophylaxis and treatment of certain forms of malaria.6,7 In addition, hydroxychloroquine is FDA-approved for the treatment of rheumatoid arthritis and systemic lupus erythematosus.7 Due to its antiviral activity, chloroquine was previously studied in the management of the Zika virus and SARS-CoV outbreaks with promising results.5 Thus, these agents have been deployed as potential therapeutic options for COVID-19.

Although the exact mechanism of antiviral activity is unknown, the proposed mechanism involves the ability of chloroquine and hydroxychloroquine to increase the pH of intracellular vacuoles.5 Recently, both in vitro and clinical studies have been conducted to examine chloroquine and hydroxychloroquine activity against SARS-CoV-2. Optimal dose and duration have yet to be determined, with commonly studied doses of 500 mg twice daily for 7 to 10 days being used for chloroquine and 200 to 800 mg daily (in divided doses) for 5 to 10 days for hydroxychloroquine.8

Literature Evaluation

A literature search was performed examining the use of chloroquine or hydroxychloroquine for the treatment of SARS-CoV-2. This search identified several in vitro studies and 8 clinical studies.9-17 The details of these clinical studies are outlined in Table 1. Although most clinical studies have not been peer-reviewed at the time of this posting, the information is still valuable in designing future trials.

An in vitro study completed in China tested the pharmacologic activity of chloroquine and hydroxychloroquine on SARS-CoV-2 infected Vero cells.9 Both chloroquine and hydroxychloroquine displayed antiviral activity against SARS-CoV-2. It was concluded that hydroxychloroquine had greater inhibitory effect on SARS-CoV-2 in vitro than chloroquine.

The majority of clinical studies examine hydroxychloroquine instead of chloroquine because of its lesser side effect profile. The only study identified examining chloroquine for SARS-CoV-2 was terminated pre-maturely and has been omitted from Table 1.10 This study, CloroCovid-19, was a parallel, double-blind, randomized, phase IIb clinical trial conducted in Brazil. The trial tested the safety and efficacy of either high-dose (600 mg twice daily for 10 days) or low-dose (450 mg twice daily on day 1, then 450 mg daily on days 2 to 5) chloroquine in treating hospitalized patients with SARS-CoV-2 infection. A QTc variation was seen in both arms with 2 patients in the high-dose arm developing ventricular tachycardia before death. The trend towards higher fatality deemed the high-dose arm unsafe, stopping the trial early.

Table 1. Summary of clinical evidence regarding use of chloroquine or hydroxychloroquine in COVID-19.11-17
Study designSubjects and treatmentResultsConclusionLimitations
Gautret 2020[a]11

Non-randomized, open-label, single-center trial

N=36 patients (mean age, 45.1 years) greater than 12 years of age with PCR documented SARS-CoV-2 from a nasopharyngeal sample

Treatment arms:
HCQ 200 mg TID for 10 days (n=20) vs control (n=16; patients who declined treatment or who were at another medical center)

Addition of azithromycin 500 mg for day 1, then 250 mg daily for 4 days, given at provider’s discretion (n=6)		Primary:
At day 6, negative PCR results found in 8 (57.1%) subjects in the HCQ group, 6 (100%) subjects treated with HCQ and azithromycin, and 2 (12.5%) subjects in the control group (p<0.001 for HCQ group vs. control group)

HCQ treatment significantly reduced viral load of COVID-19

HCQ treatment potency reinforced by synergistic effect with azithromycin

More studies needed to assess viral load reduction and improvement in clinical outcomes		Patients with QT prolongation were excluded, mitigating potential issue with concurrent administration of HCQ and azithromycin

Small sample size within a single center

Open-label trial increases potential of biased assessments

Asymptomatic patients were included

Study was not designed to discern benefit of HCQ vs. HCQ and azithromycin
Gautret 2020[b]12

Non-randomized, non-controlled, observational study

N=80 patients (median age, 52 years) greater than 18 years of age with PCR-documented SARS-CoV-2 RNA from a nasopharyngeal sample with upper or lower respiratory tract infection

Treatment arm:
HCQ 200 mg TID for 10 days combined with azithromycin (500 mg on day 1, then 250 mg daily for 4 days)

Patients with pneumonia and NEWS ≥ 5 given additional treatment of broad-spectrum antibiotic (ceftriaxone)

NEWS score based on age, respiratory rate, O2 saturation, temperature, BP, pulse, level of consciousness

Primary:
Discharge from ID unit after 3 days of treatment occurred in 65 (81.3%) patients and 3 were transferred to the ICU

12 patients (15%) required oxygen therapy after 3 days of treatment.

At day 7, 83% of patients had a negative PCR Ct value and 93% were negative at day 8

Mean length of stay in ID ward was 4.6 days

Adverse events of nausea or vomiting reported in 2.5%, diarrhea in 5%, and blurred vision in 1.2% of patients		Efficacy of HCQ plus azithromycin treatment shown in this cohort with significant clinical improvement and patient outcomes

Patients treated with HCQ plus azithromycin treatment were able to rapidly discharge from ID ward

QT prolongation should be monitored with ECG prior to treatment in future studies		Majority (92%) were considered low risk for clinical deterioration (low NEWS)

Several asymptomatic patients included

Study was uncontrolled with no comparison arm

Conclusions presented cannot be fully confirmed for benefit in disease progression or reduced infectiousness
Chen J 202013

Randomized, single-center trial

N=30 patients greater than 18 years of age with confirmed COVID-19

Treatment arms:
HCQ 400 mg daily for 5 days plus conventional treatments (n=15) vs conventional treatment only (n=15)		Primary:
At day 7, negative conversion in pharyngeal swabs was found in 13 (86.7%) cases in the HCQ group and 14 (93.3%) cases in the control group (p>0.05)

Secondary:
Median duration of hospitalization (4 days vs. 2 days, respectively) and time for body temperature normalization (1 day for both) were similar between HCQ and control groups (P>0.05 for both)

Results fail to indicate benefit in viral clearance for HCQ plus conventional treatments over solely conventional treatment

More studies with larger sample sizes and better endpoints are needed to fully consider HCQ as feasible treatment option		Small sample size

Underpowered, so unable to detect a difference if it exists

Lack of peer-review

Only available as abstract format (full text not available in English)
Chen Z 202014

Randomized, parallel-group trial

N=62 patients (mean age, 44.7 years) greater than 18 years of age with RT-PCR positive of SARS-CoV-2 and chest CT confirmation of pneumonia with either SaO2/SpO2 ratio > 93% or PaO2/FiO2 ratio > 300 mmHg

Treatment arms:
HCQ 400 mg daily for 5 days plus standard treatments (n=31) vs standard treatment only (n=31)

Standard treatment defined as oxygen therapy, antiviral agents, antibacterial agents, and Ig, with or without corticosteroids		Primary:
Changes in TTCR* were significantly reduced in HCQ group compared to control group

Body temperature recovery time (mean, SD): HCQ treatment group (2.2, 0.4 days) vs control group (3.2, 1.3) days (p=0.0008)

Cough remission time (mean days, SD): HCQ group (2.0, 0.2) vs control (3.1, 1.5) (p=0.0016)

Improvement in pneumonia: 25 (80.6%) patients in HCQ group vs 17 (54.8%) patients in control group		Study shows benefit of HCQ in treatment of mild illness with evidence in reducing risk of progression to severe illness

Future research with adequately powered studies and objective endpoints, including viral load response, are needed		Small study size

Subjective endpoints utilized

Lack of peer-review

Patients with severe disease were excluded

Patients received other anti-infectives in addition to HCQ

39 patients were afebrile at baseline (22 in HCQ; 17 in control)

23 patients did not have a cough at baseline (9 in HCQ; 16 in control)
Mahévas 202015

Non-randomized, multicenter, observational study		N=181 patients (median age, 60 years) between 18 and 80 years of age with PCR-confirmed SARS-CoV-2 infection and required oxygen by mask or nasal prongs

Treatment arms:
HCQ 600 mg daily in the first 48 hours after hospitalization plus standard of care (n=84) vs standard of care only (n=97)

In the HCQ group, 17 (20%) patients received concomitant azithromycin and 64 (76%) patients received concomitant amoxicillin and clavulanic acid		Primary:
16 (20.5%) patients in the HCQ group were transferred to the ICU or died within 7 days vs 21 (22.1%) in the no-HCQ group (RR 0.93, 95% CI 0.48 to 1.81)

Secondary:
3 (2.8%) patients in the HCQ group died within 7 days vs 4 (4.6%) in the no-HCQ group (RR 0.61, 95% CI 0.13 to 2.90)

24 (27.7%) patients in the HCQ group and 23 (24.1%) in the no-HCQ group developed ARDS within 7 days (RR 1.15, 95% CI 0.66 to 2.01)		No difference in reduction of admissions to ICU or death 7 days after hospital admission with HCQ treatment compared to standard of care only

Treatment with HCQ also did not decrease rate of ARDS		Lack of peer-review

Limited events for outcomes such as all-cause mortality

Treatment between centers were not standardized (some centers provided HCQ treatment for all patients while others did not)
Tang 202016

Randomized, controlled, multicenter, open-label trial		N=150 patients (mean age, 46.1 years) greater than 18 years of age with RT-PCR confirmed SARS-CoV-2

Treatment arms:
HCQ loading dose of 1,200 mg daily for 3 days then maintenance dose of 800 mg daily for remaining days (total treatment duration: 2 weeks for mild/moderate; 3 weeks for severe patients) plus standard of care (n=75) vs standard of care only (n=75)

Primary:
Within 28 days, negative conversion rate of HCQ group was 85.4% (95% CI, 73.8 to 93.8) and 81.3% (95% CI, 71.2 to 89.6) in the standard of care group (p-value not provided)

Within 28 days, symptom alleviation rate was 59.9% (95% CI, 45.0 to 75.3) with HCQ and 66.6% (95% CI, 39.5 to 90.9) without HCQ		Addition of HCQ failed to show benefit in reducing negative conversion rate of SARS-CoV-2 over standard of care

Alleviation of symptoms rate was not different between HCQ and non-HCQ groups

Lack of peer-review

Open-label trial increases potential of biased assessments

Negative conversion endpoint makes it difficult to attribute results to HCQ

Only 2 severe cases included in study
Magagnoli 202017

Retrospective, multicenter, cohort study		N=385 (median age, 69 years, 100% male) patients with SARS-CoV-2 within the US Veterans Health Administration medical centers

Cohort arms:
HCQ exposure (n=97), HCQ and azithromycin exposure (n=113), or no HCQ exposure (n=158) (patients were grouped based on the dispensing of a medication dose identified with bar code medication administration records)

Death occurred in 27 (27.8%) HCQ patients, 25 (22.1%) HCQ + azithromycin patients, and 18 (11.4%) no-HCQ patients (p=0.003)

Mechanical ventilation occurred in 13.3% of HCQ patients, 6.9% of HCQ + azithromycin patients, and 14.1% of no-HCQ patients (p=0.547)		Exposure to HCQ did not reduce need for mechanical ventilation

Increased mortality seen with HCQ exposure, although this may be due to several factors		Baseline demographics varied between groups introducing possible confounders, including presence of cerebrovascular disease (20.7% of HCQ, 7.1% of HCQ + azithromycin, 12% of no-HCQ)

Only included patients that died or were discharged. Patients with long hospitalizations may not be represented

HCQ group may include patients receiving only 1 dose
*TTCR defined as return of body temperature and cough relief, maintained for more than 72 hours
Abbreviations: ARDS=acute respiratory distress syndrome; BP=blood pressure; CI=confidence interval; Ct=cycle threshold; CT=computed tomography; ECG=electrocardiogram; FiO2=fraction of inspired oxygen; HCQ=hydroxychloroquine; ICU=intensive care unit; ID=infectious disease; Ig=immunoglobulin; NEWS=national early warning score; O2=oxygen; PAO2=oxygen pressure; PCR=polymerase chain reaction; RR=relative risk; RT-PCR=reverse transcription polymerase chain reaction; SaO2=arterial oxygen saturation; SD=standard deviation; SpO2=peripheral oxygen saturation; TID=three times daily; TTCR=time to clinical recovery; vs=versus.

Out of the 7 clinical studies in Table 1, results from 3 studies support the use of hydroxychloroquine and 4 studies showed no difference when used.11-17 The majority of these studies did not undergo a rigorous peer-review process at the time of this review and were only available as pre-print articles.13-17 Additionally, each study included a small sample size, which may have led to an exaggerated effect size or contributed to the inability to detect a difference in treatments if one exists. More than half of these studies utilized the endpoint of negative viral test result, which may not accurately correlate with clinical outcomes.11-13,16 In general, these studies did not include a large number of critically ill patients.

Two of the studies that showed benefit with hydroxychloroquine were performed by Gautret and colleagues.11,12 An open-label, single-center trial conducted in France by Gautret et al. evaluated virologic clearance between patients treated with or without hydroxychloroquine.11 Much critique has fallen on the study, in which the International Journal of Antimicrobial Agents states that the study does not meet the expected standards of the International Society of Antimicrobial Chemotherapy.18 Reasons for critique include the insufficient explanation for the inclusion criteria, problematic confounding variables, conflicted peer-review, and unclear data. In a follow-up study, Gautret et al. observed patients treated with a combination of hydroxychloroquine and azithromycin.12 Although the study showed an improvement in clinical course, the majority (92%) of patients were considered low risk for clinical deterioration. This may have contributed to the favorable effects observed and limits the application to severe cases. Additionally, the benefits of hydroxychloroquine are hard to ascertain without a comparator arm.

The randomized trial conducted by Chen Z. and colleagues also found benefit with hydroxychloroquine in decreasing time to clinical recovery.14 This study found a reduction in body temperature recovery time and cough remission time; however, not all patients were febrile or had a cough at baseline. The subjective endpoint utilized in this study, cough remission time, allowed for assessments to vary between investigators. Patients with severe disease were excluded from this study, limiting its application in clinical practice.

Only 1 study was performed in the United States in males admitted and discharged from the Veteran Affairs hospitals.17 This study did not show benefit in patients exposed to hydroxychloroquine. This study was based on administrative billing data and, therefore, does not consider whether hydroxychloroquine was administered in an appropriate dose and duration. This study did examine clinically meaningful outcomes of mechanical ventilation and death. While the hydroxychloroquine group had more deaths, this study did not control for confounders potentially contributing to this difference. Mahévas and colleagues also examined a clinical endpoint, death and critical care unit admission, which failed to improve with hydroxychloroquine use.15

Two randomized trials, conducted in China by Chen J. et al. and Tang et al. analyzed viral clearance in patients treated with hydroxychloroquine compared to standard treatment.13,16 Both of these studies failed to find a benefit of hydroxychloroquine treatment in viral clearance. However, both trials were limited by weak endpoints, as negative conversion rate does not account for confounders. While Chen J. et al. examined viral clearance at 7 days, Tang et al. utilized a 28-day endpoint, which may not be as clinically relevant.

Recommendations from health organizations

As the available information is rapidly evolving, it is imperative to consult various resources for guidance on the use of chloroquine and hydroxychloroquine in the treatment of COVID-19. Organizations such as the Centers for Disease Control and Prevention (CDC), WHO, the Infectious Diseases Society of America (IDSA), and the Society of Critical Care Medicine (SCCM) have issued similar guidance regarding usage of chloroquine and hydroxychloroquine.4,19-22 Although an explicit recommendation for or against chloroquine or hydroxychloroquine is not made, the CDC and WHO state that the use of any investigational therapies should preferably be restricted to randomized controlled trials. Due to studies and several case reports citing significant QT prolongation with the individual use of hydroxychloroquine or azithromycin without clear benefit of either component, the IDSA advises that hydroxychloroquine with or without azithromycin should only be used in the context of a clinical trial. The National Institutes of Health (NIH) guideline notes that no drug has been proven safe and effective as a treatment option for COVID-19. Additionally, the SCCM provided guidelines for the management of critically ill adults with COVID-19, which also determined that there is insufficient evidence to recommend the use of either agent in this treatment group.

Other organizations expressed concern on the potential adverse events associated with chloroquine and hydroxychloroquine, especially with the notable combination of hydroxychloroquine and azithromycin. The American Heart Association (AHA), the American College of Cardiology (ACC), and the Heart Rhythm Society (HRS) issued recommendations based around the increased risk of cardiac complications, such as QT prolongation and arrhythmia.23,24 The AHA, ACC, and HRS advise additional caution and monitoring be performed when administering these medications in patients with existing cardiovascular disease. Additionally, the FDA issued a safety communication warning against the use of hydroxychloroquine or chloroquine for COVID-19 in patients that are not hospitalized or enrolled in a clinical trial due to the risk of heart rhythm problems.25

Clinical considerations

Drug interactions/QT prolongation

Data on the adverse effects of the combination of hydroxychloroquine and azithromycin are limited. When used separately, both hydroxychloroquine and azithromycin have been reported to cause QT prolongation and torsade de pointes.24 In rare instances, azithromycin has been found to induce other cardiac complications such as serious arrhythmias, increased risk of sudden death, and polymorphic ventricular tachycardia. As critically ill patients and patients with existing cardiovascular conditions are at higher risk for arrhythmias, the AHA, ACC, and HRS have provided guidance on minimizing the risk.23 The recommendations include electrocardiographic/QT interval monitoring, withholding hydroxychloroquine and azithromycin in patients with baseline QT prolongation (ie, QTc ≥500 msec) or with known congenital long QT syndrome, and correction of hypokalemia to levels of >4 mEq/L and hypomagnesemia to levels of >2 mg/dL.24

Shortages and overprescribing practices

When chloroquine and hydroxychloroquine were announced as potential treatment options, concerns for the availability of the medications were raised.26,27 Shortages of these medications could possibly cause grave consequences for patients with lupus or rheumatoid arthritis. To address these concerns, the American Medical Association, American Pharmacists Association, and American Society of Health-System Pharmacists delivered a joint statement targeting physicians, pharmacists, and health systems.26 The statement opposes anticipatory and prophylactic prescribing by providers for themselves, family, and colleagues. Additionally, the statement opposes excess purchasing and stockpiling by pharmacies and hospitals.

Further addressing ramifications of supply issues, the Lupus Foundation of America, American Academy of Dermatology, American College of Rheumatology, and Arthritis Foundation issued a joint statement urging Vice President Mike Pence to act in regulating usage of these medications.27 The statement suggests Vice President Pence work in conjunction with the pharmaceutical industry, pharmacies, and the FDA to increase production and supply of these drugs, monitor inventory to report shortages, and ease access to these medications for patients in whom they are indicated.

Compounding hydroxychloroquine

Given the potential need for administration via enteral tube, information on compounding hydroxychloroquine is available. The International Journal of Pharmaceutical Compounding published a compounding recipe for a hydroxychloroquine sulfate 25 mg/mL oral solution using hydroxychloroquine sulfate tablets.28 The preparation describes crushing hydroxychloroquine tablets to a fine powder, levigating the powder with Oral Mix, and adding sufficient quantity of additional Oral Mix to meet the proper volume for the formulation. A recipe is also available utilizing Ora-Plus and water for irrigation as diluents.29 The Institute for Safe Medication Practices includes hydroxychloroquine in its List of Oral Dosage Forms That Should Not Be Crushed due to the tablet being film-coated.30

Ongoing/Upcoming trials

Numerous studies around the world are underway to analyze the use of chloroquine and hydroxychloroquine for both pre- and post-exposure prophylaxis and treatment of COVID-19. Ongoing and upcoming trials testing all treatment options against SARS-CoV-2 can be found on ClinicalTrials.gov.31 As of March 28th, 2020, the FDA issued an Emergency Use Authorization (EUA) for the use of hydroxychloroquine sulfate supplied from the Strategic National Stockpile to treat adults and adolescents who weigh 50 kg or more and are hospitalized with COVID-19 for whom a clinical trial is not available, or participation is not feasible.32 While the optimal dosing is unknown, the suggested dose under the EUA is 800 mg on the first day of treatment and then 400 mg daily for 4 to 7 days of total treatment based on clinical evaluation.

Conclusion

With preliminary results suggesting their use, chloroquine and hydroxychloroquine pose attractive treatment options for COVID-19. However, data on safety and efficacy are limited, conflicting, and low quality. Additional adequately powered studies with larger sample sizes and better endpoints need to be conducted to confirm benefit of therapy. As investigational trials continue to test hydroxychloroquine and chloroquine, cardiac complications such as QT prolongation must be addressed. Once further results are published, a stronger recommendation for or against widespread use of chloroquine and hydroxychloroquine could be made.

References

  1. Novel Coronavirus (2019-nCoV) situation reports. World Health Organization. January 21, 2020. Accessed April 7, 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
  2. Situation summary. Centers for Disease Control and Prevention. Updated April 7, 2020. Accessed April 7, 2020. https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/summary.html?CDC_AA_refVal=https://www.cdc.gov/coronavirus/2019-ncov/summary.html
  3. Coronavirus, COVID-19, SARS. Sanford Guide Web Edition. Updated April 7, 2020. Accessed April 7, 2020. https://webedition.sanfordguide.com/en/sanford-guide-online/disease-clinical-condition/coronavirus
  4. ‌Interim Clinical Guidance for Management of Patients with Confirmed Novel Coronavirus (COVID-19). Updated April 3, 2020. Accessed April 7, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html
  5. ‌Sahraei Z, Shabani M, Shokouhi S, Saffaei A. Aminoquinolines against coronavirus disease 2019 (COVID-19): Chloroquine or hydroxychloroquine. Int J Antimicrob Agents. Published online March 17, 2020. doi:10.1016/j.ijantimicag.2020.105945
  6. ‌Chloroquine phosphate. Package insert. Rising Pharmaceuticals, Inc; 2018.
  7. Plaquenil. Package insert. Concordia Pharmaceuticals Inc; 2018.
  8. Assessment of Evidence for COVID-19-Related Treatments. American Society of Health-System Pharmacists. Updated April 7, 2020. Accessed April 7, 2020. https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/ASHP-COVID-19-Evidence-Table.ashx
  9. ‌Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis. Published online March 9, 2020. doi:10.1093/cid/ciaa237
  10. ‌Borba MGS, Val F de A, Sampaio VS, et al; CloroCovid-19 Team. Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study). MedRxiv [preprint]. April 16, 2020. doi:10.1101/2020.04.07.20056424
  11. ‌Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open- label non-randomized clinical trial. Int J Antimicrob Agents. Published online March 20, 2020. doi:10.1016/j.ijantimicag.2020.105949
  12. Gautret P, Lagier JC, Parola P, 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: A pilot observational study. Travel Med Infect Dis. Published online April 11, 2020. doi:10.1016/j.tmaid.2020.101663
  13. 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 (Med Sci). Published online March 6, 2020. doi: 10.3785/j.issn. 1008-9292.2020.03.03
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  15. Mahevas M, Tran VT, 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 [preprint]. Published online April 14, 2020. doi:10.1101/2020.04.10.20060699
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  17. Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. MedRxiv [preprint]. Published online April 23, 2020. doi: 1101/2020.04.16.20065920
  18. Hydroxychloroquine study did not meet ‘expected standard.’ Medscape. Published April 8, 2020. Accessed April 19, 2020. https://www.medscape.com/viewarticle/928336.
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  20. Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. April 11, 2020. Accessed April 11, 2020. www.idsociety.org. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
  21. Coronavirus disease 2019 (COVID-19) treatment guidelines. National Institute of Health. Updated April 21, 2020. Accessed April 23, 2020. https://www.covid19treatmentguidelines.nih.gov/
  22. Alhazzani W, Møller MH, Arabi YM, et al. Surviving sepsis campaign: Guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. Published online March 27, 2020. doi:10.1097/ccm.0000000000004363
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  25. ‌ 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. U.S. Food and Drug Administration. Updated April 24, 2020. Accessed April 24, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or
  26. Joint Statement of the American Medical Association, American Pharmacists Association, and American Society of Health-System Pharmacists on inappropriate ordering, prescribing or dispensing of medications to treat COVID-19. Accessed April 13, 2020. https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/AMA-APhA-ASHP-statement-ensuring-access-to-medicines-covid19.ashx?la=en&hash=F844D66155C2505C8DFC39DFA7F7CA04786E483C ‌
  27. Lupus Foundation of America, American College of Rheumatology, American Academy of Dermatology, and Arthritis Foundation joint statement. Letter. Accessed April 13, 2020. https://www.rheumatology.org/Portals/0/Files/Joint-Statement-HCQ-LFA-ACR-AADA-AF.pdf
  28. ‌Allen LV. Hydroxychloroquine Sulfate 25 mg/mL in Oral Mix or Oral Mix SF. Int J Pharm Compd. 2017;21(6):494.
  29. Nahata MC, Pai VB. Pediatric Drug Formulations. 6th Harvey Whitney Books; 2014.
  30. Oral Dosage Forms That Should Not Be Crushed. Institute for Safe Medication Practices. February 21, 2021. Accessed April 13, 2020. https://www.ismp.org/recommendations/do-not-crush
  31. ‌Clinicaltrials.gov. Accessed April 14, 2020. https://clinicaltrials.gov/
  32. Fact sheet for health care providers emergency use authorization (EUA) of chloroquine phosphate supplied from the strategic national stockpile for treatment of COVID-19 in certain hospitalized patients. U.S. Food and Drug Administration. April 3, 2020. Accessed April 11, 2020. https://www.fda.gov/media/136535/download

Prepared by:
Steven Le, PharmD Candidate Class of 2020
University of Illinois at Chicago College of Pharmacy

Reviewed by:
Amanda Gerberich, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

May 2020

The information presented is current as April 23, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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