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A Rapid Guidance Summary from the

Penn Medicine Center for Evidence-based Practice

Last updated

April 21

July 1, 2020

10:00 pm

. All links rechecked

April 20

June 30 unless otherwise noted.

View file
nameHCQ prophylaxis update
2 final.pdf


This Rapid Guidance Summary is a description of existing guidance and evidence reviews from a variety of sources that was in effect at the time of publication. It should not be used or interpreted as a clinical practice guideline, but instead can be used in development of local recommendations and policies.

Key Questions Answered in This Summary

  • Is hydroxychloroquine effective for prevention of clinical disease in patients who have been exposed to the 2019-nCoV coronavirusSARS-CoV-2?

           Use of hydroxychloroquine for treatment of confirmed COVID-19 disease is outside the scope of this report. 

Summary of


Major Recommendations

  • Use of hydroxychloroquine or chloroquine for prevention of COVID-19 disease is not recommended outside of approved clinical trials.
  • A systematic review of clinical evidence found only one trial evaluating HCQ for preventing COVID-19 disease in persons with history of exposure to infected patients. Results of that single trial did not demonstrate reduced COVID-19 disease with hydroxychloroquine, and the risk of adverse events is possibly increased. The risk of bias in that study was high.
  • There are no hospitals medical centers using hydroxychloroquine or chloroquine for prevention of COVID-19 disease outside of approved clinical trials.

Recent Public Health Agency and Professional Society Guidelines on


Prophylactic Use of





Public health agencies


April 13

Hydroxychloroquine and chloroquine are under investigation in clinical trials for pre-exposure or post-exposure prophylaxis of SARS-CoV-2 infection, and treatment of patients with mild, moderate, and severe COVID-19.


April 2

Despite some encouraging results from clinical trials involving small cohorts of patients, the available data do not support the widespread use of chloroquine or hydroxychloroquine in patients with COVID-19.


April 9

There are currently no FDA-approved medical countermeasures for COVID-19.

Emergency use authorization for hydroxychloroquine applies only to patients hospitalized with COVID-19 disease.


March 27

WHO is actively following the ongoing clinical trials that are being conducted in response to COVID-19, including studies looking at the use of chloroquine and its derivative, hydroxychloroquine, for treatment and/or prevention. Currently, there is insufficient data to assess the efficacy of either of these medicines in treating patients with COVID-19, or in preventing them from contracting the coronavirus.

Public Health England March 25

Chloroquine and hydroxychloroquine are not licensed to treat COVID-19 related symptoms or prevent infection. Clinical trials are ongoing to test chloroquine and hydroxychloroquine as an agent in the treatment of COVID-19 or to prevent COVID-19 infection. These clinical trials are still not completed, so no conclusions have been

reached on the safety and effectiveness of this medicine to treat or prevent COVID-19.


No guidance relating to treatment or prophylaxis.



Professional societies


March 23

During this crisis, there is understandable concern over the health and safety of loved ones. However,

inappropriate prescribing of these experimental treatments to have “just in case” or for patients who are not at high risk of severe illness may lead to an inadequate supply of medications for those who need them most.

Similarly, stocking up and hoarding can also create shortages or exacerbate existing shortages. Outpatient prescriptions for these medications should include a documented diagnosis from the prescriber consistent with the FDA-approved indication or other literature-supported, off-label use

Outpatient prescriptions should be dispensed only:

a)  In coordination with discharge planning from an inpatient setting for continuity of care, or

b)  For patients with a confirmed positive test for SARS-CoV-2, or

c)  For patients designated as a Person Under Investigation (PUI).

INESS- Institut national d'excellence en santé et services sociaux (Quebec) ASHP–American Society of Health System Pharmacists

CPA–Canadian Pharmacists Association

Evidence reviews on prophylactic use of hydroxychloroquine




April 17

Only limited clinical trial data available to date to evaluate use of hydroxychloroquine for treatment or prevention of COVID-19.

June 15

The Emergency Use Authorization for hydroxychloroquine (now withdrawn) applied only to patients hospitalized with COVID-19 disease; prophylactic use was never authorized.


May 27

We recommend that chloroquine and hydroxychloroquine (± azithromycin) not be administered as treatment or prophylaxis for COVID-19, outside of the context of clinical trials.

Professional societies


June 30

The American College of Physicians specifically does not recommend use of chloroquine or hydroxychloroquine alone or in combination with azithromycin as prophylaxis against COVID-19.


June 17

For people exposed to individuals with COVID-19, only administer hydroxychloroquine for post-exposure prophylaxis in the context of randomized trials with appropriate ethical approval.


June 17

Hydroxychloroquine and chloroquine are not recommended for use for widespread prophylaxis against COVID-19. Strength of evidence: not recommended, insufficient evidence. Level of confidence: low.

CEP NOTE: NIH guidelines do not apply to prophylaxis in persons with SARS-CoV-2 exposure

Systematic Reviews With Quantitative Data Synthesis



Living Evidence June 30

For outcome of positive COVID-19 disease within 14 days of exposure to infected person: Summary risk ratio 0.83, 95% CI 0.58-1.18, p = 0.30, I2 not applicable, 1 trial, 821 patients, moderate risk of bias.

For outcome of adverse events: Summary risk ratio 2.39, 95% CI 1.83-3.11, p < 0.001, I2 not applicable, 1 trial, 701 patients, high risk of bias.

CEP NOTE: Please see linked page for current review results including forest plots of results.

CEP NOTE: The protocol for a Cochrane Review on this topic has been published, but the review is not yet completed.

Other Recent Evidence Reviews on Prophylactic Use of Hydroxychloroquine





June 30

A randomized trial of hydroxychloroquine for postexposure prophylaxis within 4 days after high-risk or moderate- risk exposure to Covid-19 showed no prevention of Covid-19 or compatible illness, although most patients did not start therapy for at least 3 days after SARS-CoV-2 exposure


June 30

A recent randomized, double-blind, placebo-controlled trial of hydroxychloroquine as post-exposure prophylaxis after a high risk exposure to COVID-19 did not show any clinical benefit. The majority of subjects enrolled (87.6%) had a high risk exposure defined as being less than 6 feet from someone with confirmed COVID-19 without a face mask or eye shield for greater than 10 minutes. Subjects were randomized to HCQ 800 mg orally once followed by 600 mg daily x 4 days vs placebo. There was no significant difference in the development of confirmed or probable COVID-19 in the HCQ group vs placebo (11.8% vs 14.3%, p = 0.35). There were more side effects, predominantly gastrointestinal in nature, in the hydroxychloroquine group.


June 27

On 26 June the UK Medicines and Healthcare products Regulatory Agency announced that it had “given the [COPCOV] clinical trial the green light to recruit more participants at the request of the COPCOV trialists, who are studying the use of hydroxychloroquine in preventing COVID-19. At the same time, MHRA reminded prescribers that “Chloroquine and hydroxychloroquine are not licensed to treat COVID-19 related symptoms or prevent infection” and that “until we have clear, definitive evidence that these treatments are safe and effective for the treatment of COVID-19, they should only be used for this purpose within a clinical trial.”

Southern Cal.

June 26

Major media outlets have reported hydroxychloroquine does not prevent COVID-19. This is based on a randomized, double-blind placebo controlled trial of 821 asymptomatic participants in which the investigators concluded there was no difference in the incidence of new illness between placebo and hydroxychloroquine. Some have argued, however, the study may not be definitive, because the participants self-reported symptoms and there was no testing, raising the question of the trial design.


June 25

Efficacy and safety of hydroxychloroquine for treatment or prevention of COVID-19 is not established.

Additional No data needed to determine whether date indicating that in vitro activity against SARSCoVSARS-CoV-2 corresponds with clinical efficacy for treatment or prevention of COVID19.

Additional data needed to substantiate initial reports of efficacy for treatment and identify optimal dose and duration. Various clinical trials are being initiated in the US and elsewhere to evaluate hydroxychloroquine for prevention of COVID19 in the healthcare setting or in household contacts of patients with the disease [see full review for trial IDs].

None of the clinical studies discussed in the review involved patients without confirmed COVID-19 diagnosis.


April 14

Current data do not support the use of hydroxychloroquine for prophylaxis or treatment of COVID-19. There are no published trials of prophylaxis.


April 3

Prophylactic use not discussed

ASHP–American Society of Health System Pharmacists SIDP–Society of Infectious Disease Pharmacists CEBM–University of Oxford Centre for Evidence-based Medicine


Only limited clinical trial data available to date to evaluate use of hydroxychloroquine for prevention of COVID- 19.

Brigham June 23

The first randomized control trial for COVID-19 post-exposure prophylaxis was published on June 3, 2020. Asymptomatic patients who had household or occupational exposures to others with COVID-19 for more than 10 minutes within 4 days of exposure were randomized to receive either placebo (n=407) or hydroxychloro- quine 800 mg once, 600 mg in 6-8 hours, then 600 mg daily for 4 additional days (n=414). The incidence of new illness compatible with COVID-19 was 11.8% in the hydroxychloroquine arm and 14.3% in the placebo arm (absolute difference -2.4%, 95% CI -7 to 2.2%, p=0.35). Side effects were more common in the hydroxychloroquine arm (40.1% vs. 16.8%), but no serious adverse reactions were reported.


June 15

Role for post-exposure prophylaxis is not compelling, at least among clinical/healthcare worker exposures

Washington June 9

A double-blind placebo-controlled RCT found that prophylactic hydroxychloroquine fails to prevent symptomatic infection after SARS-CoV-2 exposure.

Medical Center Guidance on Prophylactic Use of Hydroxychloroquine



Mass. General April 18

June 24

There is currently no proven role for post exposure prophylaxis for people healthcare workers with a known COVID-19 exposure. They should follow self-quarantine for 14-days and monitor for symptoms. Healthcare workers should follow instructions from Occupational Health.

Brigham April 17

No provision for prophylactic or outpatient use.

Cleveland April 16

In accordance with state regulations, hydroxychloroquine may not be prescribed without a confirmed diagnosis of COVID-19 disease.

Washington April 15

Post exposure prophylaxis (PEP) of COVID-19 is not currently recommended. For household contacts or health care workers with COVID-19 exposure, there is an ongoing randomized clinical trial of hydroxychloroquine PEP at UW Medicine (NCT04328961).



Penn Medicine April 10No benefit of hydroxychloroquine was seen in a double-blinded placebo randomized controlled trial.


June 23

Hydroxychloroquine is not recommended outside of the context of a clinical trial.

Penn Medicine

June 20

We do not recommend routine post-exposure prophylaxis. If signs/symptoms develop, follow treatment guidelines above.

Despite reports of efficacy of azithromycin plus hydroxychloroquine to treat SARS-CoV-2, azithromycin should not be added to hydroxychloroquine only to treat SARS-CoV-2. The efficacy of combination azithromycin and hydroxychloroquine comes from a study with significant limitations. In addition, the International Society of Antimicrobial Chemotherapy recently redacted the article because of scientific concerns.

Mt. Sinai April 10

Hydroxychloroquine is NOT recommended for use in patients without PCR-confirmed COVID-19

Johns Hopkins

April 8

Hydroxychloroquine is currently being investigated in post-exposure prophylaxis in healthcare workers (NCT04308668).

Michigan April 6

The data is not strong enough to recommend routine use of hydroxychloroquine.

Toronto April 2

Chloroquine and hydroxychloroquine (with or without azithromycin) are not recommended for patients with COVID-19 outside of approved clinical trials or where other indications would justify its use (e.g. chronic rheumatological conditions).

Yale March 24

There are currently no FDA approved medications for treatment of COVID-19; but several readily available oral medications have demonstrated possible activity against SARS CoV-2 including hydroxychloroquine, HIV-1 protease inhibitors (e.g., lopinavir-ritonavir, atazanavir, tipranavir), and azithromycin. None of these agents have been studied in large clinical trials (with or without placebo) to support their off label use in the ambulatory setting for the treatment/prevention of COVID 19 patients.

The use of these “re-purposed” medications in the outpatient setting is inappropriate, and will result in shortages, which will impact treatment of patients for whom these medications are indicated by FDA approval, established clinical experience, or for the severely ill inpatients with COVID-19.

Outpatient prescribing of hydroxychloroquine, HIV-1 protease inhibitors, and azithromycin should be reserved ONLY for patients who have medical conditions where their use has been established and there are no other alternatives.


Definition of terms

Guideline: Guidance developed by a professional society or government agency, intended for use at multiple hospitals.


Guidance sources

ACOEM- American College of Occupational and Environmental Medicine ACP–American College of Physicians

ASHP–American Society of Health System Pharmacists CEBM–University of Oxford Centre for Evidence-based Medicine EM-RAP–Emergency Medicine Reviews and Perspectives

Living Evidence–an ad hoc collaboration of Cochrane Collaboration members and hospital health technology assessment specialists

SIDP–Society of Infectious Disease Pharmacists

Update History

July 1: Updated ACP and medical center guidance. Outdated guidance removed. New section for systematic reviews, other evidence reviews updated. Conclusions strengthened.

April 21: Updated evidence reviews and medical center guidance. April 11: Initial report.

About this report

A Rapid Guidance Summary is a focused synopsis of recommendations from selected guideline issuers and health care systems, intended to provide guidance to Penn Medicine providers and administrators during times when latest guidance is urgently needed. It is not based on a complete systematic review of the evidence. Please see the CEP web site for further details on the methods for developing these reports.

Lead analyst: Matthew D. Mitchell, PhD (CEP) Evidence team leader: Emilia J. Flores, PhD, RN (CEP) Reviewer:

Reviewers: George L. Anesi, MD, MSCE, MBE (Crit. Care); Kathleen O. Degnan, MD (Medicine); Keith W. Hamilton, MD (Medicine); Nikhil K. Mull, MD (CEP)

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