Hydroxychloroquine and COVID-19

Updated 27 October 2021

Early in the pandemic, hydroxychloroquine was put forward as a potential medicine for the treatment and prevention of COVID-19. While evidence is less clear on the medicine's ability to prevent COVID-19, recent studies have shown that hydroxychloroquine is not an effective treatment for COVID-19, and that it may increase the risk of adverse events.

A 2021 Cochrane Review assessing current evidence, found that hydroxychloroquine is not beneficial for patients with COVID-19 requiring hospital care. The review assessed 14 studies, including 12 evaluating hydroxychloroquine treatment for 8569 patients with mild–severe COVID-19, and two studies investigating hydroxychloroquine for preventing COVID-19 in 3346 people exposed to the disease but without symptoms.

The review found that hydroxychloroquine does not reduce all-cause mortality in COVID-19. Of 8208 participants in nine randomised controlled trials, deaths per 100 adults with mild to critical COVID-19 were 19 in those treated with hydroxychloroquine and 18 for those receiving standard therapy or placebo (relative risk 1.09; 95% CI 0.99 to 1.19). The review also suggested that treatment with hydroxychloroquine is unlikely to alter the number of patients requiring ventilation, and may increase the risk of adverse events. For these reasons, the authors recommended that no further treatment trials of hydroxychloroquine be conducted.

For more information on the Cochrane Review, see Singh B, Ryan H, Kredo T, et al. Chloroquine or hydroxychloroquine for prevention and treatment of COVID‐19. Cochrane Database of Systematic Reviews 2021 (accessed 27 October 2021).

UPDATE 11 August 2020: National Taskforce strengthens recommendation against use of hydroxychloroquine

Following a review of available scientific and clinical data, the National COVID-19 Clinical Evidence Taskforce have strengthened their recommendation against the use of hydroxychloroquine as a treatment for COVID-19. The taskforce notes that based on available evidence "hydroxychloroquine is potentially harmful and no more effective than standard care in treating patients with COVID-19. We therefore recommend that hydroxychloroquine should not be used."

Read the recommendation

Update 5 June 2020: Lancet publication retracted

Following substantial concerns raised by the global research community regarding the integrity of the data used to inform the 22 May 2020 Lancet publication described below, the authors launched an independent third-party peer review of the database used for the paper, and provided by Surgisphere. Refusal by the company to transfer the full database has prevented the progression of this independent peer review. As a result three of the authors (MR Mehra, F Ruschitzka and AN Patel) have requested their paper be retracted.

Read the retraction

Update 4 June 2020 Lancet trial questioned

Since publication in the Lancet, the statistical analysis and data integrity of the large observational registry study described below have been called into question by a large group of researchers, statisticians, ethicists and clinicians from around the world. This group have sent an open letter to the study authors and the Lancet editor highlighting their concerns and requesting greater transparency around data sharing and independent validation of the analysis.

Read the open letter

The Director-General of WHO, Dr Tedros Adhanom Ghebreyesus, has announced that as a result of a review of the safety data, all arms of the Solidarity Trial, including hydroxychloroquine, will now continue.

Read the WHO statement

Update 27 May 2020: Hydroxychloroquine withdrawn from Solidarity trial

On 25 May 2020 Dr Tedros Adhanom Ghebreyesus, Director-General of the World Health Organization (WHO) made a statement about temporarily stopping the hydroxychloroquine arm of the Solidarity Trial.

The Solidarity trial was initiated in March 2020 to evaluate the safety and efficacy of four medicines by comparing them against standard care. The medicines are:

  • Remdesivir
  • Lopinavir/ritonavir
  • Interferon beta-1a
  • Hydroxychloroquine.

The Solidarity trial aims to rapidly discover whether any of these medicines slow disease progression or improve survival for patients with COVID-19.

The rationale for pausing the hydroxychloroquine arm from the trial was based on an ongoing comprehensive analysis and critical appraisal of all evidence available globally.  Among the evidence being analysed by the Executive Group of the WHO were data from a large multinational, observational study published in the Lancet on 22 May 2020. 

The data used to generate the results have since been questioned, and as noted above this paper is now withdrawn.

More information

    Australian hydroxychloroquine COVID-19 prevention trial

    On 20 May 2020, the Walter and Eliza Hall Institute of Medical Research announced an Australian clinical trial COVID SHIELD. This is the first Australian clinical trial to determine whether hydroxychloroquine can prevent COVID-19. The trial is a collaborative effort between the Institute in partnership with a human data science company IQVIA, and frontline and allied health professionals across Australia. The aim of the trial is to reduce the incidence of COVID-19 in Australian healthcare workers at significant risk of illness from the new coronavirus (SARS-CoV-2).

    More information

    Australian hydroxychloroquine COVID-19 treatment trial

    On 21 April 2020, the Australasian COVID-19 trial (ASCOT) was launched. The trial aims to generate clinical evidence about treatments that can be applied during the pandemic to reduce mortality or the need for mechanical ventilation in hospitalised but not yet critically ill patients with COVID-19. A key feature of the trial is that it will be applying an 'adaptive' methodology that will allow evidence about treatments to be continually updated with new information as it becomes available, while at the same time maintaining trial integrity.

    The first treatments to be trialled were planned to be lopinavir/ritonavir and hydroxychloroquine; both medicines are already in use for the treatment of other conditions. On 30 July 2020, the ASCOT Steering Committee made the decision to remove both of these trial arms, citing lack of efficacy data from other trials for these medicines, alongside the positive results demonstrated in this patient group for the antiviral medicine remdesivir.

    More information

     

    What is hydroxychloroquine?

    Hydroxychloroquine is a disease-modifying anti-rheumatic drug (DMARD)1 with a chemical structure very similar to that of chloroquine.2 Hydroxychloroquine is indicated for rheumatoid arthritis (RA), systemic lupus erythematous (SLE) and before the release of newer agents was also used for the prevention and treatment of malaria.3

    Because chloroquine is not available in Australia, this article will focus on hydroxychloroquine unless chloroquine is mentioned in the context of clinical trials or international guidelines. Chloroquine is not marketed in Australia although it has been registered with the Therapeutic Goods Administration (TGA) since 1991 for the suppression and treatment of malaria; for amoebic hepatitis; and for use in certain phases of SLE, RA and related collagen diseases.4

    Hydroxychloroquine is an immunomodulator rather than an immunosuppressant. It can attenuate the cytokine release syndrome (CRS) or ‘cytokine storm’ – an inflammatory process that occurs due to the overactivation of the immune system – by reducing CD154 expression in T-cells.2

    Immune modulation is the reason that researchers are studying hydroxychloroquine in the prevention and treatment of the effects of cytokine storm in COVID-19.

     

    What are the adverse effects?

    Hydroxychloroquine can have serious adverse effects, especially as daily doses increase (> 5 mg/kg actual weight) or accumulate over the long term (> 5 years).3

    Long-term safety data

    Long-term safety data are only available from observations of patients taking hydroxychloroquine for approved conditions such as RA and SLE. There are no long-term safety data on the use of hydroxychloroquine in COVID-19. 

    In the current context, prolonged exposure to hydroxychloroquine is only likely if it is trialed as a long-term prophylaxis against COVID-19. 

    There are several proposed clinical trials (up to 12 weeks) examining the efficacy and safety of hydroxychloroquine for pre- and post-exposure prophylaxis of COVID-19.5 

    QT interval prolongation

    Hydroxychloroquine can cause prolonged QT interval which may lead to arrhythmia and ventricular tachycardia.6

    On 24 April 2020 the US Food and Drug Administration (FDA) issued a caution against the use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or clinical trial due to the risk of adverse effects on heart rhythm.7

    Common adverse effects

    Common (> 1%) adverse effects of hydroxychloroquine include nausea, vomiting, anorexia, abdominal cramps, rash, itch, alopecia and headache.3 

    Hydroxychloroquine reduces HbA1c and there are reports of severe hypoglycaemia, although the frequency of these effects is unknown.3,6

    Toxicity from prolonged exposure

    According to the literature, the main toxicological adverse effects from prolonged exposure to hydroxychloroquine in approved conditions include:3,6,8

    • retinopathy (see ocular effects below)
    • cardiac toxicity (see cardiac effects below)
    • neuromyopathy as evidenced by abnormal nerve conduction and sensory changes. This is infrequent (0.1%–1%).3

    Cardiac effects

    Although rare (< 0.1%), cardiotoxic effects can include cardiomyopathy and conduction disorders.3,6

    Chronic cardiotoxicity should be considered when conduction disorders such as bundle branch block/ atrioventricular (AV) block or biventricular hypertrophy are diagnosed.3,6 Clinical monitoring for signs and symptoms of cardiomyopathy is advised.6

    Hydroxychloroquine prolongs the QT interval and the magnitude of this effect may increase with increasing concentrations of the drug.6 

    See ‘What about interactions with other medicines?’ below.

    Ocular effects

    As well as blurred vision, which is a common adverse effect,3 other serious ocular effects include:3,6

    • reversible corneal changes – oedema and opacities have been known to occur from 3 months to some years after commencing therapy6
    • retinopathy with changes in pigmentation and visual field defects – can progress to irreversible vision loss as daily dose and duration of treatment increase3
    • maculopathies and macular degeneration that may be irreversible.6

    In addition to increasing daily doses (> 5 mg/kg actual weight) and long-term use (> 5 years), major risk factors for retinopathy include:9

    • renal disease (eGFR < 60 mL/min/1.73m2)
    • concomitant tamoxifen use.

    Even at therapeutic doses for indicated conditions (Table 1) baseline ocular examination is recommended within the first 6–12 months of treatment, followed by regular screening.3,9,10 in the absence of specific risk factors, monitoring is not required for the first 5 years, after which annual monitoring is recommended.9

    Table 1. Usual therapeutic doses of oral hydroxychloroquine (HCQ) for adults with indicated conditions3,6

    Condition

    Initial dose to assess response

    Maintenance dose

    Rheumatoid arthritis

    400–600 mg daily for 4–12 weeks.

    200–400 mg daily (use minimum effective dose).

    Discoid or systemic lupus erythematosus

    400–800 mg daily for several weeks.

    200–400 mg daily (use minimum effective dose).

     

    What about interactions with other medicines?

    Hydroxychloroquine is thought to be incompatible with monoamine oxidase inhibitors (MAOIs).3,6

    Because hydroxychloroquine prolongs the QT interval it should not be used by patients receiving other medicines known to prolong the QT interval eg, Class IA and III antiarrhythmics, tricyclic antidepressants, antipsychotics and some antibiotics, including azithromycin, due to increased risk of ventricular arrhythmia.3,6,11

    See What's next in clinical trials?

    Other medicines that interact with hydroxychloroquine include antidiabetic agents, other antimalarial agents known to lower convulsion threshold (eg, mefloquine), digoxin and some antiepileptic medicines.6

    Tamoxifen is contraindicated due to its own retinal toxicity.3,6

     

    Is there any evidence for using hydroxychloroquine in COVID-19?

    Currently there are very limited data to support the use of hydroxychloroquine for the treatment or prevention of COVID-19.12

    Clinical evidence is emerging, but results are inconclusive (Tables 2a, 2b and 2c).

    For example, a small pilot study conducted in China13 randomised 30 patients with a confirmed diagnosis of COVID-19 to receive either standard treatment or standard treatment plus hydroxychloroquine (400 mg for 5 days). Results were similar in both groups. By day 7, more patients on standard treatment alone (93.3%) had a negative throat swab compared to those taking the hydroxychloroquine (86.7%).

    The rate of progression to pneumonia (on CT scan) was slightly reduced in the patients treated with hydroxychloroquine. One patient in the hydroxychloroquine group progressed to severe disease.13 The limitations of this study included small sample size, and a negative throat swab as the primary endpoint, which is not a clinical indication of whether the patient is at risk of more severe disease or death.

    The Australian National COVID-19 Clinical Evidence Task Force14 examined the results of this and 2 other randomised controlled trials (RCTs).15,16 (Table 2c)

    In a study of 62 patients with COVID-19 and pneumonia15 half were randomised to receive hydroxychloroquine 200 mg twice daily for 5 days plus standard treatment (oxygen, antiviral agents, antibacterial agents, immunoglobulin, with or without corticosteroids), and half received standard treatment alone.14,15 The study assessed time to clinical recovery (TTCR defined as normalised body temperature and cough relief for 72+ hours) clinical symptoms and changes on chest CT (Table 2c). The study results show that time to fever/body temperature normalisation was shorter in hydroxychloroquine group (2.2 days) than the control group (3.2 days). Time to cough remission was shorter in the hydroxychloroquine group and pneumonia improved in 25/31 (80.6%) patients receiving hydroxychloroquine compared to 17/31 (54.8%) patients in the control group.14,15

    A third RCT16 examined 150 patients with COVID-19 randomised to either hydroxychloroquine plus standard care (including, IV fluids, oxygen, haemodynamic monitoring, intensive care and the abiliy to deliver concomitant medicines), or standard care alone. The primary endpoint (28-day negative conversion rate of SARS-CoV-2) was no different in the hydroxychloroquine group (84.5%) compared with the control group (81.3%). The secondary outcomes of overall rate of symptom alleviation was not different between groups. Similarly, the median time to symptom relief in the hydroxychloroquine group (19 days) was similar to the control group (21 days).16

    Several limitations across all 3 RCTs were noted.14 These included limited number of relevant outcomes reported; severe adverse events15,16 viral clearance at day 713,15,16 and mortality16 were reported, yet none of the RCTs reported the incidence of respiratory failure/acute respiratory distress syndrome (ARDS) or requirement for mechanical ventilation/extracorporeal membrane oxygenation (ECMO).14 The Clinical EvidenceTask Force also expressed concern about the low quality of evidence for all reported outcomes due to serious risk of bias from unclear reporting13-15 of randomisation and blinding process, and lack of blinding of patients, investigators and statisticians.14,16

    Another small study from France17 reported that hydroxychloroquine alone (600 mg daily) or in combination with azithromycin (500 mg on day 1, then 250 mg/day for 4 days) reduced detection of SARS-CoV-2 in upper respiratory tract specimens compared with a non-randomised control group.

    The study did not assess clinical benefit and results were unreliable due to study limitations. These included that the trial was open label and not randomised. The accuracy of the testing was inconsistent, the number of patients needed to give statistical confidence to the results was not reached, patients were lost to follow-up and there was no opportunity to gather medium- or long-term data.

    On 21 April 2020, a relatively large US study of veterans hospitalised with COVID-19 (n=368) found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalised with COVID-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone.18

    This study was a non-randomised, retrospective analysis and, to date, has not been peer reviewed. Other limitations included a narrow demographic of predominantly African-American males aged over 65 years. Results were adjusted for confounders including comorbidities and concomitant medications, however the authors could not rule out the possibility of selection bias or residual confounders.18

    Table 2a. Preclinical data on chloroquine (CQ) and hydroxychloroquine (HCQ) in COVID-1919-22

    Reference

    Type of study

    Main results

    Comments

    Wang et al19

    in-vitro

    Antiviral activity of CQ (EC50 of 1.13 micrometres and CC50 > 100 micrometres at MOI of 0.05). High selectivity for SARS-CoV-2 rather than host cells.21

    CQ blocked viral infection at both entry and at post-entry stages of the SARS-CoV-2 infection in Vero E6 cells.22

    Yao et al20

    in-vitro

    HCQ was more potent against SARS-CoV-2 than CQ (EC50 of 0.72 micrometres and 5.47 micrometres respectively, MOI of 0.01).21

    HCQ inhibited viral infection at entry and post-entry stages; EC50 values CQ and HCQ decreased with longer incubation times providing higher intracellular concentrations and a better antiviral effect.22

    Table 2b. Clinical data on chloroquine (CQ) and hydroxychloroquine (HCQ) in COVID-1918,22-24
    Updated 13 May 2020

    Reference

    Type of study

    Main results

    Comments

    Gao et al23

    Case series

    CQ phosphate was superior to the control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus-negative conversion and shortening the disease course. No severe adverse events were reported.22

    Findings may have been a result of combining data from several ongoing trials using a variety of study designs.

    Gautret et al17

    Case control

    HCQ induced viral clearance after 6 days of treatment, either alone or in combination with AZ. Respectively, 70% and 100% negative nasopharyngeal samples among treated patients compared with 12.5% of untreated patients.22

    Limitations include small numbers (n=36), six patients lost to follow-up, limited medium or long-term data (primary outcome viral PCR status on day 6).19

    Magagnoli et al18

    (pre-print)

    Retrospective analysis

    Patients (n=368) with exposure to HCQ (n=97), HCQ + AZ (n=113) or no exposure to HCQ (n=158).

    HCQ +/- AZ did not improve mortality compared to no-HCQ. Increased overall mortality with HCQ alone.

    Limitations include non-randomised, retrospective analysis. Narrow demographic; male, predominantly African-American, aged over 65 years.

    Table 2c. Randomised controlled trials (RCTs) on HCQ in COVID-1913-16,24
    Updated 13 May 2020

    Reference

    Type of study

    Main results

    Comments

    Chen et al13

    Pilot study,
    RCT

    Patients (n=30) randomised 1:1, HCQ 400 mg /day for 5 days plus conventional treatment or conventional treatment alone (control).

    HCQ group showed negative conversion in 86.7% patients on day 7 while control group showed negative conversion in 93.3% patients by day 7 (P > 0.05).

    HCQ group received 400 mg/day for 5 days plus ‘conventional treatments’, control group received ‘conventional treatment’ yet conventional treatment was not described (in English).

    Update 13 May 2020

    Conventional treatment included: nebulised IFN, antivirals including LPV/RTV (unspecified dosage).24

    Chen et al15

    Double blind RCT, ITT analysis

    Patients (n=62) randomised 1:1, HCQ 400 mg/day for days 1– 5 + standard care or standard care alone (control).15,24

    Outcome: TTCR.

    TTCR was shorter in HCQ group compared with control group.

    Body temp recovery time significantly shortened in HCQ group, 2.2 days vs. control group, 3.2 days (P=0.0008).

    Cough remission significantly shorter in HCQ group 2.0 days vs. control group 3.1 days (P=0.0016).

    80.6% HCQ group had improved pneumonia on chest CT by day 6 compared with 54.8% control group.

    Limited number of relevant outcomes reported, risk of bias based on unclear reporting of randomisation and blinding.

    TTCR measured only by body temp or cough remission. No analysis of oxygen exchange data, extubations or other clinical data.

    Analysis of chest CT progression only based on 2 images (day 0 and day 6).

    No viral load data.

    Outcomes were statistically significant
    (p < 0.05).15,24

    Tang et al16

    Open label, RCT, ITT analysis

    150 patients randomised 1:1, HCQ (1200 mg loading dose/day on days 1–3, then 800 mg/dayfor up to 14 days for mild/moderate disease, or for up to 21 days for severe disease) + standard care (incl. antivirals), or standard care alone (incl. antivirals).

    No difference in 28 day negative conversion rate between groups.

    HCQ group showed negative conversion by Day 28 (85.4%) with median time to conversion of 8 days.

    Control group showed negative conversion by day 28 (81.3%) with median time to conversion of 7 days (P=0.341).

    Similar negative conversion rate between groups was also found at day 4, 7, 10, 14 or 21.

    Adverse effects were higher in HCQ group (30%) than control group (8.8%).24

    Study did not reach protocol sample size (n=360).

    Limited number of relevant outcomes reported.

    Unclear reporting of HCQ dose variations and antiviral medicines.

    Risk of bias due to non-blinding; trial was open label.



    Abbreviations

    AZ = azithromycin
    CC50 = 50% cytotoxic concentration
    CRP = C-reactive protein
    EC50 = 50% maximal effective concentration
    HCQ = hydroxychloroquine
    IFN = interferon
    ITT = intention to treat
    LPV/RT = lopinavir/ritonavir
    MOI = multiplicity of infection (the ratio of virions to host cells)
    PCR = polymerase chain reaction
    RCT = randomised controlled trial
    TTCR = time to clinical recovery (defined as normalised body temperature and cough relief for 72+ hours)

     

    What’s next in clinical trials?

    Multiple international clinical trials are underway to further explore the efficacy of chloroquine or hydroxychloroquine in treating patients diagnosed with COVID-19.

    Despite the known risk of QT interval prolongation with both hydroxychloroquine6 and azithromycin,11 there are also several proposed clinical trials that aim to test the efficacy of hydroxychloroquine in combination with azithromycin in the treatment of COVID-19.5

    Experts involved in developing guidelines are considering mitigation strategies to reduce the risk of potential adverse cardiac effects when using these medicines in COVID-19.25

    In addition to patients with confirmed diagnoses of COVID-19, researchers are also recruiting healthcare workers to study hydroxychloroquine in the prevention or post-exposure prophylaxis of COVID-19.5

    Find out more about clinical trials in the links below.

    Data from ongoing clinical trials across the globe are being published at a rapid rate. Evidence is being collated and presented for the public domain by a variety of reputable health organisations, including:

    And as data are emerging, important considerations for the proposed use of hydroxychloroquine for COVID-19 include the potential for:

    • an unknown number of patients receiving hydroxychloroquine during the pandemic
    • high doses used in an acute approach to viral infection compared to usual therapeutic doses for indicated conditions (Table 1).8

    These unknowns highlight the importance of waiting for results of ongoing prospective, randomised, controlled studies before widespread adoption of hydroxychloroquine in COVID-19.

     

    What do Australian guidelines say?

    The Australian guidelines for the clinical care of people with COVID-19 are maintained by the National COVID-19 Clinical Evidence Task Force.

    Their consensus recommendations state that for patients with COVID-19 illness, antiviral medications or other disease-modifying treatments should only be administered in the context of clinical trials with appropriate ethical approval. The guideline panel expressed significant concerns about the potential harms of unproven treatments, including the possibility of adverse effects and toxicity.14

     

    What about international guidelines?

    World Health Organization (WHO)

    While WHO is following ongoing clinical trials being conducted in response to COVID-19, including studies looking at chloroquine and hydroxychloroquine, it states that at this time there are insufficient data to assess the efficacy of either medicine in treating patients with COVID-19 or in preventing them from contracting the virus.26

    Europe

    The European Medicines Agency (EMA) recommends that patients and health professionals only take chloroquine and hydroxychloroquine for their authorised uses, or as part of clinical trials or national emergency use programs for the treatment of COVID-19.27

    United Kingdom

    In the UK, the National Institute for Health Care and Excellence (NICE) is developing rapid guidelines and evidence summaries in real time. At the time of this article’s publication, NICE has not developed guidance on the use of chloroquine or hydroxychloroquine in COVID-19.28

    In March 2020, the National Health Service (NHS) released letters to general practices across England strongly discouraging the use of off-label treatments outside of clinical trials.29

    Instead, the NHS is urging UK GPs to recruit patients for 3 clinical trials into COVID-19 treatments including the PRINCIPLE trial of primary care patients diagnosed with COVID-19. The PRINCIPLE trial aims to find out whether selected treatments – the first of which will be hydroxychloroquine – can help reduce:30

    • the need for hospitalisation
    • the length of stay if hospitalised
    • recovery times
    • risk of complications from COVID-19.

    United States

    The US Centers for Disease Control and Prevention (CDC) report that although there are no currently available data from randomised controlled trials, hydroxychloroquine and chloroquine are under investigation in clinical trials for the prevention and treatment of COVID-19.31

    The US Food and Drug Administration (FDA) has issued an emergency use authorisation (EUA) to facilitate the availability of chloroquine and hydroxychloroquine in the setting of the COVID-19 pandemic.32

    The FDA stated that, ‘based on the totality of scientific evidence available, it is reasonable to believe that the drug may be effective in treating COVID-19 and that, when used under the EUA conditions, known and potential benefits outweigh known and potential risks’. They added that the optimal dosing and duration of treatment for COVID-19 is unknown.32

    The EUA allows chloroquine and hydroxychloroquine to be supplied from the Strategic National Stockpile (SNS) for treatment of COVID-19 in adults and adolescents weighing 50 kg or more who are hospitalised with COVID-19 and for whom a clinical trial is not available, or participation is not feasible.32

    Australia’s TGA position

    The FDA position of ‘benefits outweighing risks’ contrasts with that of the TGA which stated on 24 March 2020 that ‘given the limited evidence for effect against COVID-19 as well as the risk of significant adverse effects, the TGA strongly discourages the use of hydroxychloroquine outside of its current indications…other than in a clinical trial setting or in a controlled environment in the treatment of severely ill patients in hospital’.33

     

    Is hydroxychloroquine being prescribed for COVID-19 in Australia?

    Recent reports of increased off-label prescribing of hydroxychloroquine have raised concerns about the safety of people who might take it incorrectly.

    There are also concerns that off-label use could result in a potential shortage of this product in Australia, impacting the health of those who need it to manage existing chronic conditions.33

    Given the limited evidence for benefit against COVID-19, and the known risks, the use of hydroxychloroquine outside of current indications is strongly discouraged.33

     

    Who is authorised to prescribe hydroxychloroquine?

    On 3 April 2020, the Poisons Standard was amended to include specialist health practitioners authorised to supply and initiate treatment with hydroxychloroquine from the following recognised specialist areas:33,34

    • dermatology
    • emergency medicine
    • intensive care medicine
    • paediatrics and child health
    • physician
    • oral medicine.

    Medical practitioners who are not one of the listed specialists cannot initiate treatment with hydroxychloroquine. General practitioners and doctors in training can only prescribe hydroxychloroquine for continued treatment of patients where initial treatment has been authorised by one of the listed specialists.33,34

    To minimise the risk of off-label prescribing, from 1 May 2020, the Pharmaceutical Benefits Scheme (PBS) listing of hydroxychloroquine will be split into separate initial and continuing treatment listings for the approved indications of autoimmune disorders and malaria. All initial and continuing prescriptions of hydroxychloroquine will change from general unrestricted to Authority Required (streamlined ).35

    In special circumstances, access to hydroxychloroquine may be granted for use in clinical trials or in controlled environments as a treatment for severely ill patients in hospital.33

     

    What about stockpiling?

    Stockpiling could result in patients being unable to access particular medicines (eg, from their local pharmacy). To prevent stockpiling of hydroxychloroquine, the TGA announced assurance of an ongoing supply of hydroxychloroquine for patients needing it to treat chronic conditions for which it is indicated.33

    Stockpiling of any medicines at this time is not advisable and could result in patients not receiving the medicines that they require.36

     

    What advice can I give patients for whom hydroxychloroquine is indicated?

    The Australian Rheumatology Association (ARA) has issued general COVID-19 advice for patients with chronic rheumatoid and other inflammatory arthritis, SLE and other autoimmune diseases.37

    The ARA recommendations are that if these patients are well they should continue their immunosuppressant medicines.

    If they develop symptoms of any significant infection, established practice is to pause their immunosuppressive medicines (including hydroxychloroquine) for the duration of the infection in consultation with their rheumatology team.

    Steroids should not be stopped abruptly and advice should be sought from their treating team.37

     

    More information

     

    References

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    2. Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J Antimicrob Chemother 2020.
    3. Australian Medicines Handbook. Hydroxychloroquine. Adelaide: AMH Pty Ltd, 2020 (accessed 1 April 2020).
    4. Therapeutic Goods Administration. Public Summary for ARTG entry: CHLORQUIN chloroquine phosphate 250 mg. Canberra: Australian Government Department of Health, 2002 (accessed 7 April 2020).
    5. US National Library of Medicine. Clinical Trials. United States: United States Department of Health and Human Services, 2020 (accessed 28 April 2020).
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    7. US Food and Drug Administration (FDA). FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside the hospital setting or a clinical trial due to risk of heart rhythm problems. Maryland: FDA, 24 April 2020 (accessed 28 April 2020).
    8. Pereira B. Challenges and cares to promote rational use of chloroquine and hydroxychloroquine in the management of coronavirus disease 2019 (COVID-19) pandemic: a timely review. J Toxicol Environ Health B Crit Rev 2020:1-5.
    9. Royal College of Ophthalmologists. Hydroxychloroquine and chloroquine retinopathy: recommendations on monitoring. London, UK: Royal College of Ophthalmologists, 2020 (accessed 20 April 2020).
    10. American Academy of Ophthalmology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). San Francisco: American Academy of Ophthalmology, 2016 (accessed 20 April 2020).
    11. Apotex Pty Ltd. APO-Azithromycin (azithromycin dihydrate) tablets product information. Macquarie Park: Apotex Pty Ltd, 2019 (accessed 28 April 2020).
    12. American Society of Health-System Pharmacists (ASHP). Assessment of evidence for COVID-19-related treatments. United States: American Society of Health-System Pharmacists, Inc., 2020 (accessed 4 April 2020).
    13. Chen J, Liu D, Liu L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ (Med Sci). 2020; 49 (accessed 1 April 2020).
    14. Australian National COVID-19 Clinical Evidence Taskforce. Australian guidelines for the clinical care of people with COVID-19. Melbourne: National COVID-19 Clinical Evidence Taskforce, 2020 (accessed 15 April 2020).
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    16. Tang W, Cao Z, Han M et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. medRxiv 2020; 2020.04.10.20060558.
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