Commentary     October 2020  

Chloroquine and Hydroxychloroquine in COVID-19: Practice Implications for Healthcare Professionals

By Tauqeer Hussain Mallhi1, Abrar Ahmad2, Muhammad hammad Butt2, Shahzadi Misbah2, Yusra Habib Khan1, Nasser Hadal Alotaibi1

Affiliations

  1. Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakaka, Al-Jouf Province, Kingdom of Saudi Arabia
  2. Faculty of Pharmacy, University of Central Punjab, Lahore, Pakistan

ABSTRACT
Chloroquine (CQ) and its derivatives such as hydroxychloroquine (HCQ) remain mainstay of therapy for malaria. These drugs are also approved for certain autoimmune diseases including systemic lupus erythematosus. The antiviral activities of these drugs and their mechanisms have been studied in vitro previously against various viruses including severe acute respiratory syndrome coronavirus (SARS-CoV). During the current coronavirus disease 2019 (COVID-19) pandemic, in vivo and in vitro investigations of these drugs have demonstrated potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The authors used the keywords to find the relevant studies, like COVID-19, SARS-CoV-2, pandemic, complications, repositioning, toxicity, overdose, treatment plan, implication strategies, prevention, chloroquine, hydroxychloroquine, clinical trials, drug interactions, and practices advice, etc., in Pubmed and Google Scholar. This review aims to provide a detailed insight of practice implications related to these drugs, which would aid healthcare professionals to ensure the safe use of these drugs during the management of patients with COVID-19 disease.

Key Words: Chloroquine, Hydroxychloroquine, COVID-19, SARS-CoV-2, Practice implications.

INTRODUCTION

The whole world is going through unprecedented crisis due to coronavirus disease 2019 (COVID-19) pandemic and there is a dire need to discover therapeutic and prophylactic drugs to combat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Drug repurposing, also known as drug repositioning, re-tasking or re-profiling, is considered as the most effective strategy during the current pandemic until specific treatments are made available. This strategy revolves around identifying new uses for approved or investigational drugs that are outside of the scope of the original medical indication. The primary benefit of this strategy over drug discovery is the use of de-risked compounds, with potentially lower overall development costs and shorter development timelines.1 Given the sharp rise in COVID-19 cases and low pace of new drug discovery and development, the drug repurposing is the need of the time.

Recently, Food and Drug Administration (FDA) approved the use of chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) for the management of COVID-19 patients, following positive preliminary results from in vitro and in vivo investigations. Though these medications have established safety profiles; but numerous studies have also demonstrated the adverse events during the use. The current manuscript underscores important practice implications which should be considered while managing COVID-19 patients with CQ or HCQ.

CQ was first discovered in 1934 and its therapeutic value was confirmed after ten years following various investigations from six countries. CQ and its derivative HCQ, are well established antimalarial agents.2 In 1947, CQ was approved for the prophylaxis of malaria. It was later added to the World Health Organization (WHO) model list of essential medicines. Being anti-parasitic agents, CQ and HCQ are FDA approved drugs for the prophylaxis and treatment of uncomplicated and CQ-sensitive malaria; and for the treatment of extra-intestinal amebiasis. Both drugs are also well known for their anti-inflammatory and immunomodulatory effects. 3 Keeping in view their antiviral potential, these drugs have been recently repurposed for the treatment and prophylaxis of COVID-19.4 It must be noted that both drugs are used as potential treatment for wide spectrum of diseases, including both infectious and non-infectious diseases including the wide range of cancers,5 systemic lupus erythematosus, primary progressive multiple sclerosis, systemic sclerosis, rheumatoid arthritis, Whipple's disease, Q fever, and several viral and fungal infections.6

CQ and HCQ are weak bases having characteristic-wide volume of distribution and are known to accumulate in the intracellular compartments of human cells such as lysosomes, endosomes and Golgi vesicles. This leads to a number of effects, specifically increasing the pH of lysosomes and endosomes.7 The mechanism of action against SARS-CoV-2 is under continuous study. The mechanism that is believed to result in inhibition of SARS-CoV-2 involves the entry of non-protonated CQ inside the cell, accumulating in the acidic compartments.8 The increasing pH might result in expansion and vacuolisation causing impairment of lysosomal and endosomal function and maturation, inhibiting the antigen presentation through the lysosomal pathway.9 This potentially reduces the post-transcriptional modification of proteins, enzyme release, receptors recycling, cellular signalling pathways activation, and cell membrane repair.10 Additional mechanisms include inhibition of ACE2 receptors, acidification at cell membrane surface (causing inhibition of viral fusion) and cytokine release immunomo-dulation.11-13

CQ and its derivatives have previously demonstrated in vitro antiviral activity against severe acute respiratory syndrome associated coronavirus (SARS-CoV) and COVID-19 disease caused by novel SARS-CoV-2.8,11,12 Though CQ has demonstrated in vitro activity against various RNA viruses, but randomised control trials in dengue and chikungunya failed to demonstrate its effectiveness.14 According to an experimental study, CQ was used in the treatment of 100 COVID-19 patients, and it showed clinical improvements with improved radiological image findings, reduced progression, and increased viral clearance.15 Another open-label and non-randomised trial in France, consisting of 36 COVID-19 patients (20 received HCQ and 16 received control), reported that treatment with HCQ (200 mg, PO, 8-hourly regimen) resulted in enhanced viral clearance as compared to the control group.

This study also reported that addition of azithromycin to the regimen in six patients resulted in better viral clearance compared to patients receiving HCQ alone.16 Different clinical trials have been conducted among patients with age ranging from 18 to 65 years in which varying dose regimens were used among patients (Table I).17-20

Safety profile of CQ and HCQ:

When taken according to prescription, CQ and its derivatives have established safety profile. However, higher doses have been reported to cause severe adverse effects. Most severe of which are retinal toxicity, diplopia, reduced visual acuity and bilateral loss of vision.21 Some studies have also linked high dose administration with severe psychiatric issues, such as hallucinations, paranoia, and suicidal thoughts.22 Dermatological effects related to CQ administration include photosensitivity and pruritus. Typically, retinopathy manifests with failure to focus between near and far objects. Neurological effects might include seizures, hallucinations, and paranoia. Intramuscular administration of CQ has been linked with hypotension that might potentially be lethal.23 FDA has advised that CQ and HCQ are linked to cardiac events as they increase QT interval and limit the use of these drugs for clinical trials and for those patients who cannot participate in the trials.24 CQ and HCQ may interact with many other drugs having potential to cause ECG abnormalities, which can result in augmented QT prolongation. These interactions must be controlled while managing the patients with COVID-19. CQ also induces haemolysis and causes problems in certain group of people, if used prophylactically in large populations.25  Table II describes the list of potential interactions along with their severity level, mechanism, and management. Moreover, the use of CQ and HCQ may pose adverse outcomes in certain pre-existing conditions.25 Table III demonstrates the interaction of these drugs with various diseases along with severity and monitoring strategies.

Drug dosing and adverse drug profile of CQ and HCQ:

The dosing of CQ should ideally be based on the body height and weight. In prophylaxis of malarial infection, 5 mg per kg of the body weight and not more than 500 mg once per week, is an appropriate regimen of dosing and HCQ (800 mg) twice daily for five days will be recommended dose for the COVID-19 patients.23

Although toxicity of CQ is rare, but it has been reported in unusually high dose ingestions or chronic intravenous administration. Retinal manifestations are most common following the poisoning of CQ. CQ toxicity is not easy to manage, but can be treated with epinephrine and diazepam along with mechanical ventilation. However, these treatment modalities require further investigations.23

Overdose of CQ and HCQ is extremely toxic and share common manifestations as for tricyclic antidepressants poisoning. Their intoxication leads to sudden onset of seizures and coma, cardiovascular collapse with sodium and potassium channels’ inhibition, which results in wide QRS and prolonged QT interval, respectively and intracellular shifting induced hypokalaemia. High dose ingestion can be managed with non-specific measures such as activated charcoal and gastric emptying. However, intravenous vasopressors and benzodiazepines are also used for symptomatic patients. Sodium bicarbonate or hypertonic saline can be used to correct arrhythmias and QRS widening. It must be noted that every case of overdose should be reported to drug and poison control centre immediately.26

It is pertinent to mention that poisoned patients must be considered for ICU admissions. Monitoring of the vital signs including blood pressure, electrocardiogram (ECG) and respiration is of utmost importance. Biochemical investigations must focus on serum electrolytes, particularly the potassium levels. Other supportive measures include cardiac resuscitation and artificial ventilation. Since dosing of CQ and HCQ varies across studies, clinicians must monitor the patients for toxidromes, particularly among those with underlying cardiovascular disorders.


Table I: Recommended dose and duration of chloroquine (CQ) and hydroxychloroquine (HCQ) in COVID-19.

Recommended dose

Duration of use

Special comments

Reference

CQ 300 mg BID

CQP 500mg BID

Maximum 10 days

For treatment

17

CQP 500 mg BID

For body weight <50 kg use CQP 500 mg per day

7 days

50 mg/kg is a fatal dose, No dosing recommendation for Children

18

CQ 600 mg stat + 300 mg after 12 hours on day 1, followed by 300 mg BID from day 2-5

Maximum 5 days

For treatment

19

HCQ 200 mg daily

CQP 500 mg BID

10 days

For Treatment

19

CQP 500 mg BID for 10 days

Minimum 5 days

Discontinue or Reduce one’s daily if GI symptoms occurs

20

HCQ 200 mg TID

10 days

Using HCQ with Azithromycin inhibits 100% viral load in 6 days

16

HCQ 400 mg BID on day 1 and on day 2-5 use 200 mg BID

5 days

HCQ effective than CQP

12

CQ: Chloroquine, CQP: Chloroquine phosphate, HCQ: Hydroxychloroquine, BID: Two times a day, TID: Three times a day.


Table II: Drug-drug interaction; its mechanism, severity level and management strategies.

Drug

Interacting drug

Mechanism

Management

Severity level

CQ, HCQ

Amiodarone

Prolongs the QT interval

Avoid co-administration

Major

CQ, HCQ

Quinidine

Prolongs the QT interval

Avoid co-administration

Major

CQ, HCQ

Sotalol

Prolongs the QT interval

Avoid co-administration

Major

CQ, HCQ

Procainamide

Prolongs the QT interval

Avoid co-administration

Major

CQ, HCQ

Vemurafenib

Prolongs the QT interval

Avoid co-administration

Major

CQ, HCQ

Vigabatrin

Prolongs the QT interval

Avoid co-administration

Major

CQ, HCQ

Citalopram

Prolongs the QT interval

Avoid co-administration

Major

CQ, HCQ

Escitalopram

Prolongs the QT interval

Avoid co-administration

Major

CQ, HCQ

Gatifloxacin

Prolongs the QT interval

Avoid co-administration

Major

CQ, HCQ

Moxifloxacin

Prolongs the QT interval

Avoid co-administration

Major

CQ

Ribociclib

↑ risk of an irregular heart rhythm

Avoid co-administration

Major

CQ

Tramadol

Tramadol rarely cause seizures

Use with caution

Major

CQ

Bupropion

↑ risk of seizures especially elderly people

Extreme caution; dose adjustment carefully.

Major

CQ, HCQ

Propafenone

Prolongs the QT interval

Avoid co-administration

Moderate

CQ, HCQ

Venlafaxine

Prolongs the QT interval

Clinical monitoring is recommended

Moderate

CQ, HCQ

Duloxetine

CQ ↑ the blood levels and effects of Duloxetine.

Need dose adjustment

Moderate

CQ, HCQ

Antacids

↓ Absorption of CQ and HCQ by magnesium trisilicate.

Separate dosage with 2-3 hours interval

Moderate

CQ, HCQ

Kaolin

↓ CQ levels absorption

Separate doses by at least 4 hours

Moderate

CQ, HCQ

Cimetidine

↓ Metabolism and clearance of CQ and HCQ.

Use alternative or take at least after 2 hours

Moderate

CQ, HCQ

Penicillamine

CQ ↑ peak plasma levels of penicillamine

Monitor acute toxicity

Moderate

CQ, HCQ

Ciprofloxacin

CQ modestly ↓ ciprofloxacin levels

Avoid co-administration

Moderate

CQ, HCQ

Atomoxetine

cause prolongation of the QT interval

Clinical monitoring is recommended

Moderate

CQ, HCQ

Digoxin

↑ levels of digoxin

Monitor digoxin levels; dose adjustment

Moderate

CQ

Ampicillin

CQ ↓ the absorption of ampicillin

Should be administered at least 2 hours apart

Moderate

CQ, HCQ

Methotrexate

CQ caused a moderate ↓ and HCQ caused a minor ↑ in the AUC of methotrexate.

Monitoring closely for reduced efficacy and adjust the dose.

Minor

CQ, HCQ

Metoprolol

CQ and HCQ ↑ the blood levels of metoprolol.

Consider use of alternative

Minor

CQ, HCQ

Ciclosporin

↑ plasma conc. of ciclosporin and impair renal function

Monitor renal function weekly

Unknown

CQ

CP

↑ plasma level and therapeutic efficacy of CQ

Monitor regularly cardiac toxicity

Unknown

HCQ

Porfimer

↑ risk of photosensitity reactions

Avoid exposure of skin and eyes to direct sunlight

Unknown

HCQ

Insulin

HCQ inhibit insulin degradation

Check blood sugar level and reduce daily dose of insulin

Unknown

HCQ

GC

↓ insulin clearance and degradation rate.

Check blood sugar level and adjust dose of GC

Unknown

HCQ

Rifampicin

↑ the metabolism and clearance of the HCQ

Avoid use of HCQ

Unknown

References: 25.  CP: Chlorpheniramine, GC: Glibenclamide, CQ: Chloroquine, HCQ: Hydroxychloroquine, AUC: Area under curve, ↑; Increases, ↓; Decreases, Major: Highly clinically significant, Moderate: Moderately clinically significant, Minor: Minimally clinically significant, Unknown: No severity level information available.


Table III: Drug-disease interactions and their monitoring strategies.

Disease

Severity level

Monitoring strategies

Ocular toxicity

Major

Use if potential benefits are anticipated to the outweigh risks

Porphyria

Major

Should not be used in these patients unless the potential benefits are anticipated to outweigh risks.

Bone marrow suppression

Moderate

Administer cautiously. A complete blood count should be performed periodically in patients on prolonged therapy. Discontinuance of drug, If any severe blood disorder appears.

Ototoxicity

Moderate

Should be administered cautiously.

Seizures

Moderate

Should be administered cautiously.

Hepatotoxicity

Moderate

Periodic evaluation of hepatic function should be performed during prolonged therapy.

Heart disease

Moderate

Therapy should be monitored.

Psoriasis

Moderate

Should not be used unless the potential benefits are anticipated to outweigh the risks.

Reference.25

The use of CQ and HCQ in children and pregnant women is proved to be safe. These drugs have few but highly fatal contraindications. Death has been reported with the use of CQ in patients with porphyria cutaneous tarda. The use of these drugs is contraindicated in patients with retinal or vision changes, except in case of acute malaria. The hypersensitivity and allergic reactions are also reported in the literature. CQ is also contraindicated in patients with the history of HCQ hypersensitivity reactions.23, 27

Risks of self-medication:

It must be noted that uncontrolled amplified dissemination of news or information by the lay press, electronic and social media may trigger self-medication of drugs among general community. It is pertinent to mention that every news channel or agency is efficiently engaged to break any new findings or studies related to the treatment and prevention of COVID-19. Such news reports may influence the people who are searching for appropriate measures to save themselves from the virus. Though these drugs have established safety profiles but their potential to pose substantial adverse effects cannot be disregarded. Any sort of self-medication during the current pandemic may aggravate the ongoing health crises, for which none of the country is readily prepared. We believe that restricted and careful media announcements, active involvements of pharmacists and drug regulators with positive support from the national health authorities will mitigate the potential risks of self-medication and subsequent drug shortage and price hike during the current pandemic.

Practice advice and precautions:

The safety of CQ and its derivatives has been well studied and established with its use over decades.28 However, several precautionary measures should be taken during the management of COVID-19 patients. These measures include blood testing to ascertain anaemia, leukopenia, thrombocytopenia, serum electrolyte disturbances, renal and hepatic dysfunction, ECG to assess QT prolongation and arrhythmias and physical examinations to observe the visual or mental disturbances. Antidepressants, antiarrhythmics and drugs having potential to prolong QT interval (quinolones, ondansetron, macrolides) must be avoided with CQ and HCQ.20 In vivo investigations have indicated no harms to foetus among pregnant women.29 Risks of long-term use include retinopathy, vascular myopathy, cardiac conduction disturbances, restrictive cardiomyopathy, and neuropathy.30 In case of COVID-19, long-term risks are not relevant unless the drugs are used in prophylaxis for extended time.26 Last, but not the least, physicians should report any unusual effect of these drugs during the management of COVID-19 patients.

Practice implications:

Since WHO has resumed CQ and HCQ trials, it is imperative to provide necessary information regarding implications of their use.  FDA has approved CQ and HCQ for the COVID-19 patients who cannot participate in the clinical trials. These medications have established safety profiles; but numerous studies have also demonstrated the adverse events during the use. During the current COVID-19 turmoil, discovery of specific antivirals is the need of the hour. This review highlights the important practice implications which could ensure the safe and effective use of these drugs in COVID-19.

CONCLUSION

A number of research studies have evaluated the effectiveness of CQ and HCQ in COVID-19. However, clinicians must consider all precautionary measures to ensure the safe and effective use of these drugs during the management of COVID-19 patients. The use of these drugs must be subjected to institutional or national guidelines and should adhere to evidence-based medicine.

CONFLICT OF INTEREST:
The authors declared no conflict of interest.

AUTHORS CONTRIBUTION:
THM, AA and MHB: Conception or design of the work.
MHB, AA, SM and YHK: Drafted the work.
THM, YHK and NHA: Revised the manuscript critically for important intellectual content.
THM, AA, MHB, SM, YHK and NHA: Provided approval for publication of the content.

REFERENCES

  1. Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, et al. Drug repurposing: Progress, challenges and recommendations. Nat Rev Drug discov 2019; 18(1):41-58. doi: 10.1038/nrd.2018.168.
  2. Coatney GR. Pitfalls in a discovery: The chronicle of chloroquine. Am J Trop Med Hyg 1963; 12(2):121-28. doi: 10.4269/ajtmh.1963.12.121.
  3. Al-Bari MAA. Chloroquine analogues in drug discovery: New directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. J Antimicrob Chemother 2015; 70(6):1608-21. doi: 10.1093/ jac/dkv018.
  4. Khan SY, Khan A, Arshad M, Tahir HM, Mukhtar MK, Ahmad KR, et al. Irrational use of antimalarial drugs in rural areas of eastern Pakistan: A random field study. BMC public Health 2012; 12(1):1-6. doi: 10.1186/1471-2458-12-941.
  5. Manic G, Obrist F, Kroemer G, Vitale I, Galluzzi L. Chloroquine and hydroxychloroquine for cancer therapy. Molecular & Cellular Oncology 2014; 1(1):1-11. doi: 10.4161/mco.29911. 
  6. Plantone D, Koudriavtseva T. Current and future use of chloroquine and hydroxychloroquine in infectious, immune, neoplastic, and neurological diseases: A mini-review. Clin Drug Investig 2018; 38(8):653-71. doi: 10.1007/ s40261-018-0656-y.
  7. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nature Revi Rheumatol 2020; 16(3):1-12. doi: 10.1038/s41584-020-0372-x.
  8. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J 2005; 2(1):69-78. doi: 10.1186/1743-422X-2-69.
  9. Mauthe M, Orhon I, Rocchi C, Zhou X, Luhr M, Hijlkema KJ, et al. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy 2018; 14(8):1435-55. doi: 10.1080/15548627.2018.1474314. 
  10. Kaufmann AM, Krise JP. Lysosomal sequestration of amine-containing drugs: Analysis and therapeutic implications. J Pharmaceutical Sciences 2007; 96(4):729-46. doi: 10.1002/ jps.20792.
  11. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 2020; 30(3):269-71. doi: 10.1038/s41422- 020-0282-0.
  12. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, 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 Infec Dis 2020; 71(15):732-9. doi: 10.1093/cid/ciaa237.
  13. Amsden G. Anti-inflammatory effects of macrolides—an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflam-matory pulmonary conditions? J Antimicrobial Chemother 2005; 55(1):10-21. doi: 10.1093/jac/dkh519.
  14. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res 2020; 1-2. doi: 10.1016/j.antiviral. 2020.104762.
  15. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Bioscience trends 2020; 14(1):72-3. doi: 10.5582/ bst.2020.01047. 
  16. Gautret P, Lagier JC, Parola P, Meddeb L, Mailhe M, Doudier B, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int J Antimicrobial Agent 2020; 56(1):105949. doi:10.1016/j.ijantimicag.2020.105949. 
  17. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discover Ther 2020; 14(1):58-60. doi: 10.5582/ddt.2020.01012.
  18. Wang Y, Zhu LQ. Pharmaceutical care recommendations for antiviral treatments in children with coronavirus disease 2019. World J Pediatrics 2020; 16(3):271-4. doi: 10.1007/ s12519-020-00353-5.
  19. Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Critical Care 2020; 57(6):279-83.
  20. Jie Z, He H, Xi H, Zhi Z. Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi 2020; 43(3):185-8.
  21. Martins AC, Cayotopa ADE, Klein WW, Schlosser AR, Silva AFd, Souza MNd, et al. Side effects of chloroquine and primaquine and symptom reduction in malaria endemic area (Mâncio Lima, Acre, Brazil). Interdisciplinary perspectives on infectious diseases 2015; 2015:1-7.
  22. Lysack J, Lysack C, Kvern B. A severe adverse reaction to mefloquine and chloroquine prophylaxis. Australian family physician 1998; 27(12):1119-20.
  23. Goel P, Gerriets V. StatPearls Publishing 2019 [Available from:https://www.ncbi.nlm.nih.gov/books/NBK551512/.
  24. Administration FaD. FDA Warns Against Use of Chloroquine Outside of Clinical Trials 2020 [Available from: https://www.wsj.com/articles/fda-warns-against-use-of-chloroquine-outside-of-clinical-trials-11587745979.
  25. Medscape. Drug interaction checker. Medscape New York, NY; 2015.
  26. Juurlink DN. Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection. CMAJ 2020; 192(17):450-3.
  27. Singh AK, Singh A, Shaikh A, Singh R, Misra A. Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 2020; 14(3):241-6.
  28. Sapp JL, Alqarawi W, MacIntyre CJ, Tadros R, Steinberg C, Roberts JD, et al. Guidance On Minimizing Risk of Drug-Induced Ventricular Arrhythmia During Treatment of COVID-19: A Statement from the Canadian Heart Rhythm Society. Canadian J Cardiol 2020; 36(6):948-51.
  29. Sarkar M, Woodland C, Koren G, Einarson AR. Pregnancy outcome following gestational exposure to azithromycin. BMC Pregnancy and Childbirth 2006; 6(1):18.
  30. Yusuf I, Sharma S, Luqmani R, Downes S. Hydroxychloro-quine retinopathy. Eye 2017; 31(6):828-45.