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ORIGINAL ARTICLE
Year : 2020  |  Volume : 13  |  Issue : 3  |  Page : 204-207  

Adverse drug reaction profile of prophylactic hydroxychloroquine for COVID-19 among doctors


Department of Pediatrics, B J Government Medical College, Pune, Maharashtra, India

Date of Submission01-May-2020
Date of Decision02-May-2020
Date of Acceptance07-May-2020
Date of Web Publication3-Jun-2020

Correspondence Address:
Rajesh K Kulkarni
Department of Pediatrics, B J Government Medical College, Pune, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mjdrdypu.mjdrdypu_220_20

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  Abstract 


Background: Recently, hydroxychloroquine (HCQ) has been advocated by the Indian Council of Medical Research for prophylaxis of COVID-19, and the Food and Drug Administration has given emergency use authorization for its use in the treatment of severe COVID-19 disease in hospitalized patients. HCQ is generally well tolerated; however, concerns about adverse effects in adults prescribed with HCQ for prophylaxis remain. Our study was designed to investigate the adverse drug reaction (ADR) profile of HCQ in prophylactic doses for COVID-19 prophylaxis among doctors. Materials and Methods: This was a cross-sectional study carried out among doctors taking HCQ prophylaxis for COVID-19. The study was carried out over 1 month from April 1, to April 30, 2020. Data regarding age, sex, comorbidities, number of doses taken, concomitant drug therapy, adherence to drug schedule, need for treatment of ADRs, and possible adverse effects were obtained from the patients. The participants were administered an online pretested, validated questionnaire to ascertain the adverse effects they noticed while taking HCQ. Results: One-hundred and forty doctors were included in the study group. Sixty-nine adverse events were documented in 44 participants (31%). The most frequently reported symptoms were headache followed by nausea, dizziness, abdominal cramps, and loose stools. Hypoglycemia was seen in three participants, all with diabetes. Sixteen participants required medication to treat the adverse effects (most commonly ibuprofen for headache), while four participants discontinued the drug due to adverse effects (two each because of hypoglycemia and one each because of nausea and loose stools). There was no statistically significant difference of age, gender, number of doses taken, or comorbidities on adverse effects. Conclusion: Almost a third of the participants reported adverse effects. Utmost care is necessary before using HCQ prophylactically for chemoprophylaxis of COVID-19.

Keywords: Adverse drug effects, chemoprophylaxis, COVID-19, doctors, hydroxychloroquine


How to cite this article:
Kulkarni RK, Kinikar AA, Jadhav T. Adverse drug reaction profile of prophylactic hydroxychloroquine for COVID-19 among doctors. Med J DY Patil Vidyapeeth 2020;13:204-7

How to cite this URL:
Kulkarni RK, Kinikar AA, Jadhav T. Adverse drug reaction profile of prophylactic hydroxychloroquine for COVID-19 among doctors. Med J DY Patil Vidyapeeth [serial online] 2020 [cited 2020 Oct 25];13:204-7. Available from: https://www.mjdrdypv.org/text.asp?2020/13/3/204/285763




  Introduction Top


Monitoring and documentation of adverse drug reactions (ADRs) encourage safe use of drugs by ensuring that benefits outweigh the risks that may be associated with the use of drugs. ADRs are responsible for significant morbidity and mortality.[1],[2]

Hydroxychloroquine (HCQ), which was initially used widely as an antimalarial drug, has also long been used as an effective treatment of chronic rheumatic diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Recently, HCQ has been advocated by the Indian Council of Medical Research (ICMR) for prophylaxis of COVID-19,[3] and the Food and Drug Administration (FDA) has given emergency use authorization (EUA) for its use in the treatment of severe COVID-19 disease in hospitalized patients.[4] Multiple mechanisms of action have been identified for HCQ that disrupt the early stage of coronavirus replication. Moreover, HCQ affects immune system activity by mediating an anti-inflammatory response, which might reduce damage due to the exaggerated inflammatory response.[5]

The ICMR, under the Ministry of Health and Family Welfare, has recommended chemoprophylaxis with HCQ (400 mg twice on day 1, and then 400 mg once a week thereafter) for asymptomatic health-care workers treating patients with suspected or confirmed COVID-19, and for asymptomatic household contacts of confirmed cases.

HCQ is generally well tolerated;[6] however, concerns about adverse effects in adults prescribed with HCQ for prophylaxis remain. The mild common adverse effects when prescribed in prophylactic doses for a short duration include abdominal pain, nausea, headache, and pruritus, whereas more severe adverse effects (and whose frequency is unknown) include bronchospasm, ventricular arrhythmias, and blurred vision.

One of the strategies by the ICMR to combat the increasing cases of COVID-19 in “hotspots” was to administer HCQ prophylactically to all high-risk contacts of a COVID-19-positive case in the community.[3] The ICMR has mandated that the drug be given to high-risk contacts only after prescription by a doctor. When used in the community setting as a prophylaxis for COVID-19 among high-risk contacts, several problems may arise including the risk of serious adverse effects and monitoring of adverse effects. For this reason, the FDA has not approved the use of HCQ outside hospital setting.[4] It would be, therefore, ideal to document and analyze the adverse effects encountered by doctors/health-care workers who are already taking the HCQ chemoprophylaxis for COVID-19 as advocated by the ICMR, before thinking of introducing HCQ prophylaxis to the hotspot areas to high-risk contacts in the community. Our study was designed to investigate the ADR profile of HCQ in prophylactic doses for COVID-19 prophylaxis among doctors.


  Materials and Methods Top


This was a cross-sectional study carried out among doctors taking HCQ prophylaxis for COVID-19. The study was carried out over 1 month from April 1, to April 30, 2020. Ethical clearance was obtained from the institutional ethics committee prior to initiation of the study (IEC, BJGMC, Pune, Ref No. BJGMC/IEC/Pharmac/ND-Dept0420050-050 Date April 03, 2020).

The study included doctors of either gender who are taking HCQ as chemoprophylaxis for COVID-19. Informed consent was obtained from the participants for participating in the study. Data regarding age, sex, comorbidities, number of doses taken, concomitant drug therapy, adherence to drug schedule, need for treatment of ADRs, and possible adverse effects were obtained from the patients. The participants were administered an online pretested, validated questionnaire to ascertain the adverse effects they noticed while taking HCQ. Due to the nature of COVID-19 and restrictions on personal interview and examination, only an online symptom questionnaire for adverse effects was administered.

Questions regarding ADRs were divided into those concerning gastrointestinal system, neurological system, visual changes, skin reactions, and miscellaneous adverse events.


  Results Top


One-hundred and forty doctors were included in the study group, with age range from 25 years to 72 years. There was a male preponderance (64%), with majority of the participants between 35 and 50 years of age [Table 1]. Comorbidities were present in 41 participants, with the most common being hypertension (in 27 participants) and diabetes (in 9 participants). More than 50% of participants had completed three doses, while 14% had taken only loading dose. Sixty-nine adverse events were documented in 44 participants (31%). The most frequently reported symptoms were headache followed by nausea, dizziness, abdominal cramps, and loose stools [Table 2]. Hypoglycemia was seen in three participants, all with diabetes. Sixteen participants required medication to treat the adverse effects (most commonly ibuprofen for headache), whereas four participants discontinued the drug due to adverse effects (two each because of hypoglycemia and one each because of nausea and loose stools). There was no statistically significant difference of age, gender, number of doses taken, or comorbidities on adverse effects.
Table 1: Preliminary data of participants receiving hydroxychloroquine (n=140)

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Table 2: Suspected adverse drug reactions in participants receiving hydroxychloroquine (figures in parentheses indicate percentages)

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  Discussion Top


HCQ is approved by the ICMR as an empiric chemoprophylaxis for COVID-19 for health-care workers working with COVID-19 cases and high-risk contacts of COVID-19 cases. The FDA has given EUA for the use of HCQ in severe cases of COVID-19. There is conflicting data on the efficacy of HCQ in the treatment of COVID-19,[7],[8],[9] and very little data are available in the published literature for safety and efficacy of chemoprophylaxis of COVID-19.

HCQ and chloroquine have been used for decades as prophylaxis in the treatment of malaria.[10] The most frequently reported adverse effects are abdominal pain, nausea, and headache (10% or more) followed by rash, pruritus, diarrhea, omitting, blurred vision, and affect liability (1% to 10%). Other uncommon adverse effects include alopecia, bleaching of hair, abnormal liver functions, dizziness, sensorimotor disorders, retinopathy, tinnitus, and nervousness. Rare adverse events for which frequency is not reported include serious skin hypersensitivity reactions, cardiac arrhythmias, cardiomyopathies, bone marrow depression, hypoglycemia, neuromyopathy, seizures, vertigo, ataxia, and psychosis.[11] The most common ADRs to HCQ in our study were headache and gastrointestinal ADRs such as nausea, abdominal pain/cramps, vomiting, and diarrhea, the incidences of which were comparable to that of published literature. Surprisingly, dizziness was reported more frequently in our study as compared to what is reported in published literature. Furthermore, tinnitus, emotional changes, and irritability were reported in our study. The adverse effects were classified as “possibly” and “probably” related to HCQ. Some of these may not be a direct adverse effect of the drug, as the stress of working during lockdown with the fear of acquiring COVID-19 disease may also have contributed to these symptoms.

Three individuals experienced hypoglycemia in our study, all of whom reported having diabetes as comorbidity. This has implications for the use of HCQ in diabetic, high-risk contacts of COVID-19 cases, particularly if it is planned to be used in the community. Blood sugar of such patients and drug interactions need to be monitored closely by physicians in such individuals.

There was no statistically significant association of age, sex, comorbidities, and number of doses of HCQ taken with ADRs in our study. A risk score has been derived and validated by Tisdale et al., for the prediction of drug-associated QT prolongation among cardiac care unit hospitalized patients.[12] The risk factors for severe COVID-19 disease (age more than 65 years and comorbidities) are also, unfortunately, risk factors for severe adverse effects to HCQ. There is an urgent need to develop similar score for all serious ADRs of HCQ to minimize the risk of drug toxicity.

Limitations of our study include small sample size for rare adverse events. This study on doctors cannot be generalized to larger population, although it may be expected that doctors are more aware of and are likely to report adverse effects correctly. Larger studies are necessary to ensure the safety of the use of HCQ as prophylaxis for COVID-19 among health-care workers and in hotspots for high-risk contacts.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
World Health Organization. Safety of Medicines. Guide to Detecting and Reporting Adverse Drug Reactions. Geneva, Switzerland: WHO; 2002. Available from: http://www.whqlibdoc.who.int/hq/2002/WHO_EDM_QSM_2002.2.pdf. [Last accessed on 2012 Oct 31].  Back to cited text no. 1
    
2.
Moore N, Lecointre D, Noblet C, Mabille M. Frequency and cost of serious adverse drug reactions in a department of general medicine. Br J Clin Pharmacol 1998;45:301-8.  Back to cited text no. 2
    
3.
National Taskforce for COVID-19 Advisory on the use of Hydroxy-chloroquine as Prophylaxis for SARS-CoV-2 Infection. Available from: https://www.mohfw.gov.in/pdf/AdvisoryontheuseofHydroxychloroquinasprophylaxi sforSARSCoV2infection.pdf. [Last accessed on 2020 Apr 28].  Back to cited text no. 3
    
4.
Food and Drug Administration. Chloroquine Phosphate or Hydroxychloroquine Sulfate Supplied from the Strategic National Stockpile for Treatment of 2019 Coronavirus Disease: Emergency use Authorization Letter. Available from: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policyframework/emer gency-use-authorization#2019-ncov. [Last retrieved on 2020 Mar 30].  Back to cited text no. 4
    
5.
Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: An old drug against today's diseases? Lancet Infect Dis 2003;3:722-7.  Back to cited text no. 5
    
6.
Sharma TS, Joyce E, Wasko MC. Anti-malarials: Are there benefits beyond mild disease? Curr Treat Options Rheum 2016;2:1-12.  Back to cited text no. 6
    
7.
Gautret P, Lagier J, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020;105949. doi: 10.1016/j.ijantimicag.2020.105949. [Epub ahead of print].  Back to cited text no. 7
    
8.
Chen Z, Hu J, Zhang Z, Jian S, Hang S, Yan D, et al. Efficacy of Hydroxychloroquine in Patients with COVID-19: Results of a Randomized Clinical Trial. 2020. [doi: https://doi.org/10.1101/2020.03.22.20040758].  Back to cited text no. 8
    
9.
Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in Patients with COVID-19: An Open-Label, Randomized, Controlled Trial. Pre-print. Available from: https://www.medrxiv.org/con tent/10.1101/2020.04.10.20060558v1. [Last retrieved on 2020 Apr 16].  Back to cited text no. 9
    
10.
Principi N, Esposito S. Chloroquine or hydroxychloroquine for the prophylaxis of COVID-19. Lancet Infect Dis 2020. doi: 10.1016/S1473-3099(20)30296-6. [Epub ahead of print]. Available from: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30296-6/fulltext. [Last accessed on 2020 Apr 28].  Back to cited text no. 10
    
11.
Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents 2020;55:105932.  Back to cited text no. 11
    
12.
Tisdale JE, Jaynes HA, Kingery JR, Mourad NA, Trujillo TN, Overholser BR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes 2013;6:479-87.  Back to cited text no. 12
    



 
 
    Tables

  [Table 1], [Table 2]


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