Overview

Hydroxychloroquine and chloroquine have been widely used for decades to treat malaria and autoimmune diseases.¹ In Malaysia, hydroxychloroquine has been approved by the Drug Control Authority (DCA) for rheumatoid arthritis, juvenile chronic arthritis, discoid and systemic lupus erythematosus (SLE), and dermatological conditions caused or aggravated by sunlight.² Meanwhile, chloroquine is approved for the treatment of malaria, giardiasis, chronic lupus erythematosus, extraintestinal amoebiasis, and chronic rheumatoid arthritis.³ There are currently three (3) products containing hydroxychloroquine and one (1) product containing chloroquine registered with the Drug Control Authority (DCA)_.⁴

Hydroxychloroquine and chloroquine are derivatives of the 4-aminoquinoline (4AQ) nucleus. Despite having the same potency, hydroxychloroquine is regarded as less toxic and more commonly used as a safer alternative to chloroquine.⁵

Idiosyncratic drug-induced hepatic impairment is one of the most challenging liver disorders to diagnose, owing to the huge number of drugs used in clinical practice, the availability of herbs and dietary supplements with hepatotoxic potential, the variety of clinical and pathological presentations, and the current absence of specific biomarkers. In most cases, the first sign of liver injury is the elevation of liver enzymes. Other less specific symptoms, such as fatigue, weakness, anorexia, nausea, vomiting, fever, chills, abdominal pain, pruritus, and skin rash, have also been linked to poorer clinical outcomes. Jaundice, encephalopathy, bleeding, and ascites are the symptoms of drug-induced hepatic impairment that may become clinically obvious when a serious injury has already taken place.⁶

Background of the Safety Issue

Following a safety review published by the Japan Pharmaceuticals and Medical Device Agency (PMDA) on the risk of hepatic impairment associated with hydroxychloroquine sulfate, the National Pharmaceutical Regulatory Agency (NPRA) has initiated a safety evaluation on hydroxychloroquine, and extended it to chloroquine-containing products after a preliminary review of the literature evidence.^7-10

According to the Japan PMDA’s review, a total of two (2) cases of hepatic impairment, one (1) of which resulted in death, were reported in Japan across a period of three fiscal years. However, no causal relationship between hydroxychloroquine and the event could be established in these cases. Globally, in four (4) of the 21 cases reported worldwide, there was a reasonably possible causal relationship between hydroxychloroquine and the event. Of these, the causal links between the two (2) reported deaths and hydroxychloroquine could not be established.⁷

The mechanisms of hepatic impairment following the use of hydroxychloroquine and chloroquine are poorly understood. However, the hepatotoxicity effects may be caused by the reactive metabolites and oxidative stress initiated by these drugs or as the result of an idiosyncratic toxic or synergistic effect associated with inflammatory responses.¹¹ Given that the liver is involved in the metabolism of both hydroxychloroquine and chloroquine, the inducible liver injury can in turn affect their metabolism and excretions.⁸

As observed in the literature, the onset of hepatic impairment symptoms ranged between eight (8) hours and one (1) year after hydroxychloroquine administration. There have also been literature cases that led to severe liver failure, which necessitated a liver transplantation or resulted in deaths. In some cases, early treatment of hepatic impairment with steroids and discontinuation of treatment with hydroxychloroquine had resulted in complete recovery.¹² Although its safety in hepatic impairment has not been well described, chloroquine is known to concentrate in the liver.⁹ In general, close monitoring of liver functions is recommended when using hydroxychloroquine and chloroquine, particularly in patients at high risk for developing hepatotoxicity.^8-10

Adverse Drug Reaction (ADR) Reports

To date, NPRA had received a total of 238 reports with 440 adverse events suspected to be related to hydroxychloroquine and 37 reports with 96 adverse events for chloroquine-containing products. In Malaysia, adverse events involving hepatic impairment, such as transaminases increased (9), alanine aminotransferase increased (5), aspartate aminotransferase increased (3), hepatic enzyme increased (2), and hepatitis (2), were only reported for hydroxychloroquine.¹³ Globally, hydroxychloroquine was linked to 483 adverse events involving hepatic impairment, while chloroquine was associated with 65 events, including liver injury, hepatotoxicity, hepatic function abnormal, and hepatic failure.¹⁴

Advice for Healthcare Professionals:

• Be aware of the potential risk of hepatic impairment associated with hydroxychloroquine or chloroquine use.
• Use hydroxychloroquine or chloroquine with caution in patients with underlying hepatic disease or alcohol misuse, or in conjunction with other known hepatotoxic drugs.
• Consider monitoring liver function in patients treated with hydroxychloroquine or chloroquine, especially during the first 10 days of treatment to allow early detection of hepatic impairment.
• Advise patients to seek medical attention immediately if they develop any signs and symptoms suggestive of hepatic impairment following the administration of hydroxychloroquine or chloroquine.
• Initiate prompt treatment in patients who exhibit clinical symptoms of hepatic impairment and elevated liver enzymes. Consider stopping hydroxychloroquine or chloroquine use and switching to an alternative therapy.
• Report all suspected adverse events associated with hydroxychloroquine or chloroquine-containing products to the NPRA.

 References:

1. Lei Z, Wu Z, Dong S, Yang D, Zhang L, Ke Z et al. Chloroquine and hydroxychloroquine in the treatment of malaria and repurposing in treating COVID-19. Pharmacology & Therapeutics. 2020;216:107672. Available from: https://doi.org/10.1016/j.pharmthera.2020.107672
2. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). PLAQUENIL (hydroxychloroquine) package insert [Internet]. 2021 Nov 18 [cited 2022 Oct 18]. Available from: http://www.npra.gov.my
3. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). AXCEL CHLOROQUINE (chloroquine) package insert [Internet]. 2016 Jul 8 [cited 2022 Oct 18]. Available from: http://www.npra.gov.my
4. National Pharmaceutical Regulatory Agency (NPRA). QUEST 3+ system [Internet]. 2022 [cited 2022 Oct 19]. Available from: https://www.npra.gov.my/index.php/my/consumers-2/maklumat/carian-produk-berdaftar-bernotifikasi.html
5. Browning D. J. (2014). Pharmacology of Chloroquine and Hydroxychloroquine. Hydroxychloroquine and Chloroquine Retinopathy, 35–63. https://doi.org/10.1007/978-1-4939-0597-3_2
6. European Association for the Study of the Liver. Electronic address: This email address is being protected from spambots. You need JavaScript enabled to view it., Clinical Practice Guideline Panel: Chair:, Panel members, EASL Governing Board representative: EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol. 2019;70(6):1222–1261. Available from : https://doi.org/10.1016/j.jhep.2019.02.014
7. Japan Pharmaceuticals and Medical Devices Agency (PMDA). Summary of Investigation Results Hydroxychloroquine sulfate [Internet]. Pmda.go.jp. 2022 [cited 2022 Oct 18]. Available from: https://www.pmda.go.jp/files/000248005.pdf
8. Cao J, Cai X, Chen M. Liver Injury in COVID-19: Caution and Management. Liver Cancer. 2020 Sep;9(5):625-626. Available from: https://doi.org/10.1159/000508696
9. Wong GL, Wong VW, Thompson A, Jia J, Hou J, Lesmana CRA, Susilo A, Tanaka Y, Chan WK, Gane E, Ong-Go AK, Lim SG, Ahn SH, Yu ML, Piratvisuth T, Chan HL; Asia-Pacific Working Group for Liver Derangement during the COVID-19 Pandemic. Management of patients with liver derangement during the COVID-19 pandemic: an Asia-Pacific position statement. Lancet Gastroenterol Hepatol. 2020 Aug;5(8):776-787. Available from: https://doi.org/10.1016/s2468-1253(20)30190-4
10. Licata A, Minissale MG, Distefano M, Montalto G. Liver injury, SARS-COV-2 infection and COVID-19: What physicians should really know? GastroHep. 2021 May;3(3):121-130. Available from: https://doi.org/10.1002/ygh2.455
11. Falcão M, Pamplona de Góes Cavalcanti L, Filgueiras Filho N, Antunes de Brito C. Case Report: Hepatotoxicity Associated with the Use of Hydroxychloroquine in a Patient with COVID-19. The American Journal of Tropical Medicine and Hygiene. 2020;102(6):1214-1216. Available from: https://doi.org/10.4269/ajtmh.20-0276
12. Gisi K, Murat Ispiroglu, Emine Kilinc. A Hydroxychloroquine-Related Acute Liver Failure Case and Review of the Literature. Journal of Clinical Toxicology [Internet]. 2021 Mar 26 [cited 2022 Oct 21];0(0):1–3. Available from: https://www.longdom.org/open-access/a-hydroxychloroquinerelated-acute-liver-failure-case-and-review-of-the-literature-67725.html
13. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2022 [cited 2022 Oct 19]. Available from: https://www.npra.gov.my (access restricted).
14. Uppsala Monitoring Centre (UMC). The WHO Global ICSR Database (VigiLyze) [Internet]. 2022 [cited 2022 Nov 10]. Available from: https://www.vigilyze.who-umc.org (access restricted).

DISCLAIMER:

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Written by: Noor'ain Shamsuddin
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Dr Azuana Ramli