Overview

Chloroquine and hydroxychloroquine are antimalarials that belong to the aminoquinoline group.¹ In Malaysia, chloroquine is approved for the treatment of malaria, giardiasis, chronic lupus erythematosus, chronic rheumatoid arthritis, amoebic hepatitis, and liver abscess.² Meanwhile, hydroxychloroquine is indicated for rheumatoid arthritis, juvenile chronic arthritis, discoid and systemic lupus erythematosus, and dermatological conditions caused or aggravated by sunlight.³

A wide spectrum of psychiatric disorders, including reports of suicidal behaviour, depression, anxiety, hallucination, and psychosis, are already known for chloroquine and hydroxychloroquine.^4-6 In Malaysia, there are currently three (3) products containing hydroxychloroquine and one (1) product containing chloroquine registered with the Drug Control Authority (DCA).⁷ 

Background of the Safety Issue

The European Medicines Agency (EMA) is updating the product information for chloroquine and hydroxychloroquine-containing products to include additional information about the risk of psychiatric disorders.^5-6 The additional events identified include aggression, delusion, paranoia, mania, attention deficit, sleep disorders, agitation and confusion.⁵

Psychiatric reactions have been observed for both substances and sometimes may become severe, both in patients with and without a history of psychiatric disorders. They have been reported to occur within the first month after starting treatment of hydroxychloroquine. However for chloroquine, data are inadequate to determine the time to onset.^5-6 Hence, it is crucial to remain vigilant for psychiatric reactions associated with chloroquine or hydroxychloroquine.

Adverse Drug Reaction Reports⁸

To date, NPRA has received 36 reports with 64 adverse events suspected to be related to chloroquine and 231 reports with 425 adverse events suspected to be associated with hydroxychloroquine. The most reported adverse events for chloroquine were vomiting (6) and nausea (6), followed by pruritus (5). For hydroxychloroquine, the most reported adverse events were ECG QT prolonged (35) and rash (27). There has been one (1) local report of psychotic disorder following the use of chloroquine, while none received for hydroxychloroquine thus far.

Advice for Healthcare Professionals

• Be vigilant with the risk of psychiatric reactions following the use of chloroquine or hydroxychloroquine, especially in the first month of treatment; psychiatric events have been reported in patients even without prior history of psychiatric disorders.
• Advise patients and caregivers on the possible psychiatric symptoms and remind them to seek medical attention as soon as possible when they notice any new or worsening symptoms.
• Report all suspected adverse events associated with chloroquine- and hydroxychloroquine-containing products to the NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (8) Jld.1] has been issued for all registration holders of products containing chloroquine and hydroxychloroquine to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

References:

1. European Medicines Agency (EMA). Pharmacovigilance Risk Assessment Committee (PRAC), Minutes of the meeting on 8-11 June 2020 [Internet]. 2020 Nov 19 [cited 2022 Apr 4]. Available at: https://www.ema.europa.eu/en/documents/minutes/minutes-prac-meeting-08-11-june-2020_en.pdf
2. National Pharmaceutical Regulatory Agency (NPRA). AXCEL CHLOROQUINE TABLET (chloroquine) [package insert]. 2016 [cited 2022 Apr 4]. The Malaysian Product Registration Database (QUEST). Available from: http://www.npra.gov.my (access restricted).
3. National Pharmaceutical Regulatory Agency (NPRA). PLAQUENIL 200MG FILM-COATED TABLETS (hydroxychloroquine) [package insert]. 2021 Nov [cited 2022 Apr 4]. The Malaysian Product Registration Database (QUEST). Available from: http://www.npra.gov.my (access restricted).
4. Medicines & Healthcare Products Regulatory Agency (MHRA). Hydroxychloroquine, chloroquine: increased risk of cardiovascular events when used with macrolide antibiotics; reminder of psychiatric reactions [Internet]. Drug Safety Update. 2022 Feb 15 [cited 2022 Apr 4]. Available from: https://www.gov.uk/drug-safety-update/hydroxychloroquine-chloroquine-increased-risk-of-cardiovascular-events-when-used-with-macrolide-antibiotics-reminder-of-psychiatric-reactions
5. European Medicines Agency (EMA). Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 23-26 November 2020 [Internet]. 2020 Nov 27 [cited 2022 Apr 4]. Available from: https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-23-26-november-2020
6. European Medicines Agency (EMA). Pharmacovigilance Risk Assessment Committee (PRAC) Recommendations on signals: Adopted at the 23-26 November 2020 PRAC meeting [Internet]. 2021 Jan 6 [cited 2022 Apr 4]. Available from: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-23-26-november-2020-prac-meeting_en.pdf
7. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2022 [cited on 2022 Apr 4]. Available from: https://www.npra.gov.my
8. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2022 [cited 2022 Apr 4]. Available from: https://www.npra.gov.my (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, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

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