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.

 

Overview of Product(s)

In Malaysia, hydroxychloroquine has been approved by the Drug Control Authority (DCA) for treatment of rheumatoid arthritis (RA), juvenile chronic arthritis, discoid, and systemic lupus erythematosus (SLE) and dermatological conditions caused or aggravated by sunlight.¹ There are currently four hydroxychloroquine-containing products registered with the DCA.²

 

Overview of Safety Concern

Congenital malformations, or birth defects, are abnormalities in body structures or functions which are present at birth and originate prenatally.³ Major congenital malformations are structural abnormalities with significant medical, social, or cosmetic impact that typically require medical intervention and contribute to the majority of deaths, morbidity and disability among affected individuals. Examples of major congenital malformations include anencephaly, cleft lip, and spina bifida.

Pregnancies in individuals with SLE or RA have a higher risk of adverse outcomes compared to pregnancies in healthy women.⁴ Hydroxychloroquine is generally considered safe and is commonly recommended before and during pregnancy to manage disease activity and minimise both maternal and foetal risks.^4-7 Most prior studies on hydroxychloroquine safety in malaria, SLE, and rheumatic disorders suggested no increased risk of common adverse obstetrical outcomes, such as spontaneous abortion, prematurity, or intrauterine growth restriction.^5,6 However, previous data on the risk of major congenital malformations from early pregnancy exposure were limited and underpowered.^4,5 The majority of these studies reported no statistically significant association between hydroxychloroquine use and congenital malformations.⁴

 

Source of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) learned from the European Medicines Agency (EMA) about the risk of major congenital malformations in children exposed to hydroxychloroquine in utero.⁸

The EMA’s evaluation of this risk was triggered by a United States population-based cohort study (Huybrechts et al., 2021), which suggested a small increase in the risk of malformations associated with first-trimester hydroxychloroquine use.^5,9 The EMA considered the study by far the largest epidemiological study on the potential teratogenic risk of hydroxychloroquine, making it more valuable than previous studies, which were too small to detect such risks. Despite some limitations, the study was well-designed, with a robust control for confounders, and was adequately powered.

Based on a review of the available data from the Huybrechts study, a plausible mechanism of action, and data submitted by marketing authorisation holders, the EMA considered that a causal relationship between hydroxychloroquine and congenital malformations is at least a reasonable possibility.^9,10 The Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) of the EMA agreed that the product information for hydroxychloroquine should be updated to include the risk of congenital malformations.

 

Background of Safety Issue

The Huybrechts study included 2,045 pregnancies exposed to hydroxychloroquine during the first trimester of pregnancy and around 3 million pregnancies not exposed to hydroxychloroquine as the reference group.⁵ The cohort was then restricted to women with rheumatic disorders, and propensity score (PS) matching was used to control for indication, demographics, comorbidities, and concomitant medications, resulting in 1,867 hydroxychloroquine-exposed and 19,080 unexposed pregnancies.

Among infants exposed to hydroxychloroquine in utero, the rate of major congenital malformations was 54.8 per 1,000 (112 events), compared to 35.3 per 1,000 in unexposed infants (112,908 events), yielding an unadjusted relative risk (RR) of 1.51 (95% CI, 1.27–1.81).⁵ After restricting the reference group to women with rheumatic disorders and adjusting for confounders, the adjusted RR was 1.26 (95% CI, 1.04–1.54). Stratified by dose, the adjusted RR was 0.95 (95% CI, 0.60–1.50) for < 400 mg daily dose and 1.33 (95% CI, 1.08–1.65) for ≥ 400 mg daily dose. Specific malformation types, including oral clefts, respiratory defects, and urinary defects, showed a 2–4 times higher risk, though estimates were imprecise. The risk of other malformations was generally under 2-fold, except for genital defects, which had an upper 95% CI limit of 4.76.

In humans, hydroxychloroquine crosses the placenta, and foetal blood concentrations are similar to maternal blood concentrations.¹ Given that hydroxychloroquine is known to inhibit cell division and DNA synthesis and that initial reports suggested an increased risk of chromosomal damage attributable to chloroquine, it is biologically plausible that hydroxychloroquine could affect rapidly dividing embryonic cells.^5,9

Despite findings indicating a potential small increase in the risk of major congenital malformations, Huybrechts et al. concluded that the benefits of hydroxychloroquine in pregnant women with rheumatic disorders may still outweigh the potential risk.⁵ Considering the drug's long half-life (more than a month), discontinuing it after conception may not effectively prevent congenital malformations and could elevate the risk of disease flares and related complications.

 

Local Adverse Drug Reaction Reports

To date, the NPRA has received 265 reports with 489 adverse events suspected to be related to hydroxychloroquine-containing products.¹¹ The most frequently reported adverse events were electrocardiogram QT prolonged (35 cases), rash (33), and pruritus (27). No congenital malformations of any type have been reported in children exposed to hydroxychloroquine in utero.

 

Regulatory Actions

On 29 November 2024, the NPRA approved a Direct Healthcare Professional Communication (DHPC) letter issued by Sanofi-Aventis Sdn. Bhd. to highlight this safety issue.¹² This letter informs healthcare professionals about the potential risk of major congenital malformations, as well as the new risks of phospholipidosis and aggravation of myasthenia gravis symptoms associated with PLAQUENIL® (hydroxychloroquine). For further information, please contact your local sales person for a copy of the DHPC.

 

Advice for Healthcare Professionals

• While NPRA is still reviewing this safety issue, be aware that a population-based cohort study suggests a small increase in the relative risk of major congenital malformations associated with hydroxychloroquine use during the first trimester of pregnancy, particularly at daily doses of ≥ 400 mg.
• Given the seriousness of the risk and its potential impact on the individual patient,
  • Carefully weigh the benefits and risks of hydroxychloroquine use before prescribing it to pregnant women or women of childbearing potential.
  • Advise patients to consult their doctor if they are planning to become pregnant or think they may be pregnant, to allow for a review of their treatment.
  • Avoid prescribing daily doses of ≥ 400 mg during the first trimester of pregnancy unless the potential benefits outweigh the risks.
• If treatment of hydroxychloroquine is necessary during pregnancy:
  • Use the lowest effective dose.
  • Ensure close monitoring during pregnancy, especially during the first trimester, for early detection of major congenital malformations.
• Report all adverse events suspected to be related to the use of hydroxychloroquine-containing products to the NPRA.

 

References: 

1. National Pharmaceutical Regulatory Agency (NPRA). PLAQUENIL (hydroxychloroquine) [Package Insert]. QUEST3+ Product Search. 2024 March [cited 2024 Sep 26]. Available from: http://www.npra.gov.my.
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2024 [cited 2024 Nov 11]. Available from: https://www.npra.gov.my
3. World Health Organization (WHO). Birth Defects Surveillance A Manual For Programme Managers [Internet]. 2014 [cited 2024 Oct 4]. Available from: https://iris.who.int/bitstream/handle/10665/110223/9789241548724_eng.pdf?sequence=1
4. Nguyen NV, Svenungsson E, Dominicus A, Altman M, Hellgren K, Simard JF, Arkema EV. Hydroxychloroquine in lupus or rheumatoid arthritis pregnancy and risk of major congenital malformations: a population-based cohort study. Rheumatology (Oxford). 2024 Mar 13:keae168. Available from: https://doi.org/10.1093/rheumatology/keae168
5. Huybrechts KF, Bateman BT, Zhu Y, Straub L, Mogun H, Kim SC, Desai RJ, Hernandez-Diaz S. Hydroxychloroquine early in pregnancy and risk of birth defects. Am J Obstet Gynecol. 2021 Mar;224(3):290.e1-290.e22. Available from: https://doi.org/10.1016/j.ajog.2020.09.007
6. Ministry of Health (MOH), Malaysia. Management of systemic lupus erythematosus [Internet]. Clinical Practice Guidelines. 2023 [cited 2024 Oct 4]. Available from: https://www.moh.gov.my/moh/resources/Penerbitan/CPG/Rheumatology/e-CPG-SLE-compressed.pdf
7. Ministry of Health (MOH), Malaysia. Management of rheumatoid arthritis [Internet]. Clinical Practice Guidelines. 2019 [cited 2024 Oct 4]. Available from: https://www.moh.gov.my/moh/resources/Penerbitan/CPG/Rheumatology/CPG_Rheumatoid_Arthritis-17052021.pdf
8. European Medicines Agency (EMA). PRAC recommendations on signals: Adopted at the 6-9 Feb 2023 PRAC meeting [Internet]. 2023 May 16 [cited 2024 Sep 26]. Available from: https://www.ema.europa.eu/en/documents/minutes/minutes-prac-meeting-6-9-february-2023_en.pdf
9. Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh). Final Lead Member State PSUR Follow-Up assessment report on hydroxychloroquine [Internet]. 2023 March 1 [cited 2024 Sep 26]. Available from: https://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Pharmacovigilance_Legislation/PSUR/Outcome_of_informal_PSUR_WS_procedures/Hydroxychloroquine_-_PSUFU_summary_AR.pdf
10. Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh). Report from the CMDh meeting held on 21-22 February 2023 [Internet]. 2023 March 1 [cited 2024 Sep 26]. Available from: https://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/CMDh_pressreleases/2023/CMDh_press_release_-_February_2023.pdf
11. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2024 [cited 2024 Nov 14]. Available from: https://www.npra.gov.my (access restricted)
12. Direct Healthcare Professional Communication (DHPC). PLAQUENIL® (Hydroxychloroquine sulphate): Potential risk of major congenital malformations and new risks of phospholipidosis and aggravation of myasthenia gravis symptoms. Sanofi-Aventis Sdn. Bhd.; 2024 Nov 29.

 

Written by: Wo Wee Kee

Reviewed/Edited by: Choo Sim Mei, Dr Rema Panickar, Noor'ain Shamsuddin, Norleen Mohamed Ali