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.

 

This information is an update to the NPRA Safety Alerts published on 4 March 2025.

 

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 five hydroxychloroquine-containing products registered with the DCA.²

 

This safety alert article addresses three safety issues as follow:

 

1) Major Congenital Malformations

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., 2001), 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 study by Huybrechts et al. 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.

 

2) Drug-Induced Phospholipidosis (DIPL)

Overview of Safety Concern

Lysosomes are cellular structures containing enzymes responsible for the degradation of proteins, nucleic acids, carbohydrates and lipids.¹¹ Drug-induced phospholipidosis (DIPL) is a form of lysosomal storage disorder, whereby the inducing medicine causes lysosomal changes, leading to accumulation of both phospholipids and the medicine within the lysosomes. This results in the formation of lysosomal lamellar bodies, seen via electron microscope.^11,12 DIPL has been associated with organ toxicity, affecting the heart, skeletal muscle, liver, lungs and kidneys.

Source of Safety Issue

The risk of DIPL was first announced by the United States Food and Drug Administration (US FDA) as a potential signal of serious risks identified by the FDA Adverse Event Reporting System (FAERS).¹³ Following the review, the US FDA mandated the update of product information of hydroxychloroquine to include the risk of DIPL.

Background of Safety Issue

The mechanism of DIPL is thought to be related to the use of cationic and amphiphilic drugs (CADs), such as hydroxychloroquine.^12,14 CADs can easily penetrate the lysosomal membrane and undergo protonation. Following this process, they are no longer able to exit the lysosome, leading to their build-up within the lysosome and impairment of lipid catabolism. This leads to the accumulation of phospholipids, a condition known as phospholipidosis.

While the exact onset of hydroxychloroquine-induced renal phospholipidosis was not reported, published literature indicated prolonged use (in years) prior to symptom onset.^12,14 However, there were also reported cases whereby lamellar bodies were detected as early as a few weeks after hydroxychloroquine initiation.¹²

 

3) Aggravation of Myasthenia Gravis (MG)

Overview of Safety Concern

Myasthenia gravis (MG) is an autoimmune disorder characterised by antibodies targeting the acetylcholine receptor, muscle-specific kinase (MuSK), lipoprotein-related protein 4 (LRP4), or agrin in the postsynaptic membrane at the neuromuscular junction (NMJ).¹⁵ Clinically, it presents with muscle weakness and fatigue that worsens when the affected muscles are used.^15,16

Source of Safety Issue

A product registration holder (PRH) for hydroxychloroquine identified this risk through the company's internal routine signal detection activities. Based on review of non-clinical safety data, the company safety database, published literature, reference pharmacovigilance textbooks and external databases, the cumulative weight of evidence is sufficient to support a causal relationship between hydroxychloroquine and aggravation of myasthenia gravis. Thus, the PRH voluntarily requested to update its product information with the risk of aggravation of MG.

Background of Safety Issue

The mechanism underlying the aggravation of MG following hydroxychloroquine use is believed to be related to the drug’s direct effect on the NMJ.¹⁷

MG may be precipitated by various factors, including infections, immunisations, surgical procedures, and certain medications.¹⁸ Some antibiotics, antiarrhythmics, anaesthetics, and neuromuscular blocking agents can impair neuromuscular transmission and exacerbate muscle weakness in individuals with MG.¹⁹ Based on published case reports, aggravation of MG is observed within a few weeks after initiation of hydroxychloroquine therapy.^20-22

 

Local Adverse Drug Reaction Reports

To date, the NPRA has received 275 reports with 503 adverse events suspected to be related to hydroxychloroquine-containing products.²³ The most frequently reported adverse events were rash (37 cases), electrocardiogram QT prolonged (35 cases), and pruritus (33). In Malaysia, no congenital malformations of any type have been reported in children exposed to hydroxychloroquine in utero, and no reports of phospholipidosis have been received. However, one (1) case of muscle-specific kinase (MuSK) myasthenia gravis was reported, sourced from the literature.

 

Regulatory Action

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.²⁴ For further information, please contact your local sales person for a copy of the DHPC. 

The NPRA has completed a review of the potential risk of major congenital malformations in children following in utero exposure, drug-induced phospholipidosis, and aggravation of myasthenia gravis associated with hydroxychloroquine. On 18 August 2025, a directive [Ruj. Kami: NPRA.600-1/9/13 (64) Jld. 1] was issued for all registration holders of products containing hydroxychloroquine to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

An infographic summarising the key safety information for healthcare professionals is available on the NPRA website under the e-Brochures section.

 

Advice for Health Care Professionals

Major Congenital Malformation

• 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.
• 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.

Drug-Induced Phospholipidosis

• Advise patients to seek medical attention if they experience symptoms of cardiac, muscular, or renal disorders as these may be indicate phospholipidosis.
• Hydroxychloroquine may need to be discontinued if DIPL is suspected or demonstrated by tissue biopsy.
• If DIPL is suspected, electron microscopy along with histopathology tests are important added investigations to confirm the diagnosis.

Aggravation of Myasthenia Gravis

• Educate patients to seek medical attention if they exhibit signs and symptoms suggestive of exacerbation of MG, such as muscular weakness that worsens after periods of activity involving the affected muscles, double vision, drooping eyelids or difficulty swallowing.
• If aggravation of MG is suspected, consider discontinuing hydroxychloroquine therapy and initiating immunosuppressant treatment.

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]. 2025 [cited 2025 July 31]. 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). Pharmacovigilance Risk Assessment Committee (PRAC). Minutes of PRAC meeting on 6-9 Feb 2023 [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. Drug-induced phospholipidosis [Internet]. 2024 March 7 [cited 2025 May 15]. Available from: https://www.medsafe.govt.nz/profs/PUArticles/March2024/Drug-induced-phospholipidosis.html
12. Menke AF, Heitplatz B, Van Marck V, Pavenstädt H, Jehn U. Hydroxychloroquine-Induced Renal Phospholipidosis: Case Report and Review of Differential Diagnoses. Case Rep Nephrol Dial. 2024 Feb 16;14(1):20-29. Available from: https://doi.org/10.1159/000536448
13. United States Food and Drug Administration (US FDA). Jan-March 2020 Potential signals of serious risks/ New safety information identified by the FDA Adverse Event Reporting System (FAERS) [Internet]. 2025 March 5 [cited 2025 May 15]. Available from: https://www.fda.gov/drugs/fdas-adverse-event-reporting-system-faers/january-march-2020-potential-signals-serious-risksnew-safety-information-identified-fda-adverse
14. Kothapalli N, Padiyar S, Nair AM, Manikuppam P, Matthai SM, Roy S, Pulimood A, Alexander S, Mathew J. Hydroxychloroquine-Induced Phospholipidosis - A Forgotten Complication of a Common Drug. Indian J Nephrol. 2024 Mar-Apr;34(2):175-177. Available from: https://doi.org/10.4103/ijn.ijn_325_22
15. Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol. 2015 Oct;14(10):1023-36. Available from: https://doi.org/10.1016/s1474-4422(15)00145-3
16. Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin Invest. 2006 Nov;116(11):2843-54. Available from: https://doi.org/10.1172/jci2989
17. Tugasworo D, Kurnianto A, Retnaningsih, Andhitara Y, Ardhini R, Budiman J. The relationship between myasthenia gravis and COVID-19: a systematic review. Egypt J Neurol Psychiatr Neurosurg. 2022;58(1):83. Available from: https://doi.org/10.1186/s41983-022-00516-3
18. Bellor Suresh A, Asuncion RMD. Myasthenia Gravis [Internet]. Statpearls. 2023 Aug 8 [cited 2025 May 15]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559331/
19. Sheikh S, Alvi U, Soliven B, Rezania K. Drugs That Induce or Cause Deterioration of Myasthenia Gravis: An Update. J Clin Med. 2021 Apr 6;10(7):1537. Available from: https://doi.org/10.3390/jcm10071537
20. Elavarasi A, Goyal V. Hydroxychloroquine and Myasthenia Gravis-Can One Take This Risk? Ann Indian Acad Neurol. 2020 May-Jun;23(3):360-361. Available from: https://doi.org/10.4103/aian.AIAN_363_20
21. Jallouli M, Saadoun D, Eymard B, Leroux G, Haroche J, Le Thi Huong D, De Gennes C, Chapelon C, Benveniste O, Wechsler B, Cacoub P, Amoura Z, Piette JC, Costedoat-Chalumeau N. The association of systemic lupus erythematosus and myasthenia gravis: a series of 17 cases, with a special focus on hydroxychloroquine use and a review of the literature. J Neurol. 2012 Jul;259(7):1290-7. Available from: https://doi.org/10.1007/s00415-011-6335-z
22. Bhaskar S, Abdul Rani MFB. MuSK-Myasthenia Gravis Unmasked by Hydroxychloroquine. Case Rep Med. 2022 Jul 15;2022:4802538. Available from: https://doi.org/10.1155/2022/4802538
23. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2025 [cited 2025 May 14]. Available from: https://www.npra.gov.my (access restricted)
24. 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: Dr. Rema Panickar, Noor'ain Shamsuddin, Norleen Mohamed Ali