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.

Overview of Product

Hydroxychloroquine (PLAQUENIL®) is indicated for the treatment of rheumatoid arthritis, juvenile chronic arthritis, discoid and systemic lupus erythematosus, and dermatological conditions caused or aggravated by sunlight.

Background of the Safety Issue

The European Medicines Agency (EMA), after reviewing the Huybrechts study, recommended updating the “Fertility, pregnancy and lactation” section of the package insert to include the risk of major congenital malformations.

The population-based cohort study, published in 2021, suggested a small increase in the relative risk (RR) of major congenital malformations (including but not limited to oral cleft, cardiac, respiratory, gastrointestinal, genital, urinary, musculoskeletal, and limb defects) linked to hydroxychloroquine use in the first trimester of pregnancy (n = 112 events), particularly at high daily dosage (≥ 400 mg daily). For a daily dose of ≥ 400 mg, the RR was 1.33 (95% CI, 1.08 – 1.65), while for a daily dose of < 400 mg, the RR was 0.95 (95% CI, 0.60 – 1.50).

Additionally, hydroxychloroquine-induced phospholipidosis (accumulation of phospholipids within cells) has been reported. This may occur in different organ systems, including cardiac, renal, nervous, or muscular systems, causing toxicity.

Aggravation of symptoms of myasthenia gravis (a chronic autoimmune neuromuscular disorder causing weakness in skeletal muscles) has also been reported in patients with myasthenia receiving hydroxychloroquine therapy. 

Advice for Health Care Professionals

Risk of major congenital malformations

• 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.
• Avoid prescribing hydroxychloroquine at daily doses of ≥ 400 mg during the first trimester of pregnancy unless the potential benefits outweigh the risks.
• If there is no alternative treatment to hydroxychloroquine during the first trimester of pregnancy,
  • Use the lowest effective dose of hydroxychloroquine.
  • Ensure close monitoring during pregnancy, especially during the first trimester, for early detection of major congenital malformations.

Risk of phospholipidosis and aggravation of myasthenia gravis symptoms

• Stay informed about the potential risks of hydroxychloroquine-induced phospholipidosis, and aggravation of myasthenic symptoms in patients with underlying myasthenia gravis.
• Discontinue hydroxychloroquine if:
  • Cardiac, renal, muscular or nerve toxicity is suspected or demonstrated by tissue biopsy.
  • Worsening symptoms of myasthenia gravis, such as generalised weakness, shortness of breath, dysphagia, and diplopia, is suspected.

Report any suspected adverse reactions associated with the use of hydroxychloroquine (PLAQUENIL^®) to the NPRA.

Regulatory Actions

The local packet insert for Plaquenil® is being updated to include new information on the risk of major congenital malformations, phospholipidosis, and aggravation of myasthenia gravis symptoms.

On 29 November 2024, the NPRA had approved a Direct Healthcare Professional Communication (DHPC) letter to be distributed by Sanofi-Aventis Sdn. Bhd. to highlight these safety issues. For further information, please contact your local sales person for a copy of the DHPC.

On 19 September 2025, the NPRA has also published a safety alert titled "Hydroxychloroquine: 1) Small Increased Risk of Major Congenital Malformations in Children Following in utero Exposure; 2) Risk of Drug-Induced Phospholipidosis; 3) Risk of Aggravation of Myasthenia Gravis". Refer to the NPRA Safety Alert for further details.

Reference

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.