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

Fluconazole is approved locally for the treatment of cryptococcosis, systemic, mucosal, or genital candidiasis, dermatomycosis, and for the prevention of fungal infections in immunosuppressed cancer patients.¹ In Malaysia, there are currently 27 fluconazole-containing products, available in oral or injection form registered with the Drug Control Authority (DCA).²

Oral fluconazole is prescribed as a single dose of 150-200 mg to treat vulvovaginal candidiasis and higher doses for systemic fungal infections.^1,3,4 Vulvovaginal candidiasis affects about 10% of pregnant women, a risk that is 2–10 times higher compared to non-pregnant women.⁴ While topical azoles are recommended as the first-line treatment during pregnancy, low-dose oral fluconazole is often used due to the potential for more severe and treatment-resistant vulvovaginal candidiasis in pregnant individuals.

Fluconazole use during pregnancy is known to be associated with spontaneous abortion and multiple congenital abnormalities.¹ Reported cases of congenital malformations include a distinct pattern of abnormal craniofacial, skeletal and heart defects, such as brachycephaly, femoral bowing, and arthrogryposis.^1,4,5

In 2017, the National Pharmaceutical Regulatory Agency (NPRA) issued a directive [Ruj. Kami: (29) dlm. BPFK/PPP/07/25 Jld.1] mandating updates to package inserts and consumer medication information leaflets (RiMUPs) for all fluconazole-containing product to address the known risks.⁵ These updates addressed the risks of spontaneous abortion in first trimester, multiple congenital malformations, and use in breastfeeding mothers.

Background of the Safety Issue

The NPRA had learned from European Medicines Agency (EMA) on the updated risk of spontaneous abortion during pregnancy and congenital malformation in children exposed to fluconazole in utero.^6-7

Based on the evaluation of available data on adverse pregnancy outcomes from the literature, case reports, and in view of a plausible mechanism of action, the EMA considers a causal relationship between fluconazole and adverse pregnancy outcomes to be at least a reasonable possibility.^6-7 The EMA concluded that product information containing fluconazole should be updated to strengthen the existing warning on the use during pregnancy and include the increased risk of spontaneous abortion in women treated with fluconazole during first and/or second trimester, cardiac malformations and birth defects as adverse pregnancy outcomes, along with precautionary measures for women of childbearing potential.

According to published observational studies, the use of oral fluconazole during the first and/or second trimesters is associated with an increased risk of spontaneous abortion compared to no use.^4,7,8 In one nested case-control study, both low (≤ 150 mg) and high-dose (> 150 mg) fluconazole were linked to an increased risk of spontaneous abortion (low dose: adjusted OR 2.23, 95% CI 1.96–2.54; high dose: adjusted OR 3.20, 95% CI 2.73–3.75).⁴ Another cohort study reported a significantly higher risk of spontaneous abortion in pregnancies exposed to oral fluconazole compared to those exposed to topical azoles.⁸

A meta-analysis of 5 observational studies found a 1.8- to 2-fold increased risk of cardiac malformations in pregnant women exposed to fluconazole during the first trimester, compared to those unexposed and/or treated with topical azoles, although available epidemiological studies show inconsistent results.^7,9 Additionally, a large observational study found a small increased risk of musculoskeletal malformations with first trimester exposure to oral fluconazole: about 1 additional case per 1000 women treated with cumulative doses ≤ 450 mg compared to those treated with topical azoles, and to around 4 additional cases per 1000 women treated with cumulative doses > 450 mg.^7,10

Adverse Drug Reaction Reports¹¹

To date, the NPRA had received a total of 331 reports with 590 adverse events suspected to be related to fluconazole-containing product. The most frequently reported adverse events were alanine aminotransferase increased (47 reports), rash maculo-papular (47), pruritus (38), and rash (30).

Locally, no cases of spontaneous abortion during pregnancy and any form of congenital malformation in children exposed to fluconazole in utero have been reported to the NPRA.

Advice for Healthcare Professionals

• While NPRA is still reviewing this safety issue, be aware of the latest available findings from studies on spontaneous abortion and congenital malformation (particularly cardiac- and musculoskeletal-related) in children exposed to fluconazole in utero during the first and/or second trimester.
• Avoid using fluconazole during pregnancy unless treating severe or life-threatening fungal infections where the benefits clearly outweigh the foetal
• Exercise caution when prescribing fluconazole to women of childbearing potential:
  • Before treatment:
    • Inform patients about the potential risks to the foetus and consider effective contraceptive measures.
  • After single dose treatment:
    • Recommend a washout period of 1 week (corresponding to 5-6 half-lives) before attempting to become pregnant.
  • For longer treatment courses:
    • Advise the use of contraception throughout the treatment period and for 1 week after the final dose.
• Report all adverse events suspected to be related to the use of fluconazole-containing products to the NPRA, including any that occur post-birth.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). DIFLUCAN (fluconazole) [Package Insert]. QUEST3+ Product Search. 2023 Oct 16 [cited 2024 Apr 22].Available from: http://www.npra.gov.my.
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2024 [cited 2024 Aug 6]. Available from: https://www.npra.gov.my
3. Ministry of Health (MOH), Malaysia. National antimicrobial guideline [Internet]. 2019 [cited 2024 Apr 29]. Available from: https://pharmacy.moh.gov.my/sites/default/files/document-upload/nag-2019-latest-9-dis-2020_0.pdf
4. Bérard A, Sheehy O, Zhao JP, Gorgui J, Bernatsky S, de Moura CS, Abrahamowicz M. Associations between low- and high-dose oral fluconazole and pregnancy outcomes: 3 nested case-control studies. CMAJ. 2019 Feb 19;191(7):E179-E187. Available from: https://doi.org/10.1503/cmaj.180963
5. National Pharmaceutical Regulatory Agency (NPRA). Direktif untuk semua produk yang mengandungi fluconazole: Pengemaskinian sisip bungkusan dan Risalah Maklumat Ubat untuk Pengguna (RIMUP) dengan maklumat keselamatan baharu berkaitan risiko spontaneous abortion serta memperkukuhkan maklumat keselamatan berkaitan multiple congenital abnormalities dan penggunaan dalam kalangan ibu menyusu [Internet]. 2017 Oct 17 [cited 2024 Apr 22]. Available from: https://www.npra.gov.my/images/Circulars_Directive/Regulatory_Information/2017/Direktif_24_2017.pdf
6. European Medicines Agency (EMA). PRAC recommendations on signals: Adopted at the 23-26 October 2023 PRAC meeting [Internet]. 2023 Dec 22 [cited 2024 Apr 22]. Available from: https://www.ema.europa.eu/en/documents/minutes/minutes-prac-meeting-23-26-october-2023_en.pdf
7. European Medicines Agency (EMA). Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s): Fluconazole [Internet]. 2023 Dec [cited 2024 Apr 22]. Available from: https://www.ema.europa.eu/en/documents/psusa/fluconazole-cmdh-scientific-conclusions-and-grounds-variation-amendments-product-information-and-timetable-implementation-psusa-00001404-202303_en.pdf
8. Mølgaard-Nielsen D, Svanström H, Melbye M, Hviid A, Pasternak B. Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth. JAMA. 2016 Jan 5;315(1):58-67. Available from: https://doi.org/10.1001/jama.2015.17844
9. Budani MC, Fensore S, Di Marzio M, Tiboni GM. Maternal use of fluconazole and congenital malformations in the progeny: A meta-analysis of the literature. Reprod Toxicol. 2021 Mar;100:42-51. Available from: https://doi.org/10.1016/j.reprotox.2020.12.018
10. Zhu Y, Bateman BT, Gray KJ, Hernandez-Diaz S, Mogun H, Straub L, Huybrechts KF. Oral fluconazole use in the first trimester and risk of congenital malformations: population based cohort study. BMJ. 2020 May 20;369:m1494. Available from: https://doi.org/10.1136/bmj.m1494
11. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2024 [cited 2024 Mar 26]. Available from: https://www.npra.gov.my (access restricted)

Written by: Wo Wee Kee

Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Norleen Mohamed Ali