Health Products Regulatory Authority (HPRA) Safety Information

February/March: Fluconazole: Update on pregnancy outcomes following use and new advice for women of childbearing potential

September 2024: Updated Recommendations of the Use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

February/March 2025: Fluconazole: Update on pregnancy outcomes following use and new advice for women of childbearing potential

Key Messages

Product information updates: recent updates have been made to reflect available data on abnormal pregnancy outcomes as well as new advice on use in women of childbearing potential.
Patient advice: before initiating treatment in women of childbearing potential, inform the patient of the potential risks to the foetus.
Washout period: after single dose treatment, a washout period of one week is recommended before pregnancy.
Contraception: for longer courses of treatment, contraception may be considered, as appropriate, in women of childbearing potential throughout the treatment period and for one week after the final dose.
Reminder of existing advice on use in pregnancy: fluconazole should not be used in standard doses and short-term treatments unless clearly necessary, and in high doses and/or in prolonged regimens except for potentially life‑threatening infections.

Fluconazole is a member of the class of triazole antifungal agents and a potent and specific inhibitor of fungal sterol synthesis. Fluconazole containing medicines are indicated in the treatment and prophylaxis of a wide range of fungal infections, including cryptococcosis, systemic candidiasis, mucosal candidiasis, genital candidiasis, prevention of fungal infections in patients with malignancy, and deep endemic mycoses in immunocompetent patients*.

Following a review by the European Medicines Agency's (EMA) Pharmacovigilance Risk Assessment Committee (PRAC), updates to product information** for fluconazole containing medicines were recommended to reflect available data on abnormal pregnancy outcomes, as follows:

Risk of spontaneous abortion

Observational studies suggest an increased risk of spontaneous abortion in women treated with fluconazole during the first and/or second trimester compared to women who were either not treated with fluconazole or received topical azoles during the same period¹.

Risk of cardiac malformations

Available epidemiological studies on cardiac malformations with the use of fluconazole during pregnancy provide inconsistent results. However, a meta-analysis of five observational studies including several thousand pregnant women exposed to fluconazole during the first trimester found a 1.8-to-2-fold increased risk of cardiac malformations when compared to no fluconazole use and/or topical azoles use².

Other birth defects

Case reports describe a pattern of birth defects among infants whose mothers received high-dose (400 to 800 mg/day) fluconazole during pregnancy for three months or more in the treatment of coccidioidomycosis. The birth defects seen in these infants include brachycephaly, ear dysplasia, giant anterior fontanelles, femoral bowing and radio-humeral synostosis. A causal relationship between fluconazole use and these birth defects is uncertain.

Advice for healthcare professionals

Based on the review of available data on adverse pregnancy outcomes, the EMA’s PRAC has recommended new advice on use of fluconazole in women of childbearing potential:

Before starting treatment in women of childbearing potential, healthcare professionals should inform patients of the potential risks to the foetus.
After a single dose treatment, a washout period of one week is recommended before becoming pregnant.
For longer courses of treatment, contraception may be considered, as appropriate, in women of childbearing potential throughout the treatment period and for one week after the final dose.
Healthcare professionals are reminded of existing advice that fluconazole should not be used during pregnancy in standard doses or for short-term treatments unless absolutely necessary. Additionally, high doses or prolonged use of fluconazole should only be considered during pregnancy for treating potentially life-threatening infections.

* Further details on fluconazole products are available at www.hpra.ie.

** The approved product information is made up of the Summary of Product Characteristics (SmPC) and Package Leaflet (PL) and is available at www.hpra.ie.

References:

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.
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;100:42-51.

This information is supplied by the Health Products Regulatory Authority (HPRA) for use in the IMF. However, the HPRA is independent and impartial to any other information contained in this formulary.

September 2024: Updated Recommendations on the Use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) During Pregnancy

Key Messages

The EMAs Pharmacovigilance Risk Assessment Committee (PRAC) has issued updated recommendations following a review of recently available data that indicates

that from the 20th week of pregnancy onward, prolonged use of systemic NSAIDs may lead to oligohydramnios due to foetal renal dysfunction. Additionally, there have

been reports of ductus arteriosus constriction following NSAID treatment during the second trimester, with most cases resolving after treatment cessation.

Systemic NSAIDs

During the first and second trimesters of pregnancy, systemic NSAIDs (including fixed-dose combinations) should not be administered unless deemed clearly necessary.
For women attempting to conceive or during the first and second trimesters, the dose should be kept as low as possible, and treatment duration should be minimised.
Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to NSAIDs for several days from gestational week 20 onward. If oligohydramnios or ductus arteriosus constriction is detected, NSAID treatment should be discontinued promptly.
If the product information already contains stricter advice regarding the use of NSAIDs during pregnancy, the stricter advice should be followed.
Healthcare professionals are reminded that currently,the used of systemic NSAIDs is contraindicated in the last pregnancy trimester.

Topical NSAIDs

The PRAC has recommended that the same precautions regarding the use, dosage, and duration of treatment for systemic NSAIDs be observed for topical NSAIDs.

Acetylsalicylic acid

The PRAC has not issued these recommendations for acetylsalicylic acid-containing products at this time.

Background information

The EMA’s PRAC has recommended that the approved product information^* for systemic (i.e. oral and injectable) NSAID-containing medicinal products, including fixed-dose combinations, should be updated with regard to the use of these products during pregnancy. The updates follow the review of available data which concluded that the use from the 20th week of pregnancy onward may cause oligohydramnios resulting from foetal renal dysfunction. It was observed that this may occur shortly after treatment initiation and was usually reversible upon treatment discontinuation. Additionally, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation.

The PRAC recommendations for systemic NSAIDs during pregnancy

During the first and second pregnancy trimesters, systemic NSAIDs should not be given unless deemed clearly necessary. If the NSAID is deemed necessary, the dose should be kept as low and the duration of treatment as short as possible. This recommendation also applies to a woman attempting to conceive.

Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to NSAIDs for several days from gestational week 20 onward. The NSAID should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

While the product information for NSAIDs will be amended to include updated advice for use during pregnancy, when stricter advice on use in pregnancy already exists, the stricter advice will remain.

These new recommendations primarily concern the first and second pregnancy trimesters; currently, the use of systemic NSAIDs is contraindicated in the last trimester of pregnancy as they may induce foetal cardiopulmonary and renal toxicity, inhibit uterine contraction, leading to delayed or prolonged labour and possibly extend the bleeding time for mothers and neonates due to anti-aggregating effects that may occur even at very low doses.

New recommendations for topical NSAIDs in pregnancy

Following several routine reviews of available data concerning medicines within the same therapeutic class, the PRAC concluded that although systemic exposure with the use of topical NSAIDs (including oromucosal formulations and transdermal patches) is typically lower compared to oral administration, it could not definitively exclude the potential risk of oligohydramnios and ductus arteriosus to the embryo/foetus.

Consequently, to date the PRAC recommended updating the product information for several topical NSAIDs, including naproxen, ketoprofen, ibuprofen and flurbiprofen products. It is recommended to avoid the use of topical NSAID products during the first and second pregnancy trimesters unless deemed clearly necessary. If deemed necessary, the dosage should be kept as low and the treatment duration as short as possible. As is the case for systemic NSAIDs, use of topical NSAIDs is contraindicated during the last trimester of pregnancy.

Healthcare professionals are advised to check relevant product information when considering the use of topical NSAIDs during pregnancy, as it is already recommended to avoid certain topical NSAIDs, like ibuprofen, during pregnancy.

Implication for Acetylsalicylic Acid-containing Products

Due to the different clinical applications and dosages of acetylsalicylic acid-containing products, and the need to evaluate the available data and the implications of the NSAID recommendations, acetylsalicylic acid-containing products are currently excluded from the implementation of PRAC recommendations to date.

The approved product information comprises the Summary of Product Characteristics (SmPC) and Package Leaflet (PL) and is available at www.hpra.ie.

Page Revised: February 2025