Birth defects in infants associated with in utero exposure to long-term, high-dose fluconazole

This is an update on the overseas case reports of rare and distinct congenital anomalies in infants exposed in utero to chronic high-dose fluconazole during the first trimester of pregnancy.

Fluconazole (Diflucan®, Pfizer) is a triazole antifungal agent licensed locally for the treatment of cryptococcosis, systemic candidiasis, mucosal candidiasis, genital candidiasis, dermatomycosis and the prevention of fungal infections in patients with malignancies who are predisposed to such infections as a result of cytotoxic chemotherapy or radiotherapy. It is also available under several generics brands*.

_{*Generic brands of fluconazole licensed locally include Apo-fluconazole®, DBL fluconazole®, Diflazon®, Exomax injection®, Fluconazole Sandoz Infusion solution®, Fluconazole Redibag Solution for Infusion®, Medoflucon®, Mycorest®, Omastin® and Stalene®.}

US Food and Drug Administration (FDA)

In August 2011, the US FDA issued a drug safety communication informing that chronic, high doses of fluconazole (400 to 800mg/day) may be associated with a rare and distinct set of birth defects in infants born to mothers treated with the drug during the first trimester of pregnancy.¹ This risk does not appear to be associated with a single dose of fluconazole 150mg for treatment of vaginal candidiasis. The US pregnancy category for fluconazole indications (other than vaginal candidiasis) has been changed from category C to D. Pregnancy category D means there is positive evidence of human foetal risk based on human data. However, for high dose fluconazole, the potential benefits from the use of the drug in pregnant women with serious or life-threatening conditions may be acceptable despite its risks.

Case reports of rare, distinct congenital anomalies

This safety alert by FDA was in response to several reports of rare, distinct congenital anomalies observed in infants whose mothers had received chronic daily treatment with 400mg to 800mg fluconazole during early pregnancy. The features seen in these infants include brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. These defects are similar to those features observed in people with Antley-Bixler** syndrome, a rare genetic disorder. Similar anomalies were also seen in animal studies following in utero fluconazole exposure.

Four of the reports involved the use of intravenous fluconazole for the treatment of coccidioidal meningitis while the fifth report involved a human immunodeficiency virus (HIV)-positive mother receiving oral fluconazole for vaginal candidiasis.

FDA added that available data in medical literature at this point in time do not suggest an association between low-dose oral fluconazole use in the first trimester of pregnancy and congenital anomalies. No consistent pattern of anomalies could be identified from published epidemiological studies of in utero exposure to low doses of fluconazole where most patients received a single dose of 150mg. However, FDA also acknowledged that most of the studies were not large enough to accurately detect an increased risk for major birth defects or a rare or unique birth defect or syndrome.

_{**Antley-Bixler syndrome is a very severe, rare, autosomal recessive congenital disorder that is characterised by malformations and deformities affecting majority of the skeleton and other areas of the body}

HSA's advisory

To date, HSA has not received any local reports of birth defects associated with in utero fluconazole exposure. Most of the local package inserts of fluconazole-containing products currently carry warnings on potential birth defects in infants associated with in utero exposure to chronic high doses of fluconazole. In view of the latest information, HSA will be working with companies to ensure that warnings on potential birth defects are further strengthened in the local package inserts of these products.

Healthcare professionals are advised to take into consideration the potential risks with long-term, high-dose use of fluconazole when prescribing the medication to women of child-bearing potential. Should chronic high-dose fluconazole be considered the treatment of choice in women of child-bearing potential, healthcare professionals are encouraged to rule out pregnancy and to emphasise the importance of using an effective birth control method. Healthcare professionals are encouraged to report any suspected adverse reactions associated with fluconazole to the Vigilance Branch of HSA.

References

1. FDA Drug Safety Communication: Use of long-term, high-dose Diflucan (fluconazole) during pregnancy may be associated with birth defects in infants.
   http://www.fda.gov/Drugs/DrugSafety/ucm266030.htm

Published: 27 Dec 2011

Safety Alerts