Safety of Fluconazole Prophylaxis in Infants

Analyzing data from completed trials to determine the safety of fluconazole for prevention of candidiasis, a life-threatening fungal infection, in premature infants.


This study evaluated the safety of fluconazole prophylaxis in premature infants by analyzing safety data from 3 completed randomized trials. Data from 783 infants (454 fluconazole arm and 329 placebo arm) were examined.

Approximately 3000 infants develop candidiasis each year, with most of the burden falling on infants born <28 weeks gestational age. Unfortunately, despite antifungal treatment, 20% of infants who develop neonatal candidiasis die as a result of the disease. Among survivors, morbidity—such as neurodevelopmental impairment—is substantial.

Fluconazole prophylaxis of older immune-compromised patients is effective in reducing candidiasis and has been shown in two placebo-controlled trials to decrease candidiasis in infants. Fluconazole prophylaxis of premature infants has been examined in several studies of very low birth weight (VLBW) infants, two of which demonstrated a decrease in candidiasis among patients receiving fluconazole compared with placebo.

The fluconazole label approved by the U.S. Food and Drug Administration indicates that efficacy has not been established in infants <6 months old. Safety issues reported in 577 children (ages 1 day – 17 years) include: vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%).

The Pediatric Trials Network conducted a secondary analysis of safety data from 3 previous randomized controlled trials of fluconazole prophylaxis in VLBW and extremely low birth weight infants:

  1. Benjamin DK Jr. et al. Fluconazole prophylaxis for the prevention of candidiasis in infants <750 grams birth weight.
  2. Manzoni P, Stolfi I, Pugni L, Decembrino L, Magnani C, Vetrano G, et al. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med. 2007; 356(24): 2483-95.
  3. Kaufman D, Boyle R, Hazen KC, Patrie JT, Robinson M, Donowitz LG. Fluconazole prophylaxis against fungal colonization and infection in preterm infants. N Engl J Med. 2001; 345(23): 1660-6.

The primary safety outcomes examined were: incidence of gastrointestinal events, adverse events, serious adverse events, and laboratory values. The study findings did not support the universal use of prophylactic fluconazole in extremely low-birth-weight infants (birth weight less than 750 g).

View study data for fluconazole prophylaxis for prevention of candidiasis in infants, secondary analysis of data from prophylaxis studysafety/PK in children supported with extracorporeal membrane oxygenation , and PK of loading dose in infants and toddlers on NICHD's Data and Specimen Hub (DASH).



Pediatric Academic Societies Annual Meeting, April 25-28, 2015

Population Pharmacokinetics of Fluconazole in Extremely Low Birth Weight Infants
Momper JD, Capparelli EV, Wade KC, Natarajan G, Gao J, Laughon M, Smith PB, Benjamin DK Jr, on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network


Published; clinical study report submitted to FDA identifier:

NICHD Data and Specimen Hub (DASH):

Principal Investigators:
P. Brian Smith, MD, MPH, MHS and Daniel K. Benjamin, MD, PhD, MPH
Duke Health, Durham, NC