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.

Summary

This study will evaluate 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) will be examined.

Approximately 3000 infants develop candidemia 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 will conduct 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. Enrollment completed; 2-year neurodevelopmental follow-up pending.
  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 to be examined will be: incidence of gastrointestinal events, adverse events, serious adverse events, and laboratory values. By cultivating a better understanding of the potential safety issues involved with treating low birth weight infants with fluconazole, the PTN hopes to bolster the use of this drug to better prevent the devastating results of candidiasis in this exceptionally vulnerable population.

Publications

Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial.
Benjamin DK Jr, Hudak ML, Duara S, Randolph DA, Bidegain M, Mundakel GT, Natarajan G, Burchfield DJ, White RD, Shattuck KE, Neu N, Bendel CM, Kim MR, Finer NN, Stewart DL, Arrieta AC, Wade KC, Kaufman DA, Manzoni P, Prather KO, Testoni D, Berezny KY, Smith PB; Fluconazole Prophylaxis Study Team.
JAMA • May 7, 2014, volume 311, issue 17, pages 1742-1749.
PMCID: PMC4110724 [Free PMC article]

Fluconazole population pharmacokinetics and dosing for prevention and treatment of invasive candidiasis in children supported with extracorporeal membrane oxygenation.
Watt KM, Gonzalez D, Benjamin DK Jr, Brouwer KL, Wade KC, Capparelli E, Barrett J, Cohen-Wolkowiez M.
Antimicrobrial Agents and Chemotherapy • July 2014, volume 59, issue 7, pages 3935-43.
PMCID: PMC4468733 [Free access available on 1/1/2016]

Editorial commentary: Fluconazole therapeutic drug monitoring in children with cancer: not today.
Cohen-Wolkowiez M, Benjamin DK Jr.
Clinical Infectious Diseases • December 2014, volume 59, issue 11, pages 1534-1536.
Free access available.

Presentations

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

OVERVIEW

Status:
Published; clinical study report submitted to FDA

ClinicalTrials.gov identifier:
NCT00734539

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

NEWS

  • The fluconazole prophylaxis study locks its database April 8, 2013 The PTN team behind the Safety of Fluconazole Prophylaxis in Infants study successfully locked the Benjamin study database last week. To evaluate the safety of fluconazole, the team is gathering randomized trial datasets from several thought leaders to perform a data meta-analysis—the Benjamin study comprises the first of these datasets. The PTN will examine safety ...