The Real-World Routine Use of Caffeine Citrate in Preterm Infants: A European Postauthorization Safety Study

Abstract

Background: Caffeine citrate is the treatment of choice for apnea of prematurity (AOP). Regulatory agencies have requested real-world data on drug utilization and safety, a postauthorization safety study, of a pharmaceutical-grade caffeine citrate, Peyona®, to confirm its benefit for preterm infants. Objectives: To investigate the clinical use, outcomes, and safety profile of this pharmaceutical-grade caffeine citrate in the routine treatment of preterm infants with a gestational age (GA) <37 weeks. Methods: We conducted a multicenter, noninterventional, prospective study in five European countries. Patients eligible for study enrollment were <37-week GA neonates who received treatment with the pharmaceutical-grade caffeine citrate and whose parents had given informed consent. Results: A total of 506 preterm infants were enrolled from 21 institutions. The pharmaceutical-grade caffeine citrate doses were administered intravenously, orally, or via both routes. The main indication of use was AOP treatment (58%) followed by AOP prophylaxis (37%). Median treatment duration was 21 days. The primary cause of study termination was AOP resolution (n = 407; 80%). Hundred and six patients (21%) required supplemental oxygen on day 28; 48 patients (9.5%) had bronchopulmonary dysplasia at 36 weeks' postmenstrual age. Twenty-three adverse drug reactions were observed in 21 neonates (4.2%); the most frequent was tachycardia (2.3%) and only one (seizures) was considered serious. Thirty-one patients (8.1%) had hepatic or renal functional impairment; the side effects were manageable, and these patients also benefitted from treatment. Conclusions: The use of this caffeine citrate is safe for the management of AOP in a real-world setting.

The Role of Caffeine in Noninvasive Respiratory Support

“…A recent cross-sectional survey of neonatologists in Thailand, Lebanon, Australia, and the US revealed that prophylactic use of methyxanthines for apnea of prematurity is common, with 62% of those surveyed reporting prophylactic use 17 . Similarly, caffeine was used for apnea prophylaxis in 37% of preterm infants in a mulitcenter prospective study in Austria, Czech Republic, Greece, Italy, and Spain 18 .…”

Caffeine modulates glucocorticoid-induced expression of CTGF in lung epithelial cells and fibroblasts

“…The methylxanthine caffeine is commonly used to reduce apnea of prematurity [39, 40]. Of note, caffeine treatment has been associated with reduced incidences of BPD [41] and the prevention of hyperoxia-mediated pulmonary inflammation and lung injury [42, 43].…”

Respiratory Care Protocols in Neonatal Intensive Care

“…The latest Cochrane review in 2010 [38] did not support routine use of prophylactic caffeine, but a series of recent retrospective studies have shown that early administration of caffeine (in the first 48 h of life) significantly reduced length of MV and improved short-term respiratory outcomes in preterm infants [39,40]. As a result, the off-label use of prophylactic caffeine has risen from 22% (at the time of the CAP trial) to 60-75% [39,41,42]. The first dose is given anytime between days 1 to 25 of life and for a duration ranging from 2 to 119 days [42].…”

“…As a result, the off-label use of prophylactic caffeine has risen from 22% (at the time of the CAP trial) to 60-75% [39,41,42]. The first dose is given anytime between days 1 to 25 of life and for a duration ranging from 2 to 119 days [42]. There are also noticeable differences in practices related to monitoring and discontinuation of caffeine.…”