is a central nervous system stimulant and seizures have been reported in cases of caffeine overdose. Extreme caution must be exercised if caffeine citrate is used in newborns with seizure disorders.
Caffeine has been shown to increase heart rate, left ventricular output, and stroke volume in published studies. Therefore, caffeine citrate should be used with caution in newborns with known cardiovascular disease. There is evidence that caffeine causes tachyarrhythmias in susceptible individuals. In newborns this is usually a simple sinus tachycardia. If there have been any unusual rhythm disturbances on a cardiotocograph (CTG) trace before the baby is born, caffeine citrate should be administered with caution.
Caffeine citrate should be administered with caution in preterm neonates with impaired renal or hepatic function (see sections 4.2 and 5.2). Doses should be adjusted by monitoring of caffeine plasma concentrations to avoid toxicity in this population.
Necrotising enterocolitis is a common cause of morbidity and mortality in premature neonates. There are reports of a possible association between the use of methylxanthines and development of necrotising enterocolitis. However, a causal relationship between caffeine or other methylxanthine use and necrotising enterocolitis has not been established. As for all preterm infants, those treated with caffeine citrate should be carefully monitored for the development of necrotising enterocolitis (see section 4.8).
Caffeine citrate should be used with caution in infants suffering gastro-oesophageal reflux, as the treatment may exacerbate this condition.
Caffeine citrate causes a generalised increase in metabolism, which may result in higher energy and nutrition requirements during therapy.
The diuresis and electrolyte loss induced by caffeine citrate may necessitate correction of fluid and electrolyte disturbances.
4.5 Interaction with other medicinal products and other forms of interaction
Inter-conversion between caffeine and theophylline occurs in preterm neonates. These active substances should not be used concurrently.
Cytochrome P450 1A2 (CYP1A2) is the major enzyme involved in the metabolism of caffeine in humans. Therefore, caffeine has the potential to interact with active substances that are substrates for CYP1A2, inhibit CYP1A2, or induce CYP1A2. However, caffeine metabolism in preterm neonates is limited due to their immature hepatic enzyme systems.
Although few data exist on interactions of caffeine with other active substances in preterm neonates, lower doses of caffeine citrate may be needed following co-administration of active substances which are reported to decrease caffeine elimination in adults (e.g., cimetidine and ketoconazole) and higher caffeine citrate doses may be needed following co-administration of active substances that increase caffeine elimination (e.g., phenobarbital and phenytoin). Where doubt exists about possible interactions, plasma caffeine concentrations should be measured.
As bacterial overgrowth in the gut is associated with the development of necrotising enterocolitis, co-administration of caffeine citrate with medicinal products that suppress gastric acid secretion (antihistamine H2 receptor blockers or proton-pump inhibitors) may in theory increase the risk of necrotising enterocolitis (see section 4.4 and 4.8).
Concurrent use of caffeine and doxapram might potentiate their stimulatory effect |
