Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Gennisium Pharma, Swen Parc de Vitrolles, Chemin de la Bastide Blanche, 13127 Vitrolles France
Pharmacotherapeutic group: Psychoanaleptics, xanthine derivatives
ATC code: N06BC01
Caffeine is structurally related to the methylxanthines theophylline and theobromine. Most of its effects have been attributed to antagonism of adenosine receptors, both A1 and A2A subtypes, demonstrated in receptor binding assays and observed at concentrations approximating those achieved therapeutically in this indication.
Caffeine’s main action is as a CNS stimulant. This is the basis of caffeine’s effect in apnoea of prematurity, for which several mechanisms have been proposed for its actions including: (1) respiratory centre stimulation, (2) increased minute ventilation, (3) decreased threshold to hypercapnia, (4) increased response to hypercapnia, (5) increased skeletal muscle tone, (6) decreased diaphragmatic fatigue, (7) increased metabolic rate, and (8) increased oxygen consumption.
The clinical efficacy of caffeine citrate was assessed in a multicentre, randomised, double-blind study that compared caffeine citrate to placebo in 85 preterm infants (gestational age 28 to <33 weeks) with apnoea of prematurity. Infants received 20 mg/kg caffeine citrate loading dose intravenously. A maintenance daily dose of 5 mg/kg caffeine citrate was then administered either intravenously or orally (through a feeding tube) for up to 10-12 days. The protocol allowed infants to be “rescued” with open-label caffeine citrate treatment if their apnoea remained uncontrolled. In that case, infants received a second loading dose of 20 mg/kg caffeine citrate after treatment day 1 and before treatment day 8.
There were more days without any apnoea under caffeine citrate treatment (3.0 days, versus 1.2 days for placebo; p=0.005); also, there was a higher percentage of patients with no apnoeas for ≥8 days (caffeine 22% versus placebo 0%).
A recent large placebo-controlled multicentre study (n=2006) investigated short-term and long-term (18-21 months) outcomes of premature infants treated with caffeine citrate. Infants randomised to caffeine citrate received an intravenous loading dose of 20 mg/kg, followed by a daily maintenance dose of 5 mg/kg. If apnoeas persisted, the daily maintenance dose could be increased to a maximum of 10 mg/kg of caffeine citrate. The maintenance doses were adjusted weekly for changes in body weight and could be given orally once an infant tolerated full enteral feedings. Caffeine therapy reduced the rate of bronchopulmonary dysplasia [odds ratio (95% CI) 0.63 (0.52 to 0.76)] and improved the rate of survival without neurodevelopmental disability [odds ratio (95% CI) 0.77 (0.64 to 0.93)].
The size and direction of caffeine effect on death and disability differed depending on the degree of respiratory support infants needed at randomisation, indicating more benefit for the supported infants [odds ratio (95%CI) for death and disability, see table below].
Death or disability according to subgroup of respiratory support at entry to study:
| Subgroups | Odds ratio (95% CI) |
|---|---|
| No support | 1.32 (0.81 to 2.14) |
| Non invasive support | 0.73 (0.52 to 1.03) |
| Endotracheal tube | 0.73 (0.57 to 0.94) |
Caffeine citrate readily dissociates in aqueous solution. The citrate moiety is rapidly metabolized on infusion or ingestion.
The onset of action of caffeine from caffeine citrate is within minutes of commencement of infusion. After oral administration of 10 mg caffeine base/kg body weight to preterm newborn infants, the peak plasma caffeine concentration (Cmax) ranged from 6 to 10 mg/l and the mean time to reach peak concentration (tmax) ranged from 30 min to 2 h. The extent of absorption is not affected by formula feeding but tmax may be prolonged.
Caffeine is rapidly distributed into the brain following caffeine citrate administration. Caffeine concentrations in the cerebrospinal fluid of preterm newborn infants approximate to their plasma levels. The mean volume of distribution (Vd) of caffeine in infants (0.8-0.9 l/kg) is slightly higher than that in adults (0.6 l/kg). Plasma protein binding data are not available for newborn infants or infants. In adults, the mean plasma protein binding in vitro is reported to be approximately 36%.
Caffeine readily crosses the placenta into the foetal circulation and is excreted into breast milk.
Caffeine metabolism in preterm newborn infants is very limited due to their immature hepatic enzyme systems and most of the active substance is eliminated in urine. Hepatic cytochrome P450 1A2 (CYP1A2) is involved in caffeine biotransformation in older individuals.
Inter-conversion between caffeine and theophylline has been reported in preterm newborn infants; caffeine levels are approximately 25% of theophylline levels after theophylline administration and approximately 3-8% of caffeine administered would be expected to convert to theophylline.
In young infants, the elimination of caffeine is much slower than that in adults due to immature hepatic and/or renal function. In newborn infants, caffeine clearance is almost entirely by renal excretion. Mean half-life (t1/2) and fraction excreted unchanged in urine (Ae) of caffeine in infants are inversely related to gestational/postmenstrual age. In newborn infants, the t1/2 is approximately 3-4 days and the Ae is approximately 86% (within 6 days). By 9 months of age, the metabolism of caffeine approximates to that seen in adults (t1/2 = 5 hours and Ae = 1%).
Studies examining the pharmacokinetics of caffeine in newborn infants with hepatic or renal insufficiency have not been conducted.
In the presence of significant renal impairment, considering the increased potential for accumulation, a reduced daily maintenance dose of caffeine is required and the doses should be guided by blood caffeine measurements. In premature infants with cholestatic hepatitis a prolonged caffeine elimination half-life with an increase of plasma levels above the normal limit of variation has been found suggesting a particular caution in the dosage of these patients (see sections 4.2 and 4.4).
Non-clinical data revealed no major hazard for humans based on studies of repeated dose toxicity of caffeine. However, at high doses convulsions in rodents were induced. At therapeutic doses some behavioural changes in newborn rats were induced, most likely as a consequence of increased adenosine receptor expression that persisted into adulthood. Caffeine was shown to be devoid of mutagenic and oncogenic risk. Teratogenic potential and effects on reproductive performance observed in animals are not relevant to its indication in the preterm infant population.
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