March 26, 2017
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"The US Food and Drug Administration (FDA) has expanded the indication for the short-acting beta-agonist albuterol sulfate inhalation powder (ProAir RespiClick, Teva) to children aged 4 to 11 years, the company announced today.





Mechanism Of Action

Caffeine is structurally related to other methylxanthines, theophylline and theobromine. It is a bronchial smooth muscle relaxant, a CNS stimulant, a cardiac muscle stimulant and a diuretic.

Although the mechanism of action of caffeine in apnea of prematurity is not known, several mechanisms have been hypothesized. These include: (1) stimulation of the respiratory center, (2) increased minute ventilation, (3 ) decreased threshold to hypercapnia, (4) increased response to hypercapnia, (5) increased skeletal muscle tone, (6) decreased d iaphragmatic fatigue, (7) increased metabolic rate, and (8) increased oxygen consumption.

Most of these effects have been attributed to antagonism of adenosine receptors, both A, and subtypes, by caffeine, which has been demonstrated in receptor binding assays and observed at concentrations approximating those achieved therapeutically.



After oral administration of 10 mg caffeine base/kg to preterm neonates, the peak plasma level (Cmax) for caffeine ranged from 6 to 10 mg/L and the mean time to reach peak concentration (Tmax) ranged from 3 0 minutes to 2 hours. The Tmax was not affected by formula feeding. The absolute bioavailability, however, was not fully examined in preterm neonates.


Caffeine is rapidly distributed into the brain. Caffeine levels in the cerebrospinal fluid of preterm neonates approximate their plasma levels. The mean volume of distribution of caffeine in infants (0.8 to 0.9 L/kg) is s lightly higher than that in adults (0.6 L/kg). Plasma protein binding data are not available for neonates or infants. In adults, the mean plasma protein binding in vitro is reported to be approximately 36%.


Hepatic cytochrome P450 1A2 (CYP1A2) is involved in caffeine biotransformation. Caffeine metabolism in preterm neonates is limited due to their immature hepatic enzyme systems.

Interconversion between caffeine and theophylline has been reported in preterm neonates; caffeine levels are approximately 25% of theophylline levels after theophylline administration and approximately 3 to 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. Mean half-life (T ½) and fraction excreted unchanged in urine (Ae) of caffeine in infants have been shown to be inversely related togestational/postconceptual age. In neonates, the T½ is approximately 3 to 4 days and the Ae, is approximately 86% (within 6 days). By 9 months of age, the metabolism of caffeine approximates that seen in adults (T½ = 5 hours and Ae = 1 %).

Special Populations

Studies examining the pharmacokinetics of caffeine in neonates with hepatic or renal insufficiency have not been conducted. Caffeine citrate should be administered with caution in preterm neonates with impaired renal or hepatic function. Serum concentrations of caffeine should be monitored and dose administration of caffeine citrate should be adjusted to avoid toxicity in this population.

Clinical Studies

One multicenter, randomized, double-blind trial compared caffeine citrate to placebo in eighty-five (85) preterm infants (gestational age 2 8 to < 33 weeks) with apnea of prematurity. Apnea of prematurity was defined as having at least 6 apnea episodes of greater than 20 seconds duration in a 24-hour period with no other identifiable cause of apnea. A 1 mL/kg (20 mg/kg caffeine citrate providing 10 mg/kg as caffeine base) loading dose of caffeine citrate was administered intravenously, followed by a 0.25 mL/kg (5 mg/kg caffeine citrate providing 2.5 mg/kg of caffeine base) daily maintenance dose administered either in travenously or orally (generally through a feeding tube). The duration of treatment in this study was limited to 10 to 12 days. The protocol allowed infants to be “rescued” with open-label caffeine citrate treatment if their apnea remained uncontrolled during the double-blind phase of the trial.

The percentage of patients without apnea on d ay 2 of treatment (24 to 48 hours after the loading dose) was significantly greater with caffeine citrate than placebo. The following table summarizes the clinically relevant endpoints evaluated in this study:

  Caffeine Citrate Placebo p-value
Number of patients evaluated1 45 37
% of patients with zero apnea events on day 2 26.7 8.1 0.03
Apnea rate on day 2 (per24hrs.) 4.9 7.2 0.134
% of patients with 50% reduction in apnea events from baseline on day2 76 57 0.07
1 Of 85 patients who received drug, 3 were not included in the efficacy analysis because they had < 6 apnea episodes/24 hours a t baseline.

In this 10 to 12 day trial, the mean number of days with zero apnea events was 3.0 in the caffeine citrate group and 1.2 in the placebo group. The mean number of days with a 50% reduction from baseline in apnea events was 6.8 in the caffeine citrate group and 4.6 in the placebo group.

Last reviewed on RxList: 7/1/2016
This monograph has been modified to include the generic and brand name in many instances.

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