Caffeine Citrate

CAFFEINE CITRATE- caffeine citrate solution
Exela Pharma Sciences, LLC

Rx Only

DESCRIPTION

Both caffeine citrate injection for intravenous administration and caffeine citrate oral solution are clear, colorless, sterile, non-pyrogenic, preservative-free, aqueous solutions adjusted to pH 4.7. Each mL contains 20 mg caffeine citrate (equivalent to 10 mg of caffeine base) prepared in solution by the addition of 10 mg caffeine anhydrous, USP to 5 mg citric acid monohydrate, USP, 8.3 mg sodium citrate dihydrate, USP and Water for Injection, USP.

Caffeine, a central nervous system stimulant, is an odorless white crystalline powder or granule, with a bitter taste. It is sparingly soluble in water and ethanol at room temperature. The chemical name of caffeine is 3,7-dihydro-1,3,7-trimethyl-1H -purine-2,6-dione. In the presence of citric acid it forms caffeine citrate salt in solution. The structural formula and molecular weight of caffeine citrate follows.

caffeine-citrate-structure
(click image for full-size original)

CLINICAL PHARMACOLOGY

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 diaphragmatic fatigue, (7) increased meta­bolic rate, and (8) increased oxygen consumption.

Most of these effects have been attributed to antagonism of adenosine recep­tors, both A1 and A2 subtypes, by caffeine, which has been demonstrated in receptor binding assays and observed at concentrations approximating those achieved therapeutically.

Pharmacokinetics

Absorption: 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 30 minutes to 2 hours. The Tmax was not affected by formula feeding. The absolute bioavail­ability, however, was not fully examined in preterm neonates.

Distribution: 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 slightly 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%.

Metabolism: 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 3-8% of caffeine adminis­tered would be expected to convert to theophylline.

Elimination: 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 (T1/2 ) and fraction excreted unchanged in urine (Ae ) of caffeine in infants have been shown to be inversely related to gestational/postconceptual age. In neonates, 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 that seen in adults (T1/2 = 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 28 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 intravenously 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 day 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:

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

In this 10 to 12 day trial, the mean number of days with zero apnea events was 3 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.

INDICATIONS AND USAGE

Caffeine citrate injection and caffeine citrate oral solution are indicated for the short term treatment of apnea of prematurity in infants between 28 and <33 weeks gestational age.

CONTRAINDICATIONS

Caffeine citrate injection and caffeine citrate oral solution are contraindicated in patients who have demonstrated hypersensitivity to any of its components.

WARNINGS

During the double-blind, placebo-controlled clinical trial, 6 cases of necro­tizing enterocolitis developed among the 85 infants studied (caffeine=46, placebo=39), with 3 cases resulting in death. Five of the six patients with necrotizing enterocolitis were randomized to or had been exposed to caffeine citrate.

Reports in the published literature have raised a question regarding the possi­ble association between the use of methylxanthines and development of necro­tizing enterocolitis, although a causal relationship between methylxanthine use and necrotizing enterocolitis has not been established. Therefore, as with all preterm infants, patients being treated with caffeine citrate should be carefully moni­tored for the development of necrotizing enterocolitis.

PRECAUTIONS

General

Apnea of prematurity is a diagnosis of exclusion. Other causes of apnea (e.g., central nervous system disorders, primary lung disease, anemia, sepsis, metabolic disturbances, cardiovascular abnormalities, or obstructive apnea) should be ruled out or properly treated prior to initiation of caffeine citrate.

Caffeine is a central nervous system stimulant and in cases of caffeine over­dose, seizures have been reported. Caffeine citrate should be used with caution in infants with seizure disorders.

The duration of treatment of apnea of prematurity in the placebo-controlled trial was limited to 10 to 12 days. The safety and efficacy of caffeine citrate for longer periods of treatment have not been established. Safety and efficacy of caffeine citrate for use in the prophylactic treatment of sudden infant death syndrome (SIDS) or prior to extubation in mechanically ventilated infants have also not been established.

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