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.
Following overdose, serum caffeine levels have ranged from approximately 24 mg/L (a post marketing spontaneous case report in which an infant exhibited irritability, poor feeding and insomnia) to 350 mg/L.
Serious toxicity has been associated with serum levels greater than 50 mg/L (see PRECAUTIONS-Laboratory Tests and DOSAGE AND ADMINISTRATION ).
Signs and symptoms reported in the literature after caffeine overdose in preterm infants include fever, tachypnea, jitteriness, insomnia, fine tremor of the extremities, hypertonia, opisthotonos, tonic-clonic movements, nonpurposeful jaw and lip movements, vomiting, hyperglycemia, elevated blood urea nitrogen, and elevated total leukocyte concentration.
Seizures have also been reported in cases of overdose.
One case of caffeine overdose complicated by development of intraventricular hemorrhage and long-term neurological sequelae has been reported.
Another case of caffeine citrate overdose (from New Zealand) of an estimated 600 mg caffeine citrate (approximately 322 mg/kg) administered over 40 minutes was complicated by tachycardia, ST depression, respiratory distress, heart failure, gastric distention, acidosis and a severe extravasation burn with tissue necrosis at the peripheral intravenous injection site.
No deaths associated with caffeine overdose have been reported in preterm infants.
Treatment of caffeine overdose is primarily symptomatic and supportive.
Caffeine levels have been shown to decrease after exchange transfusions.
Convulsions may be treated with intravenous administration of diazepam or a barbiturate such as pentobarbital sodium.
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-1 H -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 C 14 H 18 N 4 O 9 Mol.
Both caffeine citrate injection and caffeine citrate oral solution are available as clear, colorless, sterile, non-pyrogenic, preservative-free, aqueous solutions in 5 mL colorless glass vials.
The vials of caffeine citrate injection are sealed with gray rubber stopper and white flip off aluminum seal printed with “FOR INTRAVENOUS USE ONLY” in red.
The vials of caffeine citrate oral solution are sealed with gray rubber stopper and a dark blue matte finish, flip off tear off aluminum seal printed with “FOR ORAL USE ONLY – FLIP UP & TEAR” in white.
Both the injection and oral solution vials contain 3 mL solution at a concentration of 20 mg/mL caffeine citrate (60 mg/vial) equivalent to 10 mg/mL caffeine base (30 mg/vial).
Caffeine citrate injection, USP NDC 47335-289-40: 3 mL vial, individually packaged in a carton.
Caffeine citrate oral solution, USP NDC 47335-290-44: 3 mL vial (NOT CHILD-RESISTANT), 10 vials per white polypropylene child-resistant container.
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature].
For single use only.
Discard unused portion.
ATTENTION PHARMACIST: Detach “Instructions for Use” from the package insert and dispense with caffeine citrate oral solution prescription.
INDICATIONS AND USAGE
INDICATIONS & 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.
DOSAGE AND ADMINISTRATION
DOSAGE & ADMINISTRATION Prior to initiation of caffeine citrate, baseline serum levels of caffeine should be measured in infants previously treated with theophylline, since preterm infants metabolize theophylline to caffeine.
Likewise, baseline serum levels of caffeine should be measured in infants born to mothers who consumed caffeine prior to delivery, since caffeine readily crosses the placenta.
The recommended loading dose and maintenance doses of caffeine citrate follow.
Dose of Caffeine Citrate Volume Dose of Caffeine Citrate mg/kg Route Frequency Loading Dose 1 mL/kg 20 mg/kg Intravenous* (over 30 minutes) One Time Maintenance Dose 0.25 mL/kg 5 mg/kg Intravenous* (over 10 minutes) or Orally Every 24 hours** * using a syringe infusion pump ** beginning 24 hours after the loading dose NOTE THAT THE DOSE OF CAFFEINE BASE IS ONE-HALF THE DOSE WHEN EXPRESSED AS CAFFEINE CITRATE (e.g., 20 mg of caffeine citrate is equivalent to 10 mg of caffeine base).
Serum concentrations of caffeine may need to be monitored periodically throughout treatment to avoid toxicity.
Serious toxicity has been associated with serum levels greater than 50 mg/L.
Caffeine citrate injection and caffeine citrate oral solution should be inspected visually for particulate matter and discoloration prior to administration.
Vials containing discolored solution or visible particulate matter should be discarded.
To test for drug compatibility with common intravenous solutions or medications, 20 mL of caffeine citrate injection were combined with 20 mL of a solution or medication, with the exception of an Intralipid ® admixture, which was combined as 80 mL/80 mL.
The physical appearance of the combined solutions was evaluated for precipitation.
The admixtures were mixed for 10 minutes and then assayed for caffeine.
The admixtures were then continually mixed for 24 hours, with further sampling for caffeine assays at 2, 4, 8, and 24 hours.
Based on this testing, caffeine citrate injection, 60 mg/3 mL is chemically stable for 24 hours at room temperature when combined with the following test products.
Dextrose Injection, USP 5% 50% Dextrose Injection USP Intralipid ® 20% IV Fat Emulsion Aminosyn ® 8.5% Crystalline Amino Acid Solution Dopamine HCI Injection, USP 40 mg/mL diluted to 0.6 mg/mL with Dextrose Injection, USP 5% Calcium Gluconate Injection, USP 10% (0.465 mEq/Ca+2/mL) Heparin Sodium Injection, USP 1000 units/mL diluted to 1 unit/mL with Dextrose Injection, USP 5% Fentanyl Citrate Injection, USP 50 µg/mL diluted to 10 µg/mL with Dextrose Injection, USP 5%