CAFFEINE CITRATE

Caffeine citrate injection, USP for intravenous administration is a clear, colorless, sterile, non-pyrogenic, preservative-free, aqueous solution 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, 8.3 mg sodium citrate dihydrate and Water for Injection, USP. Caffeine (anhydrous) USP, a central nervous system stimulant, is an odorless white crystalline powder or granules, 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. checmical-structure

Caffeine citrate injection, USP is indicated for the treatment of apnea of prematurity.

Prior to initiation of caffeine citrate injection USP, 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 injection, USP follow. * Using a syringe infusion pump ** Beginning 24 hours after the loading dose Dose of Caffeine Citrate Injection, USP Volume Dose of Caffeine Citrate Injection, USP 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 ** 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, USP should be inspected visually for particulate matter and discoloration prior to administration. Vials containing discolored solution or visible particulate matter should be discarded. Drug Compatibility To test for drug compatibility with common intravenous solutions or medications, 20 mL of caffeine citrate injection, USP 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 USP, 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 mcg/mL diluted to 10 mcg/mL with Dextrose Injection, USP 5%

Caffeine citrate injection is contraindicated in patients who have demonstrated hypersensitivity to any of its components.

Overall, the reported number of adverse events in the double-blind period of the controlled trial was similar for the caffeine citrate and placebo groups. The following table shows adverse events that occurred in the double-blind period of the controlled trial and that were more frequent in caffeine citrate-treated patients than placebo. ADVERSE EVENTS THAT OCCURRED MORE FREQUENTLY IN CAFFEINE CITRATE-TREATED PATIENTS THAN PLACEBO DURING DOUBLE-BLIND THERAPY Adverse Event (AE) Caffeine Citrate N=46 n (%) Placebo N=39 n (%) BODY AS A WHOLE Accidental Injury 1 (2.2) 0 (0) Feeding Intolerance 4 (8.7) 2 (5.1) Sepsis 2 (4.3) 0 (0) CARDIOVASCULAR SYSTEM Hemorrhage 1 (2.2) 0 (0) DIGESTIVE SYSTEM Necrotizing Enterocolitis 2 (4.3) 1 (2.6) Gastritis 1 (2.2) 0 (0) Gastrointestinal Hemorrhage 1 (2.2) 0 (0) HEMIC AND LYMPHATIC SYSTEM Disseminated Intravascular Coagulation 1 (2.2) 0 (0) METABOLIC AND NUTRITIVE DISORDERS Acidosis 1 (2.2) 0 (0) Healing Abnormal 1 (2.2) 0 (0) NERVOUS SYSTEM Cerebral Hemorrhage 1 (2.2) 0 (0) RESPIRATORY SYSTEM Dyspnea 1 (2.2) 0 (0) Lung Edema 1 (2.2) 0 (0) SKIN AND APPENDAGES Dry Skin 1 (2.2) 0 (0) Rash 4 (8.7) 3 (7.7) Skin Breakdown 1 (2.2) 0 (0) SPECIAL SENSES Retinopathy of Prematurity 1 (2.2) 0 (0) UROGENITAL SYSTEM Kidney Failure 1 (2.2) 0 (0) In addition to the cases above, three cases of necrotizing enterocolitis were diagnosed in patients receiving caffeine citrate during the open-label phase of the study. Three of the infants who developed necrotizing enterocolitis during the trial died. All had been exposed to caffeine. Two were randomized to caffeine, and one placebo patient was “rescued” with open-label caffeine for uncontrolled apnea. Adverse events described in the published literature include: central nervous system stimulation (i.e., irritability, restlessness, jitteriness), cardiovascular effects (i.e., tachycardia, increased left ventricular output, and increased stroke volume), gastrointestinal effects (i.e., increased gastric aspirate, gastrointestinal intolerance), alterations in serum glucose (i.e., hypoglycemia and hyperglycemia), and renal effects (i.e., increased urine flow rate, increased creatinine clearance, and increased sodium and calcium excretion). Published long-term follow-up studies have not shown caffeine to adversely affect neurological development or growth parameters. A published randomized, placebo-controlled, clinical trial in premature infants with birthweights of 500 to 1,250 grams studied the safety of caffeine citrate in apnea of prematurity (NCT00182312). This trial randomized approximately 2,000 premature infants with a mean gestational age of 27 weeks at birth. The median duration of caffeine therapy was 37 days. Prior to discharge home, death, ultrasonographic signs of brain injury, and necrotizing enterocolitis were not more common in the caffeine citrate group compared to the placebo. At follow up at both 18 months and 5 years corrected age, death was not more common in the caffeine citrate treated group compared to placebo, nor did caffeine citrate use adversely affect neurodevelopmental outcomes.

Cytochrome P450 1A2 (CYP1A2) is known to be the major enzyme involved in the metabolism of caffeine. Therefore, caffeine has the potential to interact with drugs that are substrates for CYP1A2, inhibit CYP1A2, or induce CYP1A2. Few data exist on drug interactions with caffeine in preterm neonates. Based on adult data, lower doses of caffeine may be needed following coadministration of drugs which are reported to decrease caffeine elimination (e.g., cimetidine and ketoconazole) and higher caffeine doses may be needed following coadministration of drugs that increase caffeine elimination (e.g., phenobarbital and phenytoin). Caffeine administered concurrently with ketoprofen reduced the urine volume in four healthy volunteers. The clinical significance of this interaction in preterm neonates is not known. Interconversion between caffeine and theophylline has been reported in preterm neonates. The concurrent use of these drugs is not recommended.