Caffeine Citrate Oral Solution

INDICATIONS AND USAGE Caffeine citrate is indicated for the short term treatment of apnea of prematurity in infants between 28 and <33 weeks gestational age.

DOSAGE AND 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 should be inspected visually for particulate matter and discoloration prior to administration. Vials containing discolored solution or visible particulate matter should be discarded.

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

WARNINGS During the double-blind, placebo-controlled clinical trial, six cases of necrotizing enterocolitis developed among the 85 infants studied (caffeine=46, placebo=39), with three 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.

Drug Interactions 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 4 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.

ADVERSE REACTIONS 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 Feeding Intolerance Sepsis 1 (2.2) 4 (8.7) 2 (4.3) 0 (0.0) 2 (5.1) 0 (0.0) CARDIOVASCULAR SYSTEM Hemorrhage 1 (2.2) 0 (0.0) DIGESTIVE SYSTEM Necrotizing Enterocolitis Gastritis Gastrointestinal Hemorrhage 2 (4.3) 1 (2.2) 1 (2.2) 1 (2.6) 0 (0.0) 0 (0.0) HEMIC AND LYMPHATIC SYSTEM Disseminated Intravascular Coagulation 1 (2.2) 0 (0.0) METABOLIC AND NUTRITIVE DISORDERS Acidosis Healing Abnormal 1 (2.2) 1 (2.2) 0 (0.0) 0 (0.0) NERVOUS SYSTEM Cerebral Hemorrhage 1 (2.2) 0 (0.0) RESPIRATORY SYSTEM Dyspnea Lung Edema 1 (2.2) 1 (2.2) 0 (0.0) 0 (0.0) SKIN AND APPENDAGES Dry Skin Rash Skin Breakdown 1 (2.2) 4 (8.7) 1 (2.2) 0 (0.0) 3 (7.7) 0 (0.0) SPECIAL SENSES Retinopathy of Prematurity 1 (2.2) 0 (0.0) UROGENITAL SYSTEM Kidney Failure 1 (2.2) 0 (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 (hypoglycemia and hyperglycemia) and renal effects (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.

Pregnancy: Concern for the teratogenicity of caffeine is not relevant when administered to infants. In studies performed in adult animals, caffeine (as caffeine base) administered to pregnant mice as sustained release pellets at 50 mg/kg (less than the maximum recommended intravenous loading dose for infants on a mg/m 2 basis), during the period of organogenesis, caused a low incidence of c left palate and exencephaly in the fetuses. There are no adequate and well-controlled studies in pregnant women.