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P: 877-845-6371Rx Only For Intravenous Administration INDICATIONS AND USAGE Caffeine Citrate injection is indicated for the short-term treatment of apnea of prematurity in infants between 28 and <33 weeks gestational age. IMPORTANT SAFETY INFORMATION 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, 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. Cardiovascular Although no cases of cardiac toxicity were reported in the placebo-controlled trial, caffeine has been shown to increase heart rate, left ventricular output, and stroke volume in published studies. Therefore, Caffeine Citrate should be used with caution in infants with cardiovascular disease. Renal and Hepatic Systems Caffeine Citrate should be administered with caution in infants 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. Laboratory Tests 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. Serious toxicity has been reported in the literature when serum caffeine levels exceed 50 mg/L. Serum concentrations of caffeine may need to be monitored periodically throughout treatment to avoid toxicity. In clinical studies reported in the literature, cases of hypoglycemia and hyperglycemia have been observed. Therefore, serum glucose may need to be periodically monitored in infants receiving Caffeine Citrate. 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). Interconversion between caffeine and theophylline has been reported in preterm neonates. The concurrent use of these drugs is not recommended. ADVERSE REACTIONS The following adverse events occurred in the double-blind period of the controlled trial and were more frequent in Caffeine Citrate (N=46) treated patients than placebo (N=39); 8.7% feeding intolerance; 8.7% rash; 4.3% sepsis; 4.3% necrotizing enterocolitis; 2.2% accidental injury; 2.2% hemorrhage; 2.2% gastritis; 2.2% gastrointestinal hemorrhage; 2.2% disseminated intravascular coagulation; 2.2% acidosis; 2.2% healing abnormal; 2.2% cerebral hemorrhage; 2.2% dyspnea; 2.2% lung edema; 2.2% dry skin; 2.2% skin breakdown; 2.2% retinopathy of prematurity; 2.2% kidney failure. 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. OVERDOSAGE Serious toxicity has been associated with serum levels greater than 50 mg/L. Dosage and Administration 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). For additional safety information, please see Full Prescribing Information. You are encouraged to report Adverse Drug Events (ADEs) to American Regent Inc. at 1.800.734.9236
or to the FDA by visiting www.fda.gov/MedWatch or calling 1.800.FDA.1088.