Caffeine Citrate (Page 2 of 4)

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. (See CLINICAL PHARMACOLOGY , Elimination, Special Populations.)

Information for Patients

Parents/caregivers of patients receiving caffeine citrate oral solution should receive the following instructions:

  1. Caffeine citrate oral solution does not contain any preservatives and each vial is for single use only. Any unused portion of the medication should be discarded.
  2. It is important that the dose of caffeine citrate oral solution be measured accurately, i.e., with a 1cc or other appropriate syringe.
  3. Consult your physician if the baby continues to have apnea events; do not increase the dose of caffeine citrate oral solution without medical consultation.
  4. Consult your physician if the baby begins to demonstrate signs of gastroin­testinal intolerance, such as abdominal distention, vomiting, or bloody stools, or seems lethargic.
  5. Caffeine citrate oral solution should be inspected visually for particulate matter and discoloration prior to its administration. Vials containing discolored solution or visible particulate matter should be discarded.

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. 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.

In the placebo-controlled clinical trial, caffeine levels ranged from 8 to 40 mg/L. A therapeutic plasma concentration range of caffeine could not be determined from the placebo-controlled clinical trial. 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).

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year study in Sprague-Dawley rats, caffeine (as caffeine base) adminis­tered in drinking water was not carcinogenic in male rats at doses up to 102 mg/kg or in female rats at doses up to 170 mg/kg (approximately 2 and 4 times, respectively, the maximum recommended intravenous loading dose for infants on a mg/m2 basis). In an 18-month study in C57BL/6 mice, no evidence of tumorigenicity was seen at dietary doses up to 55 mg/kg (less than the max­imum recommended intravenous loading dose for infants on a mg/m2 basis).

Caffeine (as caffeine base) increased the sister chromatid exchange (SCE) SCE/cell metaphase (exposure time dependent) in an in vivo mouse metaphase analysis. Caffeine also potentiated the genotoxicity of known mutagens and enhanced the micronuclei formation (5-fold) in folate-deficient mice. However, caffeine did not increase chromosomal aberrations in in vitro Chinese hamster ovary cell (CHO) and human lymphocyte assays and was not mutagenic in an in vitro CHO/hypoxanthine guanine phosphoribosyltransferase (HGPRT) gene mutation assay, except at cytotoxic concentrations. In addition, caffeine was not clastogenic in an in vivo mouse micronucleus assay.

Caffeine (as caffeine base) administered to male rats at 50 mg/kg/day subcu­taneously (approximately equal to the maximum recommended intravenous loading dose for infants on a mg/m2 basis) for 4 days prior to mating with untreated females, caused decreased male reproductive performance in addi­tion to causing embryotoxicity. In addition, long-term exposure to high oral doses of caffeine (3 g over 7 weeks) was toxic to rat testes as manifested by spermatogenic cell degeneration.

Pregnancy: Pregnancy Category C

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/m2 basis), during the period of organogenesis, caused a low incidence of cleft palate and exencephaly in the fetuses. There are no adequate and well-controlled studies in pregnant women.

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 CitrateN=46 Placebo N=39
n (%) n (%)
BODY AS A WHOLE
Accidental Injury 1 (2.2) 0 (0.0)
Feeding Intolerance 4 (8.7) 2 (5.1)
Sepsis 2 (4.3) 0 (0.0)
CARDIOVASCULAR SYSTEM
Hemorrhage 1 (2.2) 0 (0.0)
DIGESTIVE SYSTEM
Necrotizing Enterocolitis 2 (4.3) 1 (2.6)
Gastritis 1 (2.2) 0 (0.0)
Gastrointestinal Hemorrhage 1 (2.2) 0 (0.0)
HEMIC AND LYMPHATIC SYSTEM
Disseminated Intravascular 1 (2.2) 0 (0.0)
Coagulation
METABOLIC AND NUTRITIVE DISORDERS
Acidosis 1 (2.2) 0 (0.0)
Healing Abnormal 1 (2.2) 0 (0.0)
NERVOUS SYSTEM
Cerebral Hemorrhage 1 (2.2) 0 (0.0)
RESPIRATORY SYSTEM
Dyspnea 1 (2.2) 0 (0.0)
Lung Edema 1 (2.2) 0 (0.0)
SKIN AND APPENDAGES
Dry Skin 1 (2.2) 0 (0.0)
Rash 4 (8.7) 3 (7.7)
Skin Breakdown 1 (2.2) 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.

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