"The U.S. Food and Drug Administration today approved Opsumit (macitentan), a new drug to treat adults with pulmonary arterial hypertension (PAH), a chronic, progressive and debilitating disease that can lead to death or the need for lung transpla"...
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 CAFCIT (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 CAFCIT (caffeine citrate) should be carefully monitored for the development of necrotizing enterocolitis.
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 CAFCIT (caffeine citrate) .
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 CAFCIT (caffeine citrate) for longer periods of treatment have not been established. Safety and efficacy of CAFCIT (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.
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, CAFCIT (caffeine citrate) should be used with caution in infants with cardiovascular disease.
Renal and Hepatic Systems
CAFCIT (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 CAFCIT (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 CAFCIT (caffeine citrate) Oral Solution should receive the following instructions:
- CAFCIT (caffeine citrate) does not contain any preservatives and each vial is for single use only. Any unused portion of the medication should be discarded.
- It is important that the dose of CAFCIT (caffeine citrate) be measured accurately, i.e., with a 1cc or other appropriate syringe.
- Consult your physician if the baby continues to have apnea events; do not increase the dose of CAFCIT (caffeine citrate) without medical consultation.
- Consult your physician if the baby begins to demonstrate signs of gastroin-testinal intolerance, such as abdominal distention, vomiting, or bloody stools, or seems lethargic.
- CAFCIT (caffeine citrate) should be inspected visually for particulate matter and discoloration prior to its administration. Vials containing discolored solution or visible particulate matter should be discarded.
Prior to initiation of CAFCIT (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 CAFCIT (caffeine citrate) .
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 max-imum 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 subcu-taneously (approximately equal to the maximum recommended intravenous loading dose for infants on a mg/m2 basis) for four 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 (3.0 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.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 5/4/2009
Additional Cafcit Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.