Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 17 February 2017

Indication(s)

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

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Advisory information

contraindications
CONTRAINDICATIONS CAFCIT (caffeine citrate) is contraindicated in patients who have demonstrated hypersensitivity to any of its components.
Special warnings and precautions

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 CAFCIT (caffeine citrate).

Caffeine is a central nervous system stimulant and in cases of caffeine overdose, seizures have been reported.

CAFCIT 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 CAFCIT for longer periods of treatment have not been established.

Safety and efficacy of CAFCIT 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, CAFCIT should be used with caution in infants with cardiovascular disease.

Renal and Hepatic Systems CAFCIT 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 should be adjusted to avoid toxicity in this population.

(See CLINICAL PHARMACOLOGY, Elimination and Special Populations.

) Laboratory Tests 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. 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

ADVERSE REACTIONS Overall, the reported number of adverse events in the double-blind period of the controlled trial was similar for the CAFCIT (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 CAFCIT-treated patients than placebo.

ADVERSE EVENTS THAT OCCURRED MORE FREQUENTLY IN CAFCIT-TREATED PATIENTS THAN PLACEBO DURING DOUBLE-BLIND THERAPY Adverse Event (AE) CAFCIT N=46 n (%) Placebo N=39 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 Coagulation 1 (2.2) 0 (0.0) 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 CAFCIT (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.

Usage information

Dosing and administration

DOSAGE AND ADMINISTRATION 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.

The recommended loading dose and maintenance doses of CAFCIT follow.

Dose of CAFCIT (caffeine citrate) Volume Dose of CAFCIT (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. CAFCIT 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 CAFCIT Injection 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, CAFCIT Injection, 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 %

More information

Category Value
Authorisation number NDA020793
Orphan designation No
Product NDC 0641-6164
Date Last Revised 10-03-2015
Type HUMAN PRESCRIPTION DRUG
RXCUI 849931
Marketing authorisation holder West-Ward Pharmaceutical Corp.