Clinical medicine profile
Caffeine Citrate
Therapeutic agent (verify pharmacological class)
- Route
- INTRAVENOUS
- Schedule
- POM
- ATC
- Not assigned
- PPB status
- registered
Safety essentials
The information most likely to change a prescribing or dispensing decision.
Contraindications
- Hypersensitivity to the active substance or excipients.
- Additional absolute contraindications are indication- and product-specific — consult SmPC.
Precautions
- WARNINGS Necrotizing Enterocolitis 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.
- In a published randomized, placebo-controlled, clinical trial that studied the use of caffeine citrate in apnea of prematurity in approximately 2000 patients, necrotizing enterocolitis was not more common in caffeine treated patients compared to placebo.
- As with all preterm infants, patients being treated with caffeine citrate should be carefully monitored for the development of necrotizing enterocolitis.
- Necrotizing Enterocolitis 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.
- In a published randomized, placebo-controlled, clinical trial that studied the use of caffeine citrate in apnea of prematurity in approximately 2000 patients, necrotizing enterocolitis was not more common in caffeine treated patients compared to placebo.
- As with all preterm infants, patients being treated with caffeine citrate should be carefully monitored for the development of necrotizing enterocolitis.
Dosing matrix
Population and organ-function guidance, shown together for faster comparison.
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 Injection 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 Caffeine Citrate 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, Caffeine Citrate 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%
See label paediatric section if present; otherwise use paediatric formulary — do not extrapolate adult doses.
Review renal impairment dosing; many agents need CrCl/eGFR adjustment.
- CrCl 0–120: Confirm renal dosing in product SmPC / primary label.
Review hepatic impairment dosing; monitor LFTs if agent is hepatically cleared or hepatotoxic.
Use, effects & interactions
Indications
- INDICATIONS AND USAGE Caffeine Citrate Injection is indicated for the treatment of apnea of prematurity.
- Clinical selection for Caffeine Citrate should follow culture results where relevant, Kenya STG/EML recommendations, and the current product SmPC.
- Class context: Therapeutic agent (verify pharmacological class).
- Confirm site-specific dose, duration and monitoring before prescribing.
Adverse effects
- 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 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 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.
- A published randomized, placebo-controlled, clinical trial in premature infants with birthweights of 500-1250 grams studied the safety of caffeine citrate in apnea of prematurity (NCT00182312).
- This trial randomized approximately 2000 premature infants with a mean gestational age of 27 weeks at birth.
- The median duration of caffeine therapy was 37 days.
- Prior to discharge home, death, ultrasonographic signs of brain injury, and necrotizing enterocolitis were not more common in the caffeine citrate group compared to the placebo.
- At follow up at both 18 months and 5 years corrected age, death was not more common in the caffeine citrate treated group compared to placebo, nor did caffeine citrate use adversely affect neurodevelopmental outcomes.
Drug interactions
Open multi-drug checker ↗- Professional use: confirm indication, dose, duration, monitoring and patient counselling points against current Kenya STG / EML and the product SmPC.
- Document allergy status and key interactions.
Mechanism & disposition
Mechanism of Action Caffeine is structurally related to other methylxanthines, theophylline, and theobromine.
Read complete mechanism
Mechanism of Action Caffeine is structurally related to other methylxanthines, theophylline, and theobromine. It is a bronchial smooth muscle relaxant, a CNS stimulant, a cardiac muscle stimulant, and a diuretic. Although the mechanism of action of caffeine in apnea of prematurity is not known, several mechanisms have been hypothesized. These include: (1) stimulation of the respiratory center, (2) increased minute ventilation, (3) decreased threshold to hypercapnia, (4) increased response to hypercapnia, (5) increased skeletal muscle tone, (6) decreased diaphragmatic fatigue, (7) increased metabolic rate, and (8) increased oxygen consumption. Most of these effects have been attributed to antagonism of adenosine receptors, both A 1 and A 2 subtypes, by caffeine, which has been demonstrated in receptor binding assays and observed at concentrations approximating those achieved therapeutically.
Product-specific
Product-specific
INTRAVENOUS
After oral administration of 10 mg caffeine base/kg to preterm neonates, the peak plasma level (C max ) for caffeine ranged from 6 to 10 mg/L and the mean time to reach peak concentration (T max ) ranged from 30 minutes to 2 hours. The T max was not affected by formula feeding. T...
Caffeine is rapidly distributed into the brain. Caffeine levels in the cerebrospinal fluid of preterm neonates approximate their plasma levels. The mean volume of distribution of caffeine in infants (0.8 to 0.9 L/kg) is slightly higher than that in adults (0.6 L/kg). Plasma prote...
Hepatic cytochrome P450 1A2 (CYP1A2) is involved in caffeine biotransformation. Caffeine metabolism in preterm neonates is limited due to their immature hepatic enzyme systems. Interconversion between caffeine and theophylline has been reported in preterm neonates; caffeine level...
In young infants, the elimination of caffeine is much slower than that in adults due to immature hepatic and/or renal function. Mean
(T 1/2 ) and fraction excreted unchanged in urine (A e ) of caffeine in infants have been shown to be inversely related to gestational/postconceptual age. In neonates, the T 1/2 is approximately 3 to 4 days and the A e is approximately 86% (within 6 days). By 9 months of age, the
Pregnancy, lactation & diet
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/m 2 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.
Assess infant risk vs benefit of maternal therapy; prefer agents with lactation data.
Brands & loaded prices
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Sources & review state
Decision support only. Confirm patient-specific decisions against the current product SmPC, Kenya STG/EML, and professional judgement.