Caffeine citrate (Solution) Instructions for Use

Marketing Authorization Holder

LIFE SCIENCES OHFK, LLC (Russia)

Manufactured By

Ferment Firm, LLC (Russia)

ATC Code

N06BC01 (Caffeine)

Active Substance

Caffeine citrate (BANM)

Dosage Form

Caffeine citrate

Solution for intravenous administration and oral use 20 mg/1 ml: amp. 1 ml or 3 ml 5 or 10 pcs.

Dosage Form, Packaging, and Composition

Solution for intravenous administration and oral use as a clear, colorless liquid.

Excipients : sodium hydroxide – to adjust pH to 4.7, water for injections – to 1 ml.

1 ml – ampoules of colorless glass (5) – blister packs (1) – cardboard packs (for hospitals).
1 ml – ampoules of colorless glass (5) – blister packs (2) – cardboard packs (for hospitals).
3 ml – ampoules of colorless glass (5) – blister packs (1) – cardboard packs (for hospitals).
3 ml – ampoules of colorless glass (5) – blister packs (2) – cardboard packs (for hospitals).

Clinical-Pharmacological Group

Psychostimulant and analeptic

Pharmacotherapeutic Group

Psychoanaleptics; psychostimulants, agents used in attention deficit hyperactivity disorder, and nootropic agents; xanthine derivatives

Pharmacological Action

Psychostimulant agent. In structure, caffeine is similar to methylxanthines – theophylline and theobromine. Most of its effects are associated with antagonism to adenosine receptor subtypes A₁ and A_2A, demonstrated in receptor binding assays and noted at concentrations approaching those achieved therapeutically for this indication. The main effect of caffeine is stimulation of the central nervous system. This underlies the activity of caffeine in apnea of prematurity, where it presumably exerts the following effects: stimulation of the respiratory center; increased minute ventilation; decreased sensitivity threshold to hypercapnia; enhanced response to hypercapnia; increased skeletal muscle tone; reduced diaphragmatic weakness; increased basal metabolic rate; increased oxygen consumption.

The action of caffeine is observed within a few minutes after the start of infusion.

Pharmacokinetics

Caffeine citrate easily dissociates in aqueous solutions. The citrate is rapidly metabolized upon infusion or oral administration. After oral administration of caffeine at a dose of 10 mg/kg in preterm newborns, the C_max of caffeine in plasma ranged from 6 to 10 mg/L, and the mean time to reach C_max (T_max) ranged from 30 minutes to 2 hours. Caffeine rapidly reaches the brain upon administration of caffeine citrate. The concentration of caffeine in the cerebrospinal fluid of preterm newborns is approximately equal to its concentration in plasma. The mean V_d of caffeine in infants (0.8-0.9 L/kg) is somewhat greater than in adults (0.6 L/kg). Data on plasma protein binding in newborns or infants are not available. In adults, the mean plasma protein binding in vitro is approximately 36%. Caffeine easily crosses the placental barrier into the fetal bloodstream and is excreted in breast milk.

Metabolism of caffeine in preterm newborns is very limited due to the immaturity of liver enzyme systems, and most of the active substance is excreted in the urine. The liver isoenzyme CYP1A2 is involved in the metabolism of caffeine in adults. Interconversion of caffeine and theophylline is possible in preterm newborns; after theophylline administration, the caffeine level is approximately 25% of the theophylline level; it can be expected that approximately 3-8% of the administered caffeine is transformed into theophylline.

Elimination of caffeine in infants during the first year of life proceeds significantly slower than in adults due to functional immaturity of the liver and/or kidneys. In newborns, clearance occurs almost entirely through renal excretion. The mean T_1/2 and the fraction of caffeine excreted unchanged in the urine (Ae) in infants have an inverse correlation with age. In newborns, T_1/2 is approximately 3-4 days and Ae is approximately 86% (over 6 days). By the age of 9 months, caffeine metabolism in children is approximately equal to that in adults (T_1/2 – 5 hours and Ae – 1%). In the presence of severe renal failure, due to the potential for accumulation, a reduced daily maintenance dose of caffeine is required, and doses should be determined by measuring blood caffeine levels. In preterm newborns with cholestatic hepatitis, prolongation of caffeine T_1/2 and an increase in its plasma concentration above the normal level are observed, suggesting special attention when selecting doses in such patients.

Indications

Treatment of primary apnea (cessation of breathing) in preterm newborns.

ICD codes

Dosage Regimen

Intravenous administration as a controlled intravenous infusion using a syringe infusion pump or other device for metered infusion. Loading dose – 20 mg/kg, maintenance – 5 mg/kg.

Alternatively, a maintenance dose of 5 mg/kg body weight can be administered orally via a nasogastric tube every 24 hours.

Do not use intramuscularly, subcutaneously, intrathecally, or as an intraperitoneal injection.

Should be used only in a neonatal intensive care unit (NICU) equipped with appropriate equipment for patient management and monitoring.

Treatment with caffeine citrate should be initiated under the supervision of a physician experienced in working in a neonatal intensive care unit.

Adverse Reactions

Nervous system disorders possible – central nervous system stimulation, manifesting as convulsions, irritability, agitation, syndrome of increased neuro-reflex excitability.

Cardiovascular system disorders tachycardia, arrhythmia, arterial hypertension, increased stroke volume.

Metabolism and nutrition disorders hyperglycemia.

These side effects are dose-dependent, so there is a need to determine the plasma concentration of caffeine and reduce the dose.

Adverse reactions of caffeine citrate, published in the literature and obtained in post-registration safety studies, are listed below.

Infections and infestations frequency unknown – sepsis.

Immune system disorders rare – hypersensitivity reactions.

Metabolism and nutrition disorders common – hyperglycemia, frequency unknown – hypoglycemia, poor weight gain, food intolerance.

Nervous system disorders uncommon – convulsions, frequency unknown – irritability, syndrome of increased neuro-reflex excitability, agitation, brain injury.

Ear and labyrinth disorders frequency unknown – deafness.

Cardiovascular system disorders common – tachycardia, uncommon – arrhythmia, frequency unknown – increased left ventricular output, increased stroke volume.

Gastrointestinal disorders: frequency unknown – belching, increased volume of gastric aspirate, necrotizing enterocolitis.

General disorders and administration site conditions common – irritation and inflammation at the infusion site, phlebitis.

Investigations: frequency unknown – increased urinary sodium and calcium, decreased hemoglobin level, decreased thyroxine level, increased diuresis.

Contraindications

Hypersensitivity to caffeine citrate.

With caution

Concomitant fetal cardiovascular diseases; presence of convulsive syndrome, hepatic or renal failure; excessive consumption of caffeine-containing products by the newborn’s mother immediately before delivery. Use with particular caution in patients with gastroesophageal reflux.

Use in Pregnancy and Lactation

Animal studies have shown that high doses of caffeine have embryotoxic and teratogenic effects. This influence is not significant with the short-term use of caffeine citrate in preterm newborns.

Caffeine is excreted in breast milk and easily crosses the placental barrier into the fetal bloodstream. Breastfeeding mothers of newborns receiving caffeine citrate treatment should avoid consuming food, beverages, and medications containing caffeine. In preterm newborns whose mothers consumed large amounts of caffeine before their birth, baseline plasma caffeine concentrations should be determined before initiating caffeine citrate treatment.

Special Precautions

The diagnosis of primary apnea in preterm newborns is made by exclusion. Other causes of apnea (e.g., CNS injury, congenital lung lesions, anemia, sepsis, metabolic disorders, cardiovascular abnormalities, or obstructive apnea) must be excluded/eliminated prior to initiating caffeine citrate. Lack of response to caffeine citrate treatment (confirmed, if necessary, by plasma concentration determination) may confirm that apnea is caused by another reason.

Since caffeine is a CNS stimulant, cases of seizures have been reported with caffeine overdose. Particular caution should be exercised in cases where Caffeine citrate is prescribed to newborns with pre-existing seizure disorders.

Caffeine increases heart rate, left ventricular output, and stroke volume. Caffeine citrate should be used with particular caution in newborns with cardiovascular pathologies. There is a possibility of tachyarrhythmia occurring in predisposed patients. In newborns, this usually manifests as simple sinus tachycardia. If an atypical rhythm disturbance was observed during fetal cardiotocography, then Caffeine citrate is prescribed with particular caution.

The frequency of adverse reactions in very preterm newborns with renal/hepatic insufficiency was higher compared to preterm newborns without organ damage. In this group of patients, to avoid toxic phenomena, caffeine doses should be adjusted based on plasma caffeine concentration determination results.

In newborns whose mothers consumed large amounts of caffeine before delivery, the baseline plasma caffeine concentration should be determined before initiating caffeine citrate treatment, since caffeine easily crosses the placenta into the fetal bloodstream. Breastfeeding mothers whose infants are receiving caffeine citrate treatment should not consume caffeine-containing products, beverages, or medications, since caffeine is excreted in breast milk.

In newborns who were previously prescribed theophylline, the baseline plasma caffeine concentration should be determined before initiating caffeine citrate treatment, since in preterm newborns, theophylline is metabolized to form caffeine.

Necrotizing enterocolitis is a common cause of complications and mortality in preterm newborns. There is evidence of a possible relationship between the use of methylxanthines and the development of necrotizing enterocolitis. However, a causal relationship between the use of caffeine or other methylxanthines and the development of necrotizing enterocolitis has not been established. In this regard, all preterm newborns should be carefully monitored for the absence of signs of developing necrotizing enterocolitis.

Caffeine citrate should be prescribed with particular caution to patients with gastroesophageal reflux, as treatment may worsen this condition. Caffeine citrate may cause accelerated metabolism, which can lead to increased energy and nutrient requirements during treatment.

Diuresis and electrolyte losses caused by caffeine citrate may require correction of water and electrolyte imbalance.

Drug Interactions

Interconversion of caffeine and theophylline is observed in preterm newborns. Therefore, these drugs should not be administered simultaneously. The isoenzyme CYP1A2 is the main enzyme involved in the metabolism of caffeine in adults, therefore caffeine can potentially interact with substances that are substrates for CYP1A2, inhibitors of CYP1A2, or inducers of CYP1A2. However, caffeine metabolism in preterm newborns is limited due to the immaturity of hepatic enzyme systems.

Although there is little data on the interaction of caffeine with other active substances in preterm newborns, nevertheless, lower doses of caffeine citrate are prescribed when co-administered with compounds that reduce the elimination of caffeine in adults (e.g., cimetidine and ketoconazole), and higher doses if compounds that, conversely, increase the elimination of caffeine (e.g., phenobarbital and phenytoin) are co-administered. If doubts arise about the potential interaction of prescribed substances with caffeine, the plasma concentration of caffeine should be determined.

Since excessive bacterial growth in the intestine is associated with the development of necrotizing enterocolitis, the concomitant use of caffeine citrate with drugs that suppress gastric secretion (histamine H₂-receptor blockers or proton pump inhibitors) may theoretically increase the likelihood of developing necrotizing enterocolitis.

Concomitant administration of caffeine and doxapram (a respiratory analeptic) may potentiate their stimulatory effect on the cardiorespiratory system and CNS. If simultaneous use of these drugs is indicated, then heart rate and blood pressure should be carefully monitored.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.