Caffeine Citrate

Approved Indications:

• Primary Apnea of Prematurity: Caffeine citrate is indicated for the short-term treatment of apnea of prematurity in neonates between 28 and <33 weeks’ gestational age, characterized by intermittent cessation of breathing for ≥20 seconds.
• Stimulation of Central Respiratory Drive: To increase respiratory rate and reduce hypoxic episodes in preterm neonates with immature central respiratory control.

Off-Label/Clinically Accepted Uses:

• Post-Anesthesia Respiratory Depression (adults): Occasionally used in intensive care to reverse respiratory depression.
• Neonatal Bronchopulmonary Dysplasia Prevention (BPD): Adjunctive use in premature infants at high risk of BPD.
• Neonatal extubation facilitation: Reduces the risk of extubation failure by improving respiratory drive.

Route of Administration:
Intravenous (IV) or Oral

Neonates (Apnea of Prematurity):

• Loading Dose: 20 mg/kg caffeine citrate IV or orally (equivalent to 10 mg/kg caffeine base).
• Maintenance Dose: 5 mg/kg caffeine citrate IV or orally (equivalent to 2.5 mg/kg caffeine base) once daily, starting 24 hours after the loading dose.
• Dose Adjustments: May increase up to 10 mg/kg/day based on clinical response and serum caffeine levels (target 5–20 mcg/mL).

Administration Notes:

• IV infusion over 30 minutes is recommended to minimize adverse effects.
• Oral solution should be shaken well before use and administered using calibrated syringe.

Special Populations:

• Hepatic/Renal Impairment (Neonates): Use with caution; monitor caffeine levels due to immature metabolic/excretory systems.
• Elderly & Pediatric (non-neonatal): Not recommended unless under specialist care.

Caffeine citrate exerts its therapeutic effects primarily by antagonizing adenosine receptors (A1 and A2A) in the central nervous system. Adenosine normally promotes sleep and suppresses arousal and respiration. By blocking these receptors, caffeine stimulates the medullary respiratory center, increases minute ventilation, reduces diaphragmatic fatigue, and improves skeletal muscle contraction. Additionally, caffeine enhances catecholamine release, increases cyclic AMP (cAMP) via phosphodiesterase inhibition, and enhances respiratory drive and arousal in neonates with immature respiratory control systems.

• Absorption: Well absorbed orally (almost 100% bioavailability)
• Distribution: Widely distributed; Volume of distribution (Vd): ~0.8–0.9 L/kg in neonates
• Metabolism: Metabolized slowly in neonates by hepatic CYP1A2
• Onset of Action: ~1–2 hours post oral dose
• Half-Life:
• Neonates: 72–96 hours (due to immature liver enzyme activity)
• Adults: 3–7 hours
• Peak Plasma Concentration: Reached in 30 minutes (IV), ~1 hour (oral)
• Excretion: Renal; up to 85% excreted unchanged in neonates
• Steady State: Reached in 5–7 days with daily dosing

• Pregnancy: Not assigned a formal FDA category. However, use in pregnant women is not recommended unless clearly needed, due to potential fetal exposure. Animal studies have shown some risk at high doses.
• Lactation: Caffeine is excreted in breast milk. While maternal caffeine consumption from normal dietary sources is generally safe, high concentrations (especially from IV caffeine citrate) may cause irritability or poor sleep in infants. Monitor neonates closely if mother is also consuming caffeine.

• Primary Class: Central Nervous System (CNS) Stimulant
• Subclass: Methylxanthine derivative
• Category: Respiratory stimulant for neonates

• Hypersensitivity to caffeine or any component of the formulation
• Untreated seizures or seizure disorders
• Necrotizing enterocolitis or gastrointestinal bleeding (relative contraindication in neonates)
• Cardiac arrhythmias (uncontrolled)

• Seizures: Caffeine lowers the seizure threshold; use with caution in neonates with a history of seizures.
• Cardiac Monitoring: Monitor heart rate and ECG in neonates, especially those with structural heart disease or tachycardia.
• Gastrointestinal Complications: Increased risk of necrotizing enterocolitis and feeding intolerance.
• Renal/Hepatic Immaturity: May reduce drug clearance and increase accumulation—monitor serum caffeine levels.
• Drug Accumulation Risk: Due to long half-life in neonates, monitor for signs of toxicity (jitteriness, tachycardia, vomiting, seizures).

Common (≥1%):

• Cardiovascular: Tachycardia, arrhythmia
• Gastrointestinal: Feeding intolerance, abdominal distension
• Neurological: Irritability, jitteriness, restlessness
• Metabolic: Hyperglycemia, hypokalemia, increased urine output

Serious/Rare:

• Seizures
• Intracranial hemorrhage
• Necrotizing enterocolitis
• Hypertension
• Cardiac dysrhythmias
• Sudden death (very rare; mostly in overdose or high serum levels)

Timing & Dose-Dependence:

• Adverse effects typically appear within the first 1–3 days of therapy.
• Risk increases with serum levels >20 mcg/mL.

• CYP1A2 Inhibitors (e.g., ciprofloxacin, fluvoxamine): Reduce caffeine metabolism → ↑ toxicity
• CYP1A2 Inducers (e.g., phenobarbital, phenytoin): Increase caffeine clearance → ↓ effectiveness
• Concurrent methylxanthines (e.g., theophylline): Additive toxicity → avoid use together
• Diuretics: May worsen electrolyte disturbances (e.g., hypokalemia)
• Alcohol (maternal consumption during breastfeeding): May increase CNS stimulation in the neonate

• American Academy of Pediatrics (AAP) and WHO continue to endorse caffeine citrate as the first-line pharmacologic agent for apnea of prematurity.
• Newer neonatal guidelines emphasize early initiation (within 48 hours of birth) for better long-term neurodevelopmental outcomes.
• Recent updates highlight monitoring for long-term neurobehavioral effects, though data remains reassuring at therapeutic doses.

• Oral Solution and IV Vials:
• Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C
• Protect from light
• Do not freeze
• Use within 30 minutes if drawn into syringe or diluted
• Opened vials: Discard unused portion after a single dose withdrawal (preservative-free)
• Shake oral suspension well before use