Caffeine Citrate

Registered South African indications:

• Primary apnoea of premature newborns

Contraindications

Registered contraindications in South Africa & other jurisdictions

• Hypersensitivity to caffeine or any of its excipients

Cautions

Recommendations in South Africa & other jurisdictions

• Very premature infants (<28 weeks gestational age and/or body weight <1000g) particularly when receiving parenteral nutrition
• Newborn infants whose mothers consumed large amounts of caffeine prior to delivery
• Prior treatment with theophylline
• Seizure disorders
• Known and clinically significant cardiovascular disease
• Arrythmias
• Renal impairment
• Hepatic impairment
• Gastro-oesophageal reflux (GORD)
• Fluid and electrolyte disturbances
• Patients on a controlled sodium diet
• Opening ampoules may introduce glass particles into the solution, therefore filtration prior to use is recommended

No information available

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Treatment with caffeine citrate should be initiated under the supervision of a medical practitioner experienced in neonatal intensive care. Treatment should be administered only in a neonatal intensive care unit in which adequate facilities are available for patient surveillance and monitoring

Primary apnoea of premature newborns

Loading dose in previously untreated infants

• IV: 20mg/kg body weight, admin. by slow infusion over 30 min. using a syringe infusion pump or other metered infusion device

Maintenance dose

• IV: 5mg/kg body weight, admin. by slow infusion over 10 min. every 24hrs, starting after an interval of 24 hrs from the loading dose
• Oral (sol): 5mg/kg body weight, every 24hrs after the loading dose

In preterm infants with insufficient clinical response to the recommended loading dose, a second loading dose of 10-20mg/kg maximum may be given after 24 hours. Higher maintenance doses of 10mg/kg body weight could be considered in case of insufficient response, taking into account the potential for accumulation of caffeine due to the long half-life in premature neonates and the progressively increasing capacity to metabolise caffeine in relation to post-menstrual age

The diagnosis of apnoea of prematurity may need to be reconsidered if patients do not respond adequately to a second loading dose or maintenance dose 10mg/kg/day

Apnoea of prematurity is a diagnosis of exclusion. Other causes of apnoea (e.g. CNS disorders, primary lung disease, anaemia, sepsis, metabolic disturbances, CVS abnormalities, or obstructive apnoea) should be ruled out or properly treated prior to initiation with caffeine citrate

Method of administration (IV and oral)
Caffeine citrate injection is a solution for infusion or oral administration
Intravenously: Should be administered by controlled intravenous infusion, using a syringe infusion pump or other metered infusion device only
Oral: Oral administration, such as through a nasogastric tube. Refer to individual product information for compatibility

See Additional Prescriber Points

Pregnancy

• Caution; not indicated for use in adults
• Caffeine in animal studies, at high doses, was shown to be embryotoxic and teratogenic
• These effects are not relevant with regard to short term administration in the preterm infant population

Breastfeeding

• Not indicated for use in adults
• Caffeine is excreted into breast milk and readily crosses the placenta into foetal circulation
• Breast-feeding mothers of newborn infants treated with caffeine citrate should not ingest caffeine-containing foods, beverages or medicinal products containing caffeine
• In newborn infants born to mothers who consumed large quantities of caffeine prior to delivery, baseline plasma caffeine concentrations should be measured prior to initiation of treatment with caffeine citrate

Fertility

• Effects on reproductive performance observed in animals are not relevant to its indication in preterm newborn infants

• Neonates with eGFR > 30-89 mL/min/1.73m²: No dose adjustment required 
• Neonates with eGFR < 29 mL/min/1.73m²: Caution; dose adjustment required.
  - Administer loading-dose without adjustment
  - Reduce the maintenance-dose by up to 50%
  - The next maintenance-doses should be adjusted according to the neonatal caffeine plasma concentrations

• Mild to moderate (Child-Pugh Classes A & B): No dose adjustment is recommended 
• Severe (Child-Pugh Class C): No dose adjustment is recommended
  Closely monitor caffeine plasma concentrations

• Not indicated for use in geriatric patients

Central Nervous System Disorders

• Convulsion
• Irritability
• Restlessness and jitteriness
• Brain injury

Cardiovascular Disorders

• Tachycardia
• Arrythmia
• Hypertension
• Increased stroke volume
• Increased left ventricular output

Gastrointestinal Disorders

• Regurgitation
• Increased gastric aspirate
• Necrotising enterocolitis

Genitourinary Disorders

• Increased urine output
• Increased urine sodium 
• Increased urine calcium

Endocrine and Metabolic Disorders

• Hyperglycaemia
• Hypoglycaemia
• Failure to thrive
• Feeding intolerance
• Decreased thyroxine

Skin and Subcutaneous Tissue Disorders

• Infusion site phlebitis
• Infusion site inflammation

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reaction
• Decreased haemoglobin

Sensory Disorders

• Deafness

Others

• Sepsis

• CYP1A2 substrates
• CYP1A2 inhibitors
• CYP1A2 inducers
• Medicines that decrease caffeine elimination e.g. cimetidine and ketoconazole
• Medicines that increase caffeine elimination e.g. phenobarbital and phenytoin
• Antihistamine H2 receptor blockers
• Proton pump inhibitors
• Doxapram

• Blood caffeine measurements

Blood caffeine measurements in risk situations:

• If no clinical response after second loading dose
• 2-4 hours after the previous dose when suspecting toxicity
• Very premature infants (<28 weeks gestational age and/or body weight <1000g) particularly with parenteral nutrition
• Infants with renal and hepatic impairment
• Infants with seizure disorders
• Infants with known and clinically significant cardiac disease
• Infants receiving co-administration of medicinal products known to interfere with caffeine metabolism
• Infants whose mothers consume caffeine while providing breast milk for feeding
• Infants treated with caffeine for an extended period

Baseline blood caffeine measurements:

• Infants whose mothers may have ingested large quantities of caffeine prior to delivery
• Infants who have previously been treated with theophylline

Duration of treatment

• The optimal duration of treatment has not been established
• In a study on premature newborn infants a median treatment period of 37 days was reported
• In clinical practice, treatment is usually continued until the infant has reached a post-menstrual age of 37 weeks, by which time apnoea of prematurity usually resolves spontaneously
• This limit may however be revised according to the response to treatment, the continuing presence of apnoeic episodes despite treatment, or other clinical considerations
• It is recommended that caffeine citrate administration be stopped when the patient has 5-7 days without a significant apnoeic attack
• If the patient has recurrent apnoea, caffeine citrate administration can be restarted with either a maintenance dose or half a loading dose, depending on the time interval from stopping treatment to recurrence of apnoea
• Because of the slow elimination of caffeine in this patient population, there is no requirement for dose tapering on cessation of treatment
• As there is a risk for recurrence of apnoea after cessation of caffeine treatment, monitoring of the patient should be continued for approximately 1 week

Risk situations that may require dose adjustments

• Very premature infants (<28 weeks gestational age and/or body weight <1000g) particularly with parenteral nutrition
• Infants with renal and hepatic impairment
• Infants with seizure disorders
• Infants with known and clinically significant cardiac disease
• Infants receiving co-administration of medicinal products known to interfere with caffeine metabolism
• Infants whose mothers consume caffeine while providing breast milk for feeding

Caffeine is structurally related to the methylxanthines theophylline and theobromine. Caffeine increases levels of 3'5' cyclic AMP by inhibiting phosphodiesterase. Most of its effects have been attributed to antagonism of adenosine receptors, both A and A subtypes. Caffeine's main action is as a CNS stimulant. This is the basis of caffeine's effect in apnoea of prematurity, for which several mechanisms have been proposed for its actions including: (1) respiratory centre stimulation, (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.

Injection 20mg (per 1ml)

• Cayona (Safeline)