Pharmacokinetics in children

In neonates of up to 3 months it is barely metabolized but primarily excreted in unchanged form in the urine (approx. 85%). The elimination half-life in neonates is 3–4 days. The clearance in neonates (8.9 ml/kg/hour, range 2.5-17) is directly correlated to the bodyweight and the postnatal age. The volume of distribution in neonates is 0.8–0.9 l/kg.

After oral administration of 10 mg caffeine base/kg body weight to preterm newborn infants, the peak plasma caffeine concentration (Cmax) ranged from 6 to 10 mg/L and the mean time to reach peak concentration (tmax) ranged from 30 min to 2 h [SmPC Peyona].

dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

Renal impaiment in children > 3 months

GFR ≥10 ml/min/1.73m2: Dose adjustment not required.

GFR <10 ml/min/1.73m2: A general recommendation on dose adjustment cannot be provided.

The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

The side effects on the central nervous system are usually more severe in children than in adults.

When used in premature infants, sepsis, hypoglycaemia or hyperglycaemia, retarded growth, food intolerance, irritability, nervousness, restlessness, tachycardia, increased output of the left ventricle, increased stroke volume, regurgitation, increased diuresis, increased sodium and calcium concentration in the urine, lowered Hb level, lowered thyroxine concentration, phlebitis or inflammation on the infusion site and hypersensitivity reactions have been reported. In overdoses in premature infants, convulsions can occur.

During the first three weeks, reduced weight gain was observed.

Transient falls in thyroxine (T4) have been recorded in infants at the start of therapy but these are not sustained with maintained therapy. [SmPC Peyona]

The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications

No information available on specific contra indications in children.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Symptoms of intoxication in preterm infants: hyperglycaemia, hypokalaemia, fine tremor of the extremities, restlessness, hypertonia, opisthotonus, tonic clonic movements, seizures, tachypnoea, tachycardia, vomiting, gastric irritation, gastrointestinal haemorrhage, pyrexia, jitteriness, increased blood urea and increased white blood cell count, non-purposeful jaw and lip movements. No deaths associated with caffeine overdose have been reported in preterm infants.

If large amounts of caffeine have been consumed by the mother just before delivery or if the neonate has been previously treated with theophylline, plasma caffeine levels should be determined prior to treatment.

Caution is needed in very premature neonates (<28 weeks) and neonates with impaired renal function, impaired liver function, gastroesophageal reflux, epileptic disorders and cardiovascular disorders. Be careful if unusual cardiac arrhythmias have previously been detected on a cardiotocogram (CTG). Caffeine can accumulate in premature neonates, which may require long-term monitoring. The lack of response to treatment may indicate another cause of apnea.

There are reports of a possible association between the use of methylxanthines and development of necrotising enterocolitis. However, a large multicentre study (n=2006) investigating long-term outcome of premature infants treated with caffeine citrate did not show an increased frequency of necrotising enterocolitis in the caffeine group when compared to placebo. [SmPC Peyona]

Treatment with caffeine can lead to an increased need for energy and nutrients and a disruption of the fluid and electrolyte balance.

[SmPC Peyona]

Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

• NERVOUS SYSTEM
• PSYCHOANALEPTICS

PSYCHOSTIMULANTS, AGENTS USED FOR ADHD AND NOOTROPICS

This pages provides a list of drugs from the same ATC class for comparison. This does not necessarily mean that these drugs are interchangeable.

References

1. Erenberg A, et al, Caffeine citrate for the treatment of apnea of prematurity: a double-blind, placebo-controlled study., Pharmacotherapy, 2000, 20, 644-52
2. ArandaJV, et al, Pharmacokinetic profile of caffeine in the premature newborn infant with apnea, J Pediatr, 1979, 94, 663– 668
3. FalcaoAC, et al, Population pharmacokinetics of caffeine in premature neonates, Eu J Clin Pharmacol, 1997, 52, 211– 217
4. LeeTC, et al, Population pharmacokinetics of intravenous caffeine in neonates with apnea of prematurity, Clin Pharmacol Ther, 1997, 61, 628– 640
5. Schmidt B, et al, Caffeine for Apnea of Prematurity Trial Group Long-term effects of caffeine therapy for apnea of prematurity, N Engl J Med, 2007, 357(19), 1893-902
6. Schmidt B, et al, Caffeine for Apnea of Prematurity Trial Group. Caffeine therapy for apnea of prematurity, N Engl J Med, 2006, 354(20), 2112-21
7. Chiesi Farmaceutici SpA, SmPC Peyona (EU/1/09/528/002) Rev 13, 22-12-2021, www.ema.europa.eu
8. Informatorium Medicamentorum, (Interacties, Contra-Indicaties, Bijwerkingen), Geraadpleegd 10 nov 2014
9. Informatorium Medicamentorum, (Interacties, Contra-Indicaties, Bijwerkingen), Geraadpleegd 10 nov 2014

Changes

Therapeutic Drug Monitoring

Overdose