GENCEBOK Solution for infusion Ref.[49869] Active ingredients: Caffeine

Apnoea

Apnoea of prematurity is a diagnosis of exclusion. Other causes of apnoea (e.g., central nervous system disorders, primary lung disease, anaemia, sepsis, metabolic disturbances, cardiovascular abnormalities, or obstructive apnoea) should be ruled out or properly treated prior to initiation of treatment with caffeine citrate. Failure to respond to caffeine treatment (confirmed if necessary by measurement of plasma levels) could be an indication of another cause of apnoea.

Caffeine consumption

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, since caffeine readily crosses the placenta into the foetal circulation (see sections 4.2 and 5.2).

Breast-feeding mothers of newborn infants treated with caffeine citrate should not ingest caffeinecontaining foods and beverages or medicinal products containing caffeine (see section 4.6), since caffeine is excreted into breast milk (see section 5.2).

Theophylline

In newborns previously treated with theophylline, baseline plasma caffeine concentrations should be measured prior to initiation of treatment with caffeine citrate because preterm infants metabolise theophylline to caffeine.

Seizures

Caffeine is a central nervous system stimulant and seizures have been reported in cases of caffeine overdose. Extreme caution must be exercised if caffeine citrate is used in newborns with seizure disorders.

Cardiovascular reactions

Caffeine has been shown to increase heart rate, left ventricular output, and stroke volume in published studies. Therefore, caffeine citrate should be used with caution in newborns with known cardiovascular disease. There is evidence that caffeine causes tachyarrhythmias in susceptible individuals. In newborns this is usually a simple sinus tachycardia. If there have been any unusual rhythm disturbances on a cardiotocograph (CTG) trace before the baby is born, caffeine citrate should be administered with caution.

Renal and hepatic impairment

Caffeine citrate should be administered with caution in preterm newborn infants with impaired renal or hepatic function. In a post-authorisation safety study, the frequency of adverse reactions in a small number of very premature infants with renal/hepatic impairment appeared to be higher as compared to premature infants without organ impairment (see sections 4.2, 4.8 and 5.2). Doses should be adjusted by monitoring of caffeine plasma concentrations to avoid toxicity in this population.

Necrotising enterocolitis

Necrotising enterocolitis is a common cause of morbidity and mortality in premature newborn infants. There are reports of a possible association between the use of methylxanthines and development of necrotising enterocolitis. However, a causal relationship between caffeine or other methylxanthine use and necrotising enterocolitis has not been established. As for all preterm infants, those treated with caffeine citrate should be carefully monitored for the development of necrotising enterocolitis (see section 4.8).

Caffeine citrate should be used with caution in infants suffering gastro-oesophageal reflux, as the treatment may exacerbate this condition.

Caffeine citrate causes a generalised increase in metabolism, which may result in higher energy and nutrition requirements during therapy.

The diuresis and electrolyte loss induced by caffeine citrate may necessitate correction of fluid and electrolyte disturbances.

Inter-conversion between caffeine and theophylline occurs in preterm newborn infants. These active substances should not be used concurrently.

Cytochrome P450 1A2 (CYP1A2) is the major enzyme involved in the metabolism of caffeine in humans. Therefore, caffeine has the potential to interact with active substances that are substrates for CYP1A2, inhibit CYP1A2, or induce CYP1A2. However, caffeine metabolism in preterm newborn infants is limited due to their immature hepatic enzyme systems.

Although few data exist on interactions of caffeine with other active substances in preterm newborn infants, lower doses of caffeine citrate may be needed following co-administration of active substances which are reported to decrease caffeine elimination in adults (e.g., cimetidine and ketoconazole) and higher caffeine citrate doses may be needed following co-administration of active substances that increase caffeine elimination (e.g., phenobarbital and phenytoin). Where doubt exists about possible interactions, plasma caffeine concentrations should be measured. As bacterial overgrowth in the gut is associated with the development of necrotising enterocolitis, coadministration of caffeine citrate with medicinal products that suppress gastric acid secretion (antihistamine H₂ receptor blockers or proton-pump inhibitors) may in theory increase the risk of necrotising enterocolitis (see section 4.4 and 4.8).

Concurrent use of caffeine and doxapram might potentiate their stimulatory effects on the cardiorespiratory and central nervous system. If concurrent use is indicated, cardiac rhythm and blood pressure must be carefully monitored.

Pregnancy

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 (see section 5.3).

Breast-feeding

Caffeine is excreted into breast milk and readily crosses the placenta into the foetal circulation (see section 5.2).

Breast-feeding mothers of newborn infants treated with caffeine citrate should not ingest caffeinecontaining 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 (see section 4.4).

Fertility

Effects on reproductive performance observed in animals are not relevant to its indication in the preterm newborn infants (see section 5.3).

Not relevant.

Summary of the safety profile

The known pharmacology and toxicology of caffeine and other methylxanthines predict the likely adverse reactions to caffeine citrate. Effects described include central nervous system (CNS) stimulation such as convulsion, irritability, restlessness and jitteriness, cardiac effects such as tachycardia, arrhythmia, hypertension and increased stroke volume, metabolism and nutrition disorders such as hyperglycaemia. These effects are dose related and may necessitate measurement of plasma levels and dose reduction.

Tabulated list of adverse reactions

The adverse reactions described in the short- and long-term published literature and obtained from a post-authorisation safety study that can be associated with caffeine citrate are listed below by System Organ Class and Preferred Term (MedDRA). Frequency is defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

Description of selected adverse reactions

Necrotising enterocolitis is a common cause of morbidity and mortality in premature newborn infants. There are reports of a possible association between the use of methylxanthines and development of necrotising enterocolitis. However, a causal relationship between caffeine or other methylxanthine use and necrotising enterocolitis has not been established.

In a double-blind placebo-controlled study of caffeine citrate in 85 preterm infants (see section 5.1), necrotising enterocolitis was diagnosed in the blinded phase of the study in two infants on active treatment and one on placebo, and in three infants on caffeine during the open-label phase of the study. Three of the infants who developed necrotising enterocolitis during the study died. A large multicentre study (n=2006) investigating long-term outcome of premature infants treated with caffeine citrate (see section 5.1) did not show an increased frequency of necrotising enterocolitis in the caffeine group when compared to placebo. As for all preterm infants, those treated with caffeine citrate should be carefully monitored for the development of necrotising enterocolitis (see section 4.4).

Brain injury, convulsion and deafness were observed but they were more frequent in the placebo group.

Caffeine may suppress erythropoietin synthesis and hence reduce haemoglobin concentration with prolonged treatment.

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

Available evidence does not indicate any adverse long-term reactions of neonatal caffeine therapy as regards neurodevelopmental outcome, failure to thrive or on the cardiovascular, gastrointestinal or endocrine systems. Caffeine does not appear to aggravate cerebral hypoxia or to exacerbate any resulting damage, although the possibility cannot be ruled out.

Other special populations

In a post-authorisation safety study on 506 preterm infants treated with caffeine citrate, safety data have been collected in 31 very premature infants with renal/hepatic impairment. Adverse reactions appeared to be more frequent in this subgroup with organ impairment than in other observed infants without organ impairment. Cardiac disorders (tachycardia, including one single case of arrhythmia) were mostly reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This medicinal product must not be mixed or concomitantly administered in the same intravenous line with other medicinal products except those mentioned in section 6.6.