Leitlinien & Arzneimittelsicherheit

HOS-095326 · has-adverse-reaction-information · PDF-Seite 6

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). 6 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). System Organ Class Adverse Reaction Frequency Infections and infestations Sepsis Not known Immune system disorders Hypersensitivity reaction Rare Metabolism and nutrition Hyperglycaemia Common disorders Hypoglycaemia, failure to thrive, Not known feeding intolerance Nervous system disorders Convulsion Uncommon Irritability, jitteriness, restlessness, Not known brain injury Ear and labyrinth disorders Deafness Not known Cardiac disorders Tachycardia Common Arrhythmia Uncommon Increased left ventricular output and Not known increased stroke volume Gastrointestinal disorders Regurgitation, increased gastric Not known aspirate, necrotising enterocolitis General disorders and Infusion site phlebitis, infusion s

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HOS-095322 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-095321 · has-indication-information · PDF-Seite 2

Treatment of primary apnoea of premature newborns.

HOS-095324 · has-interaction-information · PDF-Seite 5

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. 5 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, co- administration 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 cardio- respiratory and central nervous system. If concurrent use is indicated, cardiac rhythm and blood pressure must be carefully monitored.

HOS-095325 · has-pregnancy-information · PDF-Seite 6

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 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 (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).

HOS-095323 · has-warning-information · PDF-Seite 4

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 caffeine- containing 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. 4 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 o

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