Peyona

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Peyona 20 mg/ml solution for infusion and oral solution 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each ml contains 20 mg caffeine citrate (equivalent to 10 mg caffeine). 
Each 1 ml ampoule contains 20 mg caffeine citrate (equivalent to 10 mg caffeine) 
Each 3 ml ampoule contains 60 mg caffeine citrate (equivalent to 30 mg caffeine). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for infusion. 
Oral solution. 
Clear, colourless, aqueous solution at pH=4.7. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of primary apnoea of premature newborns. 
 
4.2 Posology and method of administration 
 
Treatment with caffeine citrate should be initiated under the supervision of a physician 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.  
 
Posology 
 
The recommended dose regimen in previously untreated infants is a loading dose of 20 mg caffeine 
citrate per kg body weight administered by slow intravenous infusion over 30 minutes, using a syringe 
infusion pump or other metered infusion device. After an interval of 24 hours, maintenance doses of 
5 mg per kg body weight may be administered by slow intravenous infusion over 10 minutes every 24 
hours. Alternatively, maintenance doses of 5 mg per kg body weight may be administered by oral 
administration, such as through a nasogastric tube every 24 hours.  
The recommended loading dose and maintenance doses of caffeine citrate are provided in the 
following table which clarifies the relationship between injection volumes and administered doses 
expressed as caffeine citrate.  
The dose expressed as caffeine base is one-half the dose when expressed as caffeine citrate (20 mg 
caffeine citrate are equivalent to 10 mg caffeine base).  
 

 Dose of caffeine 
citrate (Volume) 

Dose of caffeine 
citrate (mg/kg body 
weight) 

Route Frequency 

Loading dose 1.0 ml/kg body 
weight 

20 mg/kg body weight Intravenous infusion 
(over 30 minutes) 

Once 

Maintenance 
dose*  

0.25 ml/kg body 
weight 

5 mg/kg body weight Intravenous infusion 
(over 10 minutes) or by 
oral administration 

Every 24 
hours* 



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* Beginning 24 hours after the loading dose 
 
In preterm newborn infants with insufficient clinical response to the recommended loading dose, a 
second loading dose of 10 -20 mg/kg maximum may be given after 24 hours.  
Higher maintenance doses of 10 mg/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 
preterm newborn infants and the progressively increasing capacity to metabolise caffeine in relation 
to post-menstrual age (see section 5.2). Where clinically indicated, caffeine plasma levels should be 
monitored. 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 of 10 mg/kg/day (see section 4.4). 
 
Dosage adjustments and monitoring 
 
Plasma concentrations of caffeine may need to be monitored periodically throughout treatment in 
cases of incomplete clinical response or signs of toxicity.  
Additionally, doses may need to be adjusted according to medical judgment following routine 
monitoring of caffeine plasma concentrations in at risk situations such as: 
− very premature infants (< 28 weeks gestational age and/or body weight <1000 g) particularly 

when receiving parenteral nutrition  
− infants with hepatic and renal impairment (see sections 4.4 and 5.2)  
− 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 (see section 4.5) 
− infants whose mothers consume caffeine while providing breast milk for feeding. 
It is advisable to measure baseline caffeine levels in: 
− infants whose mothers may have ingested large quantities of caffeine prior to delivery (see section 

4.4) 
− infants who have previously been treated with theophylline, which is metabolized to caffeine. 
 
Caffeine has a prolonged half-life in premature newborn infants and there is potential for 
accumulation which may necessitate monitoring infants treated for an extended period (see section 
5.2). 
Blood samples for monitoring should be taken just before the next dose in the case of therapeutic 
failure and 2 to 4 hours after the previous dose when suspecting toxicity. 
 
Although a therapeutic plasma concentration range of caffeine has not been determined in the 
literature, caffeine levels in studies associated with clinical benefit ranged from 8 to 30 mg/l and no 
safety concerns have normally been raised with plasma levels below 50 mg/l.  
 
Duration of treatment  
 
The optimal duration of treatment has not been established. In a recent large multicentre study on 
preterm 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 clinical judgment in individual cases depending on the response to 
treatment, the continuing presence of apnoeic episodes despite treatment, or other clinical 
considerations. It is recommended that caffeine citrate administration should 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 a half loading dose, depending upon the time interval from stopping caffeine 
citrate 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.  



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As there is a risk for recurrence of apnoeas after cessation of caffeine citrate treatment monitoring of 
the patient should be continued for approximately one week. 
 
Hepatic and renal impairment  
 
There is limited experience in patients with renal and hepatic impairment. In a post authorisation 
safety study, the frequency of adverse reactions in a small number of very premature infants with 
renal/hepatic imparment appeared to be higher as compared to premature infants without organ 
impairment (see sections 4.4 and 4.8). 
In the presence of renal impairment, there is increased potential for accumulation. A reduced daily 
maintenance dose of caffeine citrate is required and the dose should be guided by plasma caffeine 
measurements.  
In very premature infants, clearance of caffeine does not depend on hepatic function. Hepatic caffeine 
metabolism develops progressively in the weeks following birth and for the older infants, hepatic 
disease may indicate a need for monitoring caffeine plasma levels and may require dose adjustments 
(see sections 4.4 and 5.2). 
 
Method of administration 
 
Caffeine citrate can be administered by intravenous infusion and by the oral route. The medicinal 
product must not be administered by intramuscular, subcutaneous, intrathecal or intraperitoneal 
injection. 
 
When given intravenously, caffeine citrate should be administered by controlled intravenous infusion, 
using a syringe infusion pump or other metered infusion device only. Caffeine citrate can be either 
used without dilution or diluted in sterile solutions for infusion such as glucose 50 mg/ml (5%), or 
sodium chloride 9 mg/ml (0.9%) or calcium gluconate 100 mg/ml (10%) immediately after 
withdrawal from the ampoule (see section 6.6). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  
 
4.4 Special warnings and precautions for use 
 
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 
 



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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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. 
 



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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. 
 
4.6 Fertility, pregnancy and lactation 
 
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). 
 
4.7 Effects on ability to drive and use machines 
 
Not relevant.  
 
4.8 Undesirable effects  
 
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 
 



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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). 
 

System Organ Class Adverse Reaction Frequency 

Infections and infestations Sepsis Not known 

Immune system disorders Hypersensitivity reaction Rare 

Metabolism and nutrition 
disorders 

Hyperglycaemia Common 

Hypoglycaemia, failure to thrive, 
feeding intolerance 

Not known 

Nervous system disorders Convulsion Uncommon 

Irritability, jitteriness, restlessness, 
brain injury 

Not known 

Ear and labyrinth disorders Deafness Not known 

Cardiac disorders Tachycardia Common 

Arrhythmia Uncommon 

Increased left ventricular output and 
increased stroke volume 

Not known 

Gastrointestinal disorders Regurgitation, increased gastric 
aspirate, necrotising enterocolitis 

Not known 

General disorders and 
administration site 
conditions 

Infusion site phlebitis, infusion site 
inflammation 

Common 

Investigations Urine output increased, urine sodium 
and calcium increased, haemoglobin 
decreased, thyroxine decreased 

Not known 

 
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. 



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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 Peyona, 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. 
 
4.9 Overdose 
 
Following overdose, published plasma caffeine levels have ranged from approximately 50 mg/l to 
350 mg/l.  
 
Symptoms 
 
Signs and symptoms reported in the literature after caffeine overdose in preterm infants include 
hyperglycaemia, hypokalaemia, fine tremor of the extremities, restlessness, hypertonia, opisthotonus, 
tonic clonic movements, seizures, tachypnoea, tachycardia, vomiting, gastric irritation, gastro-
intestinal haemorrhage, pyrexia, jitteriness, increased blood urea and increased white blood cell count, 
non-purposeful jaw and lip movements. One case of caffeine overdose complicated by development 
of intraventricular haemorrhage and long-term neurological sequelae has been reported. No deaths 
associated with caffeine overdose have been reported in preterm infants. 
 
Management 
 
Treatment of caffeine overdose is primarily symptomatic and supportive. Plasma potassium and 
glucose concentrations should be monitored and hypokalaemia and hyperglycaemia corrected. Plasma 
caffeine concentrations have been shown to decrease after exchange transfusion. Convulsions may be 
treated with intravenous administration of anticonvulsants (diazepam or a barbiturate such as 
pentobarbital sodium or phenobarbital). 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Psychoanaleptics, xanthine derivatives ATC code: N06BC01  
 
Mechanism of action 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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Caffeine is structurally related to the methylxanthines theophylline and theobromine.  
Most of its effects have been attributed to antagonism of adenosine receptors, both A1 and A2A 
subtypes, demonstrated in receptor binding assays and observed at concentrations approximating 
those achieved therapeutically in this indication. 
 
Pharmacodynamic effects 
 
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.  
 
Clinical efficacy and safety 
 
The clinical efficacy of caffeine citrate was assessed in a multicentre, randomised, double-blind study 
that compared caffeine citrate to placebo in 85 preterm infants (gestational age 28 to <33 weeks) with 
apnoea of prematurity. Infants received 20 mg/kg caffeine citrate loading dose intravenously. A 
maintenance daily dose of 5 mg/kg caffeine citrate was then administered either intravenously or 
orally (through a feeding tube) for up to 10-12 days. The protocol allowed infants to be “rescued” 
with open-label caffeine citrate treatment if their apnoea remained uncontrolled. In that case, infants 
received a second loading dose of 20 mg/kg caffeine citrate after treatment day 1 and before treatment 
day 8.  
There were more days without any apnoea under caffeine citrate treatment (3.0 days, versus 1.2 days 
for placebo; p=0.005); also, there was a higher percentage of patients with no apnoeas for > 8 days 
(caffeine 22% versus placebo 0%).  
A recent large placebo-controlled multicentre study (n=2006) investigated short-term and long-term 
(18-21 months) outcomes of premature infants treated with caffeine citrate. Infants randomised to 
caffeine citrate received an intravenous loading dose of 20 mg/kg, followed by a daily maintenance 
dose of 5 mg/kg. If apnoeas persisted, the daily maintenance dose could be increased to a maximum of 
10 mg/kg of caffeine citrate. The maintenance doses were adjusted weekly for changes in body weight 
and could be given orally once an infant tolerated full enteral feedings. Caffeine therapy reduced the 
rate of bronchopulmonary dysplasia [odds ratio (95% CI) 0.63 (0.52 to 0.76)] and improved the rate 
of survival without neurodevelopmental disability [odds ratio (95 %CI) 0.77 (0.64 to 0.93)].  
The size and direction of caffeine effect on death and disability differed depending on the degree of 
respiratory support infants needed at randomisation, indicating more benefit for the supported infants 
[odds ratio (95%CI) for death and disability, see table below]. 
 

Death or disability according to subgroup of respiratory support at entry to study 
Subgroups Odds ratio (95% CI) 
No support  1.32 (0.81 to 2.14) 
Non invasive support 0.73 (0.52 to 1.03) 
Endotracheal tube 0.73 (0.57 to 0.94) 

 
5.2 Pharmacokinetic properties 
 
Caffeine citrate readily dissociates in aqueous solution. The citrate moiety is rapidly metabolized on 
infusion or ingestion.  
 
Absorption  
 
The onset of action of caffeine from caffeine citrate is within minutes of commencement of infusion. 
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. The extent of absorption is not affected by formula 
feeding but tmax may be prolonged. 



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Distribution 
 
Caffeine is rapidly distributed into the brain following caffeine citrate administration. Caffeine 
concentrations in the cerebrospinal fluid of preterm newborn infants approximate to their plasma 
levels. The mean volume of distribution (Vd) of caffeine in infants (0.8-0.9 l/kg) is slightly higher than 
that in adults (0.6 L/kg). Plasma protein binding data are not available for newborn infants or infants. 
In adults, the mean plasma protein binding in vitro is reported to be approximately 36%.  
 
Caffeine readily crosses the placenta into the fetal circulation and is excreted into breast milk. 
 
Biotransformation  
 
Caffeine metabolism in preterm newborn infants is very limited due to their immature hepatic enzyme 
systems and most of the active substance is eliminated in urine. Hepatic cytochrome P450 1A2 
(CYP1A2) is involved in caffeine biotransformation in older individuals. 
Inter-conversion between caffeine and theophylline has been reported in preterm newborn infants; 
caffeine levels are approximately 25% of theophylline levels after theophylline administration and 
approximately 3-8% of caffeine administered would be expected to convert to theophylline.  
 
Elimination  
 
In young infants, the elimination of caffeine is much slower than that in adults due to immature 
hepatic and/or renal function. In newborn infants, caffeine clearance is almost entirely by renal 
excretion. Mean half-life (t1/2) and fraction excreted unchanged in urine (Ae) of caffeine in infants are 
inversely related to gestational / postmenstrual age. In newborn infants, the t1/2 is approximately 3-4 
days and the Ae is approximately 86% (within 6 days). By 9 months of age, the metabolism of 
caffeine approximates to that seen in adults (t1/2 = 5 hours and Ae = 1%).  
Studies examining the pharmacokinetics of caffeine in newborn infants with hepatic or renal 
insufficiency have not been conducted.  
In the presence of significant renal impairment, considering the increased potential for accumulation, 
a reduced daily maintenance dose of caffeine is required and the doses should be guided by blood 
caffeine measurements. In premature infants with cholestatic hepatitis a prolonged caffeine 
elimination half-life with an increase of plasma levels above the normal limit of variation has been 
found suggesting a particular caution in the dosage of these patients (see sections 4.2 and 4.4). 
 
5.3 Preclinical safety data  
 
Non-clinical data revealed no major hazard for humans based on studies of repeated dose toxicity of 
caffeine. However, at high doses convulsions in rodents were induced. At therapeutic doses some 
behavioural changes in newborn rats were induced, most likely as a consequence of increased 
adenosine receptor expression that persisted into adulthood. Caffeine was shown to be devoid of 
mutagenic and oncogenic risk. Teratogenic potential and effects on reproductive performance 
observed in animals are not relevant to its indication in the preterm infant population.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Citric acid monohydrate 
Sodium citrate  
Water for injections. 
 
6.2 Incompatibilities 
 



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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. 
 
6.3 Shelf life 
 
3 years. 
 
After opening the ampoule, the medicinal product should be used immediately. 
 
Chemical and physical compatibility of the diluted solution has been demonstrated for 24 hours at 
25ºC and at 2-8ºC. 
From a microbiological point of view, when administered with solutions for infusion the medicinal 
product should be used immediately after dilution by aseptic technique. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage condition. 
 
For storage conditions of the diluted medicinal product see section 6.3. 
 
6.5 Nature and contents of container 
 
Type I clear glass 1 ml ampoule 
Type I clear glass 3 ml ampoule 
Pack size of 10 ampoules. 
 
6.6 Special precautions for disposal and other handling 
 
Aseptic technique must be strictly observed throughout handling of the medicinal product since no 
preservative is present. 
 
Peyona should be inspected visually for particulate matter and discoloration prior to administration. 
Ampoules containing discoloured solution or visible particulate matter should be discarded. 
 
Peyona can be either used without dilution or diluted in sterile solutions for infusion such as glucose 
50 mg/ml (5%) or sodium chloride 9 mg/ml (0.9%) or calcium gluconate 100 mg/ml (10%) 
immediately after withdrawal from the ampoule.  
The diluted solution must be clear and colourless. Undiluted and diluted parenteral solutions must be 
inspected visually for particulate matter and discoloration prior to administration. The solution must 
not be used if it is discoloured or foreign particulate matter is present. 
 
For single use only. Any unused portion left in the ampoule should be discarded. Unused portions 
should not be saved for later administration. 
 
No special requirements for disposal. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
CHIESI FARMACEUTICI SpA 
Via Palermo 26/A 
43122 Parma 
ITALY 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 



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EU/1/09/528/002 1 ml ampoules 
EU/1/09/528/001 3 ml ampoules 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 02/07/2009  
Date of latest renewal: 03/03/2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
MM/YYYY 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


13 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



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A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
Alfasigma S.p.A. 
Via Enrico Fermi 
IT-65020 Alanno (PE) 
Italy 
 
Chiesi Pharmaceuticals GmbH 
Gonzagagasse 16/16 
1010 Wien 
Austria 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characterisitcs, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal products are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 

 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
• Additional risk minimisation measures 
 
The MAH shall agree with the National Competent Authorities the final text of a card suitable for 
display in neonatal intensive care units. The card shall contain the following key elements and be 
provided to all neonatal intensive care units where the medicinal product is likely to be used at launch 
of the medicinal product: 
 



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- That Peyona is for the treatment of primary apnoea 

- That treatment with Peyona must be provided in a neonatal intensive care unit and initiated 
and supervised by a physician experienced in neonatal intensive care 

- Details of the loading and maintenance dosages and that caffeine may accumulate in 
premature newborn infants because of its long half-life. 

- That the dose of caffeine expressed as caffeine base is one half the dose of caffeine expressed 
as caffeine citrate (20mg caffeine citrate is equivalent to 10mg caffeine base) and that 
prescriptions should clearly indicate that caffeine citrate is to be administered. 

- That the medicinal product should be used immediately after opening the ampoule and 
unused portions left in the ampoule should be discarded 

- That baseline plasma levels may need measuring because of an increased risk of toxicity if 

o The neonate has been previously treated with theophylline 

o The mother has been consuming large amounts of caffeine prior to delivery or breast 
feeding 

- That caffeine and theophylline should not be used concurrently 

- That if caffeine and doxapram are used concurrently, the patient should be closely monitored 

- That additional plasma caffeine monitoring and dosage adjustment may be necessary in at 
risk situations such as preterm infants: 

o With cholestatic hepatitis 

o With significant renal impairment 

o With seizure disorders 

o With cardiac disease 

o less than 28 weeks gestational age and/or body weight <1000g particularly when 
receiving parenteral nutrition 

o with co-administration of medicinal products known to interfere with caffeine 
metabolism 

- That cardiac disorders (including arrhythmias) may arise in newborn infants with pre-existing 
cardiac disease 

- That all suspected adverse reactions should be reported in accordance with national reporting 
requirements 

- In particular, if convulsions, seizures, necrotising enterocolitis, symptoms and signs of 
caffeine withdrawal, medically abnormal decrease in infant weight gain or interactions with 
other medicines are suspected as being associated with the use of caffeine citrate, these 
should be reported to <insert local name and address of Chiesi Farmaceutici S.p.A.> 

 
The MAH shall agree the text of a Dear Healthcare Professional letter with the CHMP (and if 
necessary with the National Competent Authorities) prior to launch of the medicinal product and shall 
ensure that it is provided to all physicians experienced in neonatal intensive care prior to or at the 
launch of the medicinal product in each Member State. 



16 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



17 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



18 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Peyona 20 mg/ml solution for infusion and oral solution  
Caffeine citrate 
(equivalent to 10 mg/ml of caffeine base) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 1 ml ampoule contains 20 mg of caffeine citrate (equivalent to 10 mg of caffeine base). 
Each 3 ml ampoule contains 60 mg of caffeine citrate (equivalent to 30 mg of caffeine base). 
Each ml of solution contains 20 mg of caffeine citrate (equivalent to 10 mg of caffeine base). 
 
 
3. LIST OF EXCIPIENTS 
 
Citric acid monohydrate, sodium citrate, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for infusion  
Oral solution 
10 ampoules  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
Intravenous use  
Oral use  
For single use only. 
 
 
6 SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sightand reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 



19 

 
After opening the ampoule, the medicinal product should be used immediately. 
The medicinal product must be used immediately after diluting by aseptic technique 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused portions must be discarded. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
CHIESI Farmaceutici SpA 
Via Palermo 26/A 
43122 PARMA-ITALY 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/09/528/002 1 ml ampoules 
EU/1/09/528/001 3 ml ampoules 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Peyona 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 



20 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  
 
AMPOULE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Peyona 20 mg/ml solution for infusion and oral solution  
Caffeine citrate 
(equivalent to 10 mg/ml of caffeine base) 
IV/oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
20 mg/1 ml 
60 mg/3 ml 
 
 
6. OTHER 
 
 



21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



22 

Package leaflet: Information for the user 
 

Peyona 20 mg/ml solution for infusion and oral solution 
caffeine citrate 

 
Read all of this leaflet carefully before treatment with this medicine because it contains 
important information for your newborn  
- Keep this leaflet. You may need to read it again. 
- If you have further questions, please ask your baby’s doctor. 
- If your newborn gets any side effects, talk to your baby’s doctor. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Peyona is and what it is used for 
2. What you need to know before your baby is given Peyona  
3. How to use Peyona  
4. Possible side effects 
5. How to store Peyona  
6. Contents of the pack and other information 
 
 
1. What Peyona is and what it is used for 
 
Peyona contains the active substance caffeine citrate, which is a stimulant of the central nervous 
system, belonging to a group of medicines called methylxanthines.  
 
Peyona is used in the treatment of interrupted breathing in premature babies (primary apnoea of 
premature newborns).  
These short periods when premature babies stop breathing are due to the baby’s breathing centres not 
being fully developed.  
This medicine has been shown to reduce the number of episodes of interrupted breathing in premature 
newborns. 
 
 
2. What you need to know before your baby is given Peyona  
 
Do not use Peyona: 
 
• If your newborn is allergic to caffeine citrate or any of the other ingredients of this medicine 

(listed in section 6).  
 
Warnings and precautions 
 
Talk to your baby’s doctor before your newborn is given Peyona. 
Prior to starting treatment for apnoea of prematurity with Peyona other causes of apnoea should have 
been excluded or properly treated by your baby’s doctor. 
 
Peyona should be used with caution. Please inform your baby’s doctor: 
 
• If your newborn suffers from seizures 
• If your newborn suffers from any heart disease 
• If your newborn has kidney or liver problems 
• If your newborn has frequent regurgitation 
• If your newborn produces more urine than usual 



23 

• If your newborn has a reduced weight gain or food intake 
• If you (the mother) consumed caffeine prior to delivery 
 
Other medicines and Peyona 
 
Tell your baby’s doctor if your newborn is taking, have recently taken or might take any other 
medicines. 
Please inform your baby’s doctor if your newborn has been previously treated with theophylline.  
Do not use the following medicines during the treatment with Peyona without talking to your baby’s 
doctor. The doctor may need to adjust the dose or change one of the medicines to something else:  

- theophylline (used to treat breathing difficulties) 
- doxapram (used to treat breathing difficulties) 
- cimetidine (used to treat gastric disease) 
- ketoconazole (used to treat fungine infections) 
- phenobarbital (used to treat epilepsy) 
- phenytoin (used to treat epilepsy) 

 
This medicine may increase the risk for serious intestinal disease with bloody stools (necrotising 
enterocolitis) when administered with medicines used to treat gastric disease (such as antihistamine 
H2 receptor blockers or proton-pump inhibitors that reduces gastric acid secretion). 
 
Pregnancy and breast-feeding 
 
If you (the mother) are breast-feeding while your infant is treated with Peyona, you should not drink 
coffee or take any other high caffeine product as caffeine passes into breast milk. 
 
Peyona contains sodium 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. is essentially 
‘sodium-free’. 
 
 
3. How to use Peyona  
 
Peyona should only be used in a neonatal intensive care unit in which adequate facilities are 
available for patient surveillance and monitoring. Treatment should be initiated under 
supervision of a physician experienced in neonatal intensive care. 
 
Dose 
 
Your baby’s doctor will prescribe the right amount of Peyona based on your baby’s weight.  
The starting dose is 20 mg per kg body weight (equivalent to 1 ml per kg body weight).  
The maintenance dose is 5 mg per kg body weight (equivalent to 0.25 ml per kg body weight) every 
24 hours.  
 
Route and method of administration 
 
Peyona will be infused by controlled intravenous infusion, using a syringe infusion pump or other 
metered infusion device. This method is also known as “a drip”. 
Some of the doses (maintenance doses) may be given by mouth. 
It may be needed that your baby’s doctor decides to check the levels of caffeine in a blood test 
periodically throughout treatment to avoid toxicity.  
 
Duration of treatment 
 
Your baby’s doctor will decide exactly how long your newborn must continue therapy with Peyona.  



24 

If your baby has 5 to 7 days without apnoea attacks, the doctor will stop the treatment. 
 
If your newborn receives more Peyona than he/she should 
 
Your newborn may experience fever, rapid breathing (tachypnoea), jitteriness, muscular tremor 
vomiting, high blood levels of sugar (hyperglycemia), low blood levels of potassium (hypokalaemia), 
high blood levels of certain chemicals (urea), elevated number of certain cells (leukocyte) in blood 
and seizures if he/she receives more caffeine citrate than he/she should. 
In the event of this happening treatment with Peyona should be stopped immediately and your baby’s 
doctor should treat the overdose.  
 
If you have any further questions on the use of this medicinal product, ask your baby’s doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. However, 
it is difficult to distinguish them from frequent complications occurring in premature babies and 
complications due to the disease. 
 
While under treatment with Peyona, your newborn may experience some of the following reactions: 
 
Serious side effects 
 
Side effects where the frequency cannot be estimated from the available data  

- serious intestinal disease with bloody stools (necrotising enterocolitis) 
 
The following other side effects may also be considered serious by your baby’s doctor in the context 
of the global clinical evaluation. 
 
Other side effects 
 
Common reported side effects (may affect up to 1 in 10 people) 

- local inflammatory reactions at the infusion site 
- cardiac disorders such as fast heart beat (tachycardia)  
- changes of sugar in blood or serum (hyperglycaemia) 
 

Uncommon reported side effects (may affect up to 1 in 100 people) 
- stimulation of central nervous system such as convulsion 
- cardiac disorders such as irregular heart beat (arrhythmia)  
 

Rare reported side effects (may affect up to 1 in 1,000 people)  
- allergic reactions 

 
Side effects where the frequency cannot be estimated from the available data  

- bloodstream infection (sepsis) 
- changes of sugar in blood or serum (hypoglycaemia ), failure to grow, feeding intolerance  
- stimulation of central nervous system such as irritability, nervousness and restlessness; brain 

injury 
- deafness  
- regurgitation, increase in stomach aspirate 
- increase of urine flow, increase of certain urine components (sodium and calcium)  
- changes in blood tests (reduced levels of haemoglobin after prolonged treatment and reduced 

thyroid hormone at the start of treatment) 
 
Reporting of side effects 



25 

If your newborn gets any side effects, talk to your baby’s doctor. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Peyona  
 
Keep this medicine out of the sight and reach of children. 
Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to 
the last day of that month. 
The medicinal product does not require any special storage conditions. 
Ampoules of all parenteral solutions must be inspected visually for particulate matter prior to 
administration. After opening the ampoules, the medicinal product should be used immediately. 
 
 
6. Contents of the pack and other information 
 
What Peyona contains 
 
The active substance is caffeine citrate.  
Each ml contains 20 mg caffeine citrate (equivalent to 10 mg/ml of caffeine base).  
Each 1 ml ampoule contains 20 mg caffeine citrate (equivalent to 10 mg of caffeine base). 
Each 3 ml ampoule contains 60 mg caffeine citrate (equivalent to 30 mg of caffeine base). 
The other ingredients are citric acid, sodium citrate and water for injections. 
 
What Peyona looks like and content of the pack 
 
Peyona is a solution for infusion and oral solution.  
Peyona is a clear, colourless solution, supplied in glass ampoules. Each carton contains 10 ampoules. 
 
Marketing Authorisation Holder 
Chiesi Farmaceutici S.p.A,  
Via Palermo 26/A,  
43122 Parma,  
Italy 
 
Manufacturer (Batch release) 
Alfasigma S.p.A., 
Via Enrico Fermi 1, 
Alanno (PE) 
Italy 
 
Chiesi Pharmaceuticals GmbH, 
Gonzagagasse 16/16, 
A-1010 Wien 
Austria 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Chiesi sa/nv 
Tél/Tel: + 32 (0)2 788 42 00 

Lietuva 
Chiesi Pharmaceuticals GmbH  
Tel: + 43 1 4073919 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


26 

България  
Chiesi Bulgaria EOOD 
Тел.: +359 29201205 
 

Luxembourg/Luxemburg  
Chiesi sa/nv  
Tél/Tel: + 32 (0)2 788 42 00 

Česká republika 
Chiesi CZ s.r.o. 
Tel: + 420 261221745 

Magyarország  
Chiesi Hungary Kft.  
Tel.:+36-1-429 1060 
 

Danmark  
Chiesi Pharma AB  
Tlf: + 46 8 753 35 20 
 

Malta  
Chiesi Farmaceutici S.p.A  
Tel: + 39 0521 2791 

Deutschland 
Chiesi GmbH 
Tel: + 49 40 89724-0 
 

Nederland  
Chiesi Pharmaceuticals B.V. 
Tel: +31 88 501 64 00 

Eesti 
Chiesi Pharmaceuticals GmbH  
Tel: + 43 1 4073919 
 

Norge 
Chiesi Pharma AB  
Tlf: + 46 8 753 35 20 
 

Ελλάδα 
Chiesi Hellas AEBE 
Τηλ: + 30 210 6179763  
 

Österreich 
Chiesi Pharmaceuticals GmbH  
Tel: + 43 1 4073919 
 

España 
Chiesi España, S.A.U. 
Tel: + 34 93 494 8000 

Polska 
Chiesi Poland Sp. z.o.o. 
Tel.: +48 22 620 1421 
 

France 
Chiesi S.A.S  
Tél: + 33 1 47688899 

Portugal 
Angelini Farmacêutica, Lda 
Tel: + 351 214 148 300 

 
Hrvatska 
Providens d.o.o. 
Tel.: +385 (1) 48 74 500 
 

România 
Chiesi Romania S.R.L. 
Tel: + 40 212023642 

Ireland 
Chiesi Farmaceutici S.p.A.  
Tel: + 39 0521 2791 
 

Slovenija 
Chiesi Slovenija d.o.o. 
Tel: +386-1-43 00 901 

Ísland 
Chiesi Pharma AB  
Sími: +46 8 753 35 20 
 

Slovenská republika 
Chiesi Slovakia s.r.o. 
Tel: +421 259300060 

Italia 
Chiesi Farmaceutici S.p.A. 
Tel: + 39 0521 2791 
 

Suomi/Finland 
Chiesi Pharma AB  
Puh/Tel: +46 8 753 35 20 
 

Κύπρος 
Chiesi Farmaceutici S.p.A. 
Tηλ: + 39 0521 2791 

Sverige 
Chiesi Pharma AB  
Tel: +46 8 753 35 20 
 

Latvija 
Chiesi Pharmaceuticals GmbH  
Tel: + 43 1 4073919 
 

United Kingdom 
Chiesi Ltd  
Tel: + 44 (0)161 488 5555 
 



27 

 
This leaflet was last revised in MM/YYYY 
 
Detailed information on this medicine is available on the website of the European Medicines Agency 
http://www.ema.europa.eu 
 
------------------------------------------------------------------------------------------------------------------------- 
The following information is intended for medical or healthcare professionals only: 
For detailed information refer to the enclosed Summary of Product Characteristics of PEYONA. 
 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET