ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Peyona
20 mg/ml solution for infusion and oral solution
2.
Each ml 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 a full list of excipients, see section 6.1.
3.
Solution for infusion.
Oral solution.
Clear, colourless, aqueous solution at pH=4.7.
4.
4.1
Treatment of primary apnoea of premature newborns.
4.2
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.
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*
* Beginning 24 hours after the loading dose
2
In preterm 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
premature neonates 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).
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).
Routine monitoring of plasma caffeine levels is not necessary in the majority of preterm infants.
However, 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.
Caffeine citrate can be administered by intravenous infusion and by the oral route. The product must
not be administered by intramuscular, subcutaneous, intrathecal or intraperitoneal injection
Duration of treatment
The optimal duration of treatment has not been established. In a recent large multicentre 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 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.
3
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.
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.
Patient with impaired hepatic or renal function
The safety of caffeine citrate in patients with renal insufficiency has not been established. 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).
4.3
Hypersensitivity to the active substance or to any of the excipients.
4.4
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.
In neonates 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 section 4.2 and 5.2).
Breast-feeding mothers of neonates 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).
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.
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.
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.
Caffeine citrate should be administered with caution in preterm neonates with impaired renal or
hepatic function (see sections 4.2 and 5.2). Doses should be adjusted by monitoring of caffeine plasma
concentrations to avoid toxicity in this population.
4
Necrotising enterocolitis is a common cause of morbidity and mortality in premature neonates. 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
Inter-conversion between caffeine and theophylline occurs in preterm neonates. 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 neonates is
limited due to their immature hepatic enzyme systems.
Although few data exist on interactions of caffeine with other active substances in preterm neonates,
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
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).
Caffeine is excreted into breast milk and readily crosses the placenta into the foetal circulation (see
section 5.2).
Breast-feeding mothers of neonates treated with caffeine citrate should not ingest caffeine-containing
foods, beverages or medicinal products containing caffeine.
In neonates 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).
4.7
Not relevant.
5
4.8
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 irritability, restlessness and jitteriness, and cardiac effects such as tachycardia,
hypertension and increased stroke volume. These effects are dose related and may necessitate
measurement of plasma levels and dose reduction.
The adverse reactions described in the short- and long-term published literature 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
Hypoglycaemia, hyperglycaemia,
failure to thrive, feeding intolerance
Not known
Nervous system disorders
Irritability, jitteriness, restlessness,
brain injury*, convulsion*
Not known
Ear and labyrinth disorders Deafness*
Not known
Cardiac disorders
Tachycardia, also associated with
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
* Brain injury, convulsion and deafness were observed, but were more frequent in the placebo group
**See below
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.
Necrotising enterocolitis
Necrotising enterocolitis is a common cause of morbidity and mortality in premature neonates.
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 trial 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
6
study. Three of the infants who developed necrotising enterocolitis during the trial 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).
4.9
Following overdose, published plasma caffeine levels have ranged from approximately 50 mg/l to
350 mg/l.
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.
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.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group:
Xanthine derivatives ATC code: N06BC01
Caffeine is structurally related to the methylxanthines theophylline and theobromine.
Most of its effects have been attributed to antagonism of adenosine receptors, both A
1
and A
2A
subtypes, demonstrated in receptor binding assays and observed at concentrations approximating those
achieved therapeutically in this indication.
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.
The clinical efficacy of caffeine citrate was assessed in a multicentre, randomised, double-blind trial
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 IV loading dose of 20 mg/kg, followed by a daily maintenance dose of
7
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 neonates, the
peak plasma caffeine concentration (C
max
) ranged from 6 to 10 mg/l and the mean time to reach peak
concentration (t
max
) ranged from 30 min to 2 h. The extent of absorption is not affected by formula
feeding but t
max
may be prolonged.
Distribution: Caffeine is rapidly distributed into the brain following caffeine citrate administration.
Caffeine concentrations in the cerebrospinal fluid of preterm neonates approximate to their plasma
levels. The mean volume of distribution (V
d
) 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 neonates 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 neonates 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 neonates; 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 neonates, caffeine clearance is almost entirely by renal
excretion. Mean half-life (t
1/2
) and fraction excreted unchanged in urine (A
e
) of caffeine in infants are
inversely related to gestational / postmenstrual age. In neonates, the t
1/2
is approximately 3-4 days and
the A
e
is approximately 86% (within 6 days). By 9 months of age, the metabolism of caffeine
approximates to that seen in adults (t
1/2
= 5 hours and A
e
= 1%).
Studies examining the pharmacokinetics of caffeine in neonates 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
8
Preclinical 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.
6.1
List of excipients
Citric acid monohydrate
Sodium citrate
Water for injections.
6.2
Incompatibilities
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 product should be used immediately.
From a microbiological point of view, when administered with solutions for infusion the product
should be used immediately after dilution by aseptic technique.
Chemical and physical compatibility of the diluted solution has been demonstrated for 24 hours at
25ºC and at 2-8ºC.
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 3 ml ampoule
Pack size of 10 ampoules.
9
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.
Caffeine citrate should be inspected visually for particulate matter and discoloration prior to
administration. Discard ampoules containing discoloured solution or visible particulate matter.
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.
The diluted solution must be clear and colourless. All parenteral solutions must be inspected visually
for particulate matter and discoloration prior to administration. Do not use the preparation if it is
discoloured or foreign particulate matter is present.
For single use only. Discard any unused portion left in the ampoule. Do not save unused portions for
later administration.
No special requirements for disposal.
7.
CHIESI FARMACEUTICI SpA
Via Palermo 26/A
I-43100 Parma
ITALY
8.
EU/1/09/528/001
9.
02/07/2009
10.
{MM/AAAA}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu
/
.
10
1.
Peyona
20 mg/ml solution for infusion and oral solution
2.
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).
For a full list of excipients, see section 6.1.
3.
Solution for infusion.
Oral solution.
Clear, colourless, aqueous solution at pH=4.7.
4.
4.1
Treatment of primary apnoea of premature newborns.
4.2
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.
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*
* Beginning 24 hours after the loading dose
11
In preterm 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
premature neonates 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).
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).
Routine monitoring of plasma caffeine levels is not necessary in the majority of preterm infants.
However, 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.
Caffeine citrate can be administered by intravenous infusion and by the oral route. The product must
not be administered by intramuscular, subcutaneous, intrathecal or intraperitoneal injection
Duration of treatment
The optimal duration of treatment has not been established. In a recent large multicentre 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 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.
12
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.
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.
Patient with impaired hepatic or renal function
The safety of caffeine citrate in patients with renal insufficiency has not been established. 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).
4.3
Hypersensitivity to the active substance or to any of the excipients.
4.4
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.
In neonates 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 section 4.2 and 5.2).
Breast-feeding mothers of neonates 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).
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.
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.
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.
Caffeine citrate should be administered with caution in preterm neonates with impaired renal or
hepatic function (see sections 4.2 and 5.2). Doses should be adjusted by monitoring of caffeine plasma
concentrations to avoid toxicity in this population.
13
Necrotising enterocolitis is a common cause of morbidity and mortality in premature neonates. 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
Inter-conversion between caffeine and theophylline occurs in preterm neonates. 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 neonates is
limited due to their immature hepatic enzyme systems.
Although few data exist on interactions of caffeine with other active substances in preterm neonates,
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
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).
Caffeine is excreted into breast milk and readily crosses the placenta into the foetal circulation (see
section 5.2).
Breast-feeding mothers of neonates treated with caffeine citrate should not ingest caffeine-containing
foods, beverages or medicinal products containing caffeine.
In neonates 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).
4.7
Not relevant.
14
4.8
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 irritability, restlessness and jitteriness, and cardiac effects such as tachycardia,
hypertension and increased stroke volume. These effects are dose related and may necessitate
measurement of plasma levels and dose reduction.
The adverse reactions described in the short- and long-term published literature 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
Hypoglycaemia, hyperglycaemia,
failure to thrive, feeding intolerance
Not known
Nervous system disorders
Irritability, jitteriness, restlessness,
brain injury*, convulsion*
Not known
Ear and labyrinth disorders Deafness*
Not known
Cardiac disorders
Tachycardia, also associated with
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
* Brain injury, convulsion and deafness were observed, but were more frequent in the placebo group
**See below
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.
Necrotising enterocolitis
Necrotising enterocolitis is a common cause of morbidity and mortality in premature neonates.
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 trial 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
15
study. Three of the infants who developed necrotising enterocolitis during the trial 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).
4.9
Following overdose, published plasma caffeine levels have ranged from approximately 50 mg/l to
350 mg/l.
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.
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.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group:
Xanthine derivatives ATC code: N06BC01
Caffeine is structurally related to the methylxanthines theophylline and theobromine.
Most of its effects have been attributed to antagonism of adenosine receptors, both A
1
and A
2A
subtypes, demonstrated in receptor binding assays and observed at concentrations approximating those
achieved therapeutically in this indication.
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.
The clinical efficacy of caffeine citrate was assessed in a multicentre, randomised, double-blind trial
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 IV loading dose of 20 mg/kg, followed by a daily maintenance dose of
16
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 neonates, the
peak plasma caffeine concentration (C
max
) ranged from 6 to 10 mg/l and the mean time to reach peak
concentration (t
max
) ranged from 30 min to 2 h. The extent of absorption is not affected by formula
feeding but t
max
may be prolonged.
Distribution: Caffeine is rapidly distributed into the brain following caffeine citrate administration.
Caffeine concentrations in the cerebrospinal fluid of preterm neonates approximate to their plasma
levels. The mean volume of distribution (V
d
) 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 neonates 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 neonates 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 neonates; 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 neonates, caffeine clearance is almost entirely by renal
excretion. Mean half-life (t
1/2
) and fraction excreted unchanged in urine (A
e
) of caffeine in infants are
inversely related to gestational / postmenstrual age. In neonates, the t
1/2
is approximately 3-4 days and
the A
e
is approximately 86% (within 6 days). By 9 months of age, the metabolism of caffeine
approximates to that seen in adults (t
1/2
= 5 hours and A
e
= 1%).
Studies examining the pharmacokinetics of caffeine in neonates 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
17
Preclinical 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.
6.1
List of excipients
Citric acid monohydrate
Sodium citrate
Water for injections.
6.2
Incompatibilities
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 product should be used immediately.
From a microbiological point of view, when administered with solutions for infusion the product
should be used immediately after dilution by aseptic technique.
Chemical and physical compatibility of the diluted solution has been demonstrated for 24 hours at
25ºC and at 2-8ºC.
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
Pack size of 10 ampoules.
18
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.
Caffeine citrate should be inspected visually for particulate matter and discoloration prior to
administration. Discard ampoules containing discoloured solution or visible particulate matter.
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.
The diluted solution must be clear and colourless. All parenteral solutions must be inspected visually
for particulate matter and discoloration prior to administration. Do not use the preparation if it is
discoloured or foreign particulate matter is present.
For single use only. Discard any unused portion left in the ampoule. Do not save unused portions for
later administration.
No special requirements for disposal.
7.
CHIESI FARMACEUTICI SpA
Via Palermo 26/A
I
-
43100 Parma
ITALY
8.
EU/1/09/528/002
9.
02/07/2009
10.
{MM/AAAA}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu
/
.
19
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR
BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
20
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Alfa Wasserman SpA
Via Enrico Fermi
IT-65020 Alanno (PE)
Italy
Torrex Chiesi Pharma 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 OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characterisitcs, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
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 product is likely to be used at launch of the
product:
-
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 neonates 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 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
21
-
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 neonates 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 product and shall ensure
that it is provided to all physicians experienced in neonatal intensive care prior to or at the launch of
the product in each Member State.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 05 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMEA
22
ANNEX III
LABELLING AND PACKAGE LEAFLET
23
A. LABELLING
24
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
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 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.
Solution for infusion
Oral solution
10 ampoules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use
Oral use
Read the package leaflet before use.
For single use only.
6
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
After opening the ampoule, the product should be used immediately.
The product must be used immediately after diluting by aseptic technique
9.
SPECIAL STORAGE CONDITIONS
25
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.
CHIESI Farmaceutici SpA
Via Palermo 26/A
I-43100 PARMA-ITALY
EU/1/09/528/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTION ON USE
16. INFORMATION IN BRAILLE
Peyona
26
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
AMPOULE LABEL
1.
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
60 mg/3 ml
6.
OTHER
27
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
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 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.
Solution for infusion
Oral solution
10 ampoules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use
Oral use
Read the package leaflet before use.
For single use only.
6
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
After opening the ampoule, the product should be used immediately.
The product must be used immediately after diluting by aseptic technique
9.
SPECIAL STORAGE CONDITIONS
28
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.
CHIESI Farmaceutici SpA
Via Palermo 26/A
I-43100 PARMA-ITALY
EU/1/09/528/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTION ON USE
16. INFORMATION IN BRAILLE
Peyona
29
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
AMPOULE LABEL
1.
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
6.
OTHER
30
B. PACKAGE LEAFLET
31
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 of your newborn with this medicine
-
Keep this leaflet. You may need to read it again.
-
If you have further questions, please ask your baby’s doctor.
-
If any of the side effects get serious or if you notice any side effects not listed in this leaflet, please
tell your baby’s doctor.
In this leaflet:
1.
What Peyona is and what it is used for
2.
Before using Peyona
3.
How to use Peyona
4.
How to store Peyona
6.
Further information
1.
WHAT PEYONA IS AND WHAT IT IS USED FOR
Peyona 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 neonates).
These short periods when premature babies stop breathing are due to the baby’s breathing centres not
being fully developed.
2.
BEFORE USING PEYONA
Peyona must not be used:
•
If your newborn is allergic (hypersensitive) to caffeine citrate or any of the other ingredients of
Peyona
Take special care with 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
•
If your newborn has a reduced weight gain or food intake
•
If your newborn has been previously treated with theophylline (used to treat breathing
difficulties)
•
If you (the mother) consumed caffeine prior to delivery
32
5.
Possible side effects
Taking other medicines:
Do not use the following medicines during the treatment with Peyona without talking to your 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).
Please inform your baby’s doctor if your newborn is taking or has recently taken any other medicines,
even those not prescribed.
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.
Important information about some of the ingredients of Peyona
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.
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.
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
33
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 product, ask your baby’s doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Peyona can cause side effects, although not everybody gets side effects. However,
it is difficult to distinguish them from frequent complications occurring in premature babies and
complications due to the disease.
The frequency of possible side effects listed below is defined using the following convention:
Very common
affects more than 1 user in 10
Common
affects 1 to 10 users in 100
Uncommon
affects 1 to 10 users in 1,000
Rare
affects 1 to 10 users in 10,000
Very rare
affects less than 1 user in 10,000
Not known
frequency cannot be estimated from the available data
While under treatment with Peyona, your newborn may experience some of the following reactions:
•
Common
: local inflammatory reactions at the infusion site
•
Rare
: allergic reactions
•
Frequency not known
:
- bloodstream infection (sepsis)
- changes of sugar in blood or serum (hypoglycaemia and hyperglycaemia), failure to grow,
feeding intolerance
- stimulation of central nervous system such as irritability, nervousness and restlessness; brain
injury, and seizures
- deafness
- cardiac disorders such as fast heart beat (tachycardia)
- regurgitation, increase in stomach aspirate, serious intestinal disease with bloody stools
(necrotising enterocolitis)
- 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)
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please
tell your baby’s doctor.
5.
HOW TO STORE PEYONA
Keep out of the reach and sight of children.
The medicinal product must not be used after the expiry date stated on the label.
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 product should be used immediately.
6.
FURTHER INFORMATION
34
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 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 and Manufacturer
Marketing Authorisation Holder
Chiesi Farmaceutici S.p.A,
Via Palermo 26/A,
I-43100 Parma,
Italy
Manufacturer (Batch release)
Alfa Wasserman S.p.A,
Via Enrico Fermi 1,
Alanno (PE)
Italy
Torrex Chiesi Pharma 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 Farmaceutici S.p.A.
Tlf: + 39 0521 2791
Luxembourg/Luxemburg
Chiesi Farmaceutici S.p.A.
Tlf: + 39 0521 2791
България
Torrex Chiesi Bulgaria Ltd
Тел.: +359 29201205
Magyarország
Torrex Chiesi Kft.
Tel.:++36-1-429 1060
Česká republika
Torrex Chiesi CZ s.r.o.
Tel: + 420 261221745
Malta
Chiesi Farmaceutici S.p.A
Tel: + 39 0521 2791
Danmark
Chiesi Farmaceutici S.p.A.
Tlf: + 39 0521 2791
Nederland
Chiesi Pharmaceuticals B.V.
Tel: +31 0 70 413 20 80
Deutschland
Chiesi GmbH
Tel: + 49 40 89724-0
Norge
Chiesi Farmaceutici S.p.A.
Tlf: + 39 0521 2791
35
Eesti
Torrex Chiesi Pharma GmbH
Tel: + 43 1 4073919
Österreich
Torrex Chiesi Pharma GmbH
Tel: + 43 1 4073919
Ελλάδα
Chiesi Hellas Pharmaceuticals S.A.
Τηλ: + 30 210 6179763
Polska
Torrex Chiesi Polska Sp z.o.o.
Tel.: +48 22 620 1421
España
Chiesi España, S.A
Tel: + 34 93 494 8000
Portugal
Chiesi Farmaceutici S.p.A.
Tel: + 39 0521 2791
France
Chiesi S.A.
Tél: + 33 1 47688899
România
Torrex Chiesi S.R.L.
Tel: + 40 212023642
Ireland
Trinity-Chiesi Pharmaceuticals Ltd
Tel: + 44 0161 4885555
Slovenija
Torrex Chiesi Slovenija d.o.o.
Tel: ++386-1-43 00 901
Ísland
Chiesi Farmaceutici S.p.A.
Sími: + 39 0521 2791
Slovenská republika
Torrex Chiesi Slovakia s.r.o.
Tel: ++421 259300060
Italia
Chiesi Farmaceutici S.p.A.
Tel: + 39 0521 2791
Suomi/Finland
Chiesi Farmaceutici S.p.A.
Puh/Tel: + 39 0521 2791
Κύπρος
Chiesi Farmaceutici S.p.A.
Tηλ: + 39 0521 2791
Sverige
Chiesi Farmaceutici S.p.A.
Tel: + 39 0521 2791
Latvija
Torrex Chiesi Pharma GmbH
Tel: + 43 1 4073919
United Kingdom
Chiesi Ltd
Tel: + 44 0161 4885555
Lietuva
Torrex Chiesi Pharma GmbH
Tel: + 43 1 4073919
This leaflet was last approved in:
Detailed information on this medicine is available on the website of the European Medicines Agency
(EMEA)
http://www.emea.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.
36
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 of your newborn with this medicine
-
Keep this leaflet. You may need to read it again.
-
If you have further questions, please ask your baby’s doctor.
-
If any of the side effects get serious or if you notice any side effects not listed in this leaflet, please
tell your baby’s doctor.
In this leaflet:
1.
What Peyona is and what it is used for
2.
Before using Peyona
3.
How to use Peyona
4.
How to store Peyona
6.
Further information
1.
WHAT PEYONA IS AND WHAT IT IS USED FOR
Peyona 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 neonates).
These short periods when premature babies stop breathing are due to the baby’s breathing centres not
being fully developed.
2.
BEFORE USING PEYONA
Peyona must not be used:
•
If your newborn is allergic (hypersensitive) to caffeine citrate or any of the other ingredients of
Peyona
Take special care with 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
•
If your newborn has a reduced weight gain or food intake
•
If your newborn has been previously treated with theophylline (used to treat breathing
difficulties)
•
If you (the mother) consumed caffeine prior to delivery
37
5.
Possible side effects
Taking other medicines:
Do not use the following medicines during the treatment with Peyona without talking to your 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).
Please inform your baby’s doctor if your newborn is taking or has recently taken any other medicines,
even those not prescribed.
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.
Important information about some of the ingredients of Peyona
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.
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.
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
38
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 product, ask your baby’s doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Peyona can cause side effects, although not everybody gets side effects. However,
it is difficult to distinguish them from frequent complications occurring in premature babies and
complications due to the disease.
The frequency of possible side effects listed below is defined using the following convention:
Very common
affects more than 1 user in 10
Common
affects 1 to 10 users in 100
Uncommon
affects 1 to 10 users in 1,000
Rare
affects 1 to 10 users in 10,000
Very rare
affects less than 1 user in 10,000
Not known
frequency cannot be estimated from the available data
While under treatment with Peyona, your newborn may experience some of the following reactions:
•
Common
: local inflammatory reactions at the infusion site
•
Rare
: allergic reactions
•
Frequency not known
:
- bloodstream infection (sepsis)
- changes of sugar in blood or serum (hypoglycaemia and hyperglycaemia), failure to grow,
feeding intolerance
- stimulation of central nervous system such as irritability, nervousness and restlessness; brain
injury, and seizures
- deafness
- cardiac disorders such as fast heart beat (tachycardia)
- regurgitation, increase in stomach aspirate, serious intestinal disease with bloody stools
(necrotising enterocolitis)
- 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)
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please
tell your baby’s doctor.
5.
HOW TO STORE PEYONA
Keep out of the reach and sight of children.
The medicinal product must not be used after the expiry date stated on the label.
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 product should be used immediately.
6.
FURTHER INFORMATION
39
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).
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 and Manufacturer
Marketing Authorisation Holder
Chiesi Farmaceutici S.p.A,
Via Palermo 26/A,
I-43100 Parma,
Italy
Manufacturer (Batch release)
Alfa Wasserman S.p.A,
Via Enrico Fermi 1,
Alanno (PE)
Italy
Torrex Chiesi Pharma 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 Farmaceutici S.p.A.
Tlf: + 39 0521 2791
Luxembourg/Luxemburg
Chiesi Farmaceutici S.p.A.
Tlf: + 39 0521 2791
България
Torrex Chiesi Bulgaria Ltd
Тел.: +359 29201205
Magyarország
Torrex Chiesi Kft.
Tel.:++36-1-429 1060
Česká republika
Torrex Chiesi CZ s.r.o.
Tel: + 420 261221745
Malta
Chiesi Farmaceutici S.p.A
Tel: + 39 0521 2791
Danmark
Chiesi Farmaceutici S.p.A.
Tlf: + 39 0521 2791
Nederland
Chiesi Pharmaceuticals B.V.
Tel: +31 0 70 413 20 80
Deutschland
Chiesi GmbH
Tel: + 49 40 89724-0
Norge
Chiesi Farmaceutici S.p.A.
Tlf: + 39 0521 2791
40
Eesti
Torrex Chiesi Pharma GmbH
Tel: + 43 1 4073919
Österreich
Torrex Chiesi Pharma GmbH
Tel: + 43 1 4073919
Ελλάδα
Chiesi Hellas Pharmaceuticals S.A.
Τηλ: + 30 210 6179763
Polska
Torrex Chiesi Polska Sp z.o.o.
Tel.: +48 22 620 1421
España
Chiesi España, S.A
Tel: + 34 93 494 8000
Portugal
Chiesi Farmaceutici S.p.A.
Tel: + 39 0521 2791
France
Chiesi S.A.
Tél: + 33 1 47688899
România
Torrex Chiesi S.R.L.
Tel: + 40 212023642
Ireland
Trinity-Chiesi Pharmaceuticals Ltd
Tel: + 44 0161 4885555
Slovenija
Torrex Chiesi Slovenija d.o.o.
Tel: ++386-1-43 00 901
Ísland
Chiesi Farmaceutici S.p.A.
Sími: + 39 0521 2791
Slovenská republika
Torrex Chiesi Slovakia s.r.o.
Tel: ++421 259300060
Italia
Chiesi Farmaceutici S.p.A.
Tel: + 39 0521 2791
Suomi/Finland
Chiesi Farmaceutici S.p.A.
Puh/Tel: + 39 0521 2791
Κύπρος
Chiesi Farmaceutici S.p.A.
Tηλ: + 39 0521 2791
Sverige
Chiesi Farmaceutici S.p.A.
Tel: + 39 0521 2791
Latvija
Torrex Chiesi Pharma GmbH
Tel: + 43 1 4073919
United Kingdom
Chiesi Ltd
Tel: + 44 0161 4885555
Lietuva
Torrex Chiesi Pharma GmbH
Tel: + 43 1 4073919
This leaflet was last approved in:
Detailed information on this medicine is available on the website of the European Medicines Agency
(EMEA)
http://www.emea.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.
41
Source: European Medicines Agency
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