Treatment of primary apnoea of premature newborns.

Treatment with Biocaffcit 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). 

* 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 postmenstrual 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. 
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 vial (see 
section 6.6).

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

Caffeine consumption
In newborn infants born to mothers who consumed large quantities of caffeine prior to 
delivery, baseline plasma caffeine concentrations should be measured prior to initiation 
of treatment with caffeine citrate, since caffeine readily crosses the placenta into the 
foetal circulation (see sections 4.2 and 5.2).
Breast-feeding mothers of newborn infants treated with caffeine citrate should not 
ingest caffeine-containing foods and beverages or medicinal products containing 
caffeine (see section 4.6), since caffeine is excreted into breast milk (see section 5.2). 

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

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

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

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

Necrotising enterocolitis
Necrotising enterocolitis is a common cause of morbidity and mortality in premature 
newborn infants. There are reports of a possible association between the use of methylxanthines and development of necrotising enterocolitis. However, a causal 
relationship between caffeine or other methylxanthine use and necrotising enterocolitis 
has not been established. As for all preterm infants, those treated with caffeine citrate 
should be carefully monitored for the development of necrotising enterocolitis (see section 4.8). 
Caffeine citrate should be used with caution in infants suffering gastro-oesophageal 
reflux, as the treatment may exacerbate this condition.
Caffeine citrate causes a generalised increase in metabolism, which may result in 
higher energy and nutrition requirements during therapy. 
The diuresis and electrolyte loss induced by caffeine citrate may necessitate correction 
of fluid and electrolyte disturbances.

Inter-conversion between caffeine and theophylline occurs in preterm newborn infants. 
These active substances should not be used concurrently. 
Cytochrome P450 1A2 (CYP1A2) is the major enzyme involved in the metabolism of 
caffeine in humans. Therefore, caffeine has the potential to interact with active 
substances that are substrates for CYP1A2, inhibit CYP1A2, or induce CYP1A2. 
However, caffeine metabolism in preterm newborn infants is limited due to their 
immature hepatic enzyme systems.
Although few data exist on interactions of caffeine with other active substances in 
preterm newborn infants, lower doses of caffeine citrate may be needed following coadministration 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.

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).

Not relevant.

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

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

Description of selected adverse reactions 
Necrotising enterocolitis is a common cause of morbidity and mortality in premature 
newborn infants. There are reports of a possible association between the use of 
methylxanthines and development of necrotising enterocolitis. However, a causal 
relationship between caffeine or other methylxanthine use and necrotising enterocolitis 
has not been established. 
In a double-blind placebo-controlled study of caffeine citrate in 85 preterm infants (see 
section 5.1), necrotising enterocolitis was diagnosed in the blinded phase of the study 
in two infants on active treatment and one on placebo, and in three infants on caffeine 
during the open-label phase of the study. Three of the infants who developed 
necrotising enterocolitis during the study died. A large multicentre study (n=2006) 
investigating long-term outcome of premature infants treated with caffeine citrate (see 
section 5.1) did not show an increased frequency of necrotising enterocolitis in the 

caffeine group when compared to placebo. As for all preterm infants, those treated with 
caffeine citrate should be carefully monitored for the development of necrotising 
enterocolitis (see section 4.4). 
Brain injury, convulsion and deafness were observed but they were more frequent in 
the placebo group.
Caffeine may suppress erythropoietin synthesis and hence reduce haemoglobin 
concentration with prolonged treatment.
Transient falls in thyroxine (T4) have been recorded in infants at the start of therapy 
but these are not sustained with maintained therapy.
Available evidence does not indicate any adverse long-term reactions of neonatal 
caffeine therapy as regards neurodevelopmental outcome, failure to thrive or on the 
cardiovascular, gastrointestinal or endocrine systems. Caffeine does not appear to 
aggravate cerebral hypoxia or to exacerbate any resulting damage, although the 
possibility cannot be ruled out.

Other special populations
In a post-authorisation safety study on 506 preterm infants treated with 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.
To report any side effect(s):
Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC) 
 Fax: +966-11-205-7662 
 Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340. 
 Toll free phone: 8002490000 
 E-mail: npc.drug@sfda.gov.sa 
 Website: www.sfda.gov.sa/npc 
 Other GCC States: 
 Please contact the relevant competent authority.
 

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).

Pharmacotherapeutic group: Psychoanaleptics, xanthine derivatives 
ATC code: N06BC01
Mechanism of action
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

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.

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).

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. 

- Citric acid monohydrate : 5.0 mg/ml
- Sodium citrate Dihydrate : 8.30 mg/ml
- Water For Injections to 1 ml

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.

Do not store above 30°C.
For storage conditions of the diluted medicinal product see section 6.3.

Type I clear glass Vial containing 3 ml Solution
Pack size: 10 Glass vials / Pack 

Aseptic technique must be strictly observed throughout handling of the medicinal 
product since no preservative is present.
This Product should be inspected visually for particulate matter and discoloration prior 
to administration. Vials containing discoloured solution or visible particulate matter 
should be discarded.
This Product can be either used without dilution or diluted in sterile solutions for 
infusion such as 5% glucose or 0.9% sodium chloride or 10% calcium Gluconate 
immediately after withdrawal from the Vial.
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 Vial should be discarded. Unused 
portions should not be saved for later administration.
No special requirements for disposal.