Treatment of apnoea of prematurity.

4.2 Posology and method of administration
Treatment with caffeine citrate should be initiated under the supervision of a physician 
experienced in neonatal intensive care. Treatment should be administered only in a 
neonatal intensive care unit in which adequate facilities are available for patient 
surveillance and monitoring.

Posology
The recommended doses of Biocaffcit 10mg/ml Solution for Injection are expressed 
below. Please note:
(a) The dose expressed as caffeine citrate is twice the dose expressed as caffeine base.
(b) Given orally or intravenously, caffeine is clinically effective within 4 hours. If the 
patient fails to respond within this time, a second loading dose may be given. If there is 
no clinical response to the second loading dose, caffeine blood levels should be measured 
(see 'special warnings and precautions for use' section 4.4 below)
(c) Biocaffcit 10mg/ml Solution for Injection is also effective when administered orally, 
and this route may be used alternatively without adjusting the dose.
(d) Because of the slow elimination of caffeine in this patient population, there is no 
requirement for dose tapering on cessation of treatment.
(e) Infants must be of sufficient respiratory maturity not to require positive pressure 
ventilation.

* In some cases maintenance doses higher than 10mg/kg/day (expressed as caffeine 
citrate) may be required to achieve maximal efficacy (eg in continuing apnoeic episodes 
where plasma levels indicate the dose may be safely increased)
** By intravenous infusion
*** Beginning 24 hours after the loading dose(s)

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.
Treatment should be continued until the child has reached a gestational age of 37 weeks, 
by which time apnoea of prematurity usually resolves spontaneously. This limit may 
however be revised according to clinical judgement in individual cases depending on 
response to treatment, the continuing presence of apnoeic episodes despite treatment, or 
other clinical considerations.
Please see Section 4.4 below regarding use of the filter straws.
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 impairment 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, a reduced daily maintenance dose of caffeine is 
required and the dose should be guided by blood caffeine measurements. There is 
increased potential for accumulation.
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 infant, hepatic disease may indicate a need for monitoring plasma levels and 
may require dose adjustments (see sections 4.4 and 5.2).
Adults and Children
Not applicable
Elderly
Not applicable

Method of administration
Biocaffcit 10mg/ml Injection should not be given intramuscularly; being acidic, i.m. 
injection is likely to be painful. When given intravenously, it should be given as a slow 
infusion rather than a bolus injection; there is evidence that bolus administration may 
cause sudden changes in blood pressure.

Apnoea
Apnoea of prematurity is a diagnosis of exclusion. Other causes of apnoea (e.g., central 
nervous system disorders, primary lung disease, anemia, sepsis, metabolic disturbances, 
cardiovascular abnormalities, or obstructive apnoea) should be ruled out or properly 
treated prior to initiation of treatment with caffeine citrate.
It is advisable to monitor plasma levels of caffeine periodically. However, at the 
recommended doses, frequent (more than weekly) monitoring of plasma levels is not 
normally necessary unless there are concerns regarding lack of efficacy or possible 
toxicity. In premature neonates, caffeine has a prolonged half-life. If higher maintenance 
dosages are used, the clinician should recognize this potential for accumulation and 
monitor plasma caffeine levels (see also Section 5.2).
If there is inadequate clinical response to the first loading dose, a second dose may be 
given, but if there is continued inadequate response, the plasma levels should be 
confirmed before further doses are given, as the failure to respond could be an indication 
of another cause of apnoea. Plasma levels should not normally exceed 50micrograms/ml 
(optimally 10-30micrograms/ml).
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.
Use of filter straws
Opening the vial may introduce glass particles into this solution. It is recommended that 
the solution be filtered prior to use by means of a suitable filter device.
Biocaffcit 10mg/ml Injection contains sodium
This medicinal product contains 3.04mg sodium per 1ml of the solution. To be taken into 
consideration by patients on a controlled sodium diet.

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.
Interconversion between caffeine and other xanthines such as theophylline has been 
reported in premature neonates. Therefore the concurrent use of these drugs should be 
avoided. Baseline serum levels of caffeine should be measured in patients previously 
treated with theophylline.
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.

Fertility

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

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).

Not applicable

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.
They are generally, although not exclusively, associated with serum caffeine 
concentrations ≥50micrograms/ml.

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 of overdosage from these reports include jitteriness, tachycardia, 
tachypnoea, tremor, opisthotonos, rigidity and tonic-clonic movements, hypokalaemia, , 
restlessness, , gastric irritation, gastro-intestinal haemorrhage, 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. In one case of overdose the patient developed compromised 
circulation, vomiting and seizures. Other reported effects of gross overdose include fever, 
agitation, hyperexcitability, hypertonia, gastric residues, distended abdomen, metabolic 
acidosis, hyperglycaemia and elevated urea levels. No deaths associated with caffeine 
overdose have been reported in preterm infants.
Management
Treatment of overdosage should include monitoring of blood levels of caffeine and 
supportive measures. Plasma potassium and glucose concentrations should be monitored 
and hypokalaemia and hyperglycaemia corrected.
Previous cases reported resolved satisfactorily.
In severe cases of overdose, exchange transfusion should be considered. In one case, this 
was found to reduce plasma caffeine levels by 40mg/L per 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
The desired respirogenic activity of caffeine is an expression of its central nervous 
system stimulation, although it may also increase the sensitivity of respiratory response to 
carbon dioxide levels. Caffeine increases both tidal volume and frequency of ventilation.
In the premature infant, caffeine produced increased minute ventilation, mainly due to an 
increase in inspiratory drive as shown by an increased mean respiratory flow (VΤ/T1). 
Caffeine regularises the breathing pattern, indicating that it stabilises the oscillation of the 
respiratory control system.
Caffeine also inhibits phosphodiesterase, but this effect only occurs at concentrations 
associated with toxicity, and not at therapeutic concentrations.
Caffeine increases metabolic rate, heart rate, cardiac contractility and output. It also 
increases blood flow to the kidneys, and prevents sodium and chloride from reabsorbing 
at the proximal tubules, so mild diuresis can occur.
Adenosine is a vasodilator and therefore caffeine, as its antagonist, can cause 
vasoconstriction. Hence it is a vasoconstrictor in the cerebral and splanchnic circulations. 
Elsewhere, it has a vasodilator effect due to an effect on vascular smooth muscle.
The stimulant effect may affect sleep patterns.
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. In neonates, orally administered caffeine has been shown to be rapidly and 
completely absorbed. 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.

- Sodium Chloride : 7.725 mg/ml
- Citric acid monohydrate : 5.47 mg/ml
- Sodium Hydroxide : Q.S.
- Dilute Hydrochloric Acid : Q.S.
- Water For Injections to 1 ml

This medicinal product must not be mixed 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.
No special precautions are required for storage.

Type I clear glass Vial containing 1ml or 2ml Solution
Pack size: [10 Glass vials / Pack]

Only clear solution without particulate matter should be used. For single use only. Any 
unused solution should be discarded.
There was no detectable degradation of the solution when diluted 50/50 with commercial 
glucose 5%, glucose 4% saline 0.18%, and sodium chloride 0.9% infusions, when stored 
in disposable plastic syringes at room temperature for 4 hours.