Treatment of primary apnoea of premature newborns.

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. PosologyThe 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)RouteFrequencyLoading dose1.0 ml/kg body weight20 mg/kg body weightIntravenous infusion(over 30 minutes)OnceMaintenance dose* 0.25 ml/kg body weight5 mg/kg body weightIntravenous infusion (over 10 minutes) or by oral administrationEvery 24 hours** Beginning 24 hours after the loading doseIn 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 monitoringPlasma 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.

The optimal duration of treatment has not been established. In a recent large multicentre study on preterm newborn infants a median treatment period of 37 days was reported. In clinical practice, treatment is usually continued until the infant has reached a post-menstrual age of 37 weeks, by which time apnoea of prematurity usually resolves spontaneously. This limit may however be revised according to clinical judgment in individual cases depending on the response to treatment, the continuing presence of apnoeic episodes despite treatment, or other clinical considerations. It is recommended that caffeine citrate administration should be stopped when the patient has 5-7 days without a significant apnoeic attack. If the patient has recurrent apnoea, caffeine citrate administration can be restarted with either a maintenance dose or a half loading dose, depending upon the time interval from stopping caffeine citrate to recurrence of apnoea.Because of the slow elimination of caffeine in this patient population, there is no requirement for dose tapering on cessation of treatment. 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 administrationCaffeine citrate can be administered by intravenous infusion and by the oral route. The medicinal product must not be administered by intramuscular, subcutaneous, intrathecal or intraperitoneal injection.When given intravenously, caffeine citrate should be administered by controlled intravenous infusion, using a syringe infusion pump or other metered infusion device only. Caffeine citrate can be either used without dilution or diluted in sterile solutions for infusion such as glucose 50 mg/ml (5%), or sodium chloride 9 mg/ml (0.9%) or calcium gluconate 100 mg/ml (10%) immediately after withdrawal from the ampoule (see section 6.6).

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

ApnoeaApnoea 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 consumptionIn 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). TheophyllineIn 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. SeizuresCaffeine 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 reactionsCaffeine 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 impairmentCaffeine 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 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.

PregnancyCaffeine 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).FertilityEffects 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 profileThe 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 reactionsThe adverse reactions described in the short- and long-term published literature and obtained from a post-authorisation safety study that can be associated with caffeine citrate are listed below by System Organ Class and Preferred Term (MedDRA). Frequency is defined as: very common ( 1/10), common (1/100 to 1/10), uncommon (1/1,000 to 1/100), rare (1/10,000 to 1/1,000), very rare (1/10,000) and not known (cannot be estimated from the available data).System Organ ClassAdverse ReactionFrequencyInfections and infestationsSepsisNot knownImmune system disordersHypersensitivity reactionRareHyperglycaemiaCommonMetabolism and nutrition disordersHypoglycaemia, failure to thrive, feeding intoleranceNot knownConvulsionUncommonNervous system disordersIrritability, jitteriness, restlessness, brain injury Not known

Ear and labyrinth disordersDeafnessNot knownTachycardiaCommonArrhythmiaUncommonCardiac disordersIncreased left ventricular output and increased stroke volumeNot knownGastrointestinal disordersRegurgitation, increased gastric aspirate, necrotising enterocolitisNot knownGeneral disorders and administration site conditionsInfusion site phlebitis, infusion site inflammationCommonInvestigationsUrine output increased, urine sodium and calcium increased, haemoglobin decreased, thyroxine decreasedNot known

Description of selected adverse reactions Necrotising enterocolitis is a common cause of morbidity and mortality in premature newborn infants.There are reports of a possible association between the use of methylxanthines and development of necrotising enterocolitis. However, a causal relationship between caffeine or other methylxanthine use and necrotising enterocolitis has not been established. In a double-blind placebo-controlled study of caffeine citrate in 85 preterm infants (see section 5.1), necrotising enterocolitis was diagnosed in the blinded phase of the study in two infants on active treatment and one on placebo, and in three infants on caffeine during the open-label phase of the study. Three of the infants who developed necrotising enterocolitis during the study died. A large multicentre study (n=2006) investigating long-term outcome of premature infants treated with caffeine citrate (see section 5.1) did not show an increased frequency of necrotising enterocolitis in the caffeine group when compared to placebo. As for all preterm infants, those treated with caffeine citrate should be carefully monitored for the development of necrotising enterocolitis (see section 4.4). Brain injury, convulsion and deafness were observed but they were more frequent in the placebo group.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 populationsIn a post-authorisation safety study on 506 preterm infants treated with Peyona, safety data have been collected in 31 very premature infants with renal/hepatic impairment. Adverse reactions appeared to be more frequent in this subgroup with organ impairment than in other observed infants without organ impairment. Cardiac disorders (tachycardia, including one single case of arrhythmia) were mostly reported.

Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. -To reports any side effect(s):  Saudi Arabia:  The National Pharmacovigilance and Drug Safety Centre (NPC) o Fax: +966-11-205-7662 o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340. o Toll free phone: 8002490000 o E-mail: npc.drug@sfda.gov.sa o Website: www.sfda.gov.sa/npc - In other countries: please contact the relevant competent Authority

Following overdose, published plasma caffeine levels have ranged from approximately 50 mg/l to 350 mg/l.

SymptomsSigns 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.ManagementTreatment 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 effectsCaffeine’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 safetyThe 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 studySubgroupsOdds ratio (95% CI)No support 1.32 (0.81 to 2.14)Non invasive support0.73 (0.52 to 1.03)Endotracheal tube0.73 (0.57 to 0.94)

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.

DistributionCaffeine 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 monohydrateSodium citrate Water for injections.

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.

3 years.After opening the ampoule, the medicinal product should be used immediately.Chemical and physical compatibility of the diluted solution has been demonstrated for 24 hours at 25ºC and at 2-8ºC.From a microbiological point of view, when administered with solutions for infusion the medicinal product should be used immediately after dilution by aseptic technique.

This medicinal product does not require any special storage condition.For storage conditions of the diluted medicinal product see section 6.3.

Type I clear glass 1 ml ampoulePack size of 10 ampoules.

Aseptic technique must be strictly observed throughout handling of the medicinal product since no preservative is present.Peyona should be inspected visually for particulate matter and discoloration prior to administration. Ampoules containing discoloured solution or visible particulate matter should be discarded.

Peyona can be either used without dilution or diluted in sterile solutions for infusion such as glucose 50 mg/ml (5%) or sodium chloride 9 mg/ml (0.9%) or calcium gluconate 100 mg/ml (10%) immediately after withdrawal from the ampoule. The diluted solution must be clear and colourless. Undiluted and diluted parenteral solutions must be inspected visually for particulate matter and discoloration prior to administration. The solution must not be used if it is discoloured or foreign particulate matter is present.For single use only. Any unused portion left in the ampoule should be discarded. Unused portions should not be saved for later administration.No special requirements for disposal.