GENCEBOK 10mg / ml infusion solution medication leaflet

Gencebok 10 mg/ml solution for infusion

Each ml contains 10 mg caffeine citrate (equivalent to 5 mg caffeine).

Each 1 ml ampoule contains 10 mg caffeine citrate (equivalent to 5 mg caffeine).

For the full list of excipients, see section 6.1.

Solution for infusion.

Clear, colourless, aqueous solution, with a pH of 4.8 and an osmolality of 65 to 95 mOsm/kg.

Treatment of primary apnoea of premature newborns.

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

The recommended dose regimen in previously untreated infants is a loading dose of 20 mg caffeinecitrate per kg body weight administered by slow intravenous infusion over 30 minutes, using a syringeinfusion pump or other metered infusion device. After an interval of 24 hours, maintenance doses of5 mg per kg body weight may be administered by slow intravenous infusion over 10 minutes every24 hours. Alternatively, maintenance doses of 5 mg per kg body weight may be administered by oraladministration, such as through a nasogastric tube every 24 hours.

The recommended loading dose and maintenance doses of caffeine citrate are provided in thefollowing table which clarifies the relationship between injection volumes and administered dosesexpressed as caffeine citrate.

The dose expressed as caffeine base is one-half the dose when expressed as caffeine citrate (10 mgcaffeine citrate are equivalent to 5 mg caffeine base).

Dose of caffeine Dose of caffeine Route Frequencycitrate (Volume) citrate (mg/kg bodyweight)

Loading dose 2.0 ml/kg body 20 mg/kg body weight Intravenous infusion Onceweight (over 30 minutes)

Maintenance 0.5 ml/kg body 5 mg/kg body weight Intravenous infusion Everydose* weight (over 10 minutes) or by 24 hours*oral administration

* Beginning 24 hours after the loading dose

In preterm newborn infants with insufficient clinical response to the recommended loading dose, asecond 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 insufficientresponse, taking into account the potential for accumulation of caffeine due to the long half-life inpreterm newborn infants and the progressively increasing capacity to metabolise caffeine in relation topost-menstrual age (see section 5.2). Where clinically indicated, caffeine plasma levels should bemonitored. The diagnosis of apnoea of prematurity may need to be reconsidered if patients do notrespond 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 incases of incomplete clinical response or signs of toxicity.

Additionally, doses may need to be adjusted according to medical judgment following routinemonitoring of caffeine plasma concentrations in at risk situations such as:

- very premature infants (< 28 weeks gestational age and/or body weight <1000 g) particularlywhen 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 caffeinemetabolism (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 (seesection 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 accumulationwhich 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 therapeuticfailure 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 theliterature, caffeine levels in studies associated with clinical benefit ranged from 8 to 30 mg/l and nosafety 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 onpreterm 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 of37 weeks, by which time apnoea of prematurity usually resolves spontaneously. This limit mayhowever be revised according to clinical judgment in individual cases depending on the response totreatment, the continuing presence of apnoeic episodes despite treatment, or other clinicalconsiderations. It is recommended that caffeine citrate administration should be stopped when thepatient has 5-7 days without a significant apnoeic attack.

If the patient has recurrent apnoea, caffeine citrate administration can be restarted with either amaintenance dose or a half loading dose, depending upon the time interval from stopping caffeinecitrate to recurrence of apnoea.

Because of the slow elimination of caffeine in this patient population, there is no requirement for dosetapering on cessation of treatment.

As there is a risk for recurrence of apnoeas after cessation of caffeine citrate treatment monitoring ofthe patient should be continued for approximately one week.

There is limited experience in patients with renal and hepatic impairment. In a post authorisationsafety study, the frequency of adverse reactions in a small number of very premature infants withrenal/hepatic impairment appeared to be higher as compared to premature infants without organimpairment (see sections 4.4 and 4.8).

In the presence of renal impairment, there is increased potential for accumulation. A reduced dailymaintenance dose of caffeine citrate is required and the dose should be guided by plasma caffeinemeasurements.

In very premature infants, clearance of caffeine does not depend on hepatic function. Hepatic caffeinemetabolism develops progressively in the weeks following birth and for the older infants, hepaticdisease may indicate a need for monitoring caffeine plasma levels and may require dose adjustments(see sections 4.4 and 5.2).

Caffeine citrate can be administered by intravenous infusion and by the oral route. The medicinalproduct must not be administered by intramuscular, subcutaneous, intrathecal or intraperitonealinjection.

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 eitherused without dilution or diluted in sterile solutions for infusion such as glucose 50 mg/ml (5%), orsodium chloride 9 mg/ml (0.9%) or calcium gluconate 100 mg/ml (10%) immediately after withdrawalfrom the ampoule (see section 6.6).

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

Apnoea

Apnoea of prematurity is a diagnosis of exclusion. Other causes of apnoea (e.g., central nervoussystem disorders, primary lung disease, anaemia, sepsis, metabolic disturbances, cardiovascularabnormalities, or obstructive apnoea) should be ruled out or properly treated prior to initiation oftreatment with caffeine citrate. Failure to respond to caffeine treatment (confirmed if necessary bymeasurement 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 withcaffeine citrate, since caffeine readily crosses the placenta into the foetal circulation (see sections 4.2and 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), sincecaffeine is excreted into breast milk (see section 5.2).

Theophylline

In newborns previously treated with theophylline, baseline plasma caffeine concentrations should bemeasured prior to initiation of treatment with caffeine citrate because preterm infants metabolisetheophylline to caffeine.

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

Caffeine has been shown to increase heart rate, left ventricular output, and stroke volume in publishedstudies. Therefore, caffeine citrate should be used with caution in newborns with knowncardiovascular disease. There is evidence that caffeine causes tachyarrhythmias in susceptibleindividuals. In newborns this is usually a simple sinus tachycardia. If there have been any unusualrhythm disturbances on a cardiotocograph (CTG) trace before the baby is born, caffeine citrate shouldbe administered with caution.

Caffeine citrate should be administered with caution in preterm newborn infants with impaired renal orhepatic function. In a post-authorisation safety study, the frequency of adverse reactions in a smallnumber of very premature infants with renal/hepatic impairment appeared to be higher as compared topremature infants without organ impairment (see sections 4.2, pct. 4.8 and 5.2). Doses should be adjustedby 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 ofnecrotising enterocolitis. However, a causal relationship between caffeine or other methylxanthine useand necrotising enterocolitis has not been established. As for all preterm infants, those treated withcaffeine citrate should be carefully monitored for the development of necrotising enterocolitis (seesection 4.8).

Caffeine citrate should be used with caution in infants suffering gastro-oesophageal reflux, as thetreatment may exacerbate this condition.

Caffeine citrate causes a generalised increase in metabolism, which may result in higher energy andnutrition requirements during therapy.

The diuresis and electrolyte loss induced by caffeine citrate may necessitate correction of fluid andelectrolyte disturbances.

Inter-conversion between caffeine and theophylline occurs in preterm newborn infants. These activesubstances should not be used concurrently.

Cytochrome P450 1A2 (CYP1A2) is the major enzyme involved in the metabolism of caffeine inhumans. 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 newborninfants is limited due to their immature hepatic enzyme systems.

Although few data exist on interactions of caffeine with other active substances in preterm newborninfants, lower doses of caffeine citrate may be needed following co-administration of active substanceswhich are reported to decrease caffeine elimination in adults (e.g., cimetidine and ketoconazole) andhigher caffeine citrate doses may be needed following co-administration of active substances thatincrease caffeine elimination (e.g., phenobarbital and phenytoin). Where doubt exists about possibleinteractions, 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 ofnecrotising 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 bloodpressure must be carefully monitored.

Caffeine in animal studies, at high doses, was shown to be embryotoxic and teratogenic. These effectsare not relevant with regard to short term administration in the preterm infant population (see section5.3).

Caffeine is excreted into breast milk and readily crosses the placenta into the foetal circulation (seesection 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 withcaffeine citrate (see section 4.4).

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

Not relevant.

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

The adverse reactions described in the short- and long-term published literature and obtained from apost-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 fromthe available data).

System Organ Class Adverse Reaction Frequency

Infections and infestations Sepsis Not known

Immune system disorders Hypersensitivity reaction Rare

Metabolism and nutrition Hyperglycaemia Commondisorders

Hypoglycaemia, failure to thrive, Not knownfeeding intolerance

Nervous system disorders Convulsion Uncommon

Irritability, jitteriness, restlessness, Not knownbrain injury

Ear and labyrinth disorders Deafness Not known

Cardiac disorders Tachycardia Common

Arrhythmia Uncommon

Increased left ventricular output and Not knownincreased stroke volume

Gastrointestinal disorders Regurgitation, increased gastric Not knownaspirate, necrotising enterocolitis

General disorders and Infusion site phlebitis, infusion site Commonadministration site inflammationconditions

Investigations Urine output increased, urine sodium Not knownand calcium increased, haemoglobindecreased, thyroxine decreased

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 ofnecrotising enterocolitis. However, a causal relationship between caffeine or other methylxanthine useand 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 activetreatment 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 multicentrestudy (n=2006) investigating long-term outcome of premature infants treated with caffeine citrate (seesection 5.1) did not show an increased frequency of necrotising enterocolitis in the caffeine group whencompared to placebo. As for all preterm infants, those treated with caffeine citrate should be carefullymonitored 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 withprolonged treatment.

Transient falls in thyroxine (T4) have been recorded in infants at the start of therapy but these are notsustained with maintained therapy.

Available evidence does not indicate any adverse long-term reactions of neonatal caffeine therapy asregards neurodevelopmental outcome, failure to thrive or on the cardiovascular, gastrointestinal orendocrine systems. Caffeine does not appear to aggravate cerebral hypoxia or to exacerbate any resultingdamage, although the possibility cannot be ruled out.

In a post-authorisation safety study on 506 preterm infants treated with caffeine citrate, safety data havebeen collected in 31 very premature infants with renal/hepatic impairment. Adverse reactions appearedto be more frequent in this subgroup with organ impairment than in other observed infants without organimpairment. Cardiac disorders (tachycardia, including one single case of arrhythmia) were mostlyreported.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Following overdose, published plasma caffeine levels have ranged from approximately 50 mg/l to350 mg/l.

Signs and symptoms reported in the literature after caffeine overdose in preterm infants includehyperglycaemia, 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 ofintraventricular haemorrhage and long-term neurological sequelae has been reported. No deathsassociated with caffeine overdose have been reported in preterm infants.

Treatment of caffeine overdose is primarily symptomatic and supportive. Plasma potassium andglucose concentrations should be monitored and hypokalaemia and hyperglycaemia corrected. Plasmacaffeine concentrations have been shown to decrease after exchange transfusion. Convulsions may betreated with intravenous administration of anticonvulsants (diazepam or a barbiturate such aspentobarbital sodium or phenobarbital).

Pharmacotherapeutic group: Psychoanaleptics, 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 A1 and A2Asubtypes, demonstrated in receptor binding assays and observed at concentrations approximating thoseachieved therapeutically in this indication.

Caffeine’s main action is as a CNS stimulant. This is the basis of caffeine’s effect in apnoea ofprematurity, for which several mechanisms have been proposed for its actions including: (1)respiratory centre stimulation, (2) increased minute ventilation, (3) decreased threshold tohypercapnia, (4) increased response to hypercapnia, (5) increased skeletal muscle tone, (6) decreaseddiaphragmatic fatigue, (7) increased metabolic rate, and (8) increased oxygen consumption.

The clinical efficacy of caffeine citrate was assessed in a multicentre, randomised, double-blind studythat compared caffeine citrate to placebo in 85 preterm infants (gestational age 28 to <33 weeks) withapnoea of prematurity. Infants received 20 mg/kg caffeine citrate loading dose intravenously. Amaintenance daily dose of 5 mg/kg caffeine citrate was then administered either intravenously ororally (through a feeding tube) for up to 10-12 days. The protocol allowed infants to be “rescued” withopen-label caffeine citrate treatment if their apnoea remained uncontrolled. In that case, infantsreceived a second loading dose of 20 mg/kg caffeine citrate after treatment day 1 and before treatmentday 8.

There were more days without any apnoea under caffeine citrate treatment (3.0 days, versus 1.2 daysfor 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 tocaffeine citrate received an intravenous loading dose of 20 mg/kg, followed by a daily maintenancedose of 5 mg/kg. If apnoeas persisted, the daily maintenance dose could be increased to a maximum of10 mg/kg of caffeine citrate. The maintenance doses were adjusted weekly for changes in body weightand could be given orally once an infant tolerated full enteral feedings. Caffeine therapy reduced therate of bronchopulmonary dysplasia [odds ratio (95% CI) 0.63 (0.52 to 0.76)] and improved the rate ofsurvival 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 ofrespiratory 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)

Caffeine citrate readily dissociates in aqueous solution. The citrate moiety is rapidly metabolized oninfusion or ingestion.

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 peakplasma caffeine concentration (Cmax) ranged from 6 to 10 mg/l and the mean time to reach peakconcentration (tmax) ranged from 30 min to 2 h. The extent of absorption is not affected by formulafeeding but tmax may be prolonged.

Caffeine is rapidly distributed into the brain following caffeine citrate administration. Caffeineconcentrations in the cerebrospinal fluid of preterm newborn infants approximate to their plasmalevels. The mean volume of distribution (Vd) of caffeine in infants (0.8-0.9 l/kg) is slightly higher thanthat in adults (0.6 l/kg). Plasma protein binding data are not available for newborn infants or infants. Inadults, the mean plasma protein binding in vitro is reported to be approximately 36%.

Caffeine readily crosses the placenta into the foetal circulation and is excreted into breast milk.

Caffeine metabolism in preterm newborn infants is very limited due to their immature hepatic enzymesystems 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 andapproximately 3-8% of caffeine administered would be expected to convert to theophylline.

In young infants, the elimination of caffeine is much slower than that in adults due to immaturehepatic and/or renal function. In newborn infants, caffeine clearance is almost entirely by renalexcretion. Mean half-life (t1/2) and fraction excreted unchanged in urine (Ae) of caffeine in infants areinversely 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 ofcaffeine 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 renalinsufficiency have not been conducted.

In the presence of significant renal impairment, considering the increased potential for accumulation, areduced daily maintenance dose of caffeine is required and the doses should be guided by bloodcaffeine measurements. In premature infants with cholestatic hepatitis a prolonged caffeineelimination half-life with an increase of plasma levels above the normal limit of variation has beenfound 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 ofcaffeine. However, at high doses convulsions in rodents were induced. At therapeutic doses somebehavioural changes in newborn rats were induced, most likely as a consequence of increasedadenosine receptor expression that persisted into adulthood. Caffeine was shown to be devoid ofmutagenic and oncogenic risk. Teratogenic potential and effects on reproductive performanceobserved in animals are not relevant to its indication in the preterm infant population.

Citric acid monohydrate

Sodium citrate

Water for injections.

This medicinal product must not be mixed or concomitantly administered in the same intravenous linewith 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 at25ºC.

From a microbiological point of view, when administered with solutions for infusion the medicinalproduct 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 ampoule coded by 2 blue rings.

Pack size of 50 ampoules.

Aseptic technique must be strictly observed throughout handling of the medicinal product since nopreservative is present.

Gencebok should be inspected visually for particulate matter and discoloration prior to administration.

Ampoules containing discoloured solution or visible particulate matter should be discarded.

Gencebok can be either used without dilution or diluted in sterile solutions for infusion such asglucose 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 beinspected visually for particulate matter and discoloration prior to administration. The solution mustnot 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 portionsshould not be saved for later administration.

No special requirements for disposal.

Gennisium Pharma

Swen Parc de Vitrolles

Chemin de la Bastide Blanche13127 Vitrolles - France

EU/1/20/1465/001

Date of first authorisation: 19 August 2020

{MM/YYYY}

Detailed information on this medicinal product is available on the website of the European Medicines

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