4.1. Therapeutic indications

Treatment of primary apnoea of premature newborns.

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.

Infants must be of sufficient respiratory maturity not to require positive pressure ventilation.

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).

Dose of caffeine citrate (Volume)

Dose of caffeine citrate (mg/kg body weight)

Route

Frequency

Loading dose

1.0 mL/kg body weight

20 mg/kg body weight

Intravenous infusion (over 30 minutes)

Once

Maintenance dose*

0.25 mL/kg body weight

5 mg/kg body weight

Intravenous infusion (over 10 minutes) or by oral administration

Every 24 hours*

* Beginning 24 hours after the loading dose

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).

Other formulations of caffeine citrate solution for treatment of apnoea in newborns are also available which contain a different dose strength of caffeine citrate to Fenapin 20 mg/ml Solution for Infusion. Care should be taken to avoid confusing the different products, as this may result in medication errors.

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 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 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, 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. The medicinal product must not be administered by intramuscular, subcutaneous, intrathecal or intraperitoneal injection.

Caffeine citrate 20 mg/ml Solution for infusion is also effective when administered orally, and this route may be used alternatively without adjusting the dose.

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).

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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.

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 recognise 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 50 micrograms/ml (optimally 10-30 micrograms/ml).

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

Not relevant.

4.8. Undesirable effects

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).

System Organ Class

Adverse Reaction

Frequency

Infections and infestations

Sepsis

Not known

Immune system disorders

Hypersensitivity reaction

Rare

Metabolism and nutrition disorders

Hyperglycaemia

Common

Hypoglycaemia, failure to thrive, feeding intolerance

Not known

Nervous system disorders

Convulsion

Uncommon

Irritability, jitteriness, restlessness, brain injury

Not known

Ear and labyrinth disorders

Deafness

Not known

Cardiac disorders

Tachycardia

Common

Arrhythmia

Uncommon

Increased left ventricular output and increased stroke volume

Not known

Gastrointestinal disorders

Regurgitation, increased gastric aspirate, necrotising enterocolitis

Not known

General disorders and administration site conditions

Infusion site phlebitis, infusion site inflammation

Common

Investigations

Urine output increased, urine sodium and calcium increased, haemoglobin decreased, thyroxine decreased

Not known

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 caffeine citrate, 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 reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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).