Peona

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PEYONA (PEYONA®)

Composition:

Active substance: caffeine citrate;

1 ml of the medicinal product contains 20 mg of caffeine citrate (equivalent to 10 mg of caffeine);

Excipients: citric acid monohydrate; sodium citrate; water for injections.

Pharmaceutical form. Solution for infusion and oral use.

Main physicochemical properties: clear solution without visible mechanical particles.

Pharmacotherapeutic group. Psychoanaleptics, xanthine derivatives.

ATC code N06BC01.

Pharmacological Properties

Pharmacodynamics.

Mechanism of action

Caffeine is structurally related to the methylxanthines theophylline and theobromine. Most of its effects are associated with antagonism of adenosine receptors of subtypes A₁ and A_2A, as demonstrated by receptor binding analyses, and occur at concentrations approximately equal to therapeutic concentrations for the given indications.

Pharmacodynamic effects

The primary action of caffeine is stimulation of the central nervous system. This underlies caffeine's effect in apnea of prematurity and involves several mechanisms, including:

• stimulation of respiratory centers;
• increased minute ventilation;
• reduced threshold for arterial carbon dioxide tension;
• enhanced responsiveness to carbon dioxide;
• increased skeletal muscle tone;
• reduced diaphragmatic fatigue;
• increased metabolic rate;
• increased oxygen consumption.

Therapeutic efficacy and safety

The therapeutic efficacy of caffeine citrate was evaluated in a multicenter, randomized, double-blind study comparing caffeine citrate with placebo in 85 preterm neonates (gestational age 28 to 33 weeks) with apnea of prematurity. Infants received an intravenous loading dose of caffeine of 20 mg/kg, followed by a daily intravenous or oral (via feeding tube) maintenance dose of 5 mg/kg for 10–12 days. The protocol allowed for rescue therapy with caffeine citrate if apnea remained uncontrolled. In such cases, infants received a repeat loading dose of caffeine 20 mg/kg between day 1 and day 8 of therapy.

The number of apnea-free days was greater with caffeine citrate treatment (3.0 days vs. 1.2 days with placebo, p=0.005); also, the proportion of patients without apnea for 8 or more days was higher (22% with caffeine vs. 0% with placebo).

In a recently conducted multicenter, placebo-controlled study (n=2006), short-term and long-term (18–21 months) outcomes in preterm neonates receiving caffeine citrate therapy were evaluated. Patients were randomly assigned to receive an intravenous loading dose of caffeine citrate 20 mg/kg, followed by a daily maintenance dose of 5 mg/kg. If apnea persisted, the daily maintenance dose could be increased up to a maximum of 10 mg/kg. Maintenance doses were adjusted weekly according to changes in body weight and could be administered orally if the patient was on full enteral feeding. Treatment with caffeine resulted in a reduction in the incidence of bronchopulmonary dysplasia [relative risk (95% CI) 0.63 (0.52 to 0.76)] and improved rates of survival without neurodevelopmental impairment [relative risk (95% CI) 0.77 (0.64 to 0.93)].

The effect of caffeine on mortality and disability outcomes depended on the level of respiratory support required by neonates at enrollment and demonstrated a beneficial effect in those who received it [relative risk (95% CI) of mortality and disability – see Table 1].

Table 1

Mortality and disability in the respiratory support group at study entry

Pharmacokinetics.

Caffeine citrate dissociates in aqueous solution. The citrate moiety is rapidly metabolized following infusion or oral administration.

Absorption

The effect of caffeine in caffeine citrate occurs within several minutes after initiation of infusion. After oral administration of 10 mg of caffeine per kg of body weight to preterm neonates, peak plasma concentration (C_max) ranges from 6 to 10 mg/L, and the mean time to reach peak concentration (t_max) ranges from 30 minutes to 2 hours. The extent of absorption is independent of the composition of the feeding mixture, but t_max may be prolonged.

Distribution

Caffeine rapidly reaches the brain after administration of caffeine citrate. The concentration of caffeine in cerebrospinal fluid of preterm neonates is approximately equal to that in plasma. The mean volume of distribution (V_d) of caffeine in neonates (0.8–0.9 L/kg) is slightly higher than in adult patients (0.6 L/kg). Data on plasma protein binding in neonates and infants are lacking. In adults, the mean in vitro plasma protein binding is reported to be 36%.

Caffeine crosses the placenta into the fetal circulation and is excreted into maternal breast milk.

Biotransformation

Caffeine metabolism in preterm neonates is very limited due to underdeveloped hepatic enzyme systems, and the majority of the active substance is excreted unchanged in urine. Hepatic cytochrome P450 1A2 (CYP1A2) is involved in caffeine biotransformation in older individuals.

There have been reports of mutual conversion between caffeine and theophylline in preterm neonates; caffeine levels are approximately 25% of theophylline levels after theophylline administration, and it is expected that approximately 3–8% of administered caffeine is converted to theophylline.

Elimination

In early infancy, caffeine elimination is considerably slower than in adults due to immature hepatic and/or renal function. In neonates, caffeine clearance occurs almost entirely via renal excretion. The mean elimination half-life (t_1/2) of the fraction of caffeine excreted unchanged in urine (A_e) in infants is inversely proportional to gestational age. In neonates, t_1/2 is approximately 3–4 days, and A_e is approximately 86% (over 6 days). By the ninth month of life, caffeine metabolism approaches that of adults (t_1/2 = 5 hours, A_e = 1%).

Pharmacokinetic studies of caffeine in neonates with hepatic or renal insufficiency have not been conducted.

In cases of significant liver impairment, due to the substantial potential for accumulation, the daily maintenance dose should be reduced based on serum caffeine concentration monitoring. In preterm neonates with cholestatic hepatitis, prolonged caffeine half-life and increased plasma caffeine concentrations above normal ranges have been observed; therefore, dosing in such patients requires particular caution.

Clinical characteristics.

Indications.

Treatment of primary apnea in premature newborns.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

In premature newborns, there is interconversion between caffeine and theophylline. These active substances should not be used simultaneously.

Cytochrome P450 1A2 (CYP1A2) is the main enzyme involved in caffeine metabolism in the human body. Therefore, caffeine has the potential to interact with active substances that are substrates of CYP1A2, inhibit CYP1A2, or induce CYP1A2. However, caffeine metabolism in premature newborns is limited due to the immaturity of their hepatic enzyme system.

Despite limited data on caffeine interactions with other active substances, a reduction in caffeine citrate dosage may be necessary in premature newborns after administration of active substances that decrease caffeine clearance in adults (e.g., cimetidine and ketoconazole). An increase in caffeine citrate dosage may also be required after administration of active substances that increase caffeine clearance (e.g., phenobarbital and phenytoin). If there is any doubt regarding a potential interaction, monitoring of plasma caffeine concentrations is recommended.

Since excessive gut microbial colonization may be associated with the development of necrotizing enterocolitis, concomitant administration of caffeine citrate and medicinal products that suppress gastric secretion (H2-receptor antagonists or proton pump inhibitors) may theoretically increase the risk of necrotizing enterocolitis.

Concomitant administration of caffeine and doxapram may potentiate their stimulatory effects on the cardiovascular, respiratory, and central nervous systems. If simultaneous use of these agents is indicated, careful monitoring of heart rate and blood pressure is required.

Special precautions for use.

Apnea

Apnea in preterm newborns is diagnosed by exclusion. Other causes of apnea (e.g., disorders of the central nervous system, primary pulmonary insufficiency, anemia, sepsis, metabolic disorders, cardiovascular disorders, obstructive apnea) must be excluded or appropriately treated before initiating caffeine citrate therapy. Lack of response to caffeine therapy (if necessary, confirmed by plasma concentration measurements) may indicate alternative causes of apnea.

Use of caffeine

In newborns whose mothers received high doses of caffeine prior to delivery, baseline plasma caffeine concentrations should be determined before starting caffeine citrate therapy, as caffeine crosses the placenta into the fetal circulation.

Breastfeeding mothers of infants receiving caffeine citrate therapy should avoid food, beverages, or medications containing caffeine, since caffeine is excreted into breast milk.

Theophylline

In newborns previously treated with theophylline, baseline caffeine concentration should be measured before initiating caffeine citrate therapy, as theophylline is metabolized to caffeine in newborns.

Seizures

Caffeine is a central nervous system stimulant. Seizures have been reported in cases of overdose. Caffeine citrate should be used with particular caution in newborns with conditions associated with seizure disorders.

Cardiovascular reactions

Published studies have demonstrated that caffeine administration increases heart rate, left ventricular stroke volume, and cardiac stroke volume. Therefore, caffeine citrate should be used cautiously in newborns with cardiovascular disorders. Evidence indicates caffeine may induce tachyarrhythmias in predisposed individuals. In newborns, this typically manifests as sinus tachycardia. If any unusual rhythm disturbances were observed on cardiotocography (CTG) prior to delivery, caffeine citrate should be administered with caution.

Renal and hepatic impairment

Caffeine citrate should be administered with caution to preterm newborns with impaired renal or hepatic function. In post-marketing safety studies, the incidence of adverse reactions was higher in a small number of very preterm infants with renal/hepatic impairment compared to preterm infants with normal organ function. To avoid intoxication, dosing in these patients should be guided by monitoring plasma caffeine concentrations.

Necrotizing enterocolitis

Necrotizing enterocolitis is a common cause of morbidity and mortality in preterm newborns. There have been reports suggesting a possible association between methylxanthine use and the development of necrotizing enterocolitis. However, a causal relationship between caffeine or other methylxanthines and necrotizing enterocolitis has not been established. All preterm newborns, especially those receiving caffeine citrate therapy, should be closely monitored for signs of necrotizing enterocolitis.

Caffeine citrate should be used cautiously in infants with gastroesophageal reflux, as treatment may exacerbate this condition.

Caffeine citrate increases metabolic rate, which may lead to increased energy and nutritional requirements during therapy.

Diuresis and electrolyte loss caused by caffeine citrate may require correction of fluid and electrolyte balance.

Sodium content

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

In animal studies, caffeine at high doses has shown embryotoxic and teratogenic effects. These effects are not observed with short-term administration in preterm newborns.

Lactation

Caffeine is excreted in breast milk and rapidly crosses the placenta into the fetal circulation.

Breastfeeding mothers whose newborn infants are receiving caffeine citrate therapy should avoid consuming food, beverages, or medications containing caffeine.

In newborns whose mothers received high doses of caffeine prior to delivery, baseline plasma caffeine concentration should be determined before initiating caffeine citrate therapy.

Fertility

Effects on the reproductive system observed in animals are not relevant to the use of this drug in preterm newborns.

Ability to affect reaction speed when driving or operating machinery.

Not applicable.

Method of Administration and Dosage

Initiation of therapy with caffeine citrate is permitted under the supervision of a physician experienced in resuscitation procedures in newborns. The medicinal product must be used exclusively in a neonatal intensive care unit equipped with appropriate devices for monitoring and observation.

Dosage

The recommended dose for neonates receiving caffeine therapy for the first time is 20 mg of caffeine citrate per 1 kg of body weight, administered as a slow intravenous infusion over 30 minutes using an infusion syringe pump or another controlled infusion device. Maintenance doses of 5 mg per 1 kg of body weight may be administered 24 hours after the loading dose, given as a slow intravenous infusion over 10 minutes every 24 hours. Alternatively, maintenance doses of 5 mg per 1 kg of body weight may be administered orally every 24 hours using devices such as a nasogastric tube.

The recommended loading and maintenance doses of caffeine citrate are presented in Table 2, which provides clarification on the relationship between the volume of administered drug and the amount of caffeine citrate delivered.

The dose expressed as caffeine is half the dose expressed as caffeine citrate (20 mg of caffeine citrate is equivalent to 10 mg of caffeine).

Table 2

*Initiation of administration 24 hours after the loading dose.

If an adequate therapeutic response is not achieved in preterm neonates after administration of the recommended loading dose, a second loading dose of 10–20 mg/kg may be administered 24 hours later.

If an adequate therapeutic response is not achieved, consideration may be given to increasing the maintenance dose up to 10 mg/kg, taking into account the cumulative potential of caffeine due to its prolonged elimination half-life in preterm neonates and the progressive increase in the ability to metabolize caffeine with advancing gestational age. Plasma caffeine levels should be monitored when clinically indicated. If an adequate therapeutic response is not achieved after administration of a second loading dose or a maintenance dose of 10 mg/kg/day, the diagnosis of apnea in neonates may need to be reconsidered.

Dose adjustment and monitoring

Plasma caffeine concentrations should be periodically monitored during treatment if there is no improvement in the patient's condition or if signs of intoxication appear.

The physician may also decide to adjust the dose based on plasma caffeine concentration monitoring results in the presence of risk factors such as:

• Low gestational age (< 28 weeks and/or body weight < 1000 g), particularly when receiving parenteral nutrition;
• Presence of hepatic or renal impairment in the infant;
• Presence of epilepsy in the infant;
• Clinically significant cardiac insufficiency in the infant;
• Concomitant administration of medicinal products that affect caffeine metabolism;
• Maternal caffeine intake during breastfeeding.

Baseline caffeine levels are recommended to be determined:

• In infants whose mothers consumed large amounts of caffeine prior to delivery;
• In infants previously treated with theophylline, which is metabolized to caffeine.

The elimination half-life of caffeine in preterm neonates is longer than usual, and due to its high potential for accumulation, prolonged monitoring of infants undergoing extended treatment may be required.

Blood samples for monitoring should be collected immediately before the next dose if therapeutic efficacy is lacking, and 2–4 hours after administration if intoxication is suspected.

Although the therapeutic plasma caffeine level has not been clearly defined in published sources, during clinical studies, plasma levels associated with therapeutic efficacy ranged from 8 to 30 mg/L. Safety concerns were generally not raised when caffeine levels remained below 50 mg/L.

Treatment duration

The optimal treatment duration has not been established. Results from a recent multicenter study in preterm neonates reported a treatment duration of 37 days.

In clinical practice, treatment usually continues until neonates reach a gestational age of 37 weeks, by which time primary apnea typically resolves. However, this limit may be reassessed by the physician in individual cases depending on treatment efficacy, occurrence of apnea episodes despite therapy, or other clinical factors. Caffeine citrate administration is recommended to be discontinued if no significant apnea episodes occur over a period of 5–7 days.

If apnea recurs, caffeine citrate administration should be resumed at the maintenance dose or half the loading dose, depending on the interval between discontinuation of caffeine citrate and recurrence of apnea.

Due to the delayed elimination of caffeine in this patient group, there are no requirements for dose tapering or gradual discontinuation of treatment.

Due to the risk of recurrent apnea episodes after discontinuation of caffeine citrate therapy, patient monitoring should continue for approximately one week.

Hepatic and renal impairment

Experience with use in patients with impaired renal or hepatic function is limited. In post-marketing safety studies, the frequency of adverse reactions in a small number of very preterm infants with renal/hepatic impairment was higher compared to preterm infants without organ dysfunction.

In the presence of renal impairment, the cumulative potential increases. The daily maintenance dose of caffeine citrate should be reduced according to plasma caffeine concentration levels.

In patients with very low gestational age, caffeine clearance is not dependent on liver function. Hepatic metabolism of caffeine develops gradually over several weeks after birth, and in older infants, hepatic impairment may require monitoring of plasma caffeine levels and dose adjustment.

Route of administration

Caffeine citrate can be administered by intravenous infusion or orally. Intramuscular, subcutaneous, intrathecal, or intraperitoneal injection is not permitted.

For intravenous administration, caffeine citrate should be given by controlled intravenous infusion using an infusion syringe pump or another controlled infusion device. Caffeine citrate may be administered undiluted or diluted with sterile infusion solutions such as 50 mg/mL (5%) glucose solution, 9 mg/mL (0.9%) sodium chloride, or 100 mg/mL (10%) calcium gluconate, immediately after withdrawal from the ampoule.

Children

The medicinal product is used in preterm neonates.

Overdose

According to published data, plasma caffeine levels after overdose ranged from 50 mg/L to 350 mg/L.

Symptoms

Published reports of caffeine overdose symptoms in preterm neonates include hyperglycemia, hypokalemia, fine limb tremors, agitation, hypertonia, opisthotonus, tonic-clonic seizures, epileptic seizures, tachypnea, tachycardia, vomiting, gastric irritation, gastrointestinal bleeding, fever, syndrome of increased neuromuscular excitability, elevated blood urea nitrogen, leukocytosis, and uncontrolled jaw and lip movements. One case of caffeine overdose was reported to be complicated by intraventricular hemorrhage and prolonged neurological complications. There have been no reports of fatal outcomes due to caffeine overdose in preterm neonates.

Management in case of overdose

In case of caffeine overdose, treatment is primarily symptomatic and supportive. Monitoring of potassium and glucose levels is required, with appropriate measures taken to correct hypokalemia and hyperglycemia. Studies have shown that plasma caffeine levels decrease following exchange transfusion. Seizure management may include intravenous administration of anticonvulsants (diazepam or barbiturates such as sodium pentobarbital or phenobarbital).

Adverse Reactions

Pharmacological and toxicological data on caffeine and other methylxanthines provide information on the likely adverse reactions associated with caffeine citrate, including central nervous system stimulation such as convulsions, irritability, excited state, syndrome of increased neuropsychomotor excitability, effects on the cardiovascular system such as tachycardia, hypertension, and increased cardiac stroke volume, as well as disturbances in metabolism and nutrition such as hyperglycemia. These effects are dose-dependent and may require plasma concentration monitoring and dose reduction of caffeine.

Adverse reactions that may be related to caffeine citrate and have been reported in the medical literature are listed below by system organ classes and frequency of occurrence (MedDRA).

Frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from available data).

Description of some adverse reactions

Necrotizing enterocolitis is a common factor of mortality and morbidity among premature newborns. A possible association between the use of methylxanthines and the occurrence of necrotizing enterocolitis has been reported. However, a causal relationship between the use of caffeine or other methylxanthines and necrotizing enterocolitis has not been established.

In a double-blind, placebo-controlled study of caffeine citrate involving 85 premature newborns, necrotizing enterocolitis was diagnosed during the blinded phase of the study in 2 children receiving active treatment and in 1 child receiving placebo, and in 3 children receiving caffeine during the open-label phase of the study. Three of the children who developed necrotizing enterocolitis during the study died. A large multicenter study (n=2006) on long-term outcomes in premature newborns receiving caffeine citrate therapy did not demonstrate an increased incidence of necrotizing enterocolitis in the caffeine group compared to placebo. All premature newborns receiving caffeine citrate therapy should be carefully monitored for the development of necrotizing enterocolitis.

Brain injury, seizures, and deafness have been observed, but they were more frequent in the placebo group.

Caffeine may suppress erythropoietin synthesis and, consequently, reduce hemoglobin levels with prolonged use.

Transient decreases in thyroxine (T4) levels have been observed in infants at the beginning of therapy, but these did not persist throughout the treatment period.

Available data do not indicate any long-term adverse effects of caffeine therapy on neurological development, growth retardation, or on the cardiovascular, gastrointestinal, or endocrine systems in newborns. Caffeine does not exacerbate cerebral hypoxia or worsen the outcomes of any injuries, but this possibility should not be entirely excluded.

Other special patient groups

In a post-marketing safety study involving 506 premature infants treated with the medicinal product Peiona, safety data were collected for 31 very premature infants with impaired kidney/liver function. Adverse reactions were more frequent in this subgroup with organ dysfunction compared to other children without organ impairment. Cardiac disorders (tachycardia, including one single case of arrhythmia) were mostly reported.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of the medicinal product is important. Continuous monitoring of the benefit-risk balance of the medicinal product is required.

Shelf life. 3 years.

After opening the ampoule – use the medicinal product immediately.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

Solution for infusion and oral administration, 1 ml in an ampoule; 5 ampoules in a blister pack, 2 blister packs in a cardboard box.

Prescription status. Prescription only, and only under hospital conditions.

Manufacturer.

Chiesi Pharmaceuticals GmbH.

Manufacturer's address.

Gonzagagasse 16/16, 1010 Wien, Austria.