Caffeine citrate neupharm

PACKAGE LEAFLET: INFORMATION FOR THE USER

Warning! Keep the leaflet; information on the immediate packaging is in a foreign language!
Caffeine Citrate Neupharm
20 mg/ml, solution for infusion and oral solution
Coffeini citras
Please read this leaflet carefully before using the medicine, as it contains
important information for the newborn.

• Keep this leaflet so that you can read it again if necessary.
• If you have any doubts, consult the doctor caring for the child.
• If any adverse reactions occur in the newborn, including any adverse reactions not listed in this leaflet, inform the doctor caring for the child. See section 4.

Leaflet Contents

1. What Caffeine Citrate Neupharm is and what it is used for
2. Important information before administration of Caffeine Citrate Neupharm to the newborn
3. How to use Caffeine Citrate Neupharm
4. Possible side effects
5. How to store Caffeine Citrate Neupharm
6. Contents of the pack and other information

1. What Caffeine Citrate Neupharm is and what it is used for

Caffeine Citrate Neupharm contains caffeine citrate as the active substance, which is a central nervous system stimulant belonging to a group of medicines called methylxanthines.
Caffeine Citrate Neupharm is used in the treatment of breathing disorders in premature infants (primary apnoea of prematurity).
These short episodes of breathing cessation in premature infants result from incomplete development of respiratory centres.
This medicine has been shown to reduce the number of apnoea episodes in preterm newborns.

2. Important information before using Kofeiny cytrynian Neupharm in a newborn

When not to use Kofeiny cytrynian Neupharm

• If the newborn is allergic to caffeine citrate or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Before starting treatment with Kofeiny cytrynian Neupharm in a newborn, please discuss this with the doctor caring for the child.
Before initiating treatment for apnea of prematurity with Kofeiny cytrynian Neupharm, the doctor caring for the child should exclude or appropriately treat other causes of apnea.
Kofeiny cytrynian Neupharm should be used with caution. Inform the child's doctor:

• if the newborn has seizures;
• if the newborn has heart disease;
• if the newborn has liver or kidney disease;
• if the newborn frequently vomits;
• if the amount of urine passed by the newborn has increased;
• if the newborn's weight gain or food intake has decreased;
• if the mother consumed large amounts of coffee before delivery.

Kofeiny cytrynian Neupharm and other medicines
Tell the doctor caring for the child about all medicines currently or recently administered to the newborn, as well as any medicines planned for future use.
Inform the doctor caring for the child if the newborn has previously been treated with theophylline.
Do not use the following medicines during treatment with Kofeiny cytrynian Neupharm without prior consultation with the doctor caring for the child. The doctor may decide to adjust the dose or replace one of the medicines with another:

• theophylline (used in the treatment of breathing disorders);
• doxapram (used in the treatment of breathing disorders);
• cimetidine (used in the treatment of stomach disorders);
• ketoconazole (used in the treatment of fungal infections);
• phenobarbital (used in the treatment of epilepsy);
• phenytoin (used in the treatment of epilepsy).

This medicine may increase the risk of a serious intestinal disease with bloody stools (necrotizing enterocolitis) when administered concomitantly with medicines used to treat stomach disorders (such as H2-receptor antagonist antihistamines and proton pump inhibitors, which reduce gastric acid secretion).
Pregnancy, breastfeeding, and fertility
If the mother of the newborn is breastfeeding during treatment with Kofeiny cytrynian Neupharm, she must not consume coffee or any products containing high amounts of caffeine, as caffeine passes into breast milk.
Kofeiny cytrynian Neupharm contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. the medicine is considered "sodium-free".

3. How to use Kofeiny cytrynian Neupharm

Kofeiny cytrynian Neupharm should only be administered in a neonatal intensive care unit equipped with appropriate monitoring and supervision devices.
Treatment must be initiated under the supervision of a physician experienced in neonatal intensive care.

Dosage
The physician caring for the infant will prescribe the appropriate dose of Kofeiny cytrynian Neupharm based on the infant's body weight.
The initial dose is 20 mg per kg of body weight (corresponds to 1 ml per kg of body weight).
The maintenance dose is 5 mg per kg of body weight (corresponds to 0.25 ml per kg of body weight) once every 24 hours.

Route and method of administration
Kofeiny cytrynian Neupharm will be administered intravenously via controlled intravenous infusion using a syringe pump or another infusion device with dose measurement capability. This method is commonly known as an "intravenous drip".
Some doses (maintenance doses) may be administered orally.
During treatment, periodic monitoring of caffeine levels in the infant's blood may be necessary to avoid toxicity.

Duration of treatment
The physician caring for the infant will decide how long treatment with Kofeiny cytrynian Neupharm should continue.
If the infant has not experienced apnea episodes for 5–7 days, the physician will discontinue the medication.

Overdose of Kofeiny cytrynian Neupharm
If an overdose of citrated caffeine is administered to a newborn, symptoms may include fever, rapid breathing, convulsions, muscle tremors, vomiting, high blood sugar (hyperglycemia), low blood potassium (hypokalemia), elevated blood levels of certain chemical substances (urea), increased number of certain cells (leukocytes), and seizure episodes.
In such a case, treatment with Kofeiny cytrynian Neupharm must be immediately discontinued, and the physician caring for the infant should manage the overdose.

If you have any further questions regarding the use of this medication, please consult the physician caring for the infant.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
However, it is difficult to distinguish them from the common complications occurring in premature infants and complications related to the disease.
During treatment with Kofeiny cytrynian Neupharm in newborns, the following adverse reactions may occur:
Serious adverse reactions
Adverse reactions for which frequency cannot be determined from available data

• severe intestinal disease with bloody stools (necrotizing enterocolitis).

The physician caring for the infant may also consider the adverse reactions listed below as serious, depending on the overall clinical assessment.
Other adverse reactions
Common adverse reactions (may occur in up to 1 in 10 patients):

• local inflammatory reactions at the infusion site;
• cardiac disorders such as rapid heartbeat (tachycardia);
• increased blood or serum glucose levels (hyperglycaemia).

Uncommon adverse reactions (may occur in up to 1 in 100 patients):

• central nervous system stimulation, manifesting for example as seizures;
• cardiac disorders such as irregular heartbeat (arrhythmia).

Rare adverse reactions (may occur in up to 1 in 1,000 patients):

• hypersensitivity reactions.

Adverse reactions for which frequency cannot be determined from available data:

• blood infection (sepsis);
• changes in blood or serum glucose levels (hypoglycaemia), failure to thrive, feeding intolerance;
• central nervous system stimulation including irritability, nervousness, restlessness, brain injury;
• deafness;
• regurgitation, increased volume of gastric aspirate;
• increased urine output, increased excretion of certain urinary components (sodium and calcium);
• changes in blood tests (decreased haemoglobin concentration after prolonged treatment and decreased thyroid hormone concentration at the beginning of treatment).

Reporting of adverse reactions
If any adverse symptoms occur in the newborn, including any adverse symptoms not listed in this leaflet, inform the physician caring for the infant.
Adverse reactions can also be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products,
Al. Jerozolimskie 181C, 02-222 Warsaw,
Tel.: + 48 22 49 21 301,
Fax: + 48 22 49 21 309,
Website: https://smz.ezdrowie.gov.pl
By reporting adverse reactions, additional information on the safety of the medicine can be collected.

5. How to store Kofeiny cytrynian Neupharm

Keep the medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging.
The expiry date refers to the last day of the stated month.
Do not store in a refrigerator or freeze.
Before administration, visually inspect all parenteral solutions for the presence of particulate matter.
After opening the ampoule, the medicinal product should be used immediately.

6. Contents of the packaging and other information

What Kofeiny cytrynian Neupharm contains

• The active substance is kofeiny cytrynian. One ml contains 20 mg of kofeiny cytrynianu (equivalent to 10 mg/ml of caffeine).
• The other components are: kwas cytrynowy, sodu wodorotlenek and water for injections.

What Kofeiny cytrynian Neupharm looks like and contents of the pack
Kofeiny cytrynian Neupharm is a solution for infusion and an oral solution.
Kofeiny cytrynian Neupharm is a clear, colourless solution supplied in ampoules made of colourless glass (type I), packed in a cardboard box. Each cardboard box contains 10 ampoules.
For more detailed information, please contact the marketing authorisation holder or the parallel importer.
Marketing authorisation holder in Italy, the country of export:
Monico spa
Via Ponte di Pietra 7
30173 Venice Mestre
Italy
Manufacturer:
Monico spa
Via Ponte di Pietra 7
30173 Venice Mestre
Italy
Parallel importer:
Neupharm Sp. z o.o. i wspólnicy Sp. k.
ul. Chełmska 30/34
00-725 Warsaw
Repackaged by:
LABOR Przedsiębiorstwo Farmaceutyczno-Chemiczne Sp. z o.o.
ul. Długosza 49
51-162 Wrocław
Shiraz Productions Sp. z o.o.
ul. Tymiankowa 24/28
95-054 Ksawerów
Marketing authorisation number in Italy, the country of export: 048245029
Parallel import authorisation number: 287/23

Information intended exclusively for medical professionals:

Treatment with caffeine citrate should be initiated under the supervision of a physician experienced in neonatal intensive care. The medicinal product must be administered only in a neonatal intensive care unit equipped with appropriate monitoring and patient surveillance devices.

Dosage

The recommended dosage regimen for previously untreated infants is a loading dose of 20 mg of caffeine citrate per kg of body weight, administered as a slow intravenous infusion over 30 minutes using a syringe pump or another suitable infusion device with precise measurement capability. After a 24-hour interval, a maintenance dose of 5 mg per kg of body weight may be administered every 24 hours as a slow intravenous infusion lasting 10 minutes. Alternatively, maintenance doses of 5 mg per kg of body weight may be given orally every 24 hours, for example via a nasogastric tube.

The recommended loading and maintenance doses of caffeine citrate are presented in the table below, which reflects the relationship between injection volume and administered doses of caffeine citrate.

The dose of caffeine is half the dose of caffeine citrate (20 mg of caffeine citrate corresponds to 10 mg of caffeine).

*24 hours after administration of the loading dose.
In preterm neonates with an inadequate clinical response to the recommended loading dose, a second loading dose of up to 10–20 mg/kg body weight may be administered after 24 hours.
If the response remains insufficient, consideration may be given to using a higher maintenance dose of 10 mg/kg body weight, taking into account the potential for caffeine accumulation due to its prolonged half-life in preterm neonates and the progressively increasing ability to metabolize caffeine relative to postmenstrual age. Serum caffeine concentrations should be monitored.
The diagnosis of apnea in preterm infants may need to be reconsidered in cases of inadequate response to the second loading dose or to a maintenance dose of 10 mg/kg/day.

Dose adjustment and monitoring
Periodic monitoring of serum caffeine concentrations during treatment may be necessary in cases of incomplete clinical response or signs of toxicity.
Additionally, dose adjustment may be required according to the physician’s judgment following routine monitoring of serum caffeine concentrations in situations of risk, such as:

• preterm infants born significantly early (gestational age <28 weeks and/or body weight <1000 g), particularly if receiving parenteral nutrition;
• infants with impaired liver or kidney function;
• infants with seizures;
• infants diagnosed with clinically significant heart disease;
• infants concomitantly receiving medicinal products known to affect caffeine metabolism;
• infants fed breast milk from mothers consuming caffeine-containing products.

Baseline caffeine concentration measurement is recommended in:

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

The half-life of caffeine is prolonged in preterm infants, and accumulation is possible, which may necessitate monitoring in infants receiving prolonged treatment.
Blood samples for monitoring should be taken immediately before the next dose in cases of treatment failure, and 2 to 4 hours after the previous dose in cases of suspected toxicity.
Although a definitive therapeutic range for serum caffeine concentrations has not been established in the literature, clinical benefits have been observed in studies at concentrations between 8 and 30 mg/L, and safety profiles have generally not been compromised at serum concentrations below 50 mg/L.

Duration of treatment
The optimal duration of treatment has not been established. In a recent large, multicenter study involving preterm neonates, the average duration of treatment was 37 days.
In clinical practice, treatment is usually continued until the infant reaches a postmenstrual age of 37 weeks, at which time apnea of prematurity typically resolves spontaneously. However, this limit may be adjusted based on clinical assessment of individual cases, depending on response to treatment, continued occurrence of apneic episodes despite therapy, or other clinical indications. Discontinuation of citrated caffeine is recommended if there has been no significant apneic episode for 5–7 days.
If apnea recurs, citrated caffeine administration may be resumed using either the maintenance dose or half the loading dose, depending on the interval between discontinuation of caffeine and recurrence of apnea.
Due to the slow elimination of caffeine in this patient group, there is no need to taper the dose when stopping treatment.
Because of the risk of apnea recurrence after discontinuation of citrated caffeine, patient monitoring should continue for approximately one week.

Impaired liver or kidney function
Experience with the use of this medicinal product in patients with impaired liver or kidney function is limited. In a post-marketing safety study, the frequency of adverse events in a small group of extremely preterm neonates with impaired liver or kidney function appeared higher than in preterm infants without organ dysfunction.
In cases of renal impairment, there is an increased risk of drug accumulation. The daily maintenance dose of citrated caffeine should be reduced, and dosing should be adjusted based on serum caffeine concentrations.
In extremely preterm neonates, caffeine clearance is independent of liver function. Hepatic metabolism of caffeine develops gradually in the weeks following birth, and in older infants, liver disease may necessitate monitoring of serum caffeine concentrations and dose adjustment.

Administration method
Citrated caffeine may be administered by intravenous infusion or orally. The medicinal product must not be administered by intramuscular, subcutaneous, intrathecal, or intraperitoneal injection.
For intravenous administration, citrated caffeine must be given via a controlled intravenous infusion, exclusively using a syringe pump or another device capable of precise dosing. Citrated caffeine may be used undiluted or diluted in sterile infusion solutions such as glucose 50 mg/ml (5%), sodium chloride 9 mg/ml (0.9%), or calcium gluconate 100 mg/ml (10%) immediately after withdrawal from the ampoule.

Preparation of infusion solution
Extreme care must be taken to follow aseptic technique during preparation, as the product contains no preservatives.
Before administration, Kofeiny cytrynian Neupharm should be inspected visually for the presence of particulate matter and discoloration. Ampoules containing discolored solution or visible particulates should be discarded.
Kofeiny cytrynian Neupharm may be used undiluted or diluted in sterile infusion solutions such as 5% glucose (50 mg/ml), 0.9% sodium chloride solution (9 mg/ml), or 10% calcium gluconate solution (100 mg/ml), immediately after withdrawal from the ampoule.
The diluted solution must be clear and colorless. All parenteral solutions, whether undiluted or diluted, should be inspected visually for particulate matter and discoloration before administration. The solution must not be used if discoloration or particulates are present.
For single use only. Any unused portion remaining in the ampoule must be discarded. Unused remnants must not be saved for later administration.
No special requirements for disposal.

Stability and storage conditions of the diluted medicinal product
After opening the ampoule, the medicinal product should be used immediately. Dilution must be performed using aseptic technique.

Overdose
Reported serum caffeine concentrations following overdose have ranged from 50 mg/L to 350 mg/L.

Symptoms
Objective and subjective symptoms reported in the literature following caffeine overdose in preterm infants include hyperglycemia, hypokalemia, limb tremors, restlessness, hypertonia, opisthotonus, tonic-clonic movements, seizures, rapid breathing, tachycardia, vomiting, gastrointestinal irritation, gastrointestinal bleeding, fever, tremor, increased blood urea, leukocytosis, and purposeless jaw and lip movements.
One case of caffeine overdose complicated by intraventricular hemorrhage and long-term neurological sequelae has been reported. No deaths related to caffeine overdose in preterm infants have been observed.

Management
Treatment of caffeine overdose is primarily symptomatic and supportive. Serum potassium and glucose concentrations should be monitored and hypokalemia and hyperglycemia corrected. Blood transfusion has been shown to reduce serum caffeine concentration. Tremors may be treated with intravenous anticonvulsants (diazepam or barbiturates such as sodium pentobarbital or phenobarbital).

Pharmaceutical incompatibilities
This medicinal product must not be mixed or administered in the same intravenous line with other medicinal products, except those listed in the section "Preparation of infusion solution".