Caffeine citrate neupharm

PACKAGE LEAFLET: INFORMATION FOR THE USER

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

• Keep this leaflet, so 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.

Table of contents of the leaflet

1. What is Coffeini citras Neupharm and what it is used for
2. Important information before using Coffeini citras Neupharm in newborns
3. How to use Coffeini citras Neupharm
4. Possible side effects
5. How to store Coffeini citras Neupharm
6. Contents of the packaging and other information

1. What is Coffeini citras Neupharm and what it is used for

Coffeini citras Neupharm contains the active substance caffeine citrate, which is a central nervous system stimulant belonging to a group of medicines called methylxanthines.
Coffeini citras Neupharm is used in the treatment of breathing disorders in preterm infants (primary apnoea of prematurity).
These brief periods of breathing cessation in preterm infants result from the 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 Coffeini citras Neupharm in a newborn

When not to use Coffeini citras Neupharm

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

Warnings and precautions
Before starting treatment with Coffeini citras Neupharm in a newborn, discuss this with the doctor caring for the child.
Before starting treatment for apnea of prematurity with Coffeini citras Neupharm, the doctor caring for the child should exclude or appropriately treat other causes of apnea.
Coffeini citras 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 child's mother consumed large amounts of coffee before delivery.

Coffeini citras Neupharm and other medicines
Tell the doctor caring for the child about all medicines currently used or recently used in the newborn, as well as any medicines planned for future use.
Inform the doctor if the newborn has previously been treated with theophylline.
Do not use the following medicines during treatment with Coffeini citras 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 respiratory disorders);
• doxapram (used in the treatment of respiratory 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 effects on fertility
If the mother of the newborn is breastfeeding during treatment with Coffeini citras Neupharm, she should not consume coffee or any products containing high amounts of caffeine, because caffeine passes into breast milk.

Coffeini citras Neupharm contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, meaning the medicine is considered "sodium-free".

3. How to use Coffeini citras Neupharm

Coffeini citras Neupharm should only be administered in a neonatal intensive care unit equipped with appropriate devices for patient monitoring and supervision.
Treatment must be initiated under the supervision of a physician experienced in neonatal intensive care.
Dosage
The physician caring for the child will prescribe the appropriate dose of Coffeini citras Neupharm based on the child's body weight.
The initial dose is 20 mg per kg of body weight (equivalent to 1 ml per kg of body weight).
The maintenance dose is 5 mg per kg of body weight (equivalent to 0.25 ml per kg of body weight) administered every 24 hours.
Route and method of administration
Coffeini citras Neupharm will be administered intravenously via controlled intravenous infusion using a syringe pump or another infusion delivery device with measuring capability. This method is commonly known as an "infusion".
Some doses (maintenance doses) may be administered orally.
During treatment, periodic monitoring of caffeine blood levels in the child may be necessary to avoid toxicity.
Duration of treatment
The physician caring for the child will decide how long treatment with Coffeini citras Neupharm should continue.
If the child has had no apnoea episodes for 5–7 days, the physician will discontinue the treatment.
Administration of a higher than recommended dose of Coffeini citras Neupharm
If a higher than recommended dose of caffeine citrate is administered to a newborn, symptoms may include fever, rapid breathing, seizures, muscle tremors, vomiting, high blood sugar (hyperglycaemia), low blood potassium levels (hypokalaemia), elevated blood levels of certain chemical substances (urea), increased number of certain cells (leukocytes), and seizure attacks.
In such a case, treatment with Coffeini citras Neupharm must be stopped immediately, and the physician caring for the child should manage the overdose.
If there are any further doubts regarding the use of this medicinal product, please consult the physician caring for the child.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
However, it may be difficult to distinguish them from common complications occurring in preterm infants and complications related to the underlying disease.
The following adverse reactions may occur during treatment with Coffeini citras Neupharm in newborns:
Serious adverse reactions
Adverse reactions whose frequency cannot be determined from available data

• Severe intestinal disease with bloody stools (necrotising 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 fast heart rate (tachycardia);
• Increased blood or serum glucose concentration (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 whose frequency cannot be determined from available data:

• Blood infection (sepsis);
• Changes in blood or serum glucose concentration (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 concentration of certain urinary components (sodium and calcium);
• Changes in blood test results (decreased haemoglobin concentration after long-term treatment and decreased thyroid hormone concentration at the beginning of treatment).

Reporting of adverse reactions
If any adverse reactions occur in the newborn, including any adverse reactions 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 Coffeini citras Neupharm

The medicine should be stored 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 specified month.
Do not store in a refrigerator and do not freeze.
Before administration, all parenteral solutions should be visually inspected for the presence of particulate matter. After opening the ampoule, the medicinal product should be used immediately.

6. Contents of the package and other information

What Coffeini citras Neupharm contains

• The active substance is caffeine citrate. One ml contains 20 mg of caffeine citrate (equivalent to 10 mg/ml of caffeine).
• The other components are: citric acid, sodium hydroxide and water for injections.

What Coffeini citras Neupharm looks like and contents of the pack
Coffeini citras Neupharm is a solution for infusion and oral solution.
Coffeini citras Neupharm is a clear, colourless solution supplied in ampoules made of colourless glass (type I), packed in a cardboard box. One cardboard box contains 10 ampoules.
For further information, please contact the responsible entity 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.
ul. Ługowa 85
96-320 Mszczonów
Repackaged by:
LABOR Pharmaceutical and Chemical Enterprise Sp. z o.o.
ul. Długosza 49
51-162 Wrocław
GP LABEL Ostrowski spółka jawna
ul. Obywatelska 128/152
94-104 Łódź
Marketing Authorisation Number in Italy, the country of export: 048245029
Parallel Import Licence Number: 435/24

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 should be used exclusively in a neonatal intensive care unit equipped with appropriate devices for patient monitoring and surveillance.

Dosage

The recommended dosing regimen for previously untreated infants is a loading dose of 20 mg of caffeine citrate per kg body weight, administered as a slow intravenous infusion over 30 minutes using a syringe pump or another device capable of accurate measurement. After a 24-hour interval, a maintenance dose of 5 mg per kg body weight may be administered every 24 hours as a slow intravenous infusion lasting 10 minutes. Alternatively, maintenance doses of 5 mg per kg 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 caffeine dose corresponds to half the dose of caffeine citrate (20 mg caffeine citrate equals 10 mg 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 24 hours later.
If the response remains insufficient, consideration may be given to increasing the maintenance dose to 10 mg/kg body weight, taking into account the potential for caffeine accumulation due to its long 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 of prematurity should be reconsidered if there is no adequate 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 inadequate clinical response or signs of toxicity.
Additionally, dose adjustment may be required based on physician assessment following routine monitoring of serum caffeine concentrations in high-risk situations 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 with diagnosed and clinically significant heart disease;
• Infants receiving concomitant medicinal products known to affect caffeine metabolism;
• Infants fed breast milk from mothers consuming caffeine-containing products.

Measurement of baseline caffeine concentration 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 require 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 plasma 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 has generally not been compromised at plasma 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 mean 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 individual clinical assessment, depending on response to treatment, persistent episodes of apnea despite therapy, or other clinical considerations. Discontinuation of citrated caffeine is recommended if no significant apneic episodes have occurred 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 length of the interval between discontinuation and recurrence.
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, patients should continue to be monitored 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 to be 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 according to 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.

Method of administration
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 controlled intravenous infusion using only an infusion pump or syringe driver or other device capable of accurate dosing. Citrated caffeine may be used undiluted or diluted in sterile infusion solutions such as 50 mg/ml (5%) glucose solution, 9 mg/ml (0.9%) sodium chloride solution, or 100 mg/ml (10%) calcium gluconate solution, immediately after withdrawal from the ampoule.

Preparation of infusion solution
Strict aseptic technique must be followed during preparation of the medicinal product, as it contains no preservatives.
Before administration, the product Coffeini citras Neupharm should be inspected visually for the presence of particulate matter and discoloration. Ampoules containing discolored solution or visible particulates should be discarded.
The medicinal product Coffeini citras 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. Both undiluted and diluted parenteral solutions should be inspected visually for particulate matter and discoloration before administration. Solutions showing discoloration or particulates must not be used.
For single use only. Any unused portion remaining in the ampoule must be discarded. Unused remnants should 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 range 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, tachypnea, tachycardia, vomiting, gastrointestinal irritation, gastrointestinal bleeding, fever, tremor, elevated blood urea nitrogen, 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. Caffeine serum concentrations have been shown to decrease following blood transfusion. 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 under "Preparation of infusion solution".