active substance: citrate Саffeine;
1 ml of the drug contains 20 mg caffeine citrate (equivalent to 10 mg caffeine)
auxiliary substances: citric acid monohydrate, sodium; water for injection.
Solution for infusion and oral administration.
Basic physical and chemical properties: clear solution without visible mechanical particles.
Psychoanaleptics, xanthine derivatives.
Code ATX N06BC01.
mechanism of action
Caffeine is structurally connected with methylxanthine theophylline and theobromine. Most of its effects are associated with the antagonism of adenosine receptors subtypes a 1 and a 2A , which is demonstrated by binding tests of receptors and observed at concentrations approximately equal to therapeutic concentrations in these indications.
The main action of caffeine is stimulation of the Central nervous system. It is the basis of action of caffeine for apnea in preterm infants and has several mechanisms, including:
stimulation of respiratory centers;
the increase in minute volume ventilation;
lowering the threshold carbon dioxide content in the blood
improving the response to the content of carbon dioxide in the blood
increase of skeletal muscle tone;
reduction of diaphragm fatigue;
the increased rate of metabolism;
increased oxygen consumption.
Therapeutic efficacy and safety
The therapeutic efficacy of caffeine citrate was assessed in the course of a multicenter randomized double-blind study that compared caffeine citrate to placebo in 85 preterm infants (gestational age 28 to 33 weeks), had apnoea of premature newborns. The children received an intravenous loading dose of caffeine 20 mg/kg, Then intravenous or oral (via a feeding tube) was given daily maintenance dose of 5 mg/kg for 10-12 days. The Protocol allowed us to "rescue" open-therapy caffeine citrate if the apnea remained uncontrolled. In this case, the children received a repeated shock dose of caffeine 20 mg/kg after the 1st day of therapy until the 8th day.
The number of days without apnea in caffeine citrate therapy was greater (3.0 days against 1.2 days in placebo, p = 0.005); also, the percentage of patients who did not have apnea for 8 days or more was higher (22% for caffeine against 0% for placebo).
A recent multicenter study with placebo control (n = 2006) studied short and long-term (18-21 months) indicators of premature neonates treated with caffeine citrate. Patients in randomized order received intravenously a loading dose of caffeine citrate is 20 mg/kg, and then received daily maintenance dose of 5 mg/kg. In case of preservation of apnea daily maintenance dose could be increased to a maximum of 10 mg/kg. Adjustment of maintenance doses was carried out on a weekly basis, based on changes in body weight, the dose could be administered orally if the patient is tolerating full enteral feeding. As a result of caffeine therapy, there was a decrease in the rate of bronchopulsivity dysplasia [relative risk (95% CI) 0.63 (from 0.52 to 0.76)] and an increase in survival rates without disorders of neurological development [relative risk (95% CI) 0.77 (from 0.64 to 0.93)].
The scale and direction of caffeine's impact on mortality and disability varied according to the degree of respiratory support needed by newborns with randomization, demonstrating greater effectiveness in newborns receiving support [relative risk (95% CI) of mortality and disability - see table below].
Death and disability in the group with respiratory support until the start of the study
subgroup bearer risk (95% CI)
without поддержки1,32 (0,81 to 2.14)
non-invasive поддержка0,73 (of 0.52 to 1.03)
endotracheal трубка0,73 (from 0.57 to 0.94 inch)
Caffeine citrate dissolves in an aqueous solution. Citrate group is rapidly metabolized by infusion or oral administration.
Caffeine in the caffeine citrate occurs within a few minutes after the beginning of the infusion. After taking 10 mg caffeine per 1 kg of weight to a premature newborn, the peak plasma caffeine concentration (C max ) ranges from 6 to 10 mg/l, and the average time to reach the maximum concentration (t max ) ranges from 30 minutes to 2:00. The degree of suction does not depend on the composition of the feeding mixture, but t max can be larger.
Caffeine quickly enters the brain after administration of caffeine citrate. The concentration of caffeine in the spinal fluid of premature newborns is approximately equal to the concentration in plasma. The average volume of caffeine distribution (V p ) in newborns (0.8 - 0.9 l/kg) is slightly higher than in adult patients (0.6 l/kg). Data on plasma protein binding in newborns and infants are not available. In adults, the average plasma protein binding rate in vitro is reported to be 36%.
Caffeine crosses the placenta into the bloodstream of the fetus and is excreted in breast milk.
Caffeine metabolism in preterm neonates is very limited due to insufficient development of hepatic enzyme systems, and a large part of active substance excreted in the urine. Hepatic cytochrome P450 1A2 (CYP1A2) is involved in biotransformation of caffeine in individuals who are older.
There are reports of mutual conversion between caffeine and theophylline in premature infants; caffeine levels are around 25% of theophylline levels after administration of theophylline and about 3-8% of caffeine administered is expected to convert to theophylline.
In newborns at an early age, caffeine withdrawal is significantly slower than in adults due to underdeveloped liver and/or kidney function. In newborn infants, caffeine clearance is almost entirely due to renal excretion. The average duration of half-life (t 1/2 ) of a share of caffeine, extracted in primary form in the urine (A e ) infants are inversely related to gestational/postmenstrual age. In newborns, t 1/2 is approximately 3 to 4 days, and e is approximately 86% (within 6 days). On the ninth month of the metabolism of caffeine is close to that of an adult (t 1/2 = 5:00pm, and e = 1%).
Studies of the pharmacokinetics of caffeine in neonates with hepatic or renal insufficiency have not been conducted.
In the presence of significant liver lesions, given the significant potential for accumulation, a reduction in the daily maintenance dose is required, while the dose size should be determined based on the indicators of caffeine levels in the blood. In premature newborns with cholestatic hepatitis, a longer half-life of caffeine was revealed, with an increase in the concentration of caffeine in plasma more than the rate of oscillations, which suggests the need for a particularly cautious dosage for such patients.
Treatment of primary apnea in premature newborns.
Hypersensitivity to the active substance or to any auxiliary substances.
Interaction with other medicinal products and other forms of interaction
In premature newborns there is a mutual between caffeine and theophylline. These active substances should not be used simultaneously.
Cytochrome P450 1A2 (CYP1A2) is the main enzyme involved in the metabolism of caffeine in the human body. Thus, caffeine has the potential to interact with active substances that are substrates for CYP1A2, inhibit CYP1A2, or induce CYP1A2. However, caffeine metabolism in premature infants is limited due to insufficient maturity of their hepatic enzyme system.
Despite the limited availability of data on the interaction of caffeine with other active substances in premature infants, it is possible to reduce the dose of caffeine citrate after the introduction of active substances that reduce the rate of caffeine excretion in adults (eg, cimetidine and ketoconazole). It may also be necessary to increase the dose of caffeine citrate after administration of active substances that increase the rate of caffeine (eg, phenobarbital and phenytoin). If there are doubts about the possible interaction, it is necessary to monitor the concentration of caffeine in plasma.
Since excessive development of microflora in the intestine may be associated with the development of necrotizing enterocolitis, a simultaneous administration of caffeine citrate and medicines gastric secretion depressants (H2 blocker antihistamine receptors or proton pump inhibitors) theoretically increases the risk of necrotizing enterocolitis.
Simultaneous administration of caffeine and doxapram may enhance their stimulating effect on the cardiovascular, respiratory and Central nervous system. If simultaneous use of these drugs is shown, it is necessary to conduct careful monitoring of heart rate and blood pressure.
Apnea in premature newborns is diagnosed by elimination. Other causes of apnea (e.g., Central nervous system disorders, primary lung disease, anemia, sepsis, metabolic disorders, cardiovascular disorders, obstructive apnea) should be ruled out or should be carried out their proper therapy before therapy caffeine citrate. The lack of efficiency of caffeine therapy (if necessary, confirmed by the level indicator in plasma) may indicate other causes of apnea.
the use of caffeine
In newborns whose mothers consumed large amounts of caffeine before delivery, the base concentration of caffeine in plasma should be determined prior to caffeine citrate therapy, since caffeine penetrates the placenta to the metabolism of the fetus.
Mothers of newborn children undergoing therapy with caffeine citrate should not eat foods, beverages or medicinal products that contain caffeine, because caffeine passes into breast milk.
In newborns previously treated with theophylline, it is necessary to determine the base concentration of caffeine before starting therapy with caffeine citrate, because in newborns theophylline is metabolized into caffeine.
Caffeine is a stimulant of the Central nervous system. There are reports of assaults on his overdose. With extreme caution should use of caffeine citrate for neonates with disorders associated with epileptic seizures.
In published studies, it was shown that caffeine consumption leads to an increase in heart rate, blood volume release from the left ventricle of the heart and the systemic volume of the heart. Thus caffeine citrate should be used with caution in newborns suffering from diseases of the cardiovascular system. There is evidence that caffeine causes tachyarrhythmias in susceptible to it people. In newborns, it's usually just sinus tachycardia. If there had been any unusual rhythm disturbances on cardiotocograph (CTG) before the baby is born, caffeine citrate should be administered with caution.
Renal and hepatic insufficiency
Premature newborn babies with impaired renal or liver function should be administered caffeine citrate with caution. To avoid intoxication in this category of patients it is necessary to determine the dose based on monitoring the concentration of caffeine in plasma.
Necrotic enterocolitis is a common cause of morbidity and mortality in premature infants. There are reports of a possible link between the use of methylxanthines and development of necrotizing enterocolitis. However, a causal relationship between the use of caffeine or other methylxanthines and necrotic enterocolitis is not installed. All premature newborn babies, especially those that receive treatment with caffeine citrate should undergo close monitoring for the development of necrotizing enterocolitis.
Caffeine citrate should be used with caution for children suffering gastroesophageal reflux, because treatment can enhance this condition.
Caffeine citrate speeds up the metabolism, which can lead to higher energy demand and nutrition during therapy.
Diuresis and loss of electrolytes caused by caffeine citrate may necessitate correction of water and electrolyte balance.
Use during pregnancy or breast-feeding.
In animal studies caffeine in large doses has shown embryotoxicity and teratogenicity. Such effects are not associated with short-term administration in the group of premature newborns.
Caffeine is released into breast milk and quickly penetrates the placenta into the bloodstream of the fetus.
Nursing newborns receiving therapy caffeine citrate should avoid eating foods, drinks and medicines that contain caffeine.
In newborns whose mothers consumed a large amount of caffeine before delivery, the base concentration of caffeine in plasma should be determined before treatment with caffeine citrate.
Influence on the reproductive system observed in animals is absent in premature newborns.
The ability to influence the reaction rate when driving motor transport or operating other mechanisms.
Method of application and doses
The beginning of caffeine citrate therapy is allowed under the supervision of a doctor with experience in resuscitation activities in newborns. The drug was intended solely in the neonatal intensive care unit with the appropriate equipment for surveillance and monitoring.
The recommended dose for infants being treated for the first time is 20 mg of caffeine citrate per 1 kg of body weight by a slow infusion for 30 minutes using a syringe infusion or other adjustable infusion device. After 24 hours allowed the introduction of maintenance doses of 5 mg per 1 kg of body weight by slow infusion over 10 minutes every 24 hours. As an alternative, the oral administration of supporting doses at the rate of 5 mg per 1 kg of body weight every 24 hours with the use of devices such as nasogastric probe is allowed.
The recommended shock and maintenance dose of caffeine citrate is indicated in the table explaining the ratio between the volume of the drug administered and the amount of caffeine citrate administered.
The dose expressed as a dose of caffeine is half the dose expressed in caffeine citrate (20 mg caffeine citrate is equivalent to 10 mg caffeine).
Dose of caffeine citrate (volume)Dose of caffeine citrate (mg/kg body weight)method vodenitsata
shock доза1,0 ml/kg тела20 mg/kg talenthouse (within 30 minutes)once
Maintenance dose * 0.25 ml/kg body mass 5 mg/kg telainfusion mass (within 10 minutes) or oral administration 24 hours *
* Start 24 hours after administration of the shock dose
In the absence of adequate therapeutic effect in preterm infants after the introduction of recommended dosage allowed the introduction of repeated dosage in the range of 10-20 mg/kg after 24 hours.
If there is no proper therapeutic effect, it may be considered to increase the maintenance dose of 10 mg/kg, taking into account the accumulative potential of caffeine associated with its long half-life in premature newborns and the progressive increase in the ability to metabolize caffeine with an increase in gestational age. In the presence of clinical indications, it is necessary to monitor the level of caffeine in plasma. In the absence of proper therapeutic effect after administration of repeated shock or maintenance dose of 10 mg/kg/day diagnosis of apnea in newborns may require revision.
Dose adjustment and monitoring
It is necessary to periodically monitor the concentration of caffeine in plasma during treatment, especially if there is no improvement or signs of toxicity.
It may also be necessary to adjust the dose in accordance with the decision of the doctor, based on monitoring the concentration of caffeine in plasma in the presence of risk factors, such as:
women's gestational age of fetus (less than 28 weeks) and/or low body weight (less than 1000 g), in particular when receiving parenteral nutrition;
hepatic or renal failure
clinically significant heart failure
the parallel introduction of drugs that affect the metabolism of caffeine
the mother of the child takes caffeine during breastfeeding.
It is recommended to determine the base level of caffeine:
in children whose mother used a large amount of caffeine before birth;
in children who have previously received theophylline, it is metabolized into caffeine.
The half-life of caffeine in premature newborns is a long period of normal, and due to its high potential for accumulation, longer monitoring of the condition of children who have undergone longer treatment may be required.
Blood samples for monitoring should be selected immediately before the next dose in the absence of effective therapeutic treatment and after 2 - 4:00 after administration in case of suspected toxication.
Despite the fact that the therapeutic level of caffeine in plasma is not defined in the literature, in the course of research caffeine level, associated with therapeutic efficacy, was in the range of 8 to 30 mg/l. the issue of safety is usually not raised in the case of finding caffeine level within 50 mg/l.
duration of therapy
The optimal duration of treatment is not determined. In a recent multicenter study on preterm neonates reported on the duration of therapy was 37 days.
In clinical practice, treatment usually continues until the newborn gestational age of 37 weeks, in which primary apnea usually goes away. However, this limitation may be revised by the physician in some cases, depending on the effectiveness of treatment, the availability of cases of apnea despite therapy or other clinical factors. It is recommended to stop the introduction of caffeine citrate in the absence of significant cases of apnea for 5-7 days.
In the case of repeated manifestations of apnea caffeine citrate should be restored from the maintenance dose or half of the shock dose, depending on the time interval between the cessation of caffeine citrate and the restoration of cases of apnea.
Due to delayed caffeine withdrawal in this group of patients, there are no requirements for dose reduction and discontinuation of treatment.
Due to the risk of repeated cases of apnea after discontinuation of caffeine citrate therapy, it is necessary to continue monitoring the patient's condition for about one week.
Hepatic and renal failure
The safety of caffeine citrate in patients with renal insufficiency has not been proven. In the presence of renal insufficiency, accumulation potential is growing. It is necessary to reduce the daily maintenance dose of caffeine citrate in accordance with the indicator of caffeine level in plasma.
In patients with very low gestational age, caffeine clearance is independent of liver function. The hepatic metabolism of caffeine develops gradually within a few weeks after birth, and in older infants, hepatic insufficiency may require monitoring of the level of caffeine in plasma and dose correction.
route of administration
Caffeine citrate can be administered by infusion or orally. Not allowed the introduction of the drug method intramuscular, subcutaneous, intrathecal or intraperitoneal injection.
Intravenous administration of caffeine citrate is introduced a method of controlled infusion using intravenous infusion pump or other device for the controlled infusion. Caffeine citrate can be administered without dilution or diluted with sterile solutions for infusion such as a glucose solution of 50 mg/ml (5%), sodium chloride 9 mg/ml (0.9%) or calcium gluconate 100 mg/ml (10%), immediately after extraction from the ampoule.
The drug is used in premature newborns.
According to published data, after the overdose, the level of caffeine in plasma ranged from 50 mg/l to 350 mg/l.
In the literature the message about the symptoms of caffeine overdose in preterm infants include hypoglycemia, hypokalemia, fine tremor of the extremities, restlessness, hypertonia, opisthotonus, tonic-clonic seizures, seizures, tachypnea, tachycardia, vomiting, gastric irritation, gastro-intestinal bleeding, fever , syndrome of increased neuro-reflex excitability, elevated levels of urea in the blood and leukocytosis, the uncontrolled mobility of the jaw and lips. One case of caffeine overdose is reported to have been complicated by intraventricular bleeding and prolonged neurological complications. There are no reported deaths due to caffeine overdose among premature newborns.
Actions in case of overdose
In the case of an overdose of caffeine, symptomatic and supportive therapy is mainly carried out. Potassium and glucose levels should be monitored and measures taken to correct hypokalemia and hyperglycemia. Studies have shown that the level of caffeine in plasma decreases after blood transfusion is replaced. Therapy by the court may be carried out by the introduction of anticonvulsants (diazepam or barbiturates, such as sodium pentobarbital or phenobarbital).
Information about the pharmacology and toxicology of caffeine and other methylxanthines, give information about possible adverse reactions to caffeine citrate. The described action includes stimulation of the Central nervous system, such as irritability, excited state, syndrome of increased neuro-reflex excitability, effects on the cardiovascular system, such as tachycardia, hypertension and an increase in the systemic volume of the heart. These effects are dose-dependent and may require plasma concentration measurement and dose reduction.
Adverse reactions that may be associated with caffeine citrate and reported in medical literature listed below for classes of systems of organs, and detection rate (MedDRA).
The frequency of adverse reactions is determined as follows: very often (?1/10), often (?1/100 to <1/10), infrequently (?1/1000 to <1/100), rare (?1/10000 to <1/1000), very rare (<1/10000) and unknown (it is impossible to estimate based on available data).
The class of systems organoborane reaccessed
Infection and invasivespecies
From the immune systemreaction hypersensitive
From the metabolism and pianeggiante, hyperglycemia, delayed weight gain, food nepredusmotritelen
From the nervous systemaattisesti, the syndrome of increased neuro-reflex excitability, restlessness, brain damage, storagenewsletter
From the hearing and uravnoveshennosti
From the cardiovascular systematically, is also associated with an increase in ejection of blood volume from the left ventricle and an increase in sistolicheskogo volume of the heart
From the digestive systemicrisk, increased gastric aspirate, necrotic enterocolitises
General disorders and reactions at the site of the introduction of phlebitis at the site of infusion, inflammation at the site of infusirasprostraneny
the results of the study increased urination, an increase in the level of sodium and calcium in the urine, a decrease in hemoglobin, a decrease in thyroxine is known
A description of some adverse reactions
Necrotic enterocolitis is a common cause of mortality and morbidity in premature infants. There is information about a possible connection between the use of methylxanthines and the emergence of necrotizing enterocolitis. However, a causal relationship between the use of caffeine or other methylxanthines and necrotic enterocolitis is not installed.
In a double blind study with placebo control caffeine citrate 85 premature infants with necrotizing enterocolitis was diagnosed in the blind phase of the study in 2 children who received active therapy, in 1 child who received placebo and in 3 children who received caffeine during the open phase of the study. Three of the children who had necrotic enterocolitis during the study died. A large multicenter study (n = 2006) of long-term results in premature newborns receiving caffeine citrate therapy showed no increase in the incidence of necrotic enterocolitis in the caffeine group compared to placebo. All premature newborns receiving caffeine citrate therapy should be closely monitored for the development of necrotic enterocolitis.
Brain damage, convulsions and deafness were observed, but they were more frequent in the placebo group.
Caffeine is able to suppress the synthesis of erythropoietin and therefore reduce the hemoglobin content with prolonged use.
Temporary decrease in thyroxine (T4) levels was observed in infants at the beginning of therapy, but they did not continue throughout the therapy.
The available data do not indicate any long-term adverse reactions on therapy with caffeine in neonates from neurological development, delayed weight gain or cardiovascular, digestive, or endocrine systems. Caffeine does not increase cerebral hypoxia and does not burden the consequences of any damage, but this possibility should not be completely excluded.
The message of suspected adverse reactions
The message of suspected adverse reactions after registration of the medicinal product is important. It is necessary to continue to monitor the ratio of "benefit/risk" medicines.
After opening the ampoule - immediately use the drug.
Store at a temperature not exceeding 25 ° C in its original packaging.
Keep out of reach of children.
Solution for infusion and oral administration of 1 ml in an ampoule; 5 vials in a contour cell pack, 2 contour packs in a cardboard box.
Category home away from home
On prescription, only in hospital.
Alfa Wassermann S. p. A. Alfa Wassermann S. p. A.
Chiesa PHARMACEUTICAL GmbH/Chiesi Pharmaceuticals GmbH
Manufacturer's location and address of the place of business
St. Enrico Fermi, 1 - 65020 Alanna (province of Pescara), Italy/Via Enrico Fermi, 1 - 65020 Alanno (PE), Italy.
Gonzagagasse building 16/16, 1010 Vienna, Austria/Gonzagagasse 16/16 1010 Wien, Austria.
OXAPIN 300MG NO. 30
Oxapin belongs to the category of antiepileptic drugs. It is prescribed for the treatment of partial seizures without secondary generalization or in the presence thereof. The drug can be used solo, or in combination with other means. The method of therapy depends on the age of the patient and the characteristics of his disease.
Features of oxapin medicine
Suitable for treating children from 6 years of age.
It is not recommended to take during the carrying of the child, because it can provoke developmental disorders for the fetus.
Patients suffering from heart failure during the course of Oxapin require strict weight control.
The receiving means may lead to reduced effectiveness of hormonal contraceptives.
During the course of therapy, patients may occasionally experience dizziness, drowsiness, slowing reactions.
In the treatment of Oxapin is not advisable to take alcoholic drinks.
The daily and one-time rate of Oxapin depends on the age of the patient, his health status and specific diagnosis. The treatment regimen is set by the attending physician, and patients should strictly observe it, so as not to cause deterioration.