What Is Caffeine Citrate?

Caffeine citrate injection is used to treat primary apnea in preterm neonates. ^[1] .

Drug Name: Caffeine citrate injection
Hanyu Pinyin: Ju Yuan Suan Ka Fei Yin Zhu She Ye

Drug type: Psychotropic drugs
Use classification: Drugs that mainly excite the cerebral cortex

Ingredients of caffeine citrate injection

Active ingredient: Caffeine citrate Chemical name: 1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione citrate Chemical structural formula: http: // x1 .webres.medlive.cn / drugref / ChemPreparationDetail / 201509202102000638.png
Molecular formula: C ₁₄ H ₁₈ N ₄ O ₉
Molecular weight: 386.31
Excipients: citrate monohydrate, sodium citrate, water for injection.

Characteristics of Caffeine Citrate Injection

This product is a clear, colorless liquid.

Indications for caffeine citrate injection

For the treatment of primary apnea in preterm neonates.

Caffeine citrate injection specifications

1ml: 20mg (equivalent to 10mg of caffeine)

Dosage and dosage of caffeine citrate injection

This product should be used under the guidance of a doctor with experience in neonatal intensive care.
This product should be used in a neonatal intensive care unit equipped with appropriate monitoring and monitoring equipment.
Recommended dosing regimen for newborns who have not received relevant treatment before: a loading dose of caffeine citrate 20 mg / kg body weight, using an infusion pump or other quantitative infusion device, slow intravenous infusion (30 minutes), 24 hours apart A maintenance dose of 5 mg / kg body weight is administered by slow intravenous infusion (10 minutes) every 24 hours; or, by the oral route (such as through a nasogastric tube), a maintenance dose of 5 mg is administered every 24 hours / kg body weight.
The recommended loading and maintenance doses of caffeine citrate are shown in the table below (caffeine citrate 20mg is equivalent to 10mg caffeine).
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* Maintenance dose started 24 hours after loading dose administration.
If the clinical response of the premature newborn to the recommended loading dose is insufficient, a second loading dose of 10 to 20 mg / kg body weight may be given after 24 hours.
Although caffeine has a longer half-life in premature neonates, and there is a possibility of drug accumulation, as the correction of gestational age increases, the caffeine metabolism capacity of newborns is increasing, so patients with insufficient responses can consider adopting a higher maintenance The dose is 10mg / kg body weight (see [Pharmacokinetics]). If clinically required, the concentration of caffeine in the plasma should be monitored. If the patient's response to the second loading dose or maintenance dose of 10mg / kg / day is still insufficient The diagnosis of apnea in preterm neonates should be reconsidered (see [Precautions]).
When caffeine citrate is administered intravenously, only an infusion pump or other quantitative infusion device can be used for intravenous infusion. This product can be used directly without dilution, or it can be administered after dilution with sterile solution. The diluted solution can be selected from 5% glucose solution, 0.9% sodium chloride solution or 10% calcium gluconate solution. This product should be used immediately after opening the ampoule.
When administered as an infusion, this product should be diluted aseptically from a microbiological point of view and then administered immediately.
The physical and chemical properties of the diluted solution can be maintained for 24 hours at 25 ° C and 2 ° C to 8 ° C.
Most preterm neonates do not require routine monitoring of plasma caffeine concentration. However, for patients with inadequate clinical response or toxic symptoms, the plasma blood caffeine concentration should be monitored regularly throughout the course of treatment.
In addition, if there is a high-risk situation, after the monitoring of the plasma caffeine concentration, the dosage can be appropriately adjusted according to the judgment of the doctor.
Premature neonates with small gestational age (fetal age <28 weeks, and / or weight <1000 g), especially those receiving parenteral nutrition;
· Newborns with liver and kidney palmitic acid (see [Precautions] and [Pharmacokinetics]);
· Newborns with epilepsy;
Newborns with known and clinically diagnosed severe heart disease;
· Newborns who use drugs that specifically interfere with caffeine metabolism (see [Drug Interactions]);
Breast-fed newborns whose mothers use caffeine.
It is recommended to determine the baseline caffeine concentration in the following cases:
· Newborns born to pregnant women who have taken a lot of caffeine before childbirth (see [Cautions]);
· Newborns who have been previously treated with theophylline can be metabolized to caffeine.
Caffeine has a long half-life in premature neonates and may accumulate, so it is necessary to monitor neonates who have been using this product for a long time (see [Pharmacokinetics]).
If the treatment fails, blood samples should be monitored before the next dose. If a toxic reaction is suspected, blood samples should be monitored within 2 to 4 hours after the previous dose.
Although there are only reported values of caffeine effective plasma concentration ranges, studies have shown that caffeine concentrations ranging from 8 mg / L to 30 mg / L are relevant for clinical benefit, and plasma concentrations below 50 mg / L usually do not cause safety Worry.
The administration route of caffeine citrate is intravenous infusion and oral administration. This product should not be administered by intramuscular, subcutaneous, intraspinal or intraperitoneal injection.

Course of treatment:
A recent large-scale multicenter clinical study of preterm neonates showed that the median duration of treatment was 37 days, and the ideal duration of treatment is still being studied.
In clinical treatment, treatment usually lasts until the corrected gestational age of the newborn is 37 weeks. At this time, the apnea caused by premature delivery often improves on its own.
According to the individual clinical efficacy of the patient, the duration of the onset of apnea symptoms during the treatment process, or other clinical factors, can be adjusted for the duration of the treatment. If the patient does not have an obvious apnea attack for 5 to 7 days, it is recommended to stop using citrus Sour caffeine.
If the patient has recurrent apnea symptoms, consideration should be given to restarting the administration of caffeine citrate. Depending on the interval between the withdrawal of caffeine citrate and the recurrence of apnea, a maintenance dose or a half-load dose may be used.
Because caffeine is slowly cleared in these patients, there is no need to gradually reduce the dose before stopping.
Because there is a risk of recurrence of apnea after discontinuation of caffeine citrate, patients should be continuously monitored for approximately 1 week after discontinuation.

Patients with impaired liver or kidney function:
The safety of caffeine citrate in patients with renal insufficiency has not been determined. When renal function is impaired, the possibility of drug accumulation will increase. At this time, the daily maintenance dose of caffeine citrate should be reduced. The dose is determined based on the content determination.
The elimination of caffeine in preterm neonates with a small gestational age does not depend on their liver function. In the first few weeks after birth, the neonatal liver's metabolic function gradually increases. For more mature newborns, such as emu oil liver disease, plasma monitoring is required. Caffeine concentration, and adjusted dose based on testing (see [Usage and Dosage] and [Pharmacokinetics]).

Adverse reactions of caffeine citrate injection

The known pharmacological and toxicological properties of caffeine and other methylxanthines may suggest possible adverse effects of caffeine citrate, including stimulating effects on the central nervous system, such as irritability, restlessness, and tremors; and Adverse effects on the heart, such as tachycardia, hypertension, and increased stroke output. These adverse effects are dose-dependent, and plasma drug concentrations should be measured and reduced if necessary.
The public reports of adverse reactions after short-term and long-term use of caffeine citrate are listed in the following table according to the standard medical terminology of pharmaceutical management. The incidence of adverse reactions is defined as follows: very common (1 / 10); common (1 / 100, but <1/10>: uncommon (1 / 1, 000, but <1/100), rare adverse reactions (1 / 10, 000, but <1/1, 000); very rare adverse reactions (<1/10, ooo>); unknown (the frequency of occurrence cannot be evaluated from available data).
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* Brain damage, convulsions, and deafness observed, but higher incidence in placebo control group
** Participating in caffeine below can inhibit the synthesis of erythropoietin, so long-term administration may cause a decrease in hemoglobin concentration.
A transient decrease in thyroxine (T4) concentration was observed at the beginning of treatment in neonates, but returned to normal when the maintenance dose was administered.
Existing evidence indicates that after long-term treatment with caffeine in newborns, it will not cause adverse reactions in cardiovascular, gastrointestinal tract, endocrine system, developmental retardation or nerve growth. Although it is not possible to completely eliminate the possibility of occurrence, it is not currently Caffeine was observed to aggravate brain hypoxia or exacerbate secondary brain hypoxia injury.

Necrotizing enterocolitis:
Necrotizing enterocolitis is a common disease in preterm neonates and a common cause of death. It has been reported that there may be a correlation between the use of methylxanthines and the occurrence of necrotizing enterocolitis, but caffeine Or the causal relationship between or other methylxanthines and the occurrence of necrotizing enterocolitis has not been determined.
In a double-blind placebo-controlled study of caffeine citrate administered to 85 preterm neonates, 2 and 1 neonates were diagnosed with a necrotizing small intestine during the blind trial, respectively. Colitis. During the open trial phase, 3 neonates given caffeine citrate had necrotizing enterocolitis. In the trial, 3 of the patients with necrotizing enterocolitis died. A large multicenter study (n = 2006) observed long-term administration of caffeine citrate in preterm neonates, and the results showed that compared to the placebo control group, the caffeine citrate administration group did not increase For the incidence of necrotizing enterocolitis, monitor the incidence of necrotizing enterocolitis in the early neonates given caffeine citrate (see [Precautions]).

Caffeine citrate contraindications

Those who are allergic to any of the ingredients in this product are prohibited.

Caffeine citrate injection precautions

The diagnosis of apnea in preterm neonates is precluded, and apnea due to other causes (eg, central nervous system disorder, primary lung disease, anemia, sepsis, metabolic disorders, cardiovascular abnormalities, or obstructive apnea should be excluded ), Or start treatment with caffeine citrate after appropriate treatment. When there is no response to caffeine citrate treatment (if necessary, it can be determined by measuring the plasma concentration) suggesting that apnea may be caused by other reasons.
Caffeine easily enters the fetal blood circulation system through the placenta. If the newborn mother has consumed a large amount of caffeine before delivery, the baseline plasma caffeine concentration of the newborn should be measured before caffeine citrate treatment (see [Dosage and Administration] ] And [Pharmacokinetics]).
Caffeine can be secreted through milk (see [Pharmacokinetics]). If a newborn who is treated with caffeine citrate is breast-fed, its mother must not consume or drink caffeine-containing food and beverages. Caffeine-containing drugs should be used (see [Medications for pregnant and lactating women]).
Because theophylline can be metabolized into caffeine in preterm neonates, the baseline caffeine concentration in preterm neonates who have previously been treated with theophylline should be measured before starting caffeine citrate therapy.
Caffeine is a central nervous system stimulant, and seizures have been reported in caffeine overdose. Caffeine citrate should be administered with caution in neonatal epilepsy.
Public literature reports that caffeine can increase heart rate, increase left ventricular output, and stroke volume. Therefore, neonates with known cardiovascular disease should be cautious when given caffeine citrate, and there are signs that sensitive individuals use coffee Because it can cause arrhythmias, newborns usually have simple sinus tachycardia. Caution with caffeine citrate should be used with caution when the neonatal prenatal uterine contraction chart (CTG) shows abnormal heart rhythm disorders.
Premature newborns with impaired kidney or liver function should be used mentally when giving caffeine citrate (see [Dosage and Administration] and [Pharmacokinetics]). The dose should be adjusted based on the monitoring results of plasma caffeine concentration to avoid this. Patients develop toxicity.
Necrotizing enterocolitis is a common disease in preterm neonates and a direct cause of death. There have been reports suggesting a possible correlation between the use of methylxanthines and the occurrence of necrotizing enterocolitis. However, the causal relationship between caffeine or other methylxanthines and the occurrence of necrotizing enterocolitis has not been determined. Premature neonates treated with caffeine citrate should be monitored to observe the occurrence of necrotizing enterocolitis. Situation (see [Adverse Reactions]).
Caffeine citrate should be used with caution in neonates with gastroesophageal reflux. Treatment may make the condition worse.
Caffeine citrate usually enhances metabolism, so the body requires higher energy and nutrition during treatment.
Caffeine citrate can cause polyuria and electrolyte loss, and steps may need to be taken to correct fluid and electrolyte disorders.
If your baby begins to show signs of gastrointestinal intolerance, such as bloating, vomiting or bloody stools, or chopped down listlessly, consult a physician.
In placebo-controlled clinical trials, the caffeine content ranged from 8 to 40 mg / L. In the placebo-controlled clinical trials, the therapeutic blood concentration range of caffeine could not be determined. It has been reported in the literature that when the serum caffeine content exceeds Severe toxicity occurs at 50 mg / L.
In clinical studies reported in the literature, cases of hypoglycemia and hyperglycemia have been observed. Therefore, in infants treated with this product, serum glucose levels should be monitored regularly if necessary.

Handling and other operating precautions:
Because this product does not contain preservatives, sterility should be strictly guaranteed during the entire operation of handling this product.
This product should be inspected visually before use to see if it contains visible foreign matter and discoloration. Do not use ampoules containing a color-changing solution or visible foreign matter.
The diluted solution should be colorless and clear. All injection solutions should be inspected visually before use to see whether they contain visible foreign matter and discoloration. Do not use if the solution has discolored or visible foreign matter is present.
This product is for single use only. Discard the remaining liquid in the ampoule. Do not use the remaining liquid for the next dose.

Caffeine citrate injection for pregnant and lactating women

Animal tests have shown that high doses of caffeine can cause fetal toxicity and teratogenicity, and short-term administration of caffeine in preterm neonates will not produce these toxic effects (see [Pharmacology and Toxicology]). Caffeine can be secreted through milk and easily passed The placenta enters the fetal blood circulation (see [Pharmacokinetics]).
Newborns who have been treated with caffeine citrate should not consume or drink caffeinated foods and beverages, and should not use caffeinated drugs if breastfeeding.
Newborn babies born to pregnant women who have taken a large amount of caffeine before childbirth should measure the baseline plasma caffeine concentration of the newborn before giving caffeine citrate treatment (see [Precautions]).

Caffeine citrate injection for children

See [Dosage and Administration].

Caffeine citrate injection for the elderly

This product is used for premature neonates, there is no medication for the elderly.

Caffeine citrate injection drug interactions

Caffeine and theophylline can be converted into each other in premature infants, so these active substances should not be used together.
The main enzyme that metabolizes caffeine in the human body is cytochrome P4501A2 (CYP1A2), so caffeine may interact with the substrate of CYP1A2, the inhibitor of CYP1A2 or the inducer of CYP1A2, but because the liver enzyme system of premature newborns is immature, So the liver metabolism of caffeine is limited.
Data on studies of the interactions between caffeine and other active substances in preterm neonates are scarce. If concurrent use of active substances (such as cimetidine and ketoconazole) that have been reported to slow caffeine clearance in adults, It is necessary to reduce the amount of caffeine citrate; if active substances (such as phenobarbital and phenytoin) that enhance caffeine clearance are used together, it is necessary to increase the amount of caffeine citrate. If a possible interaction cannot be determined, the plasma caffeine concentration should be determined.
Since the occurrence of necrotizing enterocolitis is related to the excessive growth of bacteria in the intestine, if caffeine citrate is used in combination with drugs that can inhibit gastric acid secretion (such as H2 receptor antagonists or proton pump inhibitors), theoretically it can increase necrosis Risk of enterocolitis (see [Precautions] and [Adverse Reactions]).
The simultaneous use of caffeine and doxapram may enhance its stimulating effect on the heart and lungs and the central nervous system. If simultaneous use is needed, the patient's heart rhythm and blood pressure should be strictly monitored.
In 4 healthy volunteers, co-administration of caffeine with ketoprofen can produce hyperuricemia. The clinical significance of this interaction in preterm infants is unknown.

Compatibility contraindication: Except for the diluted solution mentioned in [Usage and Dosage], this product is strictly forbidden to be mixed with other drugs in the same intravenous administration channel or used at the same time.

Caffeine citrate injection drug overdose

Published literature data show that plasma caffeine concentrations range from about 50 mg / l to 350 mg / l after overdose.
Symptoms reported after caffeine overdose in preterm neonates include: hyperglycemia, hypokalemia, microtremors in the extremities, restlessness, hypertonia, angular arch reflexes, tonic-clonic movements, convulsions, shortness of breath, Tachycardia, vomiting, stomach irritation, gastrointestinal bleeding, fever, tremors, increased blood urea and increased white blood cell count, and abnormal lip movements. One patient with caffeine overuse was associated with intraventricular hemorrhage and long-term neurological sequelae. There have been no reports of premature neonatal deaths related to caffeine use.
Caffeine is overdose, and symptomatic and supportive treatment measures are mainly adopted. The concentrations of potassium and glucose in the blood plasma should be monitored for timely correction of hypoglycemia and hyperglycemia. After plasma exchange therapy, the plasma caffeine concentration decreased. Convulsions can be treated by intravenous administration of anticonvulsants (such as diazepam or barbiturates such as sodium pentobarbital or phenobarbital).

Pharmacology and toxicology of caffeine citrate injection

Pharmacological effects Caffeine is structurally similar to the methylxanthines, theophylline and theobromine. Receptor binding assays have confirmed that most of its effects are due to antagonistic adenosine receptors (including A1 and A2A subtypes), These effects were observed near the concentration at which the therapeutic effect of the indication was obtained.
Caffeine is mainly used as a central nervous system stimulant, which is the basis of caffeine in the treatment of apnea in preterm neonates. Possible mechanisms of concentrated action include: stimulating the respiratory center; increasing minute ventilation; increasing the body's Sensitivity to elevated blood CO ₂ ; Improve the body's response to elevated blood CO ₂ ; Enhance skeletal muscle tension; Reduce diaphragmatic fatigue; Increase metabolic rate; Increase oxygen consumption.

Toxicology study In a 2-year study in SD rats, administered as caffeine (calculated as caffeine) drinking water solution, male rats were administered at doses of up to 102 mg / kg or female rats. No carcinogenicity up to 170 mg / kg (2 and 4 times the maximum recommended intravenous loading dose for infants in mg / m ₂ , respectively). In an 18-month study in C57BL / 6 mice, there was no evidence that caffeine was carcinogenic at dietary doses as high as 55 mg / kg (below the maximum recommended vein for infants in mg / m ₂ Loading dose).
In an in vivo mouse cell division analysis, caffeine (in terms of caffeine) increased sister chromatid calling (SCE) SCE / middle cell division (time-dependent exposure), in folic acid-deficient mice, Caffeine also enhances genotoxicity and micronucleus formation (5-fold) of known mutagens. However, in vitro hamster ovary cell (CHO) and human lymphocyte tests, caffeine did not increase chromosome aberrations; in vitro CHO / hypoxanthine guanine phosphoribosyltransferase (HGPRT) gene mutation analysis, except for cytotoxicity Outside the concentration, caffeine is not mutagenic. In addition, in vivo micronucleus tests in mice, caffeine was not teratogenic, which is likely due to the continuous increase in adenosine receptor expression (sustainable to adulthood). There is evidence that caffeine has no risk of inducing mutations in the body and tumors, and the teratogenicity and reproductive effects observed in animal experiments have nothing to do with the indications for this product (premature newborns).
Male rats and female rats for drug administration are called money losers, and caffeine (calculated as caffeine) is injected subcutaneously at 50 mg / kg / day (approximately the maximum recommended intravenous loading dose for infants in mg / m ₂ ). For 4 days, in addition to causing embryo toxicity, it also causes male fertility to decline. In addition, long-term exposure to high oral doses of caffeine (3.0 g for 7 weeks) has toxic effects on rat testes and can lead to degeneration of spermatogenic cells.
Preclinical caffeine repeated dose toxicity study data show that this product does not cause much harm to humans, but high doses can cause rodent convulsions, and therapeutic doses can cause certain behavior changes in newborn rats.

Pharmacokinetics of caffeine citrate injection

Caffeine citrate is rapidly dissociated in an aqueous solution, in which citrate molecules can be rapidly metabolized after infusion or absorption.
absorb:
The onset of caffeine in caffeine citrate occurs within a few minutes of the start of the infusion. After oral administration of 10 mg / kg body weight of caffeine to preterm neonates, the peak plasma caffeine concentration (Cmax) is 6 mg / L to 10 mg / L. The average time to peak (tmax) is 30 minutes to 2 hours. The degree of absorption is not affected by the formula feeding method, but tmax may be prolonged.
distributed:
After the administration of caffeine citrate, caffeine was quickly distributed into the brain. The concentration of caffeine in the cerebrospinal fluid of preterm neonates was close to the concentration in plasma. The average volume of caffeine (Vd) in neonates was 0.8 to 0.9 L / kg, slightly higher than adults (0.6L / kg). There is no data on the plasma protein binding rate of newborns or infants, and the average plasma protein binding rate of adults in vitro is about 36%. Caffeine easily enters the fetal blood circulation through the placenta and is secreted into milk.
Biotransformation:
As the liver enzyme system of premature newborns is immature, the metabolism of caffeine in its body is very limited, and most active substances are excreted through urine. Stem cytochrome P450 1A2 (CYP1A2) is involved in the biotransformation of caffeine in older individuals.
Inter-conversion between caffeine and theophylline in the newborns in the morning: after theophylline administration, the caffeine concentration is about 25% of the theophylline concentration, and after caffeine administration, it is estimated that about 3% to 8% caffeine Conversion to theophylline.
Clear:
Due to immature liver and / or kidney function, compared to adults, the elimination of caffeine in infants and young children is slow. The elimination of caffeine in newborns is almost completely completed by renal excretion. The average half-life of caffeine in newborns (t1 / 2) The proportion excreted as a metabolic molecule in urine (A) is inversely proportional to the gestational age / corrected gestational age. The neonatal t1 / 2 is about 3 to 4 days, and A is about 86% (within 6 days). By 9 months, infants' metabolism of caffeine is close to that of adults (t1 / 2 = 5 hours, A = 1%).
Studies on the pharmacokinetics of caffeine in neonates with liver or kidney dysfunction have not been performed.
In the case of severe impaired renal function, taking into account the possible accumulation of the drug, the daily maintenance dose of caffeine should be reduced. The dose adjustment should be based on the blood caffeine measurement results. Caffeine in preterm neonates with cholestatic hepatitis was observed The elimination half-life is prolonged, and the plasma drug concentration exceeds the normal range, which suggests that the dose of these patients should be set carefully (see [Dosage and Administration] and [Cautions]).

Storage of citrate caffeine injection

Shade below 30 ° C, and keep it tightly closed.

Packaging of caffeine citrate injection

Type 1 glass ampoules, 10 sticks / box.

Expiration date of caffeine citrate injection

36 months

Standard for Caffeine Citrate Injection

Import drug registration standard JX20120001