General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Do not take at bedtime.
Oral Solid Formulations
-Administer as directed according to specific non-prescription medication or dietary supplement label.
-Do not exceed labeled dosage.
Oral Liquid Formulations
Oral solution (caffeine citrate):
-In infants, the solution may be administered concomitantly with formula feedings.
-Use a calibrated oral syringe to measure the appropriate dose.
-Alternatively, the available intravenous injection (Cafcit) may be administered by the oral route.
-Storage of caffeine citrate oral solution: Once oral solution vial is opened, use immediately and discard the unused portion, it is preservative-free.
Extemporaneous compounding instructions for citrated caffeine oral solution (20 mg/mL caffeine citrate; 10 mg/mL anhydrous caffeine base):
NOTE: The extemporaneous preparation of caffeine oral solution is not approved by the FDA.
-Dissolve 10 grams of citrated caffeine powder (purified) in 250 mL of Sterile Water for Irrigation, USP. Stir the mixture until completely clear. Add a flavoring agent (simple syrup and cherry syrup in a 2:1 ratio) to the solution to increase the volume to 500 mL. The resulting enteral solution contains the equivalent of 20 mg/mL of caffeine citrate (10 mg/mL of anhydrous caffeine base) and is stable for 3 months when protected from light and stored at room temperature or under refrigeration.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Using a syringe infusion pump, administer caffeine citrate loading dose slowly over 30 minutes and maintenance dose over 10 minutes into a vein or into the tubing of a freely-flowing compatible IV solution.
-Administer daily IV maintenance dose at the same time each day (every 24 hours).
-Cafcit is stable for 24 hours at room temperature when mixed with the following compatible solutions: Dextrose 5% (D5W), Dextrose 50%, Aminosyn 8.5% solution, and Intralipid 20% emulsion.
-Storage of Cafcit injection: Once vial is opened, use immediately and discard the unused portion, it is preservative-free.
Compounding Instructions for preservative-free citrated caffeine injection:
NOTE: The extemporaneous preparation of caffeine injection is not approved by the FDA.
-Perform all intravenous compounding operations using aseptic techniques.
-Dissolve 10 grams of citrated caffeine powder (purified) in 250 mL of Sterile Water for Injection, USP. Transfer to a 500-mL sterile empty evacuated container (EEC) and fill to the 500-mL mark with Sterile Water for Injection, USP. Filter through a 0.22-micron filter into another 500-mL sterile EEC. Transfer injectable solution to 2-mL or 10-mL sterile glass vials and autoclave at 121 degrees C for 15 minutes and allow to cool. The resulting parenteral solution contains the equivalent of 20 mg/mL of caffeine citrate (10 mg/mL of anhydrous caffeine base) and is stable for 3 months at room temperature or under refrigeration. Each vial prepared is for single-use only. Once vial is opened, use immediately and discard the unused portion, it is preservative-free. Protect from light.
-Quality assurance testing for sterility and caffeine concentration is recommended when preparing compounded products for parenteral administration; each batch should be quarantined until testing is complete.
Caffeine may produce a variety of gastrointestinal (GI)/growth effects depending on the dose used and the patient population. Vomiting may occur in neonates who receive caffeine for apnea of prematurity. A temporary reduction in weight gain in caffeine-treated infants has been reported. In a study comparing caffeine to placebo, the mean difference in weight gain was the greatest after 2 weeks of therapy; however, published long-term follow-up studies have not shown caffeine to adversely affect growth parameters. Feeding intolerance (8.7%), gastritis (2.2%), and GI bleeding (2.2%) have also been associated with caffeine treatment in neonates. During a controlled clinical trial of caffeine citrate in premature infants (n = 85 neonates), necrotizing enterocolitis was reported in 6 patients, 5 of whom were administered caffeine. Three of the infants died. The incidence was 4.3% in caffeine-treatment groups vs. 2.6% of placebo-treated infants. In a much larger clinical trial (n = 2,000 neonates) evaluating the use of caffeine citrate in apnea of prematurity, necrotizing enterocolitis was not more common in caffeine treated patients compared to placebo. In a study evaluating the effect of caffeine on the splanchnic perfusion after a caffeine loading dose, the blood flow velocity was depressed for 2 to 3 hours after the infusion and slowly returned to baseline after approximately 6 hours. Clinicians should be alert for signs and symptoms of gastric distress, abdominal bloating, nausea, vomiting, bloody stools, and lethargy in treated infants. In all patient populations, at therapeutic or nontoxic doses, caffeine can stimulate gastric secretions and may cause GI upset (dyspepsia), nausea, loose stools, and may aggravate gastroesophageal reflux disease (GERD). Occasionally diarrhea is reported. The mild dehydration that caffeine produces may aggravate constipation. Excessive caffeine intake or intoxication in children, adolescents, and adults may cause vomiting, along with other signs of caffeine intoxication.
Caffeine is a CNS stimulant; many adverse reactions to caffeine are an extension of it's pharmacologic actions. Increased caffeine use among children and adolescents has been associated with insomnia, chronic headache, motor tics, irritability, hyperactivity, learning difficulties, and other adverse health effects. Neonates who receive caffeine for apnea may experience restlessness or irritability. At therapeutic or nontoxic doses, caffeine can commonly cause nervousness, mild tremor, and heightened attentiveness. After excessive doses, caffeine can cause considerable anxiety. Seizures and delirium are also possible. In humans, a caffeine concentration of > 50 mg/L may produce toxic symptoms. Less frequent adverse reactions with usual consumption by non-neonatal patients also include excitement, irritability, insomnia, headache, and muscle twitches.
According to the manufacturer, cerebral hemorrhage (intracranial bleeding) occurred in 2.2% (1/46) of caffeine-treated patients versus 0% (0/39) of neonates who received placebo in clinical trials. However, in a large randomized, double-blind, placebo controlled trial (n = 2006), there was no difference in the incidence of ventriculomegaly (with or without intraventricular hemorrhage) in the caffeine group (n = 93/1006) compared to the placebo group (n = 99/1000). In a later examination of the long-term efficacy and safety at 18 months corrected age, the incidence of cerebral palsy was significantly reduced in the caffeine group vs. the placebo group (4.4% vs. 7.3%, p = 0.009) and cognitive delay was also significantly reduced (33.8% vs. 38.3%, p = 0.04).
Caffeine is a mild diuretic and patients may have increased urinary frequency. Polyuria can occur. Increased creatinine clearance and increased urinary calcium (hypercalciuria) and sodium excretion are reported in the literature.
Adverse events to caffeine that have been described in the published literature include alterations in serum glucose such as hypoglycemia and hyperglycemia.
In controlled clinical trials of caffeine citrate injection in premature neonates, the following adverse events occurred more commonly in caffeine-treatment groups than with placebo: accidental injury (2.2%), bleeding (2.2%), disseminated intravascular coagulation (2.2%), dyspnea (2.2%), pulmonary edema (2.2%), metabolic acidosis (2.2%), xerosis (2.2%), rash (unspecified) (8.7%), renal failure (unspecified) (2.2%), retinopathy of prematurity (2.2%), and skin breakdown (2.2%). In neonates, intolerance or overdose of caffeine may manifest as tachypnea. No deaths have been reported in relation to overdose of caffeine in neonates.
Too much caffeine may occasionally cause rapid heartbeat. Cardiovascular effects of caffeine have been reported in the literature (i.e., palpitations, sinus tachycardia, increased left ventricular output, and increased stroke volume).
A distinct caffeine withdrawal syndrome has been described. Patients who consume or receive caffeine daily for several weeks experience notable physical and psychiatric responses including lethargy, anxiety, dizziness, or rebound headache upon caffeine withdrawal.
Caffeine with sodium benzoate injection (see separate monograph) is not recommended for use in premature neonates because the benzoate may displace bilirubin and induce kernicterus. Elevated serum concentrations of benzoate, similar to benzyl alcohol, have also been associated with neurological disturbances, hypotension, gasping respiration, and metabolic acidosis (i.e., 'gasping syndrome') in neonates. Clinicians should use Cafcit, which does not contain sodium benzoate, or use an extemporaneously compounded caffeine citrate injection in newborns and premature neonates. The safety and efficacy of the prescription use of caffeine in neonates and infants for longer than 12 days, prophylaxis of sudden infant death syndrome (SIDS), or for use prior to extubation in mechanically ventilated infants has not been established.
The OTC use of caffeine products is not recommended in children under the age of 12 years.
Caffeine is a central nervous system stimulant and should be used with caution in infants or other pediatric patients with a seizure disorder.
Caffeine should be used cautiously in those patients, including neonates, with cardiac disease or tachycardia. Caffeine can stimulate the force of contraction and can increase heart rate. It may increase left ventricular output and stroke volume. Too much caffeine, as a dietary supplement or in non-prescription medications, may occasionally cause rapid heartbeat.
Caffeine should be used cautiously in those with hepatic disease or hepatic impairment. Caffeine clearance may be delayed, leading to toxicity. Renal impairment or renal failure may also delay caffeine clearance. It should be noted that caffeine elimination is more dependent on renal clearance in premature neonates and term neonates than in older infants or adults, due to the underdeveloped hepatic metabolism and renal elimination of drugs in general. Thus monitoring of serum caffeine concentrations may be beneficial in neonates or premature neonates with renal or hepatic impairment.
Although the effects are mild, caffeine can either raise or decrease blood sugar; use with caution in patients with diabetes mellitus. In clinical studies reported in the literature, cases of hypoglycemia and hyperglycemia have been observed in neonates receiving caffeine citrate. Therefore, blood glucose may need to be periodically monitored in infants receiving caffeine citrate.
Caffeine has been shown to increase heart rate, left ventricular output, and stroke volume. Adolescents and children with hyperthyroidism may be sensitive to these cardiac effects, and should moderate their caffeine intake. Closely read labels of non-prescription drugs and dietary supplements prior to use, since some products may contain caffeine. Infants and neonates with hyperthyroidism should be monitored if they require caffeine therapy.
In neonates, there are reports in the literature suggesting a possible association between the use of methylxanthines like caffeine and the development of necrotizing enterocolitis (NEC). In a clinical trial (n = 85 neonates) evaluating the use of caffeine citrate in apnea of prematurity, necrotizing enterocolitis was reported in 6 patients, 5 of whom were administered caffeine. Three of the infants died. In a much larger clinical trial (n = 2,000 neonates) evaluating the use of caffeine citrate in apnea of prematurity, necrotizing enterocolitis was not more common in caffeine treated patients compared to placebo. Preterm neonates treated with caffeine should be monitored for the development of gastric side-effects (i.e., abdominal distension, feeding intolerance, vomiting, bloody stools, and lethargy). In all populations, caffeine can stimulate gastric secretions and may aggravate gastroesophageal reflux disease (GERD). Clinical trial data are conflicting regarding the limitation of caffeine as an effective strategy to control GERD symptoms; however, recommended lifestyle modifications for patients with GERD often include moderation of caffeine intake.
Too much caffeine may cause nervousness, irritability, sleeplessness, and occasionally, rapid heartbeat. Patients with insomnia or anxiety disorders may be advised to moderate their caffeine intake. Non-prescription medication and dietary supplement labels should be reviewed to determine if caffeine is a component of the products.
Description: Caffeine is a naturally occurring xanthine derivative used as a CNS and respiratory stimulant, or as a mild diuretic. Other xanthine derivatives include the bronchodilator theophylline and theobromine, a compound found in cocoa and chocolate. Caffeine is found in many beverages and soft drinks. Caffeine is often combined with analgesics or with ergot alkaloids for the treatment of migraine and other types of headache. Caffeine is also sold without a prescription in products marketed to treat drowsiness, or in products for mild water-weight gain. Caffeine was first approved by the FDA for use in a drug product in 1938.
Clinically, it is used both orally and parenterally as a respiratory stimulant in neonates with apnea of prematurity. Caffeine reduces the frequency of apneic episodes by 30-50% within 24 hours of administration. Additionally, studies have found that caffeine reduces the risk of bronchopulmonary dysplasia, PDA, and decreases the need for reintubation. Caffeine is preferred over theophylline in neonates due to the ease of once per day administration, reliable oral absorption, more predictable plasma concentrations, and a wide therapeutic window. A commercial preparation of parenteral caffeine, Cafcit, was FDA approved for the treatment of apnea of prematurity in October 1999, after years of availability only under orphan drug status (e.g., Neocaf). Caffeine citrate is FDA approved for use in pediatric patients as young as premature neonates.
For the treatment of neonatal apnea (i.e., apnea of prematurity):
Intravenous dosage (caffeine citrate):
Premature neonates 28 to 33 weeks of gestation: Initially, 20 to 25 mg/kg caffeine citrate (equivalent to 10 to 12.5 mg/kg anhydrous caffeine base) IV for 1 dose; then after 24 hours, begin maintenance dose of 5 to 10 mg/kg/day IV caffeine citrate (2.5 to 5 mg/kg/day anhydrous caffeine base); adjust based on clinical response and, if necessary, caffeine blood concentrations. Under most circumstances, use is for a limited duration of treatment, usually not to exceed 10 to 12 days. An initial dose of 50 mg/kg caffeine citrate IV (25 mg/kg anhydrous caffeine base) followed by a maintenance dose of 12 mg/kg caffeine citrate (6 mg/kg/day anhydrous caffeine base) has also been reported. Due to the extended half-life, caffeine should be discontinued for at least 5 to 7 days prior to discharge unless neonate is discharged with apnea monitor.
Oral dosage (caffeine citrate oral solution):
Premature neonates aged 28 and < 33 weeks of gestation: Initially, 20 to 25 mg/kg caffeine citrate (equivalent to 10 to 12.5 mg/kg anhydrous caffeine base) PO for 1 dose; then after 24 hours, begin maintenance dose of 5 to 10 mg/kg/day PO caffeine citrate (2.5 to 5 mg/kg/day anhydrous caffeine base); adjust based on clinical response and, if necessary, caffeine blood concentrations. Under most circumstances, use is for a limited duration of treatment, usually not to exceed 10 to 12 days. An initial dose of 50 mg/kg caffeine citrate (25 mg/kg anhydrous caffeine base) followed by a maintenance dose of 12 mg/kg caffeine citrate (6 mg/kg/day anhydrous caffeine base) has also been reported. Due to the extended half-life, caffeine should be discontinued for at least 5 to 7 days prior to discharge unless the neonate is discharged with an apnea monitor.
For extubation facilitation*:
Intravenous or Enteral dosage:
Premature Neonates: An initial loading dose of 20 to 25 mg/kg caffeine citrate (10 to 12.5 mg/kg anhydrous caffeine base) IV or PO for one dose is common; however, doses up to 80 mg/kg caffeine citrate (40 mg/kg anhydrous caffeine base) IV or PO have been reported. Begin maintenance dose 24 hours after load. Maintenance doses of 5 to 10 mg/kg/day caffeine citrate (2.5 to 5 mg/kg/day anhydrous caffeine base) IV or PO are common, but maintenance doses up to 20 mg/kg/day caffeine citrate (10 mg/kg/day anhydrous caffeine base) have been used. Duration of treatment may vary, but usually persists for at least 48 hours. Due to the extended half-life, caffeine should be discontinued for at least 5 to 7 days prior to discharge unless neonate is discharged with apnea monitor.
To restore mental alertness when fatigue* or drowsiness* are present:
NOTE: Many nonprescription products are not reviewed and approved by the FDA. However, they may be marketed if they comply with current regulations and policies. The FDA has not evaluated whether these products comply.
Oral dosage (caffeine tablets):
Children younger than 12 years: Use is not recommended.
Children and Adolescents 12 years and older: 100 to 200 mg (anhydrous caffeine) PO (dose dependent on product label); may repeat dose every 3 to 4 hours if needed. Do not exceed labeled dosage.
Therapeutic Drug Monitoring:
Usual therapeutic laboratory reference range for serum caffeine concentration for apnea of prematurity: 8 to 20 mg/L.
-Serum concentration monitoring is not required for every infant; however, it may be beneficial for neonates with renal and/or hepatic impairment or those not adequately responding to standard doses. When monitoring serum concentrations, measure the concentration after 48 hours of therapy.
-Prior to initiating caffeine in neonates previously treated with theophylline, measure a baseline serum caffeine concentration because preterm infants metabolize theophylline to caffeine. Also, determine baseline caffeine serum levels in infants whose mothers consumed caffeine prior to delivery, since caffeine readily crosses the placenta.
-Individualize dose to clinical response (i.e., reduction in neonatal apneic episodes of 30% to 50%), avoidance of toxicity, and serum caffeine levels.
-In the placebo-controlled clinical trial, caffeine levels ranged from 8 to 40 mg/L. A therapeutic plasma concentration range of caffeine could not be determined from the placebo-controlled clinical trial. Some infants may require concentrations of 21 to 40 mg/L to obtain clinical response; however, some infants may experience increased adverse effects at these concentrations.
-Serious toxicity has been reported in the literature when serum caffeine levels exceed 50 mg/L.
Maximum Dosage Limits:
Caffeine base 2.5-5 mg/kg/day PO or IV for maintenance dosage.
Caffeine base 2.5-5 mg/kg/day PO or IV for maintenance dosage.
< 12 years: Maximum dosage information is not available.
12 years: 1200 mg/day PO has been suggested.
1200 mg/day PO has been suggested.
Patients with Hepatic Impairment Dosing
Specific guidelines are not available. In premature infants and neonates, caffeine metabolism is limited due to immature hepatic enzyme systems; dosage adjustments may be needed in neonates with impaired hepatic function and should be guided by clinical response and serum caffeine levels.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available. Premature infants and neonates are more dependent on renal function for proper caffeine elimination; dosage adjustments may be needed in neonates and infants with impaired renal function and should be guided by clinical response and serum caffeine levels.
Monograph content under development
Mechanism of Action: Caffeine is a mild, direct stimulant at all levels of the CNS and also stimulates the heart and cardiovascular system. The related xanthine, theophylline, shares these properties and is widely used in the treatment of pulmonary disease. Both caffeine and theophylline are CNS stimulants, with theophylline exerting more dramatic effects than caffeine at higher concentrations. Caffeine also stimulates the medullary respiratory center and relaxes bronchial smooth muscle. Caffeine stimulates voluntary muscle and gastric acid secretion, increases renal blood flow, and is a mild diuretic.
While the clinical responses to caffeine are well known, the cellular mechanism of action is uncertain. Several theories have been proposed. At high concentrations, caffeine interferes with the uptake and storage of calcium by sarcoplasmic reticulum of striated muscle. While this action would explain the effects of caffeine on cardiac and skeletal muscle, it does not appear to occur at clinically achievable concentrations. Inhibition of phosphodiesterases (and subsequent accumulation of cyclic nucleotides) also does not appear to occur at clinically achievable concentrations.
It is believed that xanthines act as adenosine-receptor antagonists. Adenosine acts as an autocoid, and virtually every cell contains adenosine receptors within the plasma membrane. Adenosine exerts complex actions. It inhibits the release of neurotransmitters from presynaptic sites but works in concert with norepinephrine or angiotensin to augment their actions. Antagonism of adenosine receptors by caffeine would appear to promote neurotransmitter release, thus explaining the stimulatory effects of caffeine. A distinct syndrome has been associated with caffeine withdrawal. It is possible that the manifestations of caffeine withdrawal may be secondary to catecholamine or neurotransmitter depletion.
The following mechanisms of action are hypothesized for caffeine's action in apnea of prematurity: 1) stimulation of the respiratory center, 2) increased minute ventilation, 3) decreased threshold to hypercapnia, 4) increased response to hypercapnia, 5) increased skeletal muscle tone, 6) decreased diaphragmatic fatigue, 7) increased metabolic rate, and 8) increased oxygen consumption. All of these actions are thought to be related to adenosine receptor antagonism.
Pharmacokinetics: Caffeine is administered orally and intravenously. Therapeutic caffeine concentrations are reported to be 5-25 mg/L in adults. Caffeine is distributed rapidly to all body tissues and readily crosses the blood-brain barrier. Caffeine is roughly 36% bound to plasma proteins, the volume of distribution is 630 ml/kg, and the clearance is 90 ml/hour/kg. In adults, caffeine is partially metabolized in the liver via demethylation reactions dependent on the CYP450 1A2 isoenzyme; major metabolites include paraxanthine (80%), theobromine (12%) and theophylline (4%). The plasma half-life of caffeine is 3-7 hours in adults.
Affected cytochrome P450 isoenzymes: CYP1A2
Caffeine is a substrate of the hepatic cytochrome isoenzyme CYP1A2.
Caffeine and citrated caffeine are well absorbed from the GI tract. After oral administration, peak plasma concentrations in adults are reached within 50-75 minutes. In neonates, the oral administration of caffeine results in peak concentrations in 0.5-2 hours; formula feedings do not affect the time to maximum concentrations after oral dosing.
In premature neonates, a half-life of 52-144 hours has been reported. In two studies including 199 extremely premature neonates, the average half-life was 101 hours (mean gestational age 27.5 weeks, average postnatal age 12 days) and 144 hours (mean gestational age 28.2 weeks, average postnatal age 4 days). In a study with 17 premature neonates (mean gestational age 29.7 weeks, average postnatal age 20.7 days), the average half-life was 52.03 hours. In these studies, the volume of distribution (Vd) ranged from 780-970 ml/kg and the clearance was 4.9-6.96 ml/hour/kg. As expected, the Vd decreased and the clearance increased with rising postnatal age. Caffeine metabolism in premature neonates is limited due to their immature hepatic enzyme systems. In this population, it is interesting to note that interconversion from theophylline to caffeine has been noted. After theophylline administration, caffeine concentrations are approximately 25% of theophylline concentrations and 3-8% of caffeine would be expected to convert to theophylline. Caffeine concentrations in the cerebrospinal fluid of premature neonates are approximately the same as plasma concentrations.
Plasma half-life for neonates may vary widely, from 52-100 hours, decreasing with increasing gestational age and postnatal age. Caffeine metabolism in neonates is limited due to their immature hepatic enzyme systems, therefore the large majority of the drug is cleared by the kidneys. Unchanged caffeine and its metabolites are excreted in the urine. The fraction of caffeine excreted unchanged in the urine, from term neonates up to 1 month old, is roughly 86%. Studies have found that gestational age, postnatal age, and patient weight are all determinants in the maturation of caffeine metabolism.
Infants and Children
The mean volume of distribution of caffeine in infants (0.8-0.9 L/kg) is slightly higher than that in adults (0.6 L/kg). Young infants have a plasma half-life of caffeine of 3-4 days. By 9 months of age post-term, the plasma half-life (5 hours) approximates that of adults. During the first 3 months, unchanged caffeine is predominantly excreted in the urine, but the percentage gradually decreases to the adult value of less than 2% in infants 7-9 months of age. Additionally, the partially demethylated xanthines and urates found in adults are attained by 7-9 months of age. Cytochrome P450 (CYP) metabolism of caffeine is inhibited in neonates and infants who are breast-fed; formula feeding does not appear to affect the pharmacokinetics of caffeine in neonates and infants.
The pharmacokinetics of caffeine have not been studied in neonates with impaired hepatic function. Caffeine elimination is more dependent on renal clearance in premature neonates and neonates than in older infants or adults due to underdeveloped hepatic metabolism. However, if hepatic impairment is present, caffeine elimination may be reduced; monitor serum concentrations and adjust dosages accordingly to avoid toxicity.
The pharmacokinetics of caffeine have not been studied in neonates with impaired renal function; however, caffeine elimination is more dependent on renal clearance in premature neonates and neonates than in older infants or adults due to underdeveloped hepatic metabolism. If renal impairment is present, caffeine elimination may be reduced; monitor serum concentrations and adjust dosages accordingly to avoid toxicity.