Product Elements:
Caffeine citrate caffeine citrate caffeine citrate caffeine citric acid monohydrate sodium citrate
Indications and Usage:
Indications and usage caffeine citrate oral solution is indicated for the short term treatment of apnea of prematurity in infants between 28 and <33 weeks gestational age.
Warnings:
Warnings during the double-blind, placebo-controlled clinical trial, six cases of necrotizing enterocolitis developed among the 85 infants studied (caffeine=46, placebo=39), with three cases resulting in death. five of the six patients with necrotizing enterocolitis were randomized to or had been exposed to caffeine citrate. reports in the published literature have raised a question regarding the possible association between the use of methylxanthines and development of necrotizing enterocolitis, although a causal relationship between methylxanthine use and necrotizing enterocolitis has not been established. therefore, as with all preterm infants, patients being treated with caffeine citrate should be carefully monitored for the development of necrotizing enterocolitis.
Dosage and Administration:
Dosage and administration prior to initiation of caffeine citrate oral solution, baseline serum levels of caffeine should be measured in infants previously treated with theophylline, since preterm infants metabolize theophylline to caffeine. likewise, baseline serum levels of caffeine should be measured in infants born to mothers who consumed caffeine prior to delivery, since caffeine readily crosses the placenta. the recommended loading dose and maintenance doses of caffeine citrate follow. dose of caffeine citrate volume dose of caffeine citrate mg/kg route frequency loading dose 1 ml/kg 20 mg/kg intravenous* (over 30 minutes) one time maintenance dose 0.25 ml/kg 5 mg/kg intravenous* (over 10 minutes) or orally every 24 hours** *using a syringe infusion pump **beginning 24 hours after the loading dose note that the dose of caffeine base is one-half the dose when expressed as caffeine citrate (e.g., 20 mg of caffeine citrate is equivalent to 10 mg of caffeine base). serum concentratio
Read more...ns of caffeine may need to be monitored periodically throughout treatment to avoid toxicity. serious toxicity has been associated with serum levels greater than 50 mg/l. caffeine citrate oral solution should be inspected visually for particulate matter and discoloration prior to administration. vials containing discolored solution or visible particulate matter should be discarded.
Contraindications:
Contraindications caffeine citrate is contraindicated in patients who have demonstrated hypersensitivity to any of its components.
Adverse Reactions:
Adverse reactions overall, the reported number of adverse events in the double-blind period of the controlled trial was similar for the caffeine citrate and placebo groups. the following table shows adverse events that occurred in the double-blind period of the controlled trial and that were more frequent in caffeine citrate treated patients than placebo. adverse events that occurred more frequently in caffeine citrate treated patients than placebo during double-blind therapy adverse event (ae) caffeine citrate n=46 n (%) placebo n=39 n (%) body as a whole accidental injury feeding intolerance sepsis 1 (2.2) 4 (8.7) 2 (4.3) 0 (0) 2 (5.1) 0 (0) cardiovascular system hemorrhage 1 (2.2) 0 (0) digestive system necrotizing enterocolitis gastritis gastrointestinal hemorrhage 2 (4.3) 1 (2.2) 1 (2.2) 1 (2.6) 0 (0) 0 (0) hemic and lymphatic system disseminated intravascular coagulation 1 (2.2) 0 (0) metabolic and nutritive disorders acidosis healing abnormal 1 (2.2) 1 (2.2) 0 (0) 0 (0) nervous
Read more...system cerebral hemorrhage 1 (2.2) 0 (0) respiratory system dsypnea lung edema 1 (2.2) 1 (2.2) 0 (0) 0 (0) skin and appendages dry skin rash skin breakdown 1 (2.2) 4 (8.7) 1 (2.2) 0 (0) 3 (7.7) 0 (0) special senses retinopathy of prematurity 1 (2.2) 0 (0) urogenital system kidney failure 1 (2.2) 0 (0) in addition to the cases above, three cases of necrotizing enterocolitis were diagnosed in patients receiving caffeine citrate during the open-label phase of the study. three of the infants who developed necrotizing enterocolitis during the trial died. all had been exposed to caffeine. two were randomized to caffeine, and one placebo patient was ârescuedâ with open-label caffeine for uncontrolled apnea. adverse events described in the published literature include: central nervous system stimulation (i.e., irritability, restlessness, jitteriness), cardiovascular effects (i.e., tachycardia, increased left ventricular output, and increased stroke volume), gastrointestinal effects (i.e., increased gastric aspirate, gastrointestinal intolerance), alterations in serum glucose (i.e., hypoglycemia and hyperglycemia) and renal effects (i.e., increased urine flow rate, increased creatinine clearance, and increased sodium and calcium excretion). published long-term follow-up studies have not shown caffeine to adversely affect neurological development or growth parameters.
Adverse Reactions Table:
| Adverse Event (AE) | Caffeine Citrate N=46 n (%) | Placebo N=39 n (%) |
| BODY AS A WHOLE Accidental Injury Feeding Intolerance Sepsis | 1 (2.2) 4 (8.7) 2 (4.3) | 0 (0) 2 (5.1) 0 (0) |
| CARDIOVASCULAR SYSTEM Hemorrhage | 1 (2.2) | 0 (0) |
| DIGESTIVE SYSTEM Necrotizing Enterocolitis Gastritis Gastrointestinal Hemorrhage | 2 (4.3) 1 (2.2) 1 (2.2) | 1 (2.6) 0 (0) 0 (0) |
| HEMIC AND LYMPHATIC SYSTEM Disseminated Intravascular Coagulation | 1 (2.2) | 0 (0) |
| METABOLIC AND NUTRITIVE DISORDERS Acidosis Healing Abnormal | 1 (2.2) 1 (2.2) | 0 (0) 0 (0) |
| NERVOUS SYSTEM Cerebral Hemorrhage | 1 (2.2) | 0 (0) |
| RESPIRATORY SYSTEM Dsypnea Lung Edema | 1 (2.2) 1 (2.2) | 0 (0) 0 (0) |
| SKIN AND APPENDAGES Dry Skin Rash Skin Breakdown | 1 (2.2) 4 (8.7) 1 (2.2) | 0 (0) 3 (7.7) 0 (0) |
| SPECIAL SENSES Retinopathy of Prematurity | 1 (2.2) | 0 (0) |
| UROGENITAL SYSTEM Kidney Failure | 1 (2.2) | 0 (0) |
Overdosage:
Overdosage following overdose, serum caffeine levels have ranged from approximately 24 mg/l (a post marketing spontaneous case report in which an infant exhibited irritability, poor feeding and insomnia) to 350 mg/l. serious toxicity has been associated with serum levels greater than 50 mg/l (see precautions, laboratory tests and dosage and administration ). signs and symptoms reported in the literature after caffeine overdose in preterm infants include fever, tachypnea, jitteriness, insomnia, fine tremor of the extremities, hypertonia, opisthotonos, tonic-clonic movements, nonpurposeful jaw and lip movements, vomiting, hyperglycemia, elevated blood urea nitrogen, and elevated total leukocyte concentration. seizures have also been reported in cases of overdose. one case of caffeine overdose complicated by development of intraventricular hemorrhage and long-term neurological sequelae has been reported. another case of caffeine citrate overdose (from new zealand) of an estimated 600 mg caffeine citrate (approximately 322 mg/kg) administered over 40 minutes was complicated by tachycardia, st depression, respiratory distress, heart failure, gastric distention, acidosis and a severe extravasation burn with tissue necrosis at the peripheral intravenous injection site. no deaths associated with caffeine overdose have been reported in preterm infants. treatment of caffeine overdose is primarily symptomatic and supportive. caffeine levels have been shown to decrease after exchange transfusions. convulsions may be treated with intravenous administration of diazepam or a barbiturate such as pentobarbital sodium.
Description:
Description caffeine citrate oral solution, usp is a clear, colorless, sterile, non-pyrogenic, preservative-free, aqueous solution adjusted to ph 4.7. each ml contains 20 mg caffeine citrate (equivalent to 10 mg of caffeine base) prepared in solution by the addition of 10 mg caffeine anhydrous to 5 mg citric acid monohydrate, 8.3 mg sodium citrate dihydrate and water for injection. caffeine, a central nervous system stimulant, is an odorless white crystalline powder or granule, with a bitter taste. it is sparingly soluble in water and ethanol at room temperature. the chemical name of caffeine is 3,7-dihydro-1,3,7-trimethyl-1 h -purine-2,6-dione. in the presence of citric acid it forms caffeine citrate salt in solution. the structural formula and molecular weight of caffeine citrate follows. structure
Clinical Pharmacology:
Clinical pharmacology mechanism of action caffeine is structurally related to other methylxanthines, theophylline and theobromine. it is a bronchial smooth muscle relaxant, a cns stimulant, a cardiac muscle stimulant and a diuretic. although the mechanism of action of caffeine in apnea of prematurity is not known, several mechanisms have been hypothesized. these include: (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. most of these effects have been attributed to antagonism of adenosine receptors, both a 1 and a 2 subtypes, by caffeine, which has been demonstrated in receptor binding assays and observed at concentrations approximating those achieved therapeutically. pharmacokinetics absorption after oral administration of 10 mg caffeine base
Read more.../kg to preterm neonates, the peak plasma level (c max ) for caffeine ranged from 6 to 10 mg/l and the mean time to reach peak concentration (t max ) ranged from 30 minutes to 2 hours. the t max was not affected by formula feeding. the absolute bioavailability, however, was not fully examined in preterm neonates. distribution caffeine is rapidly distributed into the brain. caffeine levels in the cerebrospinal fluid of preterm neonates approximate their plasma levels. the mean volume of distribution of caffeine in infants (0.8 to 0.9 l/kg) is slightly higher than that in adults (0.6 l/kg). plasma protein binding data are not available for neonates or infants. in adults, the mean plasma protein binding in vitro is reported to be approximately 36%. metabolism hepatic cytochrome p450 1a2 (cyp1a2) is involved in caffeine biotransformation. caffeine metabolism in preterm neonates is limited due to their immature hepatic enzyme systems. interconversion between caffeine and theophylline has been reported in preterm neonates; caffeine levels are approximately 25% of theophylline levels after theophylline administration and approximately 3 to 8% of caffeine administered would be expected to convert to theophylline. elimination in young infants, the elimination of caffeine is much slower than that in adults due to immature hepatic and/or renal function. mean half-life (t 1/2 ) and fraction excreted unchanged in urine (a e ) of caffeine in infants have been shown to be inversely related to gestational/postconceptual age. in neonates, the t 1/2 is approximately 3 to 4 days and the a e is approximately 86% (within 6 days). by 9 months of age, the metabolism of caffeine approximates that seen in adults (t 1/2 = 5 hours and a e = 1%). special populations studies examining the pharmacokinetics of caffeine in neonates with hepatic or renal insufficiency have not been conducted. caffeine citrate should be administered with caution in preterm neonates with impaired renal or hepatic function. serum concentrations of caffeine should be monitored and dose administration of caffeine citrate should be adjusted to avoid toxicity in this population. clinical studies one multicenter, randomized, double-blind trial compared caffeine citrate to placebo in eighty-five (85) preterm infants (gestational age 28 to <33 weeks) with apnea of prematurity. apnea of prematurity was defined as having at least 6 apnea episodes of greater than 20 seconds duration in a 24-hour period with no other identifiable cause of apnea. a 1 ml/kg (20 mg/kg caffeine citrate providing 10 mg/kg as caffeine base) loading dose of caffeine citrate was administered intravenously, followed by a 0.25 ml/kg (5 mg/kg caffeine citrate providing 2.5 mg/kg of caffeine base) daily maintenance dose administered either intravenously or orally (generally through a feeding tube). the duration of treatment in this study was limited to 10 to 12 days. the protocol allowed infants to be ârescuedâ with open-label caffeine citrate treatment if their apnea remained uncontrolled during the double-blind phase of the trial. the percentage of patients without apnea on day 2 of treatment (24 to 48 hours after the loading dose) was significantly greater with caffeine citrate than placebo. the following table summarizes the clinically relevant endpoints evaluated in this study: caffeine citrate placebo p-value number of patients evaluated 1 45 37 % of patients with zero apnea events on day 2 26.7 8.1 0.03 apnea rate on day 2 (per 24 h) 4.9 7.2 0.134 % of patients with 50% reduction in apnea events from baseline on day 2 76 57 0.07 1 of 85 patients who received drug, 3 were not included in the efficacy analysis because they had <6 apnea episodes/24 hours at baseline. in this 10 to 12 day trial, the mean number of days with zero apnea events was 3 in the caffeine citrate group and 1.2 in the placebo group. the mean number of days with a 50% reduction from baseline in apnea events was 6.8 in the caffeine citrate group and 4.6 in the placebo group.
Mechanism of action caffeine is structurally related to other methylxanthines, theophylline and theobromine. it is a bronchial smooth muscle relaxant, a cns stimulant, a cardiac muscle stimulant and a diuretic. although the mechanism of action of caffeine in apnea of prematurity is not known, several mechanisms have been hypothesized. these include: (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. most of these effects have been attributed to antagonism of adenosine receptors, both a 1 and a 2 subtypes, by caffeine, which has been demonstrated in receptor binding assays and observed at concentrations approximating those achieved therapeutically.
Pharmacokinetics absorption after oral administration of 10 mg caffeine base/kg to preterm neonates, the peak plasma level (c max ) for caffeine ranged from 6 to 10 mg/l and the mean time to reach peak concentration (t max ) ranged from 30 minutes to 2 hours. the t max was not affected by formula feeding. the absolute bioavailability, however, was not fully examined in preterm neonates. distribution caffeine is rapidly distributed into the brain. caffeine levels in the cerebrospinal fluid of preterm neonates approximate their plasma levels. the mean volume of distribution of caffeine in infants (0.8 to 0.9 l/kg) is slightly higher than that in adults (0.6 l/kg). plasma protein binding data are not available for neonates or infants. in adults, the mean plasma protein binding in vitro is reported to be approximately 36%. metabolism hepatic cytochrome p450 1a2 (cyp1a2) is involved in caffeine biotransformation. caffeine metabolism in preterm neonates is limited due to their immature hepat
Read more...ic enzyme systems. interconversion between caffeine and theophylline has been reported in preterm neonates; caffeine levels are approximately 25% of theophylline levels after theophylline administration and approximately 3 to 8% of caffeine administered would be expected to convert to theophylline. elimination in young infants, the elimination of caffeine is much slower than that in adults due to immature hepatic and/or renal function. mean half-life (t 1/2 ) and fraction excreted unchanged in urine (a e ) of caffeine in infants have been shown to be inversely related to gestational/postconceptual age. in neonates, the t 1/2 is approximately 3 to 4 days and the a e is approximately 86% (within 6 days). by 9 months of age, the metabolism of caffeine approximates that seen in adults (t 1/2 = 5 hours and a e = 1%). special populations studies examining the pharmacokinetics of caffeine in neonates with hepatic or renal insufficiency have not been conducted. caffeine citrate should be administered with caution in preterm neonates with impaired renal or hepatic function. serum concentrations of caffeine should be monitored and dose administration of caffeine citrate should be adjusted to avoid toxicity in this population.
Clinical studies one multicenter, randomized, double-blind trial compared caffeine citrate to placebo in eighty-five (85) preterm infants (gestational age 28 to <33 weeks) with apnea of prematurity. apnea of prematurity was defined as having at least 6 apnea episodes of greater than 20 seconds duration in a 24-hour period with no other identifiable cause of apnea. a 1 ml/kg (20 mg/kg caffeine citrate providing 10 mg/kg as caffeine base) loading dose of caffeine citrate was administered intravenously, followed by a 0.25 ml/kg (5 mg/kg caffeine citrate providing 2.5 mg/kg of caffeine base) daily maintenance dose administered either intravenously or orally (generally through a feeding tube). the duration of treatment in this study was limited to 10 to 12 days. the protocol allowed infants to be ârescuedâ with open-label caffeine citrate treatment if their apnea remained uncontrolled during the double-blind phase of the trial. the percentage of patients without apnea on day 2 of
Read more...treatment (24 to 48 hours after the loading dose) was significantly greater with caffeine citrate than placebo. the following table summarizes the clinically relevant endpoints evaluated in this study: caffeine citrate placebo p-value number of patients evaluated 1 45 37 % of patients with zero apnea events on day 2 26.7 8.1 0.03 apnea rate on day 2 (per 24 h) 4.9 7.2 0.134 % of patients with 50% reduction in apnea events from baseline on day 2 76 57 0.07 1 of 85 patients who received drug, 3 were not included in the efficacy analysis because they had <6 apnea episodes/24 hours at baseline. in this 10 to 12 day trial, the mean number of days with zero apnea events was 3 in the caffeine citrate group and 1.2 in the placebo group. the mean number of days with a 50% reduction from baseline in apnea events was 6.8 in the caffeine citrate group and 4.6 in the placebo group.
How Supplied:
How supplied caffeine citrate oral solution, usp is available as a clear, colorless, sterile, non-pyrogenic, preservative-free, aqueous solution in colorless glass vials. the vials contain 3 ml of solution at a concentration of 20 mg/ml caffeine citrate (60 mg/vial) equivalent to 10 mg/ml caffeine base (30 mg/vial). caffeine citrate oral solution, usp product code unit of sale strength each 400603 ndc 63323-406-03 unit of 5 60 mg per 3 ml (20 mg per ml) ndc 63323-406-01 3 ml in a 6 ml single dose vial store at 20° to 25°c (68° to 77°f)[see usp controlled room temperature]. preservative free. for single use only. discard unused portion. the container closure is not made with natural rubber latex. pharmacist: dispense the âpatient informationâ leaflet with the drug product.
Package Label Principal Display Panel:
Package label - principal display - caffeine citrate oral 3 ml single dose vial label ndc 63323-406-01 400603 caffeine citrate oral solution, usp 60 mg per 3 ml (20 mg per ml) 3 ml single dose vial for oral use only rx only package label - principal display - caffeine citrate oral 3 ml single dose vial tray label ndc 63323-406-03 400603 caffeine citrate oral solution, usp 60 mg per 3 ml (20 mg per ml) 3 ml single dose vial for oral use only rx only vial tray