DailyMed Label: Caffeine Citrate Oral Solution

DailyMed Label: Caffeine Citrate Oral Solution

2023

DailyMed Prescription

Caffeine Citrate Oral Solution

Caffeine Citrate

Armas Pharmaceuticals Inc.

NDC: 72485-110

NDC: 72485-110

Caffeine Citrate Oral Solution are clear, colorless, sterile, non-pyrogenic, preservative-free, aqueous solutions 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 trisodium 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. image description

Caffeine citrate is indicated for the short term treatment of apnea of prematurity in infants between 28 and <33 weeks gestational age.

Prior to initiation of caffeine citrate, 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 concentrations 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 should be inspected visually for particulate matter and discoloration prior to administration.  Vials containing discolored solution or visible particulate matter should be discarded.

Caffeine citrate is contraindicated in patients who have demonstrated hypersensitivity to any of its components.

Apnea of prematurity is a diagnosis of exclusion. Other causes of apnea (e.g., central nervous system disorders, primary lung disease, anemia, sepsis, metabolic disturbances, cardiovascular abnormalities, or obstructive apnea) should be ruled out or properly treated prior to initiation of caffeine citrate. Caffeine is a central nervous system stimulant and in cases of caffeine overdose, seizures have been reported. Caffeine citrate should be used with caution in infants with seizure disorders. The duration of treatment of apnea of prematurity in the placebo-controlled trial was limited to 10 to 12 days. The safety and efficacy of caffeine citrate longer periods of treatment have not been established. Safety and efficacy of caffeine citrate oral solution for use in the prophylaxis treatment of sudden infant death syndrome (SIDS) or prior to extubation in mechanically ventilated infants have also not been established. Cardiovascular Although no cases of cardiac toxicity were reported in the placebo-controlled trial, caffeine has been shown to increase heart rate, left ventricular output, and stroke volume in published studies.  Therefore, caffeine citrate should be used with caution in infants with cardiovascular disease. Renal and Hepatic Systems Caffeine citrate should be administered with caution in infants with impaired renal or hepatic function. (See CLINICAL PHARMACOLOGY, Elimination, Special Populations ). Parents/caregivers of patients receiving Caffeine Citrate Oral Solution should receive the following instructions: Caffeine citrate does not contain any preservatives and each vial is for single dose only.  Any unused portion of the medication should be discarded. It is important that the dose of caffeine citrate be measured accurately, i.e., with a 1cc or other appropriate syringe. Consult your physician if the baby continues to have apnea events; do not increase the dose of caffeine citrate without medical consultation. Consult your physician if the baby begins to demonstrate signs of gastrointestinal intolerance, such as abdominal distention, vomiting, or bloody stools, or seems lethargic. Caffeine citrate should be inspected visually for particulate matter and discoloration prior to its administration. Vials containing discolored solution or visible particulate matter should be discarded. Prior to initiation of caffeine citrate, 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. 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. Serious toxicity has been reported in the literature when serum caffeine levels exceed 50 mg/L. In clinical studies reported in the literature, cases of hypoglycemia and hyperglycemia have been observed.  Therefore, serum glucose may need to be periodically monitored in infants receiving caffeine citrate. Cytochrome P450 1A2 (CYP1A2) is known to be the major enzyme involved in the metabolism of caffeine. Therefore, caffeine has the potential to interact with drugs that are substrates for CYP1A2, inhibit CYP1A2, or induce CYP1A2. Few data exist on drug interactions with caffeine in preterm neonates. Based on adult data, lower doses of caffeine may be needed following coadministration of drugs which are reported to decrease caffeine elimination (e.g., cimetidine and ketoconazole) and higher caffeine doses may be needed following coadministration of drugs that increase caffeine elimination (e.g., phenobarbital and phenytoin). Caffeine administered concurrently with ketoprofen reduced the urine volume in 4 healthy volunteers. The clinical significance of this interaction in preterm neonates is not known. Interconversion between caffeine and theophylline has been reported in preterm neonates.  The concurrent use of these drugs is not recommended. In a 2-year study in Sprague-Dawley rats, caffeine (as caffeine base) administered in drinking water was not carcinogenic in male rats at doses up to 102 mg/kg or in female rats at doses up to 170 mg/kg (approximately 2 and 4 times, respectively, the maximum recommended intravenous loading dose for  infants on a mg/m 2 basis).  In an 18-month study in C57BL/6 mice, no evidence of tumorigenicity was seen at dietary doses up to 55 mg/kg (less than the maximum recommended intravenous loading dose for infants on a mg/m 2 basis). Caffeine (as caffeine base) increased the sister chromatid exchange (SCE) SCE/cell metaphase (exposure time dependent) in an in vivo mouse metaphase analysis. Caffeine also potentiated the genotoxicity of known mutagens and enhanced the micronuclei formation (5-fold) in folate-deficient mice.  However, caffeine did not increase chromosomal aberrations in in vitro Chinese hamster ovary cell (CHO) and human lymphocyte assays and was not mutagenic in an in vitro CHO/hypoxanthine guanine phosphoribosyltransferease (HGPRT) gene mutation assay, except at cytotoxic concentrations. In addition, caffeine was not clastogenic in an in vivo mouse micronucleus assay. Caffeine (as caffeine base) administered to male rats at 50 mg/kg/day subcutaneously (approximately equal to the maximum recommended intravenous loading dose for infants on a mg/m 2 basis) for four days prior to mating with untreated females, caused decreased male reproductive performance in addition to causing embryotoxicity.  In addition, long-term exposure to high oral doses of caffeine (3 g over 7 weeks) was toxic to rat testes as manifested by spermatogenic cell degeneration. Concern for the teratogenicity of caffeine is not relevant when administered to infants.  In studies performed in adult animals, caffeine (as caffeine base) administered to pregnant mice as sustained release pellets at 50 mg/kg (less than the maximum recommended intravenous loading dose for infants on a mg/m 2 basis), during the period of organogenesis, caused a low incidence of c left palate and exencephaly in the fetuses.  There are no adequate and well-controlled studies in pregnant women.

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.

Cytochrome P450 1A2 (CYP1A2) is known to be the major enzyme involved in the metabolism of caffeine. Therefore, caffeine has the potential to interact with drugs that are substrates for CYP1A2, inhibit CYP1A2, or induce CYP1A2. Few data exist on drug interactions with caffeine in preterm neonates. Based on adult data, lower doses of caffeine may be needed following coadministration of drugs which are reported to decrease caffeine elimination (e.g., cimetidine and ketoconazole) and higher caffeine doses may be needed following coadministration of drugs that increase caffeine elimination (e.g., phenobarbital and phenytoin). Caffeine administered concurrently with ketoprofen reduced the urine volume in 4 healthy volunteers. The clinical significance of this interaction in preterm neonates is not known. Interconversion between caffeine and theophylline has been reported in preterm neonates.  The concurrent use of these drugs is not recommended.

Caffeine citrate Oral Solution, USP is available as clear, colorless, sterile, non-pyrogenic, preservative-free, aqueous solutions in 5 mL colorless glass vials.  The vials of Caffeine citrate Oral Solution, USP are sealed with a gray rubber stopper and a peel-off aluminum overseal with a blue flip-off polypropylene disk inset. Caffeine citrate Oral Solution, USP vials contain 3 mL 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 Caffeine citrate oral solution, USP 60 mg/3 mL is a clear, colorless aqueous solution, 10 vials per white polypropylene child-resistant container and is available as follows. 3 mL fill in 5 mL glass vial                                                                10 vials per white polypropylene child-resistant container.                   NDC 72485-110-10 Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Preservative Free. For single dose only. Discard unused portion. ATTENTION PHARMACIST: Detach “Instructions for Use” from the package insert and dispense with Caffeine Citrate Oral Solution prescription. Manufactured by: Micro Labs Limited Bangalore-560099, INDIA. Distributed by: Armas Pharmaceuticals, Inc. Freehold, NJ 07728 (USA) Rev. 10/2022

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 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 3-8% 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. 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 “rescued” 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 hrs.) 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.

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