Caffeine Citrate


Exela Pharma Sciences, Llc
Human Prescription Drug
NDC 51754-0501
Caffeine Citrate is a human prescription drug labeled by 'Exela Pharma Sciences, Llc'. National Drug Code (NDC) number for Caffeine Citrate is 51754-0501. This drug is available in dosage form of Solution. The names of the active, medicinal ingredients in Caffeine Citrate drug includes Caffeine Citrate - 20 mg/mL . The currest status of Caffeine Citrate drug is Active.

Drug Information:

Drug NDC: 51754-0501
The labeler code and product code segments of the National Drug Code number, separated by a hyphen. Asterisks are no longer used or included within the product code segment to indicate certain configurations of the NDC.
Proprietary Name: Caffeine Citrate
Also known as the trade name. It is the name of the product chosen by the labeler.
Product Type: Human Prescription Drug
Indicates the type of product, such as Human Prescription Drug or Human OTC Drug. This data element corresponds to the “Document Type” of the SPL submission for the listing.
Non Proprietary Name: Caffeine Citrate
Also known as the generic name, this is usually the active ingredient(s) of the product.
Labeler Name: Exela Pharma Sciences, Llc
Name of Company corresponding to the labeler code segment of the ProductNDC.
Dosage Form: Solution
The translation of the DosageForm Code submitted by the firm. There is no standard, but values may include terms like `tablet` or `solution for injection`.The complete list of codes and translations can be found www.fda.gov/edrls under Structured Product Labeling Resources.
Status: Active
FDA does not review and approve unfinished products. Therefore, all products in this file are considered unapproved.
Substance Name:CAFFEINE CITRATE - 20 mg/mL
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.
Route Details:ORAL
The translation of the Route Code submitted by the firm, indicating route of administration. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Marketing Information:

An openfda section: An annotation with additional product identifiers, such as NUII and UPC, of the drug product, if available.
Marketing Category: ANDA
Product types are broken down into several potential Marketing Categories, such as New Drug Application (NDA), Abbreviated New Drug Application (ANDA), BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.
Marketing Start Date: 21 Sep, 2006
This is the date that the labeler indicates was the start of its marketing of the drug product.
Marketing End Date: 22 Dec, 2025
This is the date the product will no longer be available on the market. If a product is no longer being manufactured, in most cases, the FDA recommends firms use the expiration date of the last lot produced as the EndMarketingDate, to reflect the potential for drug product to remain available after manufacturing has ceased. Products that are the subject of ongoing manufacturing will not ordinarily have any EndMarketingDate. Products with a value in the EndMarketingDate will be removed from the NDC Directory when the EndMarketingDate is reached.
Application Number: ANDA077304
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.
Listing Expiration Date: 31 Dec, 2023
This is the date when the listing record will expire if not updated or certified by the firm.

OpenFDA Information:

An openfda section: An annotation with additional product identifiers, such as NUII and UPC, of the drug product, if available.
Manufacturer Name:Exela Pharma Sciences, LLC
Name of manufacturer or company that makes this drug product, corresponding to the labeler code segment of the NDC.
RxCUI:849928
The RxNorm Concept Unique Identifier. RxCUI is a unique number that describes a semantic concept about the drug product, including its ingredients, strength, and dose forms.
Original Packager:Yes
Whether or not the drug has been repackaged for distribution.
UNII:U26EO4675Q
Unique Ingredient Identifier, which is a non-proprietary, free, unique, unambiguous, non-semantic, alphanumeric identifier based on a substance’s molecular structure and/or descriptive information.
Pharmacologic Class:Central Nervous System Stimulant [EPC]
Central Nervous System Stimulation [PE]
Methylxanthine [EPC]
Xanthines [CS]
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

Packaging Information:

Package NDCDescriptionMarketing Start DateMarketing End DateSample Available
51754-0501-25 VIAL in 1 CARTON (51754-0501-2) / 3 mL in 1 VIAL31 Aug, 2019N/ANo
51754-0501-310 VIAL in 1 CARTON (51754-0501-3) / 3 mL in 1 VIAL30 Mar, 2015N/ANo
Package NDC number, known as the NDC, identifies the labeler, product, and trade package size. The first segment, the labeler code, is assigned by the FDA. Description tells the size and type of packaging in sentence form. Multilevel packages will have the descriptions concatenated together.

Product Elements:

Caffeine citrate caffeine citrate caffeine citrate caffeine citric acid monohydrate trisodium citrate dihydrate water

Drug Interactions:

Drug interactions 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 four 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.

Indications and Usage:

Indications and usage caffeine citrate injection and caffeine citrate oral solution are 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 3 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.

General Precautions:

General 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 for longer periods of treatment have not been established. safety and efficacy of caffeine citrate for use in the prophylactic treatment of sudden infant death syndrome (sids) or prior to extubation in mechanically ventilated infants have also not been established.

Dosage and Administration:

Dosage and administration 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 using a syringe infusion pump (over 30 minutes) one time maintenance dose 0.25 ml/kg 5 mg/kg intravenous (over 10 minutes) or orally every 24 hours 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 ne
ed to be monitored periodically throughout treatment to avoid toxicity. serious toxicity has been associated with serum levels greater than 50 mg/l. caffeine citrate injection and 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 injection and caffeine citrate oral solution are 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-blinded therapy adverse event (ae) caffeine citrate n=46 placebo n=39 n (%) n (%) body as a whole accidental injury 1 (2.2) 0 (0.0) feeding intolerance 4 (8.7) 2 (5.1) sepsis 2 (4.3) 0 (0.0) cardiovascular system hemorrhage 1 (2.2) 0 (0.0) digestive system necrotizing enterocolitis 2 (4.3) 1 (2.6) gastritis 1 (2.2) 0 (0.0) gastrointestinal hemorrhage 1 (2.2) 0 (0.0) hemic and lymphatic system disseminated intravascular 1 (2.2) 0 (0.0) coagulation metabolic and nutritive disorders acidosis 1 (2.2) 0 (0.0) healing abnormal 1 (2.2
) 0 (0.0) nervous system cerebral hemorrhage 1 (2.2) 0 (0.0) respiratory system dyspnea 1 (2.2) 0 (0.0) lung edema 1 (2.2) 0 (0.0) skin and appendages dry skin 1 (2.2) 0 (0.0) rash 4 (8.7) 3 (7.7) skin breakdown 1 (2.2) 0 (0.0) special senses retinopathy of prematurity 1 (2.2) 0 (0.0) urogenital system kidney failure 1 (2.2) 0 (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 “rescued” with open-label caffeine for uncontrolled apnea. adverse events described in the published literature include: central nervous system stimulation (ie, irritability, restlessness, jitteriness), cardiovascular effects (ie, tachycardia, increased left ventricular output, and increased stroke volume), gastrointestinal effects (ie, increased gastric aspirate, gastrointestinal intolerance), alterations in serum glucose (ie, hypoglycemia and hyperglycemia), and renal effects (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 EVENTS THAT OCCURRED MORE FREQUENTLY IN CAFFEINE CITRATE TREATED PATIENTS THAN PLACEBO DURING DOUBLE-BLINDED THERAPY
Adverse Event (AE) Caffeine Citrate N=46 Placebo N=39
n (%) n (%)
BODY AS A WHOLE
Accidental Injury 1 (2.2) 0 (0.0)
Feeding Intolerance 4 (8.7) 2 (5.1)
Sepsis 2 (4.3) 0 (0.0)
CARDIOVASCULAR SYSTEM
Hemorrhage 1 (2.2) 0 (0.0)
DIGESTIVE SYSTEM
Necrotizing Enterocolitis 2 (4.3) 1 (2.6)
Gastritis 1 (2.2) 0 (0.0)
Gastrointestinal Hemorrhage 1 (2.2) 0 (0.0)
HEMIC AND LYMPHATIC SYSTEM
Disseminated Intravascular 1 (2.2) 0 (0.0)
Coagulation
METABOLIC AND NUTRITIVE DISORDERS
Acidosis 1 (2.2) 0 (0.0)
Healing Abnormal 1 (2.2) 0 (0.0)
NERVOUS SYSTEM
Cerebral Hemorrhage 1 (2.2) 0 (0.0)
RESPIRATORY SYSTEM
Dyspnea 1 (2.2) 0 (0.0)
Lung Edema 1 (2.2) 0 (0.0)
SKIN AND APPENDAGES
Dry Skin 1 (2.2) 0 (0.0)
Rash 4 (8.7) 3 (7.7)
Skin Breakdown 1 (2.2) 0 (0.0)
SPECIAL SENSES
Retinopathy of Prematurity 1 (2.2) 0 (0.0)
UROGENITAL SYSTEM
Kidney Failure 1 (2.2) 0 (0.0)

Drug Interactions:

Drug interactions 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 four 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.

Use in Pregnancy:

Pregnancy: pregnancy category c 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 basis), during the period of organogenesis, caused a low incidence of cleft palate and exencephaly in the fetuses. there are no adequate and well-controlled studies in pregnant women.

Overdosage:

Overdosage following overdose, serum caffeine levels have ranged from approximately 24 mg/l (a postmarketing 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, tonicclonic 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; not caffeine citrate) 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 both caffeine citrate injection for intravenous administration and 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 5.0 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. chemical 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 ba
se/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 3-4 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 "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 (24-48 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 of 85 patients who received drug, 3 were not included in the efficacy analysis because they had <6 apnea episodes/24 hours at baseline. 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

Mechanism of Action:

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:

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
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 3-8% 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 3-4 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 "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 (24-48 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 of 85 patients who received drug, 3 were not included in the efficacy analysis because they had <6 apnea episodes/24 hours at baseline. 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

Carcinogenesis and Mutagenesis and Impairment of Fertility:

Carcinogenesis, mutagenesis, impairment of fertility 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 lymphocyt
e assays and was not mutagenic in an in vitro cho/hypoxanthine guanine phosphoribosyltransferase (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/m2 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 (3.0 g over 7 weeks) was toxic to rat testes as manifested by spermatogenic cell degeneration.

Clinical Studies:

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
(24-48 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 of 85 patients who received drug, 3 were not included in the efficacy analysis because they had <6 apnea episodes/24 hours at baseline. 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

How Supplied:

How supplied both caffeine citrate injection and caffeine citrate oral solution are available as clear, colorless, sterile, nonpyrogenic, preservative-free, aqueous solutions in 3 ml colorless glass vials. the vials of caffeine citrate injection are sealed with a teflon-faced gray rubber stopper and an aluminum overseal with a white flip-off polypropylene disk inset. the vials of caffeine citrate oral solution are sealed with a teflon-faced gray rubber stopper and a peel-off aluminum overseal with a blue flip-off polypropylene disk inset. both the injection and oral solution 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 injection, usp ndc 51754-0500-1: 3 ml vial, individually packaged in a carton. caffeine citrate oral solution, usp ndc 51754-0501-2: 3 ml vial (not child-resistant), 5 vials per white polypropylene child- resistant container. ndc 51754-0501-3: 3 ml vial (not ch
ild-resistant), 10 vials per white polypropylene child-resistant container. store at 20° to 25°c (68° to 77°f) [see usp controlled room temperature]. preservative free. for single use only. discard unused portion. attention pharmacist: detach "instructions for use" from the package insert and dispense with caffeine citrate oral solution prescription. manufactured and distributed by: exela pharma sciences, llc lenoir, nc 28645 usa revised: may 2018 logo

Information for Patients:

Information for patients parents/caregivers of patients receiving caffeine citrate oral solution should receive the following instructions: 1. caffeine citrate oral solution does not contain any preservatives and each vial is for single use only. any unused portion of the medication should be discarded. 2. it is important that the dose of caffeine citrate oral solution be measured accurately, i.e., with a 1cc or other appropriate syringe. 3. consult your physician if the baby continues to have apnea events; do not increase the dose of caffeine citrate oral solution without medical consultation. 4. consult your physician if the baby begins to demonstrate signs of gastrointestinal intolerance, such as abdominal distention, vomiting, or bloody stools, or seems lethargic. 5. caffeine citrate oral solution should be inspected visually for particulate matter and discoloration prior to its administration. vials containing discolored solution or visible particulate matter should be discarded.

Package Label Principal Display Panel:

Principal display panel - 60 mg/3 ml vial label rx only ndc 51754-0501-3 caffeine citrate oral solution, usp 60 mg/3ml (20 mg/ml ) for oral use only for single use only. discard unused portion. 3 ml single dose vial vial label

Package/label principal display panel-60 mg/3 ml 5 count carton ndc 51754-0501-2 rx only caffeine citrate oral solution, usp 60 mg/3ml (20 mg/ml ) for oral use only for single use only. discard unused portion. 5 x 3 ml single dose vials 5 count carton

Package/label principal display panel-60 mg/3 ml 10 count carton ndc 51754-0501-3 rx only caffeine citrate oral solution, usp 60 mg/3ml (20 mg/ml ) for oral use only for single use only. discard unused portion. 10 x 3 ml single dose vials 10 count carton


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