NDC 72485-110 Caffeine Citrate Oral Solution

Caffeine Citrate

NDC Product Code 72485-110

NDC 72485-110-10

Package Description: 10 VIAL, SINGLE-DOSE in 1 BOX > 3 mL in 1 VIAL, SINGLE-DOSE

NDC Product Information

Caffeine Citrate Oral Solution with NDC 72485-110 is a a human prescription drug product labeled by Armas Pharmaceuticals Inc.. The generic name of Caffeine Citrate Oral Solution is caffeine citrate. The product's dosage form is solution and is administered via oral form.

Labeler Name: Armas Pharmaceuticals Inc.

Dosage Form: Solution - A clear, homogeneous liquid1 dosage form that contains one or more chemical substances dissolved in a solvent or mixture of mutually miscible solvents.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Caffeine Citrate Oral Solution Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • CAFFEINE CITRATE 60 mg/3mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • CITRIC ACID MONOHYDRATE (UNII: 2968PHW8QP)
  • TRISODIUM CITRATE DIHYDRATE (UNII: B22547B95K)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Central Nervous System Stimulant - [EPC] (Established Pharmacologic Class)
  • Methylxanthine - [EPC] (Established Pharmacologic Class)
  • Xanthines - [CS]
  • Central Nervous System Stimulation - [PE] (Physiologic Effect)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Armas Pharmaceuticals Inc.
Labeler Code: 72485
FDA Application Number: ANDA213202 What is the FDA Application Number?
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.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/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.

Start Marketing Date: 03-01-2020 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

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Caffeine Citrate Oral Solution Product Label Images

Caffeine Citrate Oral Solution Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Description

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- 1H-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.

Clinical Pharmacology

Mechanism of ActionCaffeine 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 A1 and A2 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 (Cmax) for caffeine ranged from 6 to 10 mg/L and the mean time to reach peak concentration (Tmax) ranged from 30 minutes to 2 hours.  The Tmax 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 (T1/2) and fraction excreted unchanged in urine (Ae) of caffeine in infants have been shown to be inversely related to gestational/postconceptual age. In neonates, the T1/2 is approximately 3 to 4 days and the Ae is approximately 86% (within 6 days).  By 9 months of age, the metabolism of caffeine approximates that seen in adults (T1/2 = 5 hours and Ae= 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 citratePlacebop-valueNumber of patients evaluated 14537% of patients with zero apnea events on day 226.78.10.03Apnea rate on day 2 (per 24 hrs.)4.97.20.134% of patients with 50% reduction in apnea events from baseline on day 276570.071 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.

Indications And Usage

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

Contraindications

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

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.

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 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).

Information For Patients

  • 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.

Laboratory Tests

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 citarte.

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 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.

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/m2 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/m2 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/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 g over 7 weeks) was toxic to rat testes as manifested by spermatogenic cell degeneration.

Pregnancy:

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/m2 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.

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           Sepsis1 (2.2)4 (8.7)2 (4.3)0 (0.0)2 (5.1)0 (0.0)         CARDIOVASCULAR SYSTEM           Hemorrhage1 (2.2)0 (0.0)         DIGESTIVE SYSTEM           Necrotizing Enterocolitis           Gastritis           Gastrointestinal  Hemorrhage2 (4.3)1 (2.2)1 (2.2)1 (2.6)0 (0.0)0 (0.0)         HEMIC AND LYMPHATIC SYSTEM           Disseminated Intravascular Coagulation1 (2.2)0 (0.0)         METABOLIC AND NUTRITIVE DISORDERS           Acidosis           Healing Abnormal1 (2.2)1 (2.2)0 (0.0)0 (0.0)         NERVOUS SYSTEM           Cerebral Hemorrhage1 (2.2)0 (0.0)         RESPIRATORY SYSTEM           Dyspnea           Lung Edema1 (2.2)1 (2.2)0 (0.0)0 (0.0)         SKIN AND APPENDAGES           Dry Skin           Rash           Skin Breakdown1 (2.2)4 (8.7)1 (2.2)0 (0.0)3 (7.7)0 (0.0)         SPECIAL SENSES           Retinopathy of Prematurity1 (2.2)0 (0.0)         UROGENITAL SYSTEM           Kidney Failure1 (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 (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 (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.

Overdosage

Following overdose, serum caffeine levels have ranged from approximately 50 mg/L to 350 mg/L. Signs and symptoms reported in the literature after caffeine overdose in preterm infants include fever, tachypnea, jitteriness, 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. 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.

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 VolumeDose of caffeine citrate mg/kgRouteFrequency   Loading Dose1 mL/kg20 mg/kgIntravenous* (over 30 minutes)One Time   Maintenance Dose0.25 mL/kg5 mg/kgIntravenous* (over 10 minutes) or OrallyEvery 24 hours*** using a syringe infusion pump**beginning 24 hours after the loading doseNOTE 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.

How Supplied

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, USPCaffeine 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 72485-110-10Store 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 LimitedBangalore-560099, INDIA.Distributed by:Armas Pharmaceuticals, Inc.Manalapan, NJ 07726 (USA)Revised: January 2020

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