CAFFEINE CITRATE

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.

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 Dose of Caffeine Citrate Route Frequency Volume mg/kg Loading Dose 1 mL/kg 20 mg/kg Intravenous using a syringe infusion pump One Time (over 30 minutes) Maintenance 0.25 mL/kg 5 mg/kg Intravenous Every Dose (over 10 24 hours beginning 24 hours after the loading dose minutes) or Orally 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 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. Drug Compatibility To test for drug compatibility with common intravenous solutions or medica­tions, 20 mL of caffeine citrate injection were combined with 20 mL of a solution or medication, with the exception of an Intralipid ® admixture, which was combined as 80 mL/80 mL. The physical appearance of the com­bined solutions was evaluated for precipitation. The admixtures were mixed for 10 minutes and then assayed for caffeine. The admixtures were then continu­ally mixed for 24 hours, with further sampling for caffeine assays at 2, 4, 8, and 24 hours. Based on this testing, caffeine citrate injection, 60 mg/3 mL is chemically stable for 24 hours at room temperature when combined with the following test products. Dextrose Injection, USP 5% 50% Dextrose Injection USP Intralipid ® 20% IV Fat Emulsion Aminosyn ® 8.5% Crystalline Amino Acid Solution Dopamine HCI Injection, USP 40 mg/mL diluted to 0.6 mg/mL with Dextrose Injection, USP 5% Calcium Gluconate Injection, USP 10% (0.465 mEq/Ca +2 /mL) Heparin Sodium Injection, USP 1000 units/mL diluted to 1 unit/mL with Dextrose Injection, USP 5% Fentanyl Citrate Injection, USP 50 μg/mL diluted to 10 μg/mL with Dextrose Injection, USP 5%

CONTRAINDICATIONS Caffeine citrate injection and caffeine citrate oral solution are contraindicated in patients who have demonstrated hypersensitivity to any of its components.

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 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 Coagulation 1 (2.2) 0 (0.0) 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 (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. A published randomized, placebo-controlled, clinical trial in premature infants with birthweights of 500 to 1,250 grams studied the safety of caffeine citrate in apnea of prematurity (NCT00182312). This trial randomized approximately 2,000 premature infants with a mean gestational age of 27 weeks at birth. The median duration of caffeine therapy was 37 days. Prior to discharge home, death, ultrasonographic signs of brain injury, and necrotizing enterocolitis were not more common in the caffeine citrate group compared to the placebo. At follow up at both 18 months and 5 years corrected age, death was not more common in the caffeine citrate treated group compared to placebo, nor did caffeine citrate use adversely affect neurodevelopmental outcomes. To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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.

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.

DESCRIPTION Both Caffeine Citrate Injection, USP for intravenous administration and Caffeine Citrate Oral Solution, USP 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 sodium citrate dihydrate and Water for Injection, USP. 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. Caffeine citrate C 14 H 18 N 4 O 9 MW 386.31 Structural Formula

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.

HOW SUPPLIED Both caffeine citrate injection and caffeine citrate oral solution are available as clear, color­less, sterile, non-pyrogenic, preservative-free, aqueous solutions in 5 mL colorless glass vials. The vials of caffeine citrate injection are sealed with gray rubber stopper and white flip off aluminum seal printed with “FOR INTRAVENOUS USE ONLY” in red. The vials of caffeine citrate oral solution are sealed with gray rubber stopper and a dark blue matte finish, flip off tear off aluminum seal printed with "FOR ORAL USE ONLY" "FLIP TOP & TEAR" in white. 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 47335-289-40: 3 mL vial, individually packaged in a carton. Caffeine citrate oral solution, USP NDC 47335-290-44: 3 mL vial (NOT CHILD-RESISTANT), 10 vials per white polypropylene child-resistant container. Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°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. Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 Manufactured by: Sun Pharmaceutical Industries Ltd. Halol-Baroda Highway, Halol-389 350, Gujarat, India. PJPI0274B ISS. 12/2020