Label: CAFFEINE CITRATE- caffeine citrate solution

Caffeine Citrate Oral Solution, USP is 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 USP, a central nervous system stimulant, is an odorless white crystalline powder or granule, with a bitter taste. It is sparingly soluble in water and in 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.

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 1and A 2subtypes, 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 maxwas 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 vitrois 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 1/2is 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 (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:

1Of 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.

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

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

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.

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

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.

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.

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.

* 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 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                                                                NDC 42571-346-69

10 vials per white polypropylene child-resistant container.               NDC 42571-346-69

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 by:

Micro Labs Limited

Bangalore-560099, INDIA.

Manufactured for:

Micro Labs USA Inc.

Somerset, NJ 08873  

Rev: 12/2023

Caffeine Citrate Oral Solution, USP 

Each bottle (vial) of caffeine citrate oral solution contains a total of 60 mg of caffeine citrate in 3 mL (20 mg/mL).

Information and Instructions for Use

This leaflet tells you about caffeine citrate oral solution (KAF-een SIT-rate) and how to give it to your baby.  Read the following information before giving this medicine to your baby.  Completely discuss caffeine citrate oral solution with your baby’s doctor.  Continue to discuss any questions you have about this medicine at your baby’s checkups.

After you remove your baby’s dose, throw away the open bottle (vial) and all medicine left in it.  Use each vial of caffeine citrate oral solution for only one dose.  There will be extra medicine left in the vial after one dose is removed.  Leftover medicine should not be used because caffeine citrate oral solution does not contain preservatives.  Once the vial is open, any medicine that is not used right away must be discarded.

What is caffeine citrate oral solution?

The main ingredient of caffeine citrate oral solution is caffeine citrate.  Caffeine citrate oral solution is a clear, colorless, medicine to treat apnea of prematurity - short periods when premature babies stop breathing. Apnea of prematurity is due to the baby’s breathing centers not being fully developed.

How do I give caffeine citrate oral solution to my baby?

Give caffeine citrate oral solution to your baby once a day, at about the same time each day. Your baby’s doctor will prescribe the right amount of caffeine citrate oral solution based on your baby’s weight and age. Carefully follow the doctor’s dosing instructions.

Measure the dose of caffeine citrate oral solution carefully. Your baby’s doctor, nurse, or pharmacist will give you a suitable syringe or supply of syringes to measure small but accurate doses of caffeine citrate oral solution.

Never change (increase or decrease) your baby’s dose without speaking to your baby's doctor.

If your baby continues to have periods of apnea, call your baby's doctor right away.Caffeine citrate oral solution can be swallowed by mouth or given through a feeding tube. Based on your baby’s own situation, your baby's doctor or other healthcare professional should teach you how to give caffeine citrate oral solution correctly.

Caffeine citrate oral solution should be clear and colorless. Before giving caffeine citrate oral solution, look for small particles, cloudiness, or discoloration in the medicine.  Do not use vials that contain cloudy or discolored medicine, or any visible particles.

Caffeine citrate oral solution does NOTcontain any preservatives.  Do not open the vial until it is time for your baby to receive the dose of medicine.  Use each vial only once. After you remove your baby’s dose, throw away the vial and all medicine left in the opened vial.

Ten (10) vials of caffeine citrate oral solution are packaged in a child-resistant container.  Caffeine citrate oral solution vials are NOT CHILD-RESISTANT. Always store vials of caffeine citrate oral solution in the child-resistant container.  Follow the instructions below to open the child-resistant container, to open a vial of caffeine citrate oral solution, and to remove a dose of medicine from the vial.

To open the child-resistant containerthat holds the vials of caffeine citrate oral solution : (Instructions with pictures are also printed on the top of the container)

1. Hold the bottom-half of the child-resistant container with one hand and push the lower semicircular section on the front of the container with your thumb.
2. With your other hand, pull the cover up until you hear it click.
3. While holding the ends of the bottom-half of the container with both hands, place both index fingers on the two semicircular locking tabs on the sides of the container. Press the two tabs and raise the cover up.

  To open a vialof caffeine citrate oral solution:

1. Hold the blue plastic top between the thumb and index finger. Use your thumb to flip the blue plastic top completely off the vial.
2. Carefully lift up the metal ring.
3. Pull the metal ring away from the vial and then pull it down towards the bottom of the vial without twisting the ring.
4. After you pull the ring down and the metal band around the top of the vial is completely broken through, carefully remove the rest of the metal band by pulling it out and away from the vial.
5. Being careful not to spill any medicine, remove the rubber stopper from the top of the vial.

To remove the prescribed dose from the vial:

You will need a small syringe to measure the exact amount of medicine that your baby’s doctor prescribed.  Your baby’s doctor, nurse or pharmacist will give you this small syringe. Note that a milliliter (ml) is the same as a cubic centimeter (cc).

Insert the tip of the syringe in the medicine and pull up on the plunger to draw the medicine into the syringe. Remove slightly more of the medicine than the exact amount to be given to your baby.

Turn the syringe tip up so that any air in it rises to the top. Remove the air by gently pushing up on the syringe plunger. Continue to push the syringe plunger up to remove any extra medicine in the syringe, until only the exact number of milliliters (or cubic centimeters) that your baby’s doctor prescribed remains in the syringe.

Give the caffeine citrate oral solution to your baby as your baby's doctor instructed.

Throw away the sharp metal pieces, the rubber stopper, the open vial, and any medicine that remains in it after your baby receives the dose.

What are the possible side effects of caffeine citrate oral solution?

Your baby may or may not develop side effects from taking caffeine citrate oral solution. Each baby is different. If your baby develops one or more of the following symptoms, speak with your baby’s doctor right away:

• restlessness, jitteriness or shakiness
• faster heart beat
• increased urination (increased diaper wetting)

The following symptoms may be caused by serious bowel or stomach problems. Call your baby’s doctor right away if your baby develops:

• bloated abdomen (stomach area)
• vomiting
• bloody stools (bloody bowel movements)
• loss of energy, lethargy (acting sluggish)

This is not a complete list of side effects reported with caffeine citrate oral solution.  If you have a concern about your baby, speak with your baby’s doctor.  If you want more information about caffeine citrate oral solution, speak with your baby’s doctor or pharmacist.

Manufactured by:

Micro Labs Limited

Bangalore-560 099, INDIA.

Manufactured for:

Micro Labs USA Inc.

Somerset, NJ 08873

Rev: 12/2023

NDC 42571-346-69
Caffeine Citrate  Oral Solution, USP
60 mg/3 mL (20 mg/mL)
For Oral Use Only
For single use only; discrad unused portion.
Rx Only
3 mL Single-Dose Vial
MICRO LABS

NDC 42571-346-69
Caffeine Citrate  Oral Solution, USP
60 mg/3 mL (20 mg/mL)
For Oral Use Only
For single use only; discrad unused portion.
Rx Only
3 mL x 10 Single-Dose Vials
MICRO LABS