Caffeine citrate

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

Caffeine Citrate Oral Solution, USP

SAGENT™

Each bottle (vial) of caffeine citrate 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 and how to give it to your baby. Read the following information before giving this medicine to your baby. Completely discuss caffeine citrate 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 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 does not contain preservatives. Once the vial is open, any medicine that is not used right away must be discarded.

What is caffeine citrate?

The main ingredient of caffeine citrate is caffeine citrate. Caffeine citrate 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 to my baby?

Give caffeine citrate 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 based on your baby's weight and age. Carefully follow the doctor's dosing instructions.

Measure the dose of caffeine citrate 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.

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 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 correctly.

Caffeine citrate should be clear and colorless. Before giving caffeine citrate, 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 does NOT contain 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 are packaged in a childresistant container. Caffeine citrate vials are NOT CHILDRESISTANT. Always store vials of caffeine citrate in the child-resistant container.

Follow the instructions below to open the child-resistant container, to open a vial of caffeine citrate, and to remove a dose of medicine from the vial.

To open the child-resistant container that holds the vials of caffeine citrate: (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.
4. Press the two tabs and raise the cover up.

To open a vial of caffeine citrate:

1. Hold the plastic top between the thumb and index finger. Use your thumb to flip the 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).

1. 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 amounttobe given to your baby.
2. 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.
3. Give the caffeine citrate to your baby as your baby's doctor instructed.
4. 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 possible side effects of caffeine citrate?

Your baby may or may not develop side effects from taking caffeine citrate. 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. If you have a concern about your baby, speak with your baby's doctor. If you want more information about caffeine citrate, speak with your baby's doctor or pharmacist.

To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc. at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Caffeine citrate should not be given to a child who has had an allergic reaction to it in the past.

Before using caffeine citrate, tell the doctor if your child is allergic to any drugs, or if the child has:

• seizures;
• heart disease;
• kidney disease;
• liver disease; or
• high or low blood sugar.

If your child has any of these conditions, he or she may need a dose adjustment or special tests to safely take this medication.

This medication may be harmful to an unborn baby and should not be taken by a woman who is pregnant. Caffeine citrate should also not be taken by a woman who is breast-feeding a baby.

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 openlabel 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 in to lerance), 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.

To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc., at 1-866-625-1618 or FDA at 1-800-FD A-1088 or www.fda.gov/medwatch .

Read the entire FDA prescribing information for Cafcit (Caffeine Citrate)

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Caffeine citrate is for short-term use only. Do not use this medicine for longer than 12 days without the advice of your child's doctor.

Measure liquid medicine with the dosing syringe provided, or with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.

Do not use the medicine if it has changed colors or has particles in it. Call your pharmacist for new medication.

Each bottle of caffeine citrate is for one use only, even if your child does not use the entire bottle for a single dose. Throw away any medicine left over in the bottle after measuring your child's dose.

Call your doctor if your child's symptoms do not improve after using caffeine citrate.

While using caffeine citrate, your child may need frequent blood tests.

Caffeine citrate contains no preservative. Do not open a bottle of this medicine until you are ready to give the dose.

Store at room temperature away from moisture and heat.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

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

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.

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.  Serum concentrations of caffeine should be monitored and dose administration of Caffeine Citrate should be adjusted to avoid toxicity in this population (see CLINICAL  PHARMACOLOGY, Pharmacokinetics,  Elimination and Special Populations).

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.  Serum concentrations of caffeine may need to be monitored periodically throughout treatment to avoid toxicity.

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.

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.

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 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 4 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:

Teratogenic Effects: 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/m2 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.

Prior to initiation of Caffeine Citrate injection, 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 injection 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 1,000 units/mL diluted to 1 unit/mL with Dextrose Injection, USP 5%

• Fentanyl Citrate Injection, USP 50 mcg/mL diluted to 10 mcg/mL with Dextrose Injection, USP 5%