CAFFEINE CITRATE: Package Insert and Label Information (Page 2 of 2)

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, 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. Another case of caffeine citrate overdose (from New Zealand) 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.

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* (over 30 minutes)	One Time
Maintenance Dose	0.25 mL/kg	5 mg/kg	Intravenous* (over 10 minutes) or Orally	Every 24 hours**

*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.

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 USP, 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 mcg/mL diluted to 10 mcg/mL with Dextrose Injection, USP 5%

HOW SUPPLIED

Caffeine citrate injection USP is available as a clear, colorless, sterile, non-pyrogenic, preservative-free, aqueous solution in 3 mL colorless glass vials. The vials are a clear USP Type I 5 mL glass vial with grey chlorobutyl rubber stoppers with white colored, flip off aluminum seals.

The injection 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 60 mg/3 mL is a clear, colorless aqueous solution, individually packaged in a carton and is available as follows.

3 mL fill in 5 mL glass vial

Mono Carton of 5 mL glass vial NDC 72485-104-01

3 mL Single Dose Vial packaged in a carton of 10 NDC 72485-104-10

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Preservative free. For single use only. Discard unused portion.

To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA, Inc. at 1-855-839-8195 or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch.

For Product Inquiry call 1-855-839-8195

Manufactured by:
Micro Labs Limited
Bangalore-560 099, INDIA.

Distributed by:
Armas Pharmaceuticals, Inc.
Manalapan, NJ 07726 (USA)

Revised: November 2020

For Intravenous Use Only

For single use only;
discard unused portion

Sterile, Nonpyrogenic,
Preservative Free

Packaging

CAFFEINE CITRATE caffeine citrate injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:72485-104 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CAFFEINE CITRATE (CAFFEINE) CAFFEINE CITRATE 60 mg in 3 mL

Inactive Ingredients Ingredient Name Strength CITRIC ACID MONOHYDRATE TRISODIUM CITRATE DIHYDRATE WATER

Packaging # Item Code Package Description Multilevel Packaging 1 NDC:72485-104-01 1 VIAL, GLASS in 1 CARTON contains a VIAL, GLASS 1 3 mL in 1 VIAL, GLASS This package is contained within the CARTON (72485-104-01) 2 NDC:72485-104-10 10 CARTON in 1 BOX contains a CARTON 2 1 VIAL, GLASS in 1 CARTON This package is contained within the BOX (72485-104-10) and contains a VIAL, GLASS 2 3 mL in 1 VIAL, GLASS This package is contained within a CARTON and a BOX (72485-104-10)

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA207400 01/01/2020

Labeler — Armas Pharmaceuticals Inc. (098405973)

Revised: 01/2022 Armas Pharmaceuticals Inc.