shunned [33:<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 Cafcit 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 Cafcit group and 4.6 in the placebo group. Indications and Usage for Cafcit Cafcit (caffeine citrate) is indicated for the short-term treatment of apnea of prematurity in infants between 28 and> <33 weeks gestational age. Contraindications Cafcit (caffeine citrate) is contraindicated in patients who have demonstrated hypersensitivity to any of its components. Warnings During the double-blind, placebo-controlled clinical trial, 6 cases of necrotizing enterocolitis developed among the 85 infants studied (caffeine=46, placebo=39), with 3 cases resulting in death. Five of the six patients with necrotizing enterocolitis were randomized to or had been exposed to Cafcit (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 Cafcit should be carefully monitored for the development of necrotizing enterocolitis. Precautions 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 Cafcit (caffeine citrate). Caffeine is a central nervous system stimulant and in cases of caffeine overdose, seizures have been reported. Cafcit 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 Cafcit for longer periods of treatment have not been established. Safety and efficacy of Cafcit 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, Cafcit should be used with caution in infants with cardiovascular disease. Renal and Hepatic Systems Cafcit should be administered with caution in infants with impaired renal or hepatic function. Serum concentrations of caffeine should be monitored and dose administration of Cafcit should be adjusted to avoid toxicity in this population. (See CLINICAL PHARMACOLOGY , Elimination and Special Populations .) Laboratory Tests Prior to initiation of Cafcit (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 Cafcit. 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/m 2 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/m 2 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/m 2 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 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/m 2 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. Adverse Reactions Overall, the reported number of adverse events in the double-blind period of the controlled trial was similar for the Cafcit (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 Cafcit-treated patients than placebo. ADVERSE EVENTS THAT OCCURRED MORE FREQUENTLY IN Cafcit-TREATED PATIENTS THAN PLACEBO DURING DOUBLE-BLIND THERAPY Adverse Event (AE) Cafcit N=46 n (%) Placebo N=39 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 Cafcit (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. 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; not Cafcit) 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. Cafcit Dosage and Administration Prior to initiation of Cafcit (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 Cafcit follow. Dose of Cafcit (caffeine citrate) Volume Dose of Cafcit (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. Cafcit 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 Cafcit 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, Cafcit 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 mcg/mL diluted to 10 mcg/mL with Dextrose Injection, USP 5% How is Cafcit Supplied Cafcit Injection (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 sealed with a teflon-faced gray rubber stopper and an aluminum overseal with a white flip-off printed with FOR INTRAVENOUS USE ONLY in red. The 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). Cafcit Injection (caffeine citrate injection, USP) is supplied as: NDC 0641-6164-10, 3 mL Single Dose Vial packaged in a carton of 10 Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Not made with natural rubber latex. Preservative free. For single dose only. Discard unused portion. To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceutical Corp. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . For Product Inquiry call 1-877-845-0689. Manufactured by: WEST-WARD PHARMACEUTICALS Eatontown, NJ 07724 USA Revised February 2015 462-708-00 PRINCIPAL DISPLAY PANELS Cafcit INJECTION (caffeine citrate injection, USP) 60 mg/3 mL (20 mg/mL) For Intravenous Use Only 3 mL Single Dose Vial NDC 0641-6164-10 Rx only Cafcit INJECTION (caffeine citrate injection, USP) 60 mg/3 mL (20 mg/mL) For Intravenous Use Only 10 x 3 mL Single Dose Vials Cafcit caffeine citrate injection Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0641-6164 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CAFFEINE CITRATE (CAFFEINE) CAFFEINE CITRATE 20 mg in 1 mL Inactive Ingredients Ingredient Name Strength CITRIC ACID MONOHYDRATE 5 mg in 1 mL SODIUM CITRATE 8.3 mg in 1 mL WATER Packaging # Item Code Package Description 1 NDC:0641-6164-10 10 VIAL in 1 BOX 1 NDC:0641-6164-01 3 mL in 1 VIAL Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA020793 11/04/2008 Labeler - West-Ward Pharmaceutical Corp. (946499746) Revised: 03/2015 West-Ward Pharmaceutical Corp. Next Interactions Print this page Add to My Med List More about Cafcit (caffeine) Side Effects During Pregnancy or Breastfeeding Dosage Information Drug Interactions Support Group Pricing & Coupons En Español 0 Reviews Add your own review/rating Generic Availability Drug class: CNS stimulants Consumer resources Cafcit Cafcit Intravenous (Advanced Reading) Cafcit Oral (Advanced Reading) Professional resources Caffeine and Sodium Benzoate Injection (FDA) Related treatment guides Apnea of Prematurity Hypersomnia> ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx OTC Availability Rx and/or OTC Pregnancy Category Risk depends on usage N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA WADA Class Anti-Doping Classification Manufacturer West-Ward Pharmaceuticals Drug Class CNS stimulants Related Drugs CNS stimulants Adderall , phentermine , methylphenidate , Vyvanse , Ritalin , modafinil Hypersomnia caffeine , Vivarin , NoDoz , Stay Awake , NoDoz Maximum Strength , More... Apnea of Prematurity theophylline , caffeine , aminophylline , Theo-24 , Theo-Dur , Theochron , Quibron-T / SR , Uniphyl , Theolair , Phyllocontin , More... Cafcit Rating No Reviews - Be the first! No Reviews - Be the first! Not Rated - Be the first!} } you need to be
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