ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are also described elsewhere in the labeling:Arrhythmias with Concomitant Cardiac Glycoside Use [see Warnings and Precautions (5.1)] End-Organ Damage due to Intravascular Ceftriaxone-Calcium Precipitates [see Warnings and Precautions (5.2)] Tissue Necrosis and Calcinosis [see Warnings and Precautions (5.3)] Hypotension, Bradycardia, and Cardiac Arrhythmias [see Warnings and Precautions (5.4)] Aluminum toxicity [see Warnings and Precautions (5.5)] The following adverse reactions associated with the use of calcium gluconate were identified in the literature. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to estimate their frequency reliably or to establish causal relationship to drug exposure. Cardiovascular: Vasodilation, decreased blood pressure, bradycardia, cardiac arrhythmia, syncope, cardiac arrestAdministration site reactions: Local soft tissue inflammation, local necrosis, calcinosis cutis and calcification due to extravasation Arrhythmias with Concomitant Cardiac Glycoside Use [see Warnings and Precautions (5.1)] End-Organ Damage due to Intravascular Ceftriaxone-Calcium Precipitates [see Warnings and Precautions (5.2)] Tissue Necrosis and Calcinosis [see Warnings and Precautions (5.3)] Hypotension, Bradycardia, and Cardiac Arrhythmias [see Warnings and Precautions (5.4)] Aluminum toxicity [see Warnings and Precautions (5.5)] The most common adverse events with Calcium Gluconate Injection are local soft tissue inflammation and necrosis, calcinosis cutis and calcification that are related to extravasation. Other adverse events include vasodilation, decreased blood pressure, bradycardia, cardiac arrhythmia, syncope, and cardiac arrest. (6) To report SUSPECTED ADVERSE REACTIONS, contact B. Braun Medical Inc. at 1-800-227-2862 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of Calcium Gluconate Injection. Calcium gluconate was not mutagenic with or without metabolic activation in the Ames test with Salmonella typhimurium (strains TA-1535, TA-1537, and TA-1538) or Saccharomyces cerevisiae (Strain D4). Fertility studies in animals have not been conducted with calcium gluconate administered by the intravenous route.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Intravenous administration of calcium gluconate increases serum ionized calcium level. Calcium gluconate dissociates into ionized calcium in plasma. Ionized calcium and gluconate are normal constituents of body fluids. 12.3 Pharmacokinetics. AbsorptionCalcium Gluconate Injection is 100% bioavailable following intravenous injection. Metabolism Calcium itself does not undergo direct metabolism. The release of ionized calcium from intravenous administration of calcium gluconate is direct and does not seem to be affected by the first pass through the liver.DistributionCalcium in the body is distributed mainly in skeleton (99%). Only 1% of the total body calcium is distributed within the extracellular fluids and soft tissues. About 50% of total serum calcium is in the ionized form and represents the biologically active part. 8% to 10% serum calcium is bound to organic and inorganic acid and approximately 40% is protein-bound (primarily to albumin). EliminationStudies have shown relationship between urinary calcium excretion and the intravenous administration of calcium gluconate, with significant increase in urinary calcium excretion observed after the intravenous administration of calcium gluconate.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Calcium Gluconate Injection is contraindicated in:HypercalcemiaNeonates (28 days of age or younger) receiving ceftriaxone [see Warnings and Precautions (5.2)] Hypercalcemia. Neonates (28 days of age or younger) receiving ceftriaxone [see Warnings and Precautions (5.2)] Hypercalcemia (4) Neonates (28 days of age or younger) receiving ceftriaxone (4) Hypercalcemia (4) Neonates (28 days of age or younger) receiving ceftriaxone (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Calcium Gluconate Injection 10,000 mg per 100 mL (100 mg per mL) Pharmacy Bulk Package is sterile, preservative-free, nonpyrogenic, supersaturated solution of calcium gluconate, form of calcium, for intravenous use after dilution. Calcium Gluconate is calcium D-gluconate (1:2) monohydrate. The structural formula is: Molecular formula: C12H 22CaO14o H2O Molecular weight: 448.39 Solubility in water: 3.5 g/100 mL at 25CCalcium Gluconate Injection is available as 10,000 mg per 100 mL (100 mg per mL) in pharmacy bulk package. Each mL of Calcium Gluconate Injection contains 100 mg of calcium gluconate (equivalent to 94 mg of calcium gluconate and 4.5 mg of calcium saccharate tetrahydrate), hydrochloric acid and/or sodium hydroxide for pH adjustment (6.0 to 8.2) and sterile water for injection, q.s. It contains no antimicrobial agent.Each mL of Calcium Gluconate Injection contains 9.3 mg (0.465 mEq) of elemental calcium.Not made with natural rubber latex, PVC or DEHP.. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Contains 100 mg of calcium gluconate per mL which contains 9.3 mg (0.465 mEq) of elemental calcium (2.1) See Full Prescribing Information (FPI) for dilution instructions, administration rates, and appropriate monitoring (2.1)Individualize the dose within the recommended range in adults and pediatric patients depending on the severity of symptoms of hypocalcemia, the serum calcium level, and the acuity of onset of hypocalcemia. See Table in the FPI for dosing recommendations in mg of calcium gluconate for neonates, pediatric and adult patients. (2.2)Measure serum calcium during intermittent infusions every to hours and during continuous infusion every to hours. (2.3)Calcium Gluconate Injection is not physically compatible with fluids containing phosphate or bicarbonate. Precipitation may result if mixed. See FPI for all drug incompatibilities. (2.5)Supplied in pharmacy bulk package (PBP). For PBP, dispense single doses to many patients in pharmacy admixture program; use within hours of puncture (2.6). Contains 100 mg of calcium gluconate per mL which contains 9.3 mg (0.465 mEq) of elemental calcium (2.1) See Full Prescribing Information (FPI) for dilution instructions, administration rates, and appropriate monitoring (2.1). Individualize the dose within the recommended range in adults and pediatric patients depending on the severity of symptoms of hypocalcemia, the serum calcium level, and the acuity of onset of hypocalcemia. See Table in the FPI for dosing recommendations in mg of calcium gluconate for neonates, pediatric and adult patients. (2.2). Measure serum calcium during intermittent infusions every to hours and during continuous infusion every to hours. (2.3). Calcium Gluconate Injection is not physically compatible with fluids containing phosphate or bicarbonate. Precipitation may result if mixed. See FPI for all drug incompatibilities. (2.5). Supplied in pharmacy bulk package (PBP). For PBP, dispense single doses to many patients in pharmacy admixture program; use within hours of puncture (2.6). 2.1 Important Administration Instructions. Calcium Gluconate Injection contains 100 mg of calcium gluconate per mL which contains 9.3 mg (i.e., 0.465 mEq) of elemental calcium.Dilute Calcium Gluconate Injection prior to use in 5% dextrose or normal saline and assess for potential drug or IV fluid incompatibilities [see Dosage and Administration (2.5)]. Inspect Calcium Gluconate Injection visually prior to administration. The solution should appear clear and colorless to slightly yellow. Do not administer if there is particulate matter or discoloration. Use the diluted solution immediately after preparation.Administer Calcium Gluconate Injection intravenously via secure intravenous line to avoid calcinosis cutis and tissue necrosis [see Warnings and Precautions (5.3)]. Administer Calcium Gluconate Injection by bolus administration or continuous infusion:For bolus intravenous administration:Dilute the dose [see Dosage and Administration (2.2)] of Calcium Gluconate Injection in 5% dextrose or normal saline to concentration of 10-50 mg/mL prior to administration. Administer the dose slowly and DO NOT exceed an infusion rate of 200 mg/minute in adults or 100 mg/minute in pediatric patients, including neonates. Monitor patients, vitals and electrocardiograph (ECG) during administration [see Warnings and Precautions (5.4)]. For continuous intravenous infusion:Dilute Calcium Gluconate Injection in 5% dextrose or normal saline to concentration of 5.8-10 mg/mL prior to administration. Administer at the rate recommended in Table [see Dosage and Administration (2.2)] and monitor patients, vitals, calcium and ECG during the infusion [see Warnings and Precautions (5.4)].Calcium Gluconate Injection is supplied in pharmacy bulk packages [see Dosage and Administration (2.6)]. Calcium Gluconate Injection contains 100 mg of calcium gluconate per mL which contains 9.3 mg (i.e., 0.465 mEq) of elemental calcium.. Dilute Calcium Gluconate Injection prior to use in 5% dextrose or normal saline and assess for potential drug or IV fluid incompatibilities [see Dosage and Administration (2.5)]. Inspect Calcium Gluconate Injection visually prior to administration. The solution should appear clear and colorless to slightly yellow. Do not administer if there is particulate matter or discoloration. Use the diluted solution immediately after preparation.. Administer Calcium Gluconate Injection intravenously via secure intravenous line to avoid calcinosis cutis and tissue necrosis [see Warnings and Precautions (5.3)]. Administer Calcium Gluconate Injection by bolus administration or continuous infusion:. Dilute the dose [see Dosage and Administration (2.2)] of Calcium Gluconate Injection in 5% dextrose or normal saline to concentration of 10-50 mg/mL prior to administration. Administer the dose slowly and DO NOT exceed an infusion rate of 200 mg/minute in adults or 100 mg/minute in pediatric patients, including neonates. Monitor patients, vitals and electrocardiograph (ECG) during administration [see Warnings and Precautions (5.4)]. Dilute Calcium Gluconate Injection in 5% dextrose or normal saline to concentration of 5.8-10 mg/mL prior to administration. Administer at the rate recommended in Table [see Dosage and Administration (2.2)] and monitor patients, vitals, calcium and ECG during the infusion [see Warnings and Precautions (5.4)].. Calcium Gluconate Injection is supplied in pharmacy bulk packages [see Dosage and Administration (2.6)]. 2.2 Recommended Dosage. Individualize the dose of Calcium Gluconate Injection within the recommended range depending on the severity of symptoms of hypocalcemia, the serum calcium level, and the acuity of onset of hypocalcemia. Table provides dosing recommendations for Calcium Gluconate Injection in mg of calcium gluconate for neonates, pediatric and adult patients.Table 1. Dosing Recommendations in mg of Calcium Gluconate for Neonate, Pediatric, and Adult PatientsPatient PopulationInitial DoseSubsequent Doses (if needed)Bolus Continuous InfusionNeonate (<= month)100 200 mg/kg 100 200 mg/kg every hours Initiate at 17 33 mg/kg/hour Pediatric (> month to< 17 years)29 60 mg/kg 29 60 mg/kg every hours Initiate at - 13 mg/kg/hour Adult1000 2000 mg 1000 2000 mg every hours Initiate at 5.4 21.5 mg/kg/hour For bolus administration, DO NOT exceed an infusion rate of: 200 mg/minute in adult patients100 mg/minute in pediatric patients For continuous infusions, adjust rate as needed based on serum calcium levels 200 mg/minute in adult patients. 100 mg/minute in pediatric patients. 2.3 Serum Calcium Monitoring. Measure serum calcium every to hours during intermittent infusions with Calcium Gluconate Injection and measure serum calcium every to hours during continuous infusion.. 2.4 Dosage in Renal Impairment. For patients with renal impairment, initiate Calcium Gluconate Injection at the lowest dose of the recommended dose ranges for all age groups and monitor serum calcium levels every hours. 2.5 Drug Incompatibilities. Do not mix Calcium Gluconate Injection with ceftriaxone. Concurrent use of intravenous ceftriaxone and Calcium Gluconate Injection can lead to the formation of ceftriaxone-calcium precipitates. Concomitant use of ceftriaxone and intravenous calcium-containing products is contraindicated in neonates (28 days of age or younger) [see Contraindications (4)]. In patients older than 28 days of age, ceftriaxone and calcium-containing products may be administered sequentially, provided the infusion lines are thoroughly flushed between infusions with compatible fluid. Ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions via Y-site in any age group [see Warnings and Precautions (5.2), Drug Interactions (7.3)]. Do not mix Calcium Gluconate Injection with fluids containing bicarbonate or phosphate. Calcium Gluconate Injection is not physically compatible with fluids containing phosphate or bicarbonate. Precipitation may result if mixed.Do not mix Calcium Gluconate Injection with minocycline injection. Calcium complexes minocycline rendering it inactive. Do not mix Calcium Gluconate Injection with ceftriaxone. Concurrent use of intravenous ceftriaxone and Calcium Gluconate Injection can lead to the formation of ceftriaxone-calcium precipitates. Concomitant use of ceftriaxone and intravenous calcium-containing products is contraindicated in neonates (28 days of age or younger) [see Contraindications (4)]. In patients older than 28 days of age, ceftriaxone and calcium-containing products may be administered sequentially, provided the infusion lines are thoroughly flushed between infusions with compatible fluid. Ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions via Y-site in any age group [see Warnings and Precautions (5.2), Drug Interactions (7.3)]. Do not mix Calcium Gluconate Injection with fluids containing bicarbonate or phosphate. Calcium Gluconate Injection is not physically compatible with fluids containing phosphate or bicarbonate. Precipitation may result if mixed.. Do not mix Calcium Gluconate Injection with minocycline injection. Calcium complexes minocycline rendering it inactive. 2.6 Preparation of Pharmacy Bulk Package. The pharmacy bulk package (PBP) of Calcium Gluconate Injection is intended for dispensing of single doses to multiple patients in pharmacy admixture program. Penetrate the container closure only one time with suitable sterile transfer device or dispensing set that allows measured dispensing of the contents. Use the PBP only in suitable ISO Class work area such as laminar flow hood (or an equivalent clean air compounding area). Complete dispensing from the pharmacy bulk vial within hours after the container closure is penetrated. Each dose dispensed from the Pharmacy Bulk Package must be used immediately.CAUTION: DO NOT ADD SUPPLEMENTARY MEDICATION.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration or admixture and final infusate should be inspected for cloudiness or precipitation immediately after mixing, prior to administration, and periodically during administration, whenever solution and container permit. Use of final filter is recommended during administration of all parenteral solutions where possible.This solution is intended for use in the preparation of sterile, intravenous admixtures.Protect from light until use.When compounding admixtures, use aseptic technique. Mix thoroughly.Do not store any unused portion.Identify Two Ports (See Figure A). To aseptically remove the set port closure: hold container below the set port and grasp the foil tab between the thumb and forefinger then pull the tab in two steps as shown in Figure Steps and 2. The foil tab maintains port sterility; therefore, it should be removed in suitable environment such as laminar flow hood. Attach suitable transfer device or compounding set (See Figure C). Refer to complete directions of accompanying device. Hang container using hole on the lower flap. Once container closure has been penetrated, withdrawal of contents should be completed within hours. Identify Two Ports (See Figure A). To aseptically remove the set port closure: hold container below the set port and grasp the foil tab between the thumb and forefinger then pull the tab in two steps as shown in Figure Steps and 2. The foil tab maintains port sterility; therefore, it should be removed in suitable environment such as laminar flow hood. Attach suitable transfer device or compounding set (See Figure C). Refer to complete directions of accompanying device. Hang container using hole on the lower flap. Once container closure has been penetrated, withdrawal of contents should be completed within hours. Figure A. Figure B. Figure C.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Calcium Gluconate Injection is clear, colorless to slightly yellow, solution available in the following:Pharmacy bulk package: 10,000 mg per 100 mL (100 mg per mL) Each mL of Calcium Gluconate Injection contains 9.3 mg (0.465 mEq) of elemental calcium. Pharmacy bulk package: 10,000 mg per 100 mL (100 mg per mL) Injection: (3)Pharmacy bulk package: 10,000 mg per 100 mL (100 mg per mL) Pharmacy bulk package: 10,000 mg per 100 mL (100 mg per mL).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Cardiac Glycoside: Synergistic arrhythmias may occur if calcium and cardiac glycosides are administered together. (7.1) Calcium Channel Blockers: Administration of calcium may reduce the response. (7.2) Drugs that may cause hypercalcemia: Vitamin D, vitamin A, thiazide diuretics, estrogen, calcipotriene and teriparatide administration may cause hypercalcemia. Monitor plasma calcium concentrations in patients taking these drugs concurrently. (7.3) Cardiac Glycoside: Synergistic arrhythmias may occur if calcium and cardiac glycosides are administered together. (7.1) Calcium Channel Blockers: Administration of calcium may reduce the response. (7.2) Drugs that may cause hypercalcemia: Vitamin D, vitamin A, thiazide diuretics, estrogen, calcipotriene and teriparatide administration may cause hypercalcemia. Monitor plasma calcium concentrations in patients taking these drugs concurrently. (7.3) 7.1 Cardiac Glycosides. Hypercalcemia increases the risk of digoxin toxicity, while digoxin may be therapeutically ineffective in the presence of hypocalcemia. Synergistic arrhythmias may occur if calcium and cardiac glycosides are administered together. Avoid administration of Calcium Gluconate Injection in patients receiving cardiac glycosides; if considered necessary, administer Calcium Gluconate Injection slowly in small amounts and monitor ECG closely during administration. 7.2 Calcium Channel Blockers. Administration of calcium may reduce the response to calcium channel blockers.. 7.3 Drugs that may cause Hypercalcemia. Vitamin D, vitamin A, thiazide diuretics, estrogen, calcipotriene and teriparatide administration may cause hypercalcemia. Monitor plasma calcium concentrations in patients taking these drugs concurrently.

GERIATRIC USE SECTION.

8.5 Geriatric Use. In general dose selection for an elderly patient should start at the lowest dose of the recommended dose range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Calcium Gluconate Injection is clear, colorless to slightly yellow solution supplied sterile and nonpyrogenic in 100 mL Fill PAB(R) containers packaged 24 per case, as follows:Calcium Gluconate Total Product Strength (Concentration) Package Configuration NDCREF10,000 mg calcium gluconate per 100 mL (100 mg per mL) 24 100 mL pharmacy bulk package containers0264-5600-52 D5600-52 Store at 20 to 25C (68 to 77F); excursions permitted between 15 to 30C (59 to 86F). [See USP Controlled Room Temperature.] Do not freeze.Protect from light until use.Preservative Free. Discard any unused portion in the Pharmacy Bulk Package within hours after initial closure puncture.Each dose dispensed from the Pharmacy Bulk Package must be used immediately.The diluted solution must be used immediately.NOTE: Supersaturated solutions are prone to precipitation. The precipitate, if present, may be dissolved by warming to 60 to 80C, with occasional agitation, until the solution becomes clear. Shake vigorously. Allow to cool to room temperature before dispensing. Use injection only if clear immediately prior to use.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Calcium Gluconate Injection is indicated for pediatric and adult patients for the treatment of acute symptomatic hypocalcemia. Limitations of UseThe safety of Calcium Gluconate Injection for long term use has not been established.. Calcium Gluconate Injection is form of calcium indicated for pediatric and adult patients for the treatment of acute symptomatic hypocalcemia. (1) Limitations of Use: The safety of Calcium Gluconate Injection for long term use has not been established. (1) Calcium Gluconate Injection is form of calcium indicated for pediatric and adult patients for the treatment of acute symptomatic hypocalcemia. (1) Limitations of Use: The safety of Calcium Gluconate Injection for long term use has not been established. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient that the risks associated with infusion including local tissue inflammation, local necrosis and calcinosis [see Warnings and Precautions (5.3)].

LABOR & DELIVERY SECTION.

8.2 Lactation. Risk summaryCalcium is present in human milk as natural component of human milk. It is not known whether intravenous administration of Calcium Gluconate Injection can alter calcium concentration in human milk. There are no data on the effects of Calcium Gluconate Injection on the breastfed infant, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Calcium Gluconate Injection and any potential adverse effects on the breastfed child from Calcium Gluconate Injection or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Intravenous administration of calcium gluconate increases serum ionized calcium level. Calcium gluconate dissociates into ionized calcium in plasma. Ionized calcium and gluconate are normal constituents of body fluids.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of Calcium Gluconate Injection. Calcium gluconate was not mutagenic with or without metabolic activation in the Ames test with Salmonella typhimurium (strains TA-1535, TA-1537, and TA-1538) or Saccharomyces cerevisiae (Strain D4). Fertility studies in animals have not been conducted with calcium gluconate administered by the intravenous route.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdosage of Calcium Gluconate Injection may result in hypercalcemia. Symptoms of hypercalcemia typically develop when the total serum calcium concentration is >=12 mg/dL. Neurologic symptoms include depression, weakness, fatigue, and confusion at lower levels, with patients experiencing hallucinations, disorientation, hypotonicity, seizures, and coma. Effects on the kidney include diminished ability to concentrate urine and diuresis. If overdose of Calcium Gluconate Injection occurs immediately discontinue administration and provide supportive treatments to restore intravascular volume as well as promote calcium excretion in the urine if necessary.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 100 mL CONTAINER LABEL. NDC 0264-5600-52 100 mL Calcium Gluconate Injection, USP10,000 mg per 100 mL (100 mg per mL)WARNING: Pharmacy Bulk Package -Not for Direct InfusionConcentrated solution: MUST BE DILUTEDFor preparation of intravenous admixtures only.Preservative free. Sterile. Protect from light until use. Each mL contains: Calcium gluconate 94 mg; calcium saccharate (tetrahydrate) 4.5 mg; water for injection, q.s. Concentration: 0.465 mEq/mL. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment. Osmolarity (Calc.): 292 mOsmol/L Contains no more than 400 mcg/L of aluminum. Preparation of Pharmacy Bulk Package: This pharmacy bulk package (PBP) is intended for dispensing of single doses tomultiple patients in pharmacy admixture program. Penetrate the containerclosure only one time with suitable sterile transfer device or dispensing set thatallows measured dispensing of the contents.Use the PBP only in suitable ISO Class work area such as laminar flow hood(or an equivalent clean air compounding area). Complete dispensing from thePBP within hours after the container closure is penetrated.Dispensed aliquots must be used immediately and cannot be stored.See insert for further details.Supersaturated solutions are prone to precipitation. See insert for further details.Store at 20 to 25C (68to 77F); excursions permitted between 15 to 30C (59 to86F). [See USP Controlled Room Temperature]. Do not freeze. Use only if solution is clearand seal intact. Not made with natural rubber latex, PVC or DEHP.Rx only Affix accompanying label fordate and time of expiry.REF D5600-52 B. Braun Medical Inc.Bethlehem, PA 18018-3524 USA1-800-227-2862Prepared in USA. API from India.Y94-003-464 LD-335-2LOT EXP. D5600-52 Container Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of Calcium Gluconate Injection have been established in pediatric patients for the treatment of acute, symptomatic hypocalcemia. Pediatric approval for Calcium Gluconate Injection, including doses, is not based on adequate and well-controlled clinical studies. Safety and dosing recommendations in pediatric patients are based on published literature and clinical experience[see Dosage and Administration (2.2)]. Concomitant use of ceftriaxone and Calcium Gluconate Injection is contraindicated in neonates (28 days of age or younger) due to reports of fatal outcomes associated with the presence of lung and kidney ceftriaxone-calcium precipitates. In patients older than 28 days of age, ceftriaxone and Calcium Gluconate Injection may be administered sequentially, provided the infusion lines are thoroughly flushed between infusions with compatible fluid [see Contraindications (4) and Warnings and Precautions (5.2)]. This product contains up to 400 mcg/L aluminum which may be toxic, particularly for premature neonates due to immature renal function. Parenteral administration of aluminum greater than to mcg/kg/day is associated with central nervous system and bone toxicity[see Warnings and Precautions (5.5)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionCalcium Gluconate Injection is 100% bioavailable following intravenous injection. Metabolism Calcium itself does not undergo direct metabolism. The release of ionized calcium from intravenous administration of calcium gluconate is direct and does not seem to be affected by the first pass through the liver.DistributionCalcium in the body is distributed mainly in skeleton (99%). Only 1% of the total body calcium is distributed within the extracellular fluids and soft tissues. About 50% of total serum calcium is in the ionized form and represents the biologically active part. 8% to 10% serum calcium is bound to organic and inorganic acid and approximately 40% is protein-bound (primarily to albumin). EliminationStudies have shown relationship between urinary calcium excretion and the intravenous administration of calcium gluconate, with significant increase in urinary calcium excretion observed after the intravenous administration of calcium gluconate.

PREGNANCY SECTION.

8.1 Pregnancy. Risk summaryLimited available data with Calcium Gluconate Injection use in pregnant women are insufficient to inform drug associated risk of adverse developmental outcomes. There are risks to the mother and the fetus associated with hypocalcemia in pregnancy[see Clinical Considerations]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.Clinical ConsiderationsDisease-associated maternal riskMaternal hypocalcemia can result in an increased rate of spontaneous abortion, premature and dysfunctional labor, and possibly preeclampsia. Fetal/Neonatal adverse reactionsInfants born to mothers with hypocalcemia can have associated fetal and neonatal hyperparathyroidism, which in turn can cause fetal and neonatal skeletal demineralization, subperiosteal bone resorption, osteitis fibrosa cystica and neonatal seizures. Infants born to mothers with hypocalcemia should be carefully monitored for signs of hypocalcemia or hypercalcemia, including neuromuscular irritability, apnea, cyanosis and cardiac rhythm disorders.

SPL UNCLASSIFIED SECTION.

2.4 Dosage in Renal Impairment. For patients with renal impairment, initiate Calcium Gluconate Injection at the lowest dose of the recommended dose ranges for all age groups and monitor serum calcium levels every hours.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Geriatric use: Dosing in elderly patients should be cautious, usually starting at the low end of the dosage range. (8.5) Renal impairment: Initiate with the lower limit of the dosage range and monitor serum calcium levels every hours. (8.6, 2.4) Geriatric use: Dosing in elderly patients should be cautious, usually starting at the low end of the dosage range. (8.5) Renal impairment: Initiate with the lower limit of the dosage range and monitor serum calcium levels every hours. (8.6, 2.4) 8.1 Pregnancy. Risk summaryLimited available data with Calcium Gluconate Injection use in pregnant women are insufficient to inform drug associated risk of adverse developmental outcomes. There are risks to the mother and the fetus associated with hypocalcemia in pregnancy[see Clinical Considerations]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.Clinical ConsiderationsDisease-associated maternal riskMaternal hypocalcemia can result in an increased rate of spontaneous abortion, premature and dysfunctional labor, and possibly preeclampsia. Fetal/Neonatal adverse reactionsInfants born to mothers with hypocalcemia can have associated fetal and neonatal hyperparathyroidism, which in turn can cause fetal and neonatal skeletal demineralization, subperiosteal bone resorption, osteitis fibrosa cystica and neonatal seizures. Infants born to mothers with hypocalcemia should be carefully monitored for signs of hypocalcemia or hypercalcemia, including neuromuscular irritability, apnea, cyanosis and cardiac rhythm disorders.. 8.2 Lactation. Risk summaryCalcium is present in human milk as natural component of human milk. It is not known whether intravenous administration of Calcium Gluconate Injection can alter calcium concentration in human milk. There are no data on the effects of Calcium Gluconate Injection on the breastfed infant, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Calcium Gluconate Injection and any potential adverse effects on the breastfed child from Calcium Gluconate Injection or from the underlying maternal condition. 8.4 Pediatric Use. The safety and effectiveness of Calcium Gluconate Injection have been established in pediatric patients for the treatment of acute, symptomatic hypocalcemia. Pediatric approval for Calcium Gluconate Injection, including doses, is not based on adequate and well-controlled clinical studies. Safety and dosing recommendations in pediatric patients are based on published literature and clinical experience[see Dosage and Administration (2.2)]. Concomitant use of ceftriaxone and Calcium Gluconate Injection is contraindicated in neonates (28 days of age or younger) due to reports of fatal outcomes associated with the presence of lung and kidney ceftriaxone-calcium precipitates. In patients older than 28 days of age, ceftriaxone and Calcium Gluconate Injection may be administered sequentially, provided the infusion lines are thoroughly flushed between infusions with compatible fluid [see Contraindications (4) and Warnings and Precautions (5.2)]. This product contains up to 400 mcg/L aluminum which may be toxic, particularly for premature neonates due to immature renal function. Parenteral administration of aluminum greater than to mcg/kg/day is associated with central nervous system and bone toxicity[see Warnings and Precautions (5.5)]. 8.5 Geriatric Use. In general dose selection for an elderly patient should start at the lowest dose of the recommended dose range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.. 8.6 Renal Impairment. For patients with renal impairment, initiate Calcium Gluconate Injection at the lowest dose of the recommended dose ranges across all age groups. Monitor serum calcium levels every hours [see Dosage and Administration (2.4)]. 8.7 Hepatic Impairment. Hepatic function does not impact the availability of ionized calcium after calcium gluconate intravenous administration. Dose adjustment in hepatically impaired patients may not be necessary.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Arrhythmias with Concomitant Cardiac Glycoside Use: If concomitant therapy is necessary, Calcium Gluconate Injection should be given slowly in small amounts and close ECG monitoring is recommended (5.1) End-Organ Damage due to Intravascular Ceftriaxone-Calcium Precipitates: Concurrent use of intravenous ceftriaxone may cause life-threatening precipitates. Cases of fatal outcomes in neonates have occurred. (4, 5.2) Tissue Necrosis and Calcinosis: Calcinosis cutis can occur with or without extravasation of Calcium Gluconate Injection. Tissue necrosis, ulceration, and secondary infection are the most serious complications. If extravasation occurs or clinical manifestations of calcinosis cutis are noted, immediately discontinue intravenous administration at that site and treat as needed. (5.3) Hypotension, Bradycardia, and Cardiac Arrhythmias with Rapid Administration: To avoid adverse reactions that may follow rapid intravenous administration, Calcium Gluconate Injection should be diluted with 5% dextrose or normal saline and infused slowly, with careful ECG monitoring for cardiac arrhythmias. (5.4) Aluminum Toxicity: This product contains aluminum, up to 400 mcg per liter, that may be toxic. (5.5) Arrhythmias with Concomitant Cardiac Glycoside Use: If concomitant therapy is necessary, Calcium Gluconate Injection should be given slowly in small amounts and close ECG monitoring is recommended (5.1) End-Organ Damage due to Intravascular Ceftriaxone-Calcium Precipitates: Concurrent use of intravenous ceftriaxone may cause life-threatening precipitates. Cases of fatal outcomes in neonates have occurred. (4, 5.2) Tissue Necrosis and Calcinosis: Calcinosis cutis can occur with or without extravasation of Calcium Gluconate Injection. Tissue necrosis, ulceration, and secondary infection are the most serious complications. If extravasation occurs or clinical manifestations of calcinosis cutis are noted, immediately discontinue intravenous administration at that site and treat as needed. (5.3) Hypotension, Bradycardia, and Cardiac Arrhythmias with Rapid Administration: To avoid adverse reactions that may follow rapid intravenous administration, Calcium Gluconate Injection should be diluted with 5% dextrose or normal saline and infused slowly, with careful ECG monitoring for cardiac arrhythmias. (5.4) Aluminum Toxicity: This product contains aluminum, up to 400 mcg per liter, that may be toxic. (5.5) 5.1 Arrhythmias with Concomitant Cardiac Glycoside Use. Cardiac arrhythmias may occur if calcium and cardiac glycosides are administered together. Hypercalcemia increases the risk of digoxin toxicity. Administration of Calcium Gluconate Injection should be avoided in patients receiving cardiac glycosides. If concomitant therapy is necessary, Calcium Gluconate Injection should be given slowly in small amounts and with close ECG monitoring[see Drug Interactions (7.1)]. 5.2 End-Organ Damage due to Intravascular Ceftriaxone-Calcium Precipitates. Concomitant use of ceftriaxone and Calcium Gluconate Injection is contraindicated in neonates (28 days of age or younger) due to cases of fatal outcomes in neonates in which crystalline material was observed in the lungs and kidneys at autopsy after ceftriaxone and calcium were administrated simultaneously through the same intravenous line. Concomitant administration can lead to the formation of ceftriaxone calcium precipitates that may act as emboli, resulting in vascular spasm or infarction [see Contraindications (4)]. In patients older than 28 days of age, ceftriaxone and Calcium Gluconate Injection may be administered sequentially, provided the infusion lines are thoroughly flushed between infusions with compatible fluid. Do not administer Ceftriaxone simultaneously with Calcium Gluconate Injection via Y-site in any age group. 5.3 Tissue Necrosis and Calcinosis. Intravenous administration of Calcium Gluconate Injection and local trauma may result in calcinosis cutis due to transient increase in local calcium concentration. Calcinosis cutis can occur with or without extravasation of Calcium Gluconate Injection, is characterized by abnormal dermal deposits of calcium salts, and clinically manifests as papules, plaques, or nodules that may be associated with erythema, swelling, or induration. Tissue necrosis, ulceration, and secondary infection are the most serious complications.If extravasation occurs or clinical manifestations of calcinosis cutis are noted, immediately discontinue intravenous administration at that site and treat as needed.. 5.4 Hypotension, Bradycardia, and Cardiac Arrhythmias with Rapid Administration. Rapid injection of Calcium Gluconate Injection may cause vasodilation, decreased blood pressure, bradycardia, cardiac arrhythmias, syncope and cardiac arrest. To avoid adverse reactions that may follow rapid intravenous administration, Calcium Gluconate Injection should be diluted with 5% dextrose or normal saline and infused slowly. If rapid intravenous bolus of Calcium Gluconate Injection is required, the rate of intravenous administration should not exceed 200 mg/minute in adults and 100 mg/minute in pediatric patients and ECG monitoring during administration is recommended[see Dosage and Administration (2.1)]. 5.5 Aluminum Toxicity. Calcium Gluconate Injection contains aluminum, up to 400 mcg per liter, that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than mcg/kg/day to mcg/kg/day accumulate aluminum levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.