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 in Sodium Chloride 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.

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 Fresenius Kabi USA, LLC at 1-800-551-7176 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 in Sodium Chloride 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.. MetabolismCalcium 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 in Sodium Chloride 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 in Sodium Chloride Injection is sterile, preservative-free, nonpyrogenic, solution of calcium gluconate, form of calcium, for intravenous use.Calcium Gluconate is calcium D-gluconate (1:2) monohydrate. The structural formula is:Molecular formula: C12H22CaO14o H2OMolecular weight: 448.39Solubility in water: 3.5 g/100 mL at 25CCalcium Gluconate in Sodium Chloride Injection is available as 1,000 mg per 50 mL (18.8 mg per mL) or 2,000 mg per 100 mL (18.8 mg per mL) in single-dose bags.Each mL of Calcium Gluconate in Sodium Chloride Injection contains 20 mg of calcium gluconate (equivalent to 18.8 mg of calcium gluconate and 0.9 mg of calcium saccharate tetrahydrate), hydrochloric acid and/or sodium hydroxide for pH adjustment (6.0 to 8.2) and sodium chloride 6.75 mg/mL as tonicity adjustor.Each mL of Calcium Gluconate in Sodium Chloride Injection contains 1.86 mg (0.093 mEq) of elemental calcium.. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Contains 20 mg of calcium gluconate per mL which contains 1.86 mg (0.093 mEq) of elemental calcium (2.1)Administer intravenously (bolus or continuous infusion) via secure intravenous line (2.1)See Full Prescribing Information (FPI) for administration rates and appropriate monitoring (2.1)Do not dilute Calcium Gluconate in Sodium Chloride Injection prior to use. Any unused portion should be discarded (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). Contains 20 mg of calcium gluconate per mL which contains 1.86 mg (0.093 mEq) of elemental calcium (2.1). Administer intravenously (bolus or continuous infusion) via secure intravenous line (2.1). See Full Prescribing Information (FPI) for administration rates and appropriate monitoring (2.1). Do not dilute Calcium Gluconate in Sodium Chloride Injection prior to use. Any unused portion should be discarded (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). 2.1 Important Administration Instructions. Calcium Gluconate in Sodium Chloride Injection contains 20 mg of calcium gluconate per mL which contains 1.86 mg (i.e. 0.093 mEq) of elemental calcium. See Table for amounts of elemental calcium in Calcium Gluconate in Sodium Chloride Injection.Table 1. Amount of Calcium Gluconate and Elemental CalciumTotal Strength per Total VolumeStrength per mLTotal Amount of Elemental Calcium (mg) per Total VolumeTotal Amount of Elemental Calcium (mEq) per Total Volume1,000 mg per 50 mL20 mg/mL93 mg per 50 mL4.65 mEq per 50 mL2,000 mg per 100 mL20 mg/mL186 mg per 100 mL9.3 mEq per 100 mLDo not dilute Calcium Gluconate in Sodium Chloride Injection prior to use. Any unused portion should be discarded. [see Dosage and Administration (2.5)]. Inspect Calcium Gluconate in Sodium Chloride Injection visually prior to administration. The solution should appear clear and colorless. Do not administer if there is particulate matter or discoloration.Administer Calcium Gluconate in Sodium Chloride Injection intravenously via secure intravenous line to avoid calcinosis cutis and tissue necrosis [see Warnings and Precautions (5.3)].Administer Calcium Gluconate in Sodium Chloride Injection by continuous infusion 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)].Check solution container composition, lot number, and expiry date.Do not admix with other drugs.Do not use solution containers in series connections.Do not remove solution container from its overwrap until immediately before use.The intact port cap provides visual tamper evidence. Do not use if port cap is prematurely removed. Maintain strict aseptic technique during handling.INSTRUCTIONS FOR USE:Always inspect the solution container before and after removal from the overwrap.Place the solution container on clean, flat surface. Remove the solution container from the overwrap.Check the solution container for leaks by squeezing firmly. If leaks are found, discard.Do not use if the solution is cloudy or precipitate is present.To Prepare for Administration:Immediately before inserting the infusion set, break off BLUE Infusion Port Cap with the arrow pointing away from the solution container.Use non-vented infusion set or close the air-inlet on vented set.Close the roller clamp of the infusion setHold the base of the BLUE infusion port, twist and push spike until fully inserted.The BLUE infusion port contains self-sealing septum that helps prevent leakage after removing the spike. The infusion port is not intended to be spiked more than once.Suspend solution container from hanger hole.For Single Use Only. Discard unused portion.. Calcium Gluconate in Sodium Chloride Injection contains 20 mg of calcium gluconate per mL which contains 1.86 mg (i.e. 0.093 mEq) of elemental calcium. See Table for amounts of elemental calcium in Calcium Gluconate in Sodium Chloride Injection.. Do not dilute Calcium Gluconate in Sodium Chloride Injection prior to use. Any unused portion should be discarded. [see Dosage and Administration (2.5)]. Inspect Calcium Gluconate in Sodium Chloride Injection visually prior to administration. The solution should appear clear and colorless. Do not administer if there is particulate matter or discoloration.. Administer Calcium Gluconate in Sodium Chloride Injection intravenously via secure intravenous line to avoid calcinosis cutis and tissue necrosis [see Warnings and Precautions (5.3)].. Administer Calcium Gluconate in Sodium Chloride Injection by continuous infusion 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)].. Check solution container composition, lot number, and expiry date.. Do not admix with other drugs.. Do not use solution containers in series connections.. Do not remove solution container from its overwrap until immediately before use.. The intact port cap provides visual tamper evidence. Do not use if port cap is prematurely removed. Maintain strict aseptic technique during handling.. Always inspect the solution container before and after removal from the overwrap.. Place the solution container on clean, flat surface. Remove the solution container from the overwrap.. Check the solution container for leaks by squeezing firmly. If leaks are found, discard.. Do not use if the solution is cloudy or precipitate is present.. Immediately before inserting the infusion set, break off BLUE Infusion Port Cap with the arrow pointing away from the solution container.. Use non-vented infusion set or close the air-inlet on vented set.. Close the roller clamp of the infusion set. Hold the base of the BLUE infusion port, twist and push spike until fully inserted.. The BLUE infusion port contains self-sealing septum that helps prevent leakage after removing the spike. The infusion port is not intended to be spiked more than once.. Suspend solution container from hanger hole.. For Single Use Only. Discard unused portion.. 2.2 Recommended Dosage. Individualize the dose of Calcium Gluconate in Sodium Chloride 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 in Sodium Chloride Injection in mg of calcium gluconate for neonates, pediatric and adult patients.Table 2. Dosing Recommendations in mg of Calcium Gluconate for Neonate, Pediatric, and Adult PatientsPatient PopulationInitial DoseSubsequent Doses (if needed)BolusContinuous InfusionNeonate(<= month) 100 200 mg/kg 100 200 mg/kgevery hoursInitiate at 17-33 mg/kg/hour Pediatric(> month to< 17 years)29 60 mg/kg 29 60 mg/kgevery hoursInitiate at 8-13 mg/kg/hour Adult1000 2000 mg 1000 2000 mgevery hoursInitiate at 5.4 21.5 mg/kg/hourFor 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 in Sodium Chloride 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 in Sodium Chloride 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 in Sodium Chloride Injection with ceftriaxone. Concurrent use of intravenous ceftriaxone and Calcium Gluconate in Sodium Chloride 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 in Sodium Chloride 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 in Sodium Chloride Injection with minocycline injection. Calcium complexes minocycline rendering it inactive.. Do not mix Calcium Gluconate in Sodium Chloride Injection with ceftriaxone. Concurrent use of intravenous ceftriaxone and Calcium Gluconate in Sodium Chloride 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 in Sodium Chloride 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 in Sodium Chloride Injection with minocycline injection. Calcium complexes minocycline rendering it inactive.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Calcium Gluconate in Sodium Chloride Injection is clear, colorless solution available in the following:Injection:Calcium gluconate 1,000 mg per 50 mL (20 mg per mL) single-dose container.Calcium gluconate 2,000 mg per 100 mL (20 mg per mL) single-dose container.Each mL of Calcium Gluconate in Sodium Chloride Injection contains 20 mg of calcium gluconate which contains 1.86 mg (0.093 mEq) of elemental calcium.. Calcium gluconate 1,000 mg per 50 mL (20 mg per mL) single-dose container.. Calcium gluconate 2,000 mg per 100 mL (20 mg per mL) single-dose container.. Injection: (3)Single-dose container: 1,000 mg per 50 mL (20 mg per mL)Single-dose container: 2,000 mg per 100 mL (20 mg per mL). Single-dose container: 1,000 mg per 50 mL (20 mg per mL). Single-dose container: 2,000 mg per 100 mL (20 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 in Sodium Chloride Injection in patients receiving cardiac glycosides; if considered necessary, administer Calcium Gluconate in Sodium Chloride 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 in Sodium Chloride Injection is clear, colorless solution supplied as follows:Product CodeUnit of SaleStrengthUnit of Use271621NDC 65219-162-10Unit of 24 1,000 mg per 50 mL (20 mg/mL)NDC 65219-162-0150 mL fill volume in 100 mL free flex(R) bag271645NDC 65219-164-50Unit of 24 2,000 mg per 100 mL (20 mg per mL)NDC 65219-164-01100 mL free flex(R) bag The container closure is not made with natural rubber latex. Non-PVC, Non-DEHP, Sterile. Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Preservative Free. Discard any unused portion in the single-dose container immediately.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Calcium Gluconate in Sodium Chloride Injection is indicated for pediatric and adult patients for the treatment of acute symptomatic hypocalcemia.. Calcium Gluconate in Sodium Chloride 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 in Sodium Chloride 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). Limitations of UseThe safety of Calcium Gluconate Injection for long term use has not been established.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient of the risks associated with infusion of Calcium Gluconate in Sodium Chloride Injection including local tissue inflammation, local necrosis and calcinosis. [see Warnings and Precautions (5.3)].Manufactured for:Lake Zurich, IL 60047Made in Norwaywww.fresenius-kabi.com/us451705. Advise the patient of the risks associated with infusion of Calcium Gluconate in Sodium Chloride Injection including local tissue inflammation, local necrosis and calcinosis. [see Warnings and Precautions (5.3)].. Fresenius Kabi Logo.

LACTATION 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 in Sodium Chloride 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 in Sodium Chloride Injection and any potential adverse effects on the breastfed child from Calcium Gluconate in Sodium Chloride 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.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdosage of Calcium Gluconate in Sodium Chloride 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 in Sodium Chloride 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.

PACKAGE LABEL PRINCIPAL DISPLAY Calcium Gluconate g Bag Label NDC 65219-162-01CALCIUM GLUCONATE in Sodium Chloride Injection1 TOTAL1,000 mg per 50 mL(20 mg per mL)Do Not Dilute. PACKAGE LABEL PRINCIPAL DISPLAY Calcium Gluconate g Bag Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of Calcium Gluconate in Sodium Chloride Injection have been established in pediatric patients for the treatment of acute, symptomatic hypocalcemia.Pediatric approval for Calcium Gluconate in Sodium Chloride 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 in Sodium Chloride 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 100 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.. MetabolismCalcium 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 Considerations. Disease-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.

Limitations of UseThe safety of Calcium Gluconate Injection for long term use has not been established.

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 Considerations. Disease-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 in Sodium Chloride 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 in Sodium Chloride Injection and any potential adverse effects on the breastfed child from Calcium Gluconate in Sodium Chloride Injection or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of Calcium Gluconate in Sodium Chloride Injection have been established in pediatric patients for the treatment of acute, symptomatic hypocalcemia.Pediatric approval for Calcium Gluconate in Sodium Chloride 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 in Sodium Chloride 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 100 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 in Sodium Chloride 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 in Sodium Chloride 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. Do not administer ceftriaxone simultaneously with Calcium Gluconate in Sodium Chloride via Y-site in any age group. 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 in Sodium Chloride 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 in Sodium Chloride Injection should be infused slowly, with careful ECG monitoring for cardiac arrhythmias. (5.4)Aluminum Toxicity: This product contains aluminum, up to 100 mcg per liter, that may be toxic. (5.5). Arrhythmias with Concomitant Cardiac Glycoside Use: If concomitant therapy is necessary, Calcium Gluconate in Sodium Chloride 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. Do not administer ceftriaxone simultaneously with Calcium Gluconate in Sodium Chloride via Y-site in any age group. 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 in Sodium Chloride 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 in Sodium Chloride Injection should be infused slowly, with careful ECG monitoring for cardiac arrhythmias. (5.4). Aluminum Toxicity: This product contains aluminum, up to 100 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 in Sodium Chloride Injection should be avoided in patients receiving cardiac glycosides. If concomitant therapy is necessary, Calcium Gluconate in Sodium Chloride 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 in Sodium Chloride 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 in Sodium Chloride 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 in Sodium Chloride Injection via Y-site in any age group.. 5.3 Tissue Necrosis and Calcinosis. Intravenous administration of Calcium Gluconate in Sodium Chloride 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 in Sodium Chloride 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 in Sodium Chloride 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 in Sodium Chloride Injection should be 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 in Sodium Chloride Injection contains aluminum, up to 100 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.