CALCIUM GLUCONATE

Calcium gluconate in sodium chloride injection is a sterile, clear, colorless, preservative-free, nonpyrogenic, solution of calcium gluconate, a form of calcium, for intravenous use. The chemical name of calcium gluconate monohydrate, USP is calcium D-gluconate (1:2) monohydrate. The structural formula is Molecular formula: C 12 H 22 CaO 14 • H 2 O Molecular weight: 448.39 g/mol Solubility in water: 3.5 g/100 mL at 25°C Calcium gluconate monohydrate, USP is a white, crystalline granules or powder. It is soluble in boiling water, sparingly soluble in water and insoluble in alcohol. Calcium 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) filled in single-dose infusion 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), 6.75 mg sodium chloride as tonicity adjustor, hydrochloric acid and/or sodium hydroxide for pH adjustment (6.0 to 8.2) and water for injection. Each mL of calcium gluconate in sodium chloride injection contains 1.86 mg (0.093 mEq) of elemental calcium. 1

Calcium gluconate in sodium chloride injection is indicated for pediatric and adult patients for the treatment of acute symptomatic hypocalcemia. Limitations of Use The safety of calcium gluconate injection for long term use has not been established. Calcium gluconate in sodium chloride injection is a 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 )

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 a 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 2 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 4 hours to 6 hours and during continuous infusion every 1 hour to 4 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 1 for amounts of elemental calcium in calcium gluconate in sodium chloride injection. Table 1: Amount of Calcium Gluconate and Elemental Calcium Total Strength per Total Volume Strength per mL Total Amount of Elemental Calcium (mg) per Total Volume Total Amount of Elemental Calcium (mEq) per Total Volume 1,000 mg per 50 mL 20 mg/mL 93 mg per 50 mL 4.65 mEq per 50 mL 2,000 mg per 100 mL 20 mg/mL 186 mg per 100 mL 9.3 mEq per 100 mL 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 a 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 2 [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. The intact twist-off port cap provides visual tamper evidence. Do not use if twist-off 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 a 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 a precipitate is present. To Prepare for Administration Immediately before inserting the infusion set, remove twist-off port from the bag. Use a non-vented infusion set or close the air-inlet on a vented set. Close the roller clamp of the infusion set. Hold the base of the infusion port and push spike until fully inserted. The infusion port is not intended to be spiked more than once. Suspend solution container from hanger hole. For single-dose 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 2 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 Patients Patient Population Initial Dose Subsequent Doses (if needed) Bolus Continuous Infusion Neonate (≤ 1 month) 100 mg/kg to 200 mg/kg 100 mg/kg to 200 mg/kg every 6 hours Initiate at 17 mg/kg/hour to 33 mg/kg/hour Pediatric (> 1 month to < 17 years) 29 mg/kg to 60 mg/kg 29 mg/kg to 60 mg/kg every 6 hours Initiate at 8 mg/kg/hour to 13 mg/kg/hour Adult 1,000 mg to 2,000 mg 1,000 mg to 2,000 mg every 6 hours Initiate at 5.4 mg/kg/hour to 21.5 mg/kg/hour For bolus administration, DO NOT exceed an infusion rate of: 200 mg/minute in adult patients 100 mg/minute in pediatric patients For continuous infusions, adjust rate as needed based on serum calcium levels. 2.3 Serum Calcium Monitoring Measure serum calcium every 4 hours to 6 hours during intermittent infusions with calcium gluconate in sodium chloride injection and measure serum calcium every 1 hour to 4 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 4 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 a compatible fluid. Ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions via a 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.

Calcium gluconate in sodium chloride injection is contraindicated in: 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 )

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 a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Cardiovascular : Vasodilation, decreased blood pressure, bradycardia, cardiac arrhythmia, syncope, cardiac arrest. Administration site reactions : Local soft tissue inflammation, local necrosis, calcinosis cutis and calcification due to extravasation. 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 Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.