CALCIUM GLUCONATE

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 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.

4 CONTRAINDICATIONS 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 )

11 DESCRIPTION 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

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 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.

1 INDICATIONS AND USAGE 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 )

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.

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 ) 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.

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 Absorption Calcium 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. Distribution Calcium 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). Elimination Studies have shown a relationship between urinary calcium excretion and the intravenous administration of calcium gluconate, with a significant increase in urinary calcium excretion observed after the intravenous administration of calcium gluconate.

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 Absorption Calcium 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. Distribution Calcium 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). Elimination Studies have shown a relationship between urinary calcium excretion and the intravenous administration of calcium gluconate, with a significant increase in urinary calcium excretion observed after the intravenous administration of calcium gluconate.

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3 DOSAGE FORMS AND STRENGTHS Calcium Gluconate in Sodium Chloride Injection is a 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. Injection: 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)

CALCIUM GLUCONATE calcium gluconate CALCIUM GLUCONATE MONOHYDRATE CALCIUM CATION CALCIUM SACCHARATE HYDROCHLORIC ACID SODIUM HYDROXIDE SODIUM CHLORIDE WATER CALCIUM GLUCONATE calcium gluconate CALCIUM GLUCONATE MONOHYDRATE CALCIUM CATION CALCIUM SACCHARATE HYDROCHLORIC ACID SODIUM HYDROXIDE SODIUM CHLORIDE WATER

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.

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.

ANDA217174

CALCIUM GLUCONATE

calcium gluconate

80830-2363

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL NDC 80830-2362-1 Calcium Gluconate in Sodium Chloride Injection, 20 mg/mL (1,000 mg/50 mL) Rx only Intravenous Bag Label Amneal Pharmaceuticals LLC NDC 80830-2362-1 Calcium Gluconate in Sodium Chloride Injection, 20 mg/mL (1,000 mg/50 mL) Rx only Pouch Label Amneal Pharmaceuticals LLC NDC 80830-2362-9 Calcium Gluconate in Sodium Chloride Injection, 20 mg/mL (1,000 mg/50 mL) Rx only 24 x 50 mL Carton Label Amneal Pharmaceuticals LLC NDC 80830-2363-1 Calcium Gluconate in Sodium Chloride Injection, 20 mg/mL (2,000 mg/100 mL) Rx only Intravenous Bag Label Amneal Pharmaceuticals LLC NDC 80830-2363-1 Calcium Gluconate in Sodium Chloride Injection, 20 mg/mL (2,000 mg/100 mL) Rx only Pouch Label Amneal Pharmaceuticals LLC NDC 80830-2363-9 Calcium Gluconate in Sodium Chloride Injection, 20 mg/mL (2,000 mg/100 mL) Rx only 24 x 100 mL Carton Label Amneal Pharmaceuticals LLC 1 1 1 1 1 1

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 by: Puniska Healthcare Pvt. Ltd. (A Subsidiary of Amneal Pharmaceuticals Pvt. Ltd.) Ahmedabad 382110, INDIA Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 07-2023-00

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 4 hours. ( 8.6 , 2.4 ) 8.1 Pregnancy Risk summary Limited available data with calcium gluconate injection use in pregnant women are insufficient to inform a 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% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal risk Maternal hypocalcemia can result in an increased rate of spontaneous abortion, premature and dysfunctional labor and possibly preeclampsia. Fetal/Neonatal adverse reactions Infants 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 summary Calcium is present in human milk as a 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 mother’s 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 a 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 4 mcg/kg/day to 5 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 4 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Calcium Gluconate in Sodium Chloride Injection is a clear, colorless solution supplied as follows: Strength Each Unit of Sale 1,000 mg per 50 mL (20 mg per mL) NDC 80830-2362-1 1 Single-dose Intravenous Bag in an Overwrap NDC 80830-2362-9 Unit of 24 2,000 mg per 100 mL (20 mg per mL) NDC 80830-2363-1 1 Single-dose Intravenous Bag in an Overwrap NDC 80830-2363-9 Unit of 24 The container closure is not made with natural rubber latex. Non-PVC, Non-DEHP, Sterile. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Product should be used within 60 days of removal from overwrap. Preservative Free. Discard any unused portion in the single-dose container immediately.