calcium gluconate

1 INDICATIONS & USAGE Calcium Gluconate 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 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 )

2 DOSAGE & ADMINISTRATION • Contains 100 mg of calcium gluconate per mL which contains 9.3 mg (0.465 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 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 1 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 to 6 hours and during continuous infusion every 1 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 ) • Supplied in a single-dose vial. 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 a 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 a 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 a concentration of 5.8-10 mg/mL prior to administration. Administer at the rate recommended in Table 1 [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 single-dose vials. 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 1 provides dosing recommendations for Calcium Gluconate Injection in mg of calcium gluconate for neonates, pediatric and adult patients. Ta ble 1. 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 – 200 mg/kg 100 - 200 mg/kg every 6 hours Initiate at 17-33 mg/kg/hour Pediatric (> 1 month to < 17 years) 29 - 60 mg/kg 29 - 60 mg/kg every 6 hours Initiate at 8-13 mg/kg/hour Adult 1000 - 2000 mg 1000 - 2000 mg every 6 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 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 to 6 hours during intermittent infusions with C…

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 ) 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 a 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 a compatible fluid. Do not administer Ceftriaxone simultaneously with Calcium Gluconate Injection via a 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…

4 CONTRAINDICATIONS Calcium Gluconate 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 )

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 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.

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 2-4% and 15-20%, respectively. Clin ical 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.

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 Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.