Calcium Gluconate

1 INDICATIONS AND 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 )

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.

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 ) 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 or pharmacy bulk package (PBP). For PBP, dispense single-doses to many patients in a pharmacy admixture program; use within 4 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 intravenous 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 mg/mL to 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 mg/mL to 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 and 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 1 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 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 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 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 to 21.5 mg/kg/hour For bolus administration, DO NOT exceed an infusion rate of:

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.

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 monitoring during admi

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 )

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.