Calcium Chloride

6 ADVERSE REACTIONS The following serious adverse reactions are also described elsewhere in the labeling: • End-Organ Damage due to Intravascular Ceftriaxone-Calcium Precipitates [see Warnings and Precautions (5.1) ] • Hypotension, Bradycardia, Arrhythmias, and Syncope with Rapid Administration [see Warnings and Precautions (5.2) ] • Arrhythmias with Concomitant Digoxin Use [see Warnings and Precautions (5.3) ] • Tissue Necrosis and Calcinosis [see Warnings and Precautions (5.4) ] • Aluminum toxicity [see Warnings and Precautions (5.5) ] The following adverse reactions have been identified in literature and postmarketing reports of calcium chloride. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: • Nervous system disorders: Paraesthesia (upon rapid injection), calcium taste • General disorders and administration site conditions: Sense of oppression, sense of “heat wave”, local burning sensation, injection site extravasation, injection site reactions • Cardiovascular disorders: Peripheral vasodilatation, decreased blood pressure Adverse reactions have included paraesthesia (upon rapid injection), calcium taste, sense of oppression, sense of “heat wave”, local burning sensation, injection site extravasation, injection site reactions, peripheral vasodilatation, and decreased blood pressure. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS Calcium Chloride Injection is contraindicated in: • Patients with ventricular fibrillation • Patients with asystole and electromechanical dissociation Newborns (up to 28 days of age) if they require (or are expected to require) ceftriaxone intravenous treatment because of the risk of precipitation of ceftriaxone-calcium, regardless of whether these products would be received at different times or through separate intravenous lines [see Warnings and Precautions (5.1) ] . Calcium Chloride Injection is contraindicated in: • Patients with ventricular fibrillation. ( 4 ) • Patients with asystole and electromechanical dissociation. ( 4 ) • Newborns (up to 28 days of age) if they require (or are expected to require) ceftriaxone intravenous treatment, regardless of whether these products would be received at different times or through separate intravenous lines. ( 4 , 5.1 )

11 DESCRIPTION 10% Calcium Chloride Injection, USP is a sterile, nonpyrogenic, hypertonic solution for single administration only. Each mL contains 100 mg (1.4 mEq/mL) of calcium chloride, dihydrate (1.4 mEq each of Ca ++ and Cl - ) in water for injection. It is provided in a 10 mL single-dose syringe for intravenous injection. The solution contains no bacteriostat, antimicrobial agent or added buffer. The pH of 10% Calcium Chloride Injection, USP is 5.5 to 7.5 when diluted with water for injection to make a 5% solution. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. The osmolar concentration is 2.04 mOsmol/mL (calc.). 10% Calcium Chloride Injection, USP is oxygen sensitive. Calcium Chloride, USP dihydrate is chemically designated CaCl 2 • 2H 2 O (dihydrate) and is described as white, odorless fragments or granules freely soluble in water. Calcium Chloride Injection, USP contains no more than 1,000 mcg/L of aluminum [see Warnings and Precautions (5.2) ] .

2 DOSAGE AND ADMINISTRATION • Administer Calcium Chloride Injection by slow intravenous infusion (not to exceed 1 mL/minute), in a central or deep vein . ( 2.1 ) • Do not use intramuscularly or subcutaneously. ( 2.1 ) • Do not administer unless solution is clear and seal is intact. ( 2.1 ) • Stop the administration if the patient complains of any administration-related discomfort, it may be resumed when symptoms disappear. ( 2.1 ) • The recommended adult dose is from 200 mg to 1,000 mg. ( 2.2 ) • The recommended pediatric dose is from 2.7 to 5 mg/kg of calcium chloride. ( 2.2 ) • Repeated injections may be required because of rapid calcium excretion. ( 2.2 ) • See the full prescribing information for the recommended starting dose in patients with renal impairment. ( 2.3 ) • Do not mix Calcium Chloride Injection with ceftriaxone or administer these products simultaneously via a Y-site because concurrent use can lead to the formation of ceftriaxone-calcium precipitates. ( 2.4 ) 2.1 Important Administration Instructions Administer Calcium Chloride Injection by slow intravenous infusion in a central or deep vein in adults and pediatric patients (with or without renal impairment); do not administer by bolus [see Warnings and Precautions (5.2 , 5.4) ] . The maximum recommended infusion rate is 1 mL/minute (100 mg/minute). Additional important administration instructions regarding Calcium Chloride Injection are as follows: • Do not use intramuscularly or subcutaneously to avoid tissue necrosis calcinosis cutis [see Warnings and Precautions (5.4) ] . • Visually inspect for particulate matter and discoloration prior to administration (the solution is clear, and the seal is intact). Do not administer if the solution is unclear or the seal is not intact. • Stop the administration if the patient complains of any administration-related discomfort; administration may be resumed when symptoms disappear. • Discard the unused portion. • If time permits, allow the solution to warm to body temperature. 2.2 Recommended Dosage and Administration The recommended dose range of Calcium Chloride Injection in: • Adults is from 200 mg to 1,000 mg. • Pediatric patients is from 2.7 to 5 mg/kg of calcium chloride. Dosing of this Calcium Chloride Injection product is not possible in patients who require doses less than 200 mg because the recommended dose cannot be achieved with the supplied syringe. For patients who require doses less than 200 mg, use another calcium chloride injection product that allows dosing of less than 200 mg. Individualize the dose for a patient within these dose ranges depending on serum ionized calcium level, severity of hypocalcemia symptoms, and the acuity of hypocalcemia onset. Repeated injections may be required because of rapid excretion of calcium. 2.3 Recommended Starting Dose in Patients with Renal Impairment The recommended starting dose of Calcium Chloride Injection in [see Use in Specific Populations (8.6) ] : • Adults with renal impairment is 200 mg. • Pediatric patients is 2.7 mg/kg of calcium chloride. 2.4 Drug Incompatibilities Do not mix Calcium Chloride Injection with other drugs simultaneously. Do not mix Calcium Chloride Injection with ceftriaxone or administer these products simultaneously via a Y-site because concurrent use can lead to the formation of ceftriaxone-calcium precipitates [see Warnings and Precautions (5.1) ] : • In neonates (28 days of age or younger), concomitant use of Calcium Chloride Injection and ceftriaxone is contraindicated [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.

1 INDICATIONS AND USAGE Calcium Chloride Injection is indicated for the treatment of adult and pediatric patients with acute symptomatic hypocalcemia. Limitations of Use The safety and effectiveness of Calcium Chloride Injection for long-term use has not been established. Calcium Chloride Injection is a form of calcium indicated for the treatment of adult and pediatric and patients with acute symptomatic hypocalcemia. ( 1 ) Limitations of Use : The safety and effectiveness of Calcium Chloride Injection for long-term use has not been established.

10 OVERDOSAGE Overdosage of Calcium Chloride Injection may lead to hypercalcemia. Symptoms of hypercalcemia typically develop when the total serum calcium concentration is ≥12 mg/dL, and include shortening of QT interval, bradycardia, hypertension, anorexia, nausea, vomiting, bowel hypomotility and constipation, muscle weakness, bone pain, decreased concentration, depression, weakness, fatigue, confusion, hallucinations, disorientation, hypotonicity, seizures, and coma. Hypercalcemia effects on kidney include diminished ability to concentrate urine and diuresis. In the event of overdosage, promptly discontinue Calcium Chloride Injection , the patient should be re-evaluated and appropriate countermeasures should be instituted, if necessary [see Warnings and Precautions (5) , Adverse Reactions (6) ] .

7 DRUG INTERACTIONS • Digoxin: Avoid concomitant use with Calcium Chloride Injection. If concomitant use is unavoidable, monitor ECG closely during administration of Calcium Chloride Injection. ( 5.3 , 7.1 ) • Calcium Channel Blockers: Avoid concomitant use with Calcium Chloride Injection. If concomitant use is unavoidable, monitor blood pressure closely during administration of Calcium Chloride Injection. ( 7.2 ) • Drugs That Increase the Risk of Hypercalcemia: Increase the frequency of calcium concentration monitoring in patients taking Calcium Chloride Injection concomitantly with other drugs that increase the risk of hypercalcemia. ( 7.3 ) 7.1 Digoxin Avoid the concomitant use of Calcium Chloride Injection with digoxin. If concomitant use is unavoidable, monitor ECG closely during administration of Calcium Chloride Injection. Synergistic arrhythmias may occur with concomitant use. The use of Calcium Chloride Injection may result in hypercalcemia which increases the risk of digoxin toxicity [see Warnings and Precautions (5.3) ] . 7.2 Calcium Channel Blockers Concomitant use of Calcium Chloride Injection and calcium channel blockers may reduce the response to calcium channel blockers. Avoid concomitant use. If concomitant use is unavoidable, monitor blood pressure closely during administration of Calcium Chloride Injection. 7.3 Drugs That Increase the Risk of Hypercalcemia Increase frequency of monitoring of calcium concentrations in patients taking concomitant Calcium Chloride Injection and other drugs that increase the risk of hypercalcemia (e.g., calcipotriene, estrogen, lithium, parathyroid hormone, teriparatide, thiazide diuretics, Vitamin A, and Vitamin D).

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Intravenous administration of calcium chloride increases serum ionized calcium concentration. Calcium chloride dissociates into ionized calcium in plasma. 12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of Calcium Chloride Injection have not been fully characterized. 12.3 Pharmacokinetics Absorption Calcium Chloride Injection is 100% bioavailable following intravenous injection. Distribution Calcium in the body is distributed mainly in skeleton (99%) and 1% 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, respectively; and approximately 40% is protein-bound (primarily to albumin). Elimination Metabolism Calcium itself does not undergo direct metabolism. Excretion Calcium is excreted by the kidney through a combination of glomerular filtration and tubular reabsorption. A significant increase in urinary excretion of calcium was observed during and after intravenous infusion of calcium chloride. Specific Populations The effect of age, sex, race, ethnicity, renal or hepatic impairment on the pharmacokinetics of calcium have not been evaluated in clinical studies.

12.1 Mechanism of Action Intravenous administration of calcium chloride increases serum ionized calcium concentration. Calcium chloride dissociates into ionized calcium in plasma.

12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of Calcium Chloride Injection have not been fully characterized.

12.3 Pharmacokinetics Absorption Calcium Chloride Injection is 100% bioavailable following intravenous injection. Distribution Calcium in the body is distributed mainly in skeleton (99%) and 1% 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, respectively; and approximately 40% is protein-bound (primarily to albumin). Elimination Metabolism Calcium itself does not undergo direct metabolism. Excretion Calcium is excreted by the kidney through a combination of glomerular filtration and tubular reabsorption. A significant increase in urinary excretion of calcium was observed during and after intravenous infusion of calcium chloride. Specific Populations The effect of age, sex, race, ethnicity, renal or hepatic impairment on the pharmacokinetics of calcium have not been evaluated in clinical studies.

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3 DOSAGE FORMS AND STRENGTHS Calcium Chloride Injection, USP (single-dose) supplied as: • 10% (1,000 mg/10 mL) (100 mg/mL) in an Ansyr ® Plastic Syringe • 10% (1,000 mg/10 mL) (100 mg/mL) in a LifeShield ® Abboject ® Glass Syringe The 100 mg/mL concentration represents 27 mg or 1.4 mEq of elemental calcium per mL of solution. Calcium Chloride Injection, USP (single-dose) is supplied as: ( 3 ) • 10% (1,000 mg/10 mL) (100 mg/mL) in an Ansyr ® Plastic Syringe • 10% (1,000 mg/10 mL) (100 mg/mL) in a LifeShield ® Abboject ® Glass Syringe The 100 mg/mL concentration represents 27 mg or 1.4 mEq of elemental calcium per mL of solution. ( 3 )

Calcium Chloride CALCIUM CHLORIDE CALCIUM CHLORIDE CALCIUM CATION CHLORIDE ION WATER HYDROCHLORIC ACID SODIUM HYDROXIDE Calcium Chloride CALCIUM CHLORIDE CALCIUM CHLORIDE CALCIUM CATION CHLORIDE ION WATER HYDROCHLORIC ACID SODIUM HYDROXIDE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and fertility have not been assessed with Calcium Chloride Injection.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and fertility have not been assessed with Calcium Chloride Injection.

NDA021117

Calcium Chloride

CALCIUM CHLORIDE

0409-1631

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL 10 mL Single-Dose Syringe - Discard Unused Portion NDC 0409-1631-40 10% Calcium Chloride Injection, USP 1000 mg/10 mL (100 mg/mL) For Intravenous use only. 2.04 mOsmol/mL (calc.). pH (5.5 to 7.5). Contains no more than 1,000 mcg/L of aluminum. Hospira Distributed by Hospira, Inc., Lake Forest, IL 60045 USA Rx only RL-7161 PRINCIPAL DISPLAY PANEL - 10 mL Syringe Label

17 PATIENT COUNSELING INFORMATION Inform patients or caregivers of the following risks of Calcium Chloride Injection: Arrhythmias with Concomitant Digoxin Use Arrhythmias may occur if Calcium Chloride Injection and Digoxin are administered together [see Warnings and Precautions (5.3) ] . Tissue Necrosis and Calcinosis Administration of Calcium Chloride Injection may result in calcinosis cutis including tissue necrosis, ulceration, and secondary infection. [see Warnings and Precautions (5.4) ] . Aluminum Toxicity Calcium Chloride Injection contains aluminum that may be toxic [see Warnings and Precautions (5.5) ] . Distributed by Hospira, Inc., Lake Forest, IL 60045 USA Abboject ® is a trademark of Abbott Laboratories LifeShield ® is the trademark of ICU Medical, Inc. and is used under license. LAB-1022-3.0 Logo

8.5 Geriatric Use Clinical studies of Calcium Chloride Injection did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

8.4 Pediatric Use The safety and effectiveness of Calcium Chloride Injection for the treatment of acute symptomatic hypocalcemia have been established in pediatric patients. The use of Calcium Chloride Injection is contraindicated in newborns if they require (or are expected to require) ceftriaxone intravenous treatment because of the risk of precipitation of ceftriaxone-calcium, regardless of whether these products would be received at different times or through separate intravenous lines [see Contraindications (4) and Warnings and Precautions (5.1) ] . In pediatric patients older than 28 days of age, Calcium Chloride Injection and ceftriaxone intravenous solutions may be administered sequentially one after another if infusion lines at different sites are used, infusion lines are replaced, or infusion lines are thoroughly flushed between infusions with physiological salt solution to avoid precipitation. Do not mix or administer Calcium Chloride Injection simultaneously with ceftriaxone, even if using different infusion lines or different infusion sites as it can lead to precipitation of ceftriaxone-calcium. Calcium Chloride Injection contains aluminum that may be associated with central nervous system and bone toxicity. Because of immature renal function, preterm infants receiving prolonged parenteral nutrition treatment with Calcium Chloride Injection may be at higher risk of aluminum toxicity [see Warnings and Precautions (5.2)] .

8.1 Pregnancy Risk Summary Administration of Calcium Chloride Injection for the treatment of acute symptomatic hypocalcemia during pregnancy is not expected to cause major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with development of hypocalcemia during pregnancy (see Clinical Considerations) . Animal reproduction studies have not been conducted with Calcium Chloride Injection. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 and/or Embryo/Fetal/Neonatal Risk Maternal hypocalcemia can result in an increased rate of spontaneous abortion, premature and dysfunctional labor, and possibly preeclampsia. Infants born to mothers with hypocalcemia can develop fetal and neonatal hyperparathyroidism, which in turn can cause fetal and neonatal skeletal demineralization, subperiosteal bone resorption, osteitis fibrosa cystica and neonatal seizures.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Administration of Calcium Chloride Injection for the treatment of acute symptomatic hypocalcemia during pregnancy is not expected to cause major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with development of hypocalcemia during pregnancy (see Clinical Considerations) . Animal reproduction studies have not been conducted with Calcium Chloride Injection. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 and/or Embryo/Fetal/Neonatal Risk Maternal hypocalcemia can result in an increased rate of spontaneous abortion, premature and dysfunctional labor, and possibly preeclampsia. Infants born to mothers with hypocalcemia can develop fetal and neonatal hyperparathyroidism, which in turn can cause fetal and neonatal skeletal demineralization, subperiosteal bone resorption, osteitis fibrosa cystica and neonatal seizures. 8.2 Lactation Risk Summary Calcium is present in human milk. Administration of the approved recommended dose of Calcium Chloride Injection to the mother is not expected to cause harm to a breastfed infant. There is no information on the effects of Calcium Chloride 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 Chloride Injection and any potential adverse effects on the breastfed infant from Calcium Chloride Injection or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of Calcium Chloride Injection for the treatment of acute symptomatic hypocalcemia have been established in pediatric patients. The use of Calcium Chloride Injection is contraindicated in newborns if they require (or are expected to require) ceftriaxone intravenous treatment because of the risk of precipitation of ceftriaxone-calcium, regardless of whether these products would be received at different times or through separate intravenous lines [see Contraindications (4) and Warnings and Precautions (5.1) ] . In pediatric patients older than 28 days of age, Calcium Chloride Injection and ceftriaxone intravenous solutions may be administered sequentially one after another if infusion lines at different sites are used, infusion lines are replaced, or infusion lines are thoroughly flushed between infusions with physiological salt solution to avoid precipitation. Do not mix or administer Calcium Chloride Injection simultaneously with ceftriaxone, even if using different infusion lines or different infusion sites as it can lead to precipitation of ceftriaxone-calcium. Calcium Chloride Injection contains aluminum that may be associated with central nervous system and bone toxicity. Because of immature renal function, preterm infants receiving prolonged parenteral nutrition treatment with Calcium Chloride Injection may be at higher risk of aluminum toxicity [see Warnings and Precautions (5.2)] . 8.5 Geriatric Use Clinical studies of Calcium Chloride Injection did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients. 8.6 Renal Impairment The use of Calcium Chloride Injection in patients with renal impairment may increase the risk of a higher calcium-phosphorus product. For patients with renal impairment, initiate Calcium Chloride Injection at the lowest recommended dose within the recommended dose range [see Dosage and Administration (2.2) ] . Monitor serum calcium levels frequently based on the severity of the renal impairment and the risk of a high calcium-phosphorus product (e.g., every 4 hours).

16 HOW SUPPLIED/STORAGE AND HANDLING Calcium Chloride Injection, USP (clear solution) is supplied in single-dose syringes as follows: Unit of Sale and Product Description Strength NDC Bundle of 10 10 mL Ansyr ® Plastic Syringe 10% (1,000 mg/10 mL) (100 mg/mL) 0409-1631-10 Bundle of 10 10 mL LifeShield ® Abboject ® Glass Syringe with Luer Lock Adapter and protected needle 10% (1,000 mg/10 mL) (100 mg/mL) 0409-4928-34 The 100 mg/mL concentration represents 27 mg or 1.4 mEq of elemental calcium per mL of solution. Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature.]