Calcium Chloride Dihydrate

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.

Calcium chloride injection, USP (single-dose) supplied as: 10% (1,000 mg/10 mL) (100 mg/mL) in a 10 mL vial 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) 1,000 mg/10 mL (100 mg/mL) in a 10 mL vial The 100 mg/mL concentration represents 27 mg or 1.4 mEq of elemental calcium per mL of solution. (3)

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)

End-Organ Damage due to Intravascular Ceftriaxone-Calcium Precipitates: Calcium chloride injection is contraindicated in newborns (up to 28 days of age) if they require (or are expected to require) ceftriaxone intravenous treatment. In patients older than 28 days of age, do not mix or administer simultaneously with ceftriaxone intravenous solutions, even via different infusion lines or at different infusion sites as it can lead to precipitation of ceftriaxone-calcium. (5.1) Hypotension, Bradycardia, Arrhythmias, and Syncope with Rapid Administration: Too rapid an injection exceeding 1 mL/minute may lead to hypotension and syncope. (2.1, 5.2) Arrhythmias with Concomitant Digoxin Use: Avoid use of calcium chloride injection in patients receiving digoxin. Closely monitor ECG and calcium levels if concomitant therapy is necessary. (5.3, 7.1) Tissue Necrosis and Calcinosis: Administer calcium chloride injection slowly through a small needle into a large vein to minimize the risk of tissue necrosis, ulceration and calcinosis. Avoid extravasation or accidental injection into perivascular tissues. Immediately discontinue administration should perivascular infiltration occur. (2.1, 5.4) Aluminum Toxicity: Risk of toxicity with prolonged administration if kidney function is impaired. Premature neonates are particularly at risk. When prescribing calcium chloride injection in patients receiving parenteral nutrition solutions, limit the total daily patient exposure to aluminum to no more than 5 mcg/kg/day. (5.5)

5.1 End-Organ Damage due to Intravascular Ceftriaxone-Calcium Precipitates The use of calcium chloride injection is contraindicated in 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 Contraindications (4)]. Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys in premature and full-term newborns aged less than 1 month have occurred when ceftriaxone and calcium were administered either simultaneously or non-simultaneously and through different intravenous lines. In-vitro studies demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium compared to other age groups. In 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 [see Dosage and Administration (2.4)] .

5.2 Hypotension, Bradycardia, Arrhythmias, and Syncope with Rapid Administration Rapid injection of calcium chloride injection may cause vasodilation, decreased blood pressure, bradycardia, arrhythmias, syncope, and cardiac arrest. It is particularly important to prevent a high concentration of calcium from reaching the heart because of the risk of syncope. Too rapid an injection exceeding 1 mL/minute may lead to hypotension and cardiac syncope [see Dosage and Administration (2.1)].

5.3 Arrhythmias with Concomitant Digoxin Use Arrhythmias may occur if calcium chloride injection and digoxin are administered together. Hypercalcemia resulting from an overdose of calcium chloride injection increases the risk of digoxin toxicity. Avoid the use of calcium chloride injection in patients receiving digoxin. If concomitant therapy is necessary, closely monitor ECG and calcium levels [see Drug Interactions (7.1)] .

5.4 Tissue Necrosis and Calcinosis Administration of calcium chloride injection in patients with 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 chloride 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. To minimize the risk of tissue necrosis, ulceration and calcinosis, administer calcium chloride injection slowly through a small needle into a large vein [see Dosage and Administration (2.1)]. Avoid extravasation or accidental injection into perivascular tissues. Should perivascular infiltration occur, immediately discontinue intravenous administration at that site and treat as needed.

5.5 Aluminum Toxicity Calcium chloride injection contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature (preterm) neonates and preterm infants, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day can accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower amounts of aluminum. Exposure to aluminum from calcium chloride injection at the recommended dose is not more than 10 mcg [see Dosage and Administration (2.2) and Description (11)]. When prescribing calcium chloride injection in patients receiving parenteral nutrition solutions, limit the total daily patient exposure to aluminum to no more than 5 mcg/kg/day.

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 Somerset Therapeutics, LLC at 1- 800-417-9175 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

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).

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).

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