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.

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 Section 4.4]. 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 Section 4.4].

·            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.

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.

Recommended Starting Dose in Patients with Renal Impairment

The recommended starting dose of Calcium Chloride Injection in:

·                 Adults with renal impairment is 200 mg.

·                 Pediatric patients is 2.7 mg/kg of calcium chloride.

Special populations:

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 Section 4.3 and Section 4.4].

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.

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.

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. 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).

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 Section 4.3]. 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 Section 4.2].

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 Section 4.2].

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 Section 4.5].

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 Section 4.2]. Avoid extravasation or accidental injection into perivascular tissues. Should perivascular infiltration occur, immediately discontinue intravenous administration at that site and treat as needed.

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 Section 4.4].

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.

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).

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.

Breastfeeding

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.

Fertility

Fertility have not been assessed with Calcium Chloride Injection

Information is not available.

The following serious adverse reactions are also described elsewhere in the labelling [see Section 4.4]:

·            End-Organ Damage due to Intravascular Ceftriaxone-Calcium Precipitates

·                 Hypotension, Bradycardia, Arrhythmias, and Syncope with Rapid Administration

·                 Arrhythmias with Concomitant Digoxin Use

·                 Tissue Necrosis and Calcinosis

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions according to their local requirements.

·                 Saudi Arabia:

·                 Other GCC States

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 Section 4.4 and Section 4.8].

Mechanism of Action

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

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.

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.

Carcinogenesis and Mutagenesis

Carcinogenicity, and mutagenicity have not been assessed with Calcium Chloride Injection.

Carbon activated or Charcoal activated

Water for injection

May contain hydrochloric acid and/or sodium hydroxide for pH adjustment.

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 Section 4.4]

·            In neonates (28 days of age or younger), concomitant use of Calcium Chloride Injection and ceftriaxone is contraindicated [see Section 4.3].

·            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.

Store at 20 to 25°C.

Calcium Chloride Injection is supplied in single-dose syringes.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.