FDA label 308e0113-aeb5-2471-e063-6294a90ad4ef

WARNINGS AND PRECAUTIONS 2.1 Hypocalcemia REGIOCIT solution contains no calcium, and may lead to systemic ionized hypocalcemia due to loss of calcium bound to citrate in the effluent and/or in the case of systemic citrate accumulation. Calcium reinfusion is required during use of REGIOCIT and blood calcium concentrations (ionized and total) must be monitored. 2.3 Hypomagnesemia REGIOCIT solution contains no magnesium. Use of the REGIOCIT solution may result in hypomagnesemia due to CRRT effluent losses. Magnesium levels must be monitored as infusion of magnesium may be necessary. 2.4 Hypoglycemia REGIOCIT solution contains no dextrose. Administration of REGIOCIT solution may lead to hypoglycemia. Blood glucose levels must be monitored regularly. 2.5 Hypokalemia REGIOCIT solution contains no potassium. The serum potassium concentration must be monitored before and during CRRT. 2.6 Metabolic Alkalosis REGIOCIT solution contains citrate, which contributes to the overall buffer load. Metabolization of 1 mol of citrate generates 3 mol of bicarbonate. Additional sodium bicarbonate (or buffer source) contained in the CRRT fluids or in other fluids administered during therapy may increase the risk of metabolic alkalosis. Metabolic alkalosis may occur if the net citrate administration rate exceeds that which is necessary to maintain acid–base balance. If metabolic alkalosis occurs, decrease the citrate dose, and/or increase the dialysate/replacement flow rate (when applicable) or change the composition of the CRRT solution. 2.7 Metabolic Acidosis Metabolic acidosis may occur if metabolic clearance of citrate by the liver or skeletal muscle is impaired. If citrate accumulation develops and/or metabolic acidosis develops or worsens during therapy with REGIOCIT solution, the infusion rate may need to be decreased or its administration stopped. 2.8 Use in Patients with Mild to Moderate Hepatic Impairment Metabolism of citrate (to bicarbonate) may be impaired in patients with hepatic impairment, resulting in accumulation of citrate. If REGIOCIT solution is administered to patients with mild to moderate hepatic impairment, frequent monitoring of pH, electrolytes, total-to-ionized calcium ratio, and systemic ionized calcium is important to avoid electrolyte and/or acid–base imbalance. 2.9 Hypoosmolarity/Hypotonicity REGIOCIT solution is hypoosmolar/hypotonic relative to standard CRRT replacement fluids and should be used with caution in patients with traumatic brain injury, cerebral edema, or increased intracranial pressure.

WARNINGS AND PRECAUTIONS There have been reports of system failure due to apparent operator error during administration of CRRT with REGIOCIT solution, leading to serious adverse events, including life-threatening hypocalcemia. Plasma electrolyte and acid-base parameters should be closely monitored during CRRT, and appropriate action taken if imbalances of electrolytes or acid-base balance are detected. Instructions for use of REGIOCIT and CRRT must be strictly followed. Cautionary statements are provided in WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hematologic, Hepatic / Biliary / Pancreatic, and Monitoring and Laboratory Tests, and in DRUG INTERACTIONS to avoid the following when performing the CRRT procedure: - Hypercalcemia - Hyponatremia - Fluid retention, dehydration - Nausea, vomiting - Muscle spasms Citrate Accumulation Special attention is required in patients with liver failure, including hepatic cirrhosis or acute hepatic failure, or in shock, since metabolism of citrate may be markedly reduced and patients may be thus exposed to citrate accumulation. In these circumstances, more frequent monitoring of citrate accumulation should be undertaken. With systemic citrate accumulation, metabolic acidosis and ionized hypocalcemia may ensue, and the ratio of total to ionized calcium in the blood rises. If total/ionized calcium ratio rises above 2.3, REGIOCIT infusion should be reduced or stopped. CRRT may then be continued without anticoagulation, or by using other means of anticoagulation. REGIOCIT is contraindicated in patients with severe hepatic impairment or in circulatory shock with muscle hypoperfusion (see CONTRAINDICATIONS ). Excessive infusion of citrate can lead to acute hypocalcemia and metabolic alkalosis, with neurologic and cardiac complications. Treatment consists of discontinuation of the citrate infusion and infusion of calcium. Endocrine and Metabolism Hypocalcemia REGIOCIT solution contains no calcium, and may lead to systemic ionized hypocalcemia, due to loss of calcium bound to citrate in the effluent and/or in the case of systemic citrate accumulation (see DOSAGE AND ADMINISTRATION , Administration ). Electrolyte and Acid–Base Balance REGIOCIT solution contains citrate, which can influence the patient’s electrolyte and acid–base balance. Plasma electrolyte and acid–base parameters should be closely monitored during CRRT. Closely monitor sodium, magnesium, potassium, phosphate, and calcium. Infusion of electrolytes may be needed to supplement any loss. Hypercalcemia Medicinal products containing calcium used for maintenance of calcium homeostasis in CRRT patients can increase the risk of hypercalcemia, and can result in a reduced anticoagulation effect. Care should be taken to avoid excessive titration in administering calcium as this can lead to hypercalcemia. Frequent monitoring of pH, electrolytes, total-to-ionized calcium ratio, and systemic ionized calcium is important to avoid electrolyte and/or acid-base imbalance. Hypomagnesemia REGIOCIT solution contains no magnesium. Use of the REGIOCIT solution may result in hypomagnesemia due to CRRT effluent losses (see DOSAGE AND ADMINISTRATION, Administration ). Hypoglycemia REGIOCIT solution contains no dextrose. Administration of REGIOCIT solution may lead to hypoglycemia. Blood glucose levels should be monitored regularly. Hypokalemia REGIOCIT solution contains no potassium. The serum potassium concentration must be monitored before and during CRRT. Metabolic Alkalosis REGIOCIT solution contains citrate, which contributes to the overall buffer load. Additional sodium bicarbonate (or buffer source) contained in the CRRT fluids or in other fluids administered during therapy may increase the risk of metabolic alkalosis. Metabolic alkalosis may occur if the net citrate administration rate exceeds that which is necessary to maintain acid–base balance. If metabolic alkalosis occurs, decrease the citrate dose, and/or increase the dialysate flow rate or change the composition of the CRRT solution. Blood calcium levels, pH and bicarbonate should be monitored regularly in patients with metabolic alkalosis since this condition may potentiate hypocalcemia. Metabolic Acidosis Metabolic acidosis may occur if metabolic clearance of citrate by the liver or skeletal muscle is impaired (see CONTRAINDICATIONS ). If citrate accumulation develops and/or metabolic acidosis develops or worsens during therapy with REGIOCIT, the infusion rate may need to be decreased or its administration stopped. Hypo-osmolarity/Hypotonicity REGIOCIT solution is hypo-osmolar/hypotonic relative to standard CRRT replacement fluids and should be used with caution in patients with traumatic brain injury, cerebral edema, or increased intracranial pressure. Instructions for use of REGIOCIT must be strictly followed. Incorrect use of the access ports or other restrictions to fluid flow may lead to incorrect patient weight loss and may result in machine alarms being set off. Continuing treatment without resolving the originating cause may lead to patient injury or death. Careful ongoing assessment is required of all solutions infused during REGIOCIT administration, whether related to CRRT dialysis fluids or to other solutions infused systemically. REGIOCIT has a physiological sodium level of 140 mmol/L. However, sodium losses occurring during CRRT must be balanced as part of overall fluid and electrolyte management to avoid a drop in blood sodium level leading to systemic hyponatremia. Hematologic Hemodynamic Status and Fluid Balance The patient’s hematocrit, hemodynamic status and fluid balance should be monitored throughout the procedure. - In case of hypervolemia, the net ultrafiltration rate prescribed for the CRRT device can be increased, and/or the rate of administration of solutions other than replacement fluid and/or dialysate can be reduced. - In case of hypovolemia, the net ultrafiltration rate prescribed for the CRRT device can be reduced, and/or the rate of administration of solutions other than replacement fluid and/or dialysate can be increased. Hepatic/Biliary/Pancreatic Use in Patients with Mild to Moderate Hepatic Impairment Systemic metabolism of citrate to bicarbonate may be impaired in patients with hepatic impairment, resulting in accumulation of citrate. If REGIOCIT solution is administered to patients with mild to moderate hepatic impairment, frequent monitoring of pH, electrolytes, total-to-ionized calcium ratio, and systemic ionized calcium is important to avoid electrolyte and/or acid–base imbalance (see CONTRAINDICATIONS ). Monitoring and Laboratory Tests Plasma electrolyte and acid–base parameters should be closely monitored during CRRT. Closely monitor sodium, magnesium, potassium, phosphate, calcium, blood glucose levels, hematocrit, hemodynamic status and fluid balance, pH, bicarbonate, total-to-ionized calcium ratio, and systemic ionized calcium. Infusion of electrolytes may be needed to supplement any loss. Special Populations Pregnant Women There are no adequate data from the use of REGIOCIT solution in pregnant women. Physicians should carefully consider the potential risks and benefits for each specific patient before administering REGIOCIT solution. Breast-feeding There are no adequate data from the use of REGIOCIT solution in lactating women. Physicians should carefully consider the potential risks and benefits for each specific patient before administering REGIOCIT solution. It is unknown if the drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised. Pediatrics Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. Geriatrics Geriatrics (> 65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is not associated with differences in safety or effectiveness. ADVERSE REACTIONS Adverse Reaction Overview The following adverse reactions represent those adverse reactions that are thought to have an association with the use of REGIOCIT solution or that may occur in conjunction with performing the CRRT procedure: Adverse reactions reported with other CRRT products include: - Hypotension - Hypocalcemia (due to excessive and uncorrected effect of citrate in the body) - Other electrolyte imbalances (hypomagnesemia, hypokalemia, hypophosphatemia) - Acid–base balance disorders (including metabolic alkalosis, metabolic acidosis) - Hypoglycemia - Fluid imbalance Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. In an open-label randomised study, 54 patients were administered RCA with an equimolar solution of citrate, sodium and chloride, as contained in REGIOCIT solution, and 49 received systemic anticoagulation with unfractionated heparin (UFH) while undergoing CRRT using continuous venovenous hemodiafiltration. Adverse events related to metabolic disorders occurred in 26% of patients in the RCA-treated group, compared to 28% of patients in the UFH-treated group. These adverse events were generally transient and reversible. Metabolic alkalosis was seen in 6% of patients treated with RCA, compared to none treated with UFH, and metabolic acidosis was reported in 6% and 2% of patients in the RCA and UFH groups, respectively. Six patients treated with RCA experienced severe hypocalcemia, compared to one patient treated with UFH. In a second hemodiafiltration trial which evaluated 19 patients randomised to an equimolar solution of citrate, sodium and chloride, as contained in REGIOCIT solution, and 11 patients randomised to UFH anticoagulation, Hypocalcemia requiring intervention was reported in 3 patients treated with RCA, with 2 of these patients requiring treatment interruption of RCA. Post-Market Adverse Reactions To date, adverse events reported in the post-marketing setting for REGIOCIT appear to be consistent with those listed above in Adverse Reaction Overview.