olization 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.

itrate 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.

placement fluid is not recommended, since the calcium provided by these solutions may counteract the anticoagulant effect of citrate in the circuit. 1.2 suggested dosing the rate at which regiocit solution is administered depends on the targeted citrate dose and the prescribed blood flow rate. the pre-filter infusion rate of regiocit solution is indexed to the blood flow rate to achieve a target blood citrate concentration of 3 mmol/l of blood (see table 1). flow rate for anticoagulation of the extracorporeal circuit should be titrated to achieve a post-filter concentration of ionized calcium in the range of 0.25 to 0.35 mmol/l. table 1: regiocit solution flow rates to achieve citrate dose of 3 mmol/l of blood prior to initiating therapy, the patient’s systemic ionized calcium concentration should be within the normal physiologic range (1.0 to 1.2 mmol/l) by adjustment of calcium supplementation. a separate infusion of calcium is always required during use of regiocit, due to loss in the effluent. calcium solution infusion is commenced at the rate of 4 mmol/h, when commencing therapy (see table 4). adjust or stop calcium infusion according to physician’s prescription when regiocit is stopped. citrate also acts as a buffer source (due to conversion to bicarbonate); the infusion rate of regiocit solution must be considered in relation to the rate at which buffer administration occurs from other sources (e.g., dialysate and/or replacement fluid). regiocit solution must be used together with a dialysis solution/replacement solution with appropriate bicarbonate concentration. table 1 1.3 laboratory monitoring monitoring of the post-filter blood ionized calcium (ica), systemic blood ica, and total blood calcium levels in conjunction with other laboratory and clinical parameters such as acid-base balance and serum electrolytes are essential to guide appropriate regiocit solution dosage based on the desired level of anticoagulation. levels should be taken at baseline, 1 hour after initiation (or adjustment), and every 6 hours (see table 2). rapidly decreasing systemic ionized calcium levels are an early indicator of citrate accumulation. measurement of total calcium and assessment of total-to-ionized calcium ratio is necessary. citrate accumulation causes systemic ionized calcium levels to drop and the ratio of total-to-ionized calcium increases (total-to-ionized calcium ratio > 2.5). in the presence of impaired citrate metabolism, a progressively higher calcium infusion rate is required to maintain the systemic ionized calcium concentration within the intended target. when a total-to-ionized-calcium ratio > 2.5 is recorded, any one of the following abnormalities reported concurrently increases the likelihood of citrate accumulation: o a rapid decline in systemic ica concentration despite adequate calcium compensation o a rapid decrease in ph or a decrease in base excess o a rapid increase in anion gap in order to avoid metabolic alkalosis, acid-base balance and systemic ionized calcium can be measured using blood gas analysis. if metabolic alkalosis or citrate accumulation is suspected, decrease the citrate dose while tolerating a post-filter ionized calcium of < 0.5 mmol/l. this can be achieved by either decreasing the blood flow rate to decrease the overall citrate load, increasing the dialysate/replacement flow rate (when applicable) to increase the citrate removal, or decreasing the citrate flow to decrease the citrate dose. dialysate solutions contain bicarbonate below or above physiological range of 22 to 26 mmol/l, and increasing or decreasing the flow rates of the dialysate solutions can impact the acid-base status of the patient. plasma levels of sodium, magnesium, potassium, and glucose, and phosphate should be monitored regularly and should be supplemented as needed. table 2 provides a summary of the most important parameters to be monitored during rca therapy, as well as options for adjustment. table 2: monitoring and adjustment during rca therapy table 3 provides the regiocit solution flow rate adjustment based on a citrate dose adjustment of 0.5 mmol/l. table 3: regiocit solution flowrate adjustment based on a citrate dose adjustment of 0.5 mmol/l table 4 provides recommendations to maintain a systemic ionized calcium level between 1.0 mmol/l and 1.2 mmol/l. table 4: sliding scale of calcium infusion table 2 1 of 2 table 2 2 of 2 table 3 table 4

an appropriate bicarbonate concentration. • dose reduction may be needed in patients with mild to moderate hepatic impairment. in these patients, more frequent monitoring of citrate accumulation is advised. regiocit solution should not be administered to patients with reduced liver and muscle perfusion, e.g., during conditions such as septic shock and lactic acidosis, or in patients with severe hepatic impairment, due to limited citrate metabolism (see contraindications). • a separate systemic infusion of calcium is always required to prevent or treat hypocalcemia. adjust calcium infusion depending on measured serum total-to-ionized calcium ratio and ionized calcium levels, to maintain values in the physiologic range. adjust or stop calcium infusion according to the direction of the attending physician when regiocit solution has been stopped. • magnesium may need to be supplemented intravenously, based on systemic serum magnesium levels. recommended dose and dosage adjustment the rate at which regiocit solution is administered depends on the targeted citrate dose and the prescribed blood flow rate (bfr). the prescription of the product must consider the flow rates of the effluent and other therapeutic fluids, the patient’s fluid removal requirements, additional fluid inputs and outputs, and the desired acid-base and electrolyte balance. regiocit solution should be prescribed and its administration (dose, infusion rate, and cumulative volume) established only by critical care or nephrology physicians experienced in administration of crrt. the pre-filter infusion rate of regiocit solution (based on its concentration) is indexed to the blood flow rate to achieve a target blood citrate concentration of 3 to 4 mmol/l in the blood. flow rate for anticoagulation of the extracorporeal circuit should be titrated to achieve a post-filter concentration of ionized calcium in the range 0.25 to 0.35 mmol/l. the patient’s systemic ionized calcium concentration should be maintained in the normal physiologic range by adjustment of calcium supplementation. administration monitoring of the post-filter blood ionized calcium (ica), systemic blood ica, and total blood calcium levels in conjunction with other laboratory and clinical parameters is essential to guide appropriate regiocit solution dosage based on the desired level of anticoagulation (see warnings and precautions). plasma levels of sodium, magnesium, potassium, and phosphate should also be monitored regularly and these electrolytes supplemented as needed. regiocit solution may be warmed to 37°c to enhance patient comfort. warming of the product prior to use should be done with dry heat only. solution should not be heated in water or in a microwave oven due to the potential for patient injury or discomfort. regiocit solution should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. do not administer unless the solution is clear and the seal is intact.

’s blood, but also prevents any depletion of the patient’s calcium stores which may result from the loss of calcium (bound to citrate) in the crrt effluent fluid. pharmacodynamics citrate provides anticoagulation by its ability to form complexes with ionized calcium, making it unavailable to the clotting cascade. in regiocit, sodium concentration has been set to 140 mmol/l as critically ill patients may develop severe hyponatremia. chloride is set to the level required to balance cations as the solution is hydrogen carbonate free. sodium and chloride are normal constituents of the human body and are considered to be pharmacologically inactive. citrate is a normal metabolite in the human body that acts as a first intermediate substance in the krebs cycle. regiocit does not contain potassium or glucose. two studies provide information on the dose/response relationship between citrate concentration and anticoagulation. in one study, ex-vivo anticoagulation with anticoagulant citrate dextrose formula a (acd-a) in blood collected from six healthy volunteers was studied. the study concluded that the clinically relevant effects of citrate anticoagulation rely solely on the disturbed formation of the calcium-dependent coagulation factors complexes. in this study, the anticoagulation effects of citrate were monitored either by methods that quantify clot formation (i.e., activated clotting time) or by direct assessment of ionized calcium levels. the correlation between concentrations of ionized calcium and clotting times revealed almost no anticoagulant effect when ionized calcium levels were up to or above 0.50 mmol/l, while clotting times showed a steep increase when calcium levels were decreased below 0.50 mmol/l. with respect to maximum effect, 5.65 mmol/l citrate induced clotting times of infinity in all samples. pharmacokinetics citrate is a normal metabolite in the human body and an intermediate substance in the krebs cycle. this physiological pathway is capable of processing high amounts of citric acid as long as it occurs at low concentrations. the krebs cycle takes place in the mitochondria, and all cells that contain these cellular organelles can metabolize citrate. tissues rich in mitochondria such as liver, skeletal muscles, and kidney therefore have a higher capacity for citrate generation and elimination. absorption: absorption of sodium and chloride is determined by the patient’s clinical condition, metabolic status, and residual renal function. distribution: extracellular citrate can be transported from the blood across the plasma membrane by a group of proteins i.e. the plasma membrane citrate transporters (pmcts) into the cells and then metabolized in various organs and tissues. metabolism: citrate is an intermediate in the central metabolic pathway called krebs cycle as mentioned above. citrate is rapidly metabolized mainly in the liver, but can also be metabolized by other organs/tissues. elimination: any excess of circulating citrate is normally excreted via the kidneys. special populations and conditions hepatic insufficiency: when treating decompensated cirrhosis patients, one should also consider: • impairment of citrate metabolism due to failure of microcirculation and oxidative metabolism (lactic acidosis and/or shock), • impaired muscular utilization of citrate (cachexia, high doses of vasopressors), • citrate load associated with blood products.