SODIUM: 23,383 Adverse Event Reports & Safety Profile

DESCRIPTION Sodium Chloride Injection, USP solutions are sterile and nonpyrogenic. They are parenteral solutions containing various concentrations of sodium chloride in water for injection intended for intravenous administration after admixing with an ADD-Vantage vial, or single-dose powdered drug vials with 20 mm closure using the ADD-Vantage ADDAPTOR™ (WARNING: DO NOT USE WITH CHEMOTHERAPY AGENTS) .

Each

100 mL of 0.45% Sodium Chloride Injection, USP contains 450 mg sodium chloride in water for injection. Electrolytes per 1000 mL: sodium 77 mEq; chloride 77 mEq. The osmolarity is 154 mOsmol/L (calc.), which is hypotonic.

Each

100 mL of 0.9% Sodium Chloride Injection, USP contains 900 mg sodium chloride in water for injection. Electrolytes per 1000 mL: sodium 154 mEq; chloride 154 mEq. The osmolarity is 308 mOsmol/L (calc.), which is isotonic. The pH for both concentrations is 5.6 (4.5 to 7.0). The solutions contain no bacteriostat, antimicrobial agent or added buffer and each is intended only as a single-dose injection. When smaller doses are required the unused portion should be discarded. The solutions are parenteral fluid and electrolyte replenishers.

Sodium

Chloride, USP is chemically designated NaCl, a white crystalline powder freely soluble in water. Water for Injection, USP is chemically designated H 2 O. The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period.

Rx only For use with the AMICUS Separator only . Store at Controlled Room Temperature. Protect from freezing. Avoid excessive heat. Definition of "Controlled Room Temperature": "A temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15°C and 30°C (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses. Provided the mean kinetic temperature remains in the allowed range, transient spikes up to 40°C are permitted as long as they do not exceed 24 hours ... The mean kinetic temperature is a calculated value that may be used as an isothermal storage temperature that simulates the non isothermal effects of storage temperature variations." Reference: United States Pharmacopeia, General Notices.

United States Pharmacopeial

Convention, Inc. 12601 Twinbrook Parkway, Rockville, MD. Dispose of waste in appropriate biohazard container or according to local regulatory requirements. Indications and Usage: InterSol solution is an isotonic solution designed to replace a proportion of the plasma used in the storage of AMICUS™-derived leukoreduced apheresis platelets under standard blood banking conditions. There is no direct therapeutic effect to be expected from the formulation. The solution should never be infused directly into a patient. InterSol platelets are leukocyte-reduced apheresis platelet concentrates that are stored in a mix of 65% InterSol and 35% plasma, nominal. InterSol platelets prepared within the range of Table 1 may be stored for up to 5 days at 20-24°C, with continuous agitation. table1

DOSAGE AND ADMINISTRATION

1.1 Administration Instructions Renal Replacement Solution: Not for direct intravenous infusion. The recommended effluent volume for patients receiving CRRT for acute kidney injury (AKI) is 20 to 25 mL/kg/h. This usually requires a higher prescription of effluent volume. The prescription of REGIOCIT solution 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. The mode of therapy, solute formulations, flow rates and length of therapy should be selected by the physician responsible for managing treatment depending on the clinical condition of the patient as well as the patient’s fluid, electrolyte, acid base and glucose balance. Dialysate and replacement fluid formulations and flow rates are prescribed in accordance with the patient’s clinical needs. The use of a calcium-containing dialysate or replacement 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: A rapid decline in systemic iCa concentration despite adequate calcium compensation A rapid decrease in pH or a decrease in base excess 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

DOSAGE AND ADMINISTRATION For Extracorporeal use only. Not for direct intravenous infusion. REGIOCIT solution is used as a renal replacement solution. The product has an osmolarity of 244 mOsm/L and a pH of approximately 7.4.

Dosing Considerations

Dosing considerations of the drug: REGIOCIT solution should not be used for direct intravenous infusion. The product must be used in pre-dilution mode only, with appropriate extracorporeal renal replacement equipment intended for CRRT, using an integrated pre-blood pump for RCA. In addition to providing anticoagulation to the extracorporeal circuit and hemofilters, citrate also acts as a buffer source due to its metabolic conversion to bicarbonate systemically. Thus, the infusion rate of REGIOCIT solution to be administered should take into account the rate at which buffer administration occurs from other sources, e.g., dialysate and/or replacement fluid. The product must be used together with a dialysis/replacement solution at 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.

CONTRAINDICATIONS Contraindications for the use of REGIOCIT include: Severe liver failure Shock with muscle hypoperfusion Known hypersensitivity to any component of REGIOCIT Adverse Event Reporting Report adverse events or quality problems experienced with the use of this product. Healthcare facilities and prescribing health care providers or their designee receiving REGIOCIT will track all medication errors associated with the use of and all serious adverse events that are considered to be potentially attributable to REGIOCIT use and must report these to FDA using one of the following methods: Complete and submit a MedWatch form online ( www.fda.gov/medwatch/report.htm ) Complete and submit FDA Form 3500 (health professional) by fax (1-800-FDA-0178) (this form can be found via link above).

Call

1-800-FDA-1088 for questions. Submitted reports should state, “use of REGIOCIT was under an EUA” at the beginning of the question “Describe Event” for further analysis.

Contact Baxter Healthcare

Corporation at 1-866-888-2472 or [email protected] What is an EUA? The United States FDA has made REGIOCIT available to treat patients in an ICU during the COVID-19 pandemic under an emergency access mechanism called an Emergency Use Authorization (EUA). The EUA is supported by a Secretary of Health and Human Service (HHS) declaration that circumstances exist to justify the emergency use of drugs and biological products during the COVID-19 pandemic. REGIOCIT made available under an EUA have not undergone the same type of review as an FDA-approved product. FDA may issue an EUA when certain criteria are met, which includes that there are no adequate, approved, available alternatives. In addition, the FDA decision is based on the totality of scientific evidence available showing that it is reasonable to believe that REGIOCIT may be effective for use as a replacement solution in adult patients treated with Continuous Renal Replacement Therapy (CRRT) and requiring regional citrate anticoagulation (RCA) of the extracorporeal circuit in an ICU setting during the Coronavirus Disease 2019 (COVID-19) pandemic, and that the known and potential benefits of REGIOCIT for such use outweigh the known and potential risks of REGIOCIT. This EUA for REGIOCIT is in effect for the duration of the COVID-19 declaration justifying emergency use of the products, unless terminated or revoked (after which the products may no longer be needed). The EUA will end when the declaration is terminated or revoked or when there is a change in the approval status of the product such that an EUA is no longer needed. This communication and product information is available on Baxter Healthcare’s website: To access COVID-19 Resources, product details, product use information, and the comprehensive Prismaflex Control Unit Operator’s Manual and PrisMax Control Unit Operator’s Manual please visit the Baxter Healthcare Acute Therapies website at http://www.renalacute.com FDA’s webpage also includes links to patient fact sheet and manufacturer’s instructions https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#covidtherapeutics .

CONTRAINDICATIONS REGIOCIT solution is contraindicated in: patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Dosage Forms, Strengths, Composition and Packaging. severe liver failure shock with muscle hypoperfusion

REACTIONS The most frequently reported adverse reactions (incidence ≥ 6%) are vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals USA Inc. Pennington, NJ 08534 at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data were obtained from 316 patients who received Sodium Phenylacetate and Sodium Benzoate Injection as emergency (rescue) or prospective treatment for hyperammonemia as part of an uncontrolled, open-label study. The study population included patients between the ages of 0 to 53 years with a mean (SD) of 6.2 (8.54) years; 51% were male and 49% were female who had the following diagnoses: OTC (46%), ASS (22%), CPS (12%), ASL (2%), ARG (<1%), THN (<1%), and other (18%). Adverse reactions were reported with similar frequency in patients with OTC, ASS, CPS, and diagnoses categorized as "other." Nervous system disorders were more frequent in patients with OTC and CPS, compared with patients with ASS and patients with "other" diagnoses. Convulsions and mental impairment were reported in patients with OTC and CPS. These observations are consistent with literature reports that patients with enzyme deficiencies occurring earlier in the urea cycle (i.e., OTC and CPS) tend to be more severely affected. Adverse reactions profiles differed by age group. Patients ≤30 days of age had more blood and lymphatic system disorders and vascular disorders (specifically hypotension), while patients > 30 days of age had more gastrointestinal disorders (specifically nausea, vomiting and diarrhea). Less common adverse reactions (<3% of patients) that are characterized as severe are listed below by body system. BLOOD AND LYMPHATIC SYSTEM DISORDERS: coagulopathy, pancytopenia, thrombocytopenia. CARDIAC DISORDERS: atrial rupture, bradycardia, cardiac or cardiopulmonary arrest/failure, cardiogenic shock, cardiomyopathy, pericardial effusion. EYE DISORDERS: blindness. GASTROINTESTINAL DISORDERS: abdominal distension, gastrointestinal hemorrhage. GENERAL DISORDERS AND ADMINISTRATION-SITE CONDITIONS: asthenia, brain death, chest pain, multiorgan failure, edema. HEPATOBILIARY DISORDERS: cholestasis, hepatic artery stenosis, hepatic failure/hepatotoxicity, jaundice. INFECTIONS AND INFESTATIONS: sepsis/septic shock. INJURY, POISONING AND PROCEDURAL COMPLICATIONS: brain herniation, subdural hematoma, overdose. INVESTIGATIONS: blood carbon dioxide changes, blood glucose changes, blood pH increased, cardiac output decreased, pCO 2 changes, respiratory rate increased. METABOLISM AND NUTRITION DISORDERS: alkalosis, dehydration, fluid overload/retention, hypoglycemia, hyperkalemia, hypernatremia, alkalosis, tetany. NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED: hemangioma acquired. NERVOUS SYSTEM DISORDERS: areflexia, ataxia, brain infarction, brain hemorrhage, cerebral atrophy, clonus, depressed level of consciousness, encephalopathy, nerve paralysis, intracranial pressure increased, subdural hematoma, tremor. PSYCHIATRIC DISORDERS: acute psychosis, aggression, confusional state, hallucinations. RENAL AND URINARY DISORDERS: anuria, renal failure, urinary retention. RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: acute respiratory distress syndrome, dyspnea, hypercapnia, hyperventilation, Kussmaul respiration, pneumonia aspiration, pneumothorax, pulmonary hemorrhage, pulmonary edema, respiratory acidosis or alkalosis, respiratory arrest/failure. SKIN AND SUBCUTANEOUS TISSUE DISORDERS: alopecia, blister, pruritus generalized, rash, urticarial. VASCULAR DISORDERS: flushing, hemorrhage, hypertension, phlebothrombosis/thrombosis.

Table

2 : Adverse Reactions Occurring in ≥3% of Patients Treated with Sodium Phenylacetate and Sodium Benzoate Injection Patients N=316 Number of patients with any adverse event 163 (52%) Blood and lymphatic system disorders 35 (11%)

Anemia

12 (4%) Disseminated intravascular coagulation 11 (3%) Cardiac disorders 28 (9%) Gastrointestinal disorders 42 (13%)

Diarrhea

10 (3%)

Nausea

9 (3%)

Vomiting

29 (9%) General disorders and administration-site conditions 45 (14%) Injection-site reaction 11 (3%)

Pyrexia

17 (5%)

Infections

39 (12%) Urinary tract infection 9 (3%) Injury, poisoning and procedural complications 12 (4%)

Investigations

32 (10%) Metabolism and nutrition disorders 67 (21%)

Acidosis

8 (3%)

Hyperammonemia

17 (5%)

Hyperglycemia

22 (7%)

Hypocalcemia

8 (3%)

Hypokalemia

23 (7%) Metabolic acidosis 13 (4%) Nervous system disorders 71 (22%) Brain edema 17 (5%)

Coma

10 (3%)

Convulsions

19 (6%) Mental impairment 18 (6%) Psychiatric disorders 16 (5%)

Agitation

8 (3%) Renal and urinary disorders 14 (4%) Respiratory, thoracic and mediastinal disorders 47 (15%) Respiratory distress 9 (3%) Skin and subcutaneous tissue disorders 19 (6%) Vascular disorders 19 (6%)

Hypotension

14 (4%)

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.

PRECAUTIONS: General Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers.

Laboratory Tests

Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation.

Drug Interactions

Caution must be exercised in the administration of 0.45% Sodium chloride injection to patients receiving corticosteroids or corticotropin. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies have not been performed with 0.45% Sodium chloride injection to evaluate the potential for carcinogenesis, mutagenesis or impairment of fertility.

Pregnancy Teratogenic Effects Pregnancy

Category C Animal reproduction studies have not been conducted with 0.45% Sodium chloride injection. It is also not known whether 0.45% Sodium chloride injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 0.45% Sodium chloride injection should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of 0.45% Sodium chloride injection on labor and delivery. Caution should be exercised when administering this drug during labor and delivery.

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when 0.45% Sodium chloride injection is administered to a nursing mother.

Pediatric Use

The use of 0.45% Sodium chloride injection in pediatric patients is based on clinical practice. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. The infusion of hypotonic fluids (0.45% Sodium chloride injection) together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency.

Geriatric Use

Clinical studies of 0.45% Sodium chloride injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Carcinogenesis, Mutagenesis, Impairment of Fertility Studies have not been performed with 0.45% Sodium chloride injection to evaluate the potential for carcinogenesis, mutagenesis or impairment of fertility.

Pregnancy Teratogenic Effects Pregnancy

Category C Animal reproduction studies have not been conducted with 0.45% Sodium chloride injection. It is also not known whether 0.45% Sodium chloride injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 0.45% Sodium chloride injection should be given to a pregnant woman only if clearly needed.

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when 0.45% Sodium chloride injection is administered to a nursing mother.

Pediatric Use

The use of 0.45% Sodium chloride injection in pediatric patients is based on clinical practice. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. The infusion of hypotonic fluids (0.45% Sodium chloride injection) together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency.

DRUG INTERACTIONS Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies have not been performed with Sodium Chloride Injection, USP to evaluate the potential for carcinogenesis, mutagenesis or impairment of fertility. Pregnancy: Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with Sodium Chloride Injection, USP. It is also not known whether Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

Sodium Chloride

Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery.

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a nursing mother.

Pediatric Use

The use of Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. The infusion of hypotonic fluids (0.45% Sodium Chloride Injection, USP) together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency.

Geriatric Use

Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Active ingredient (in each spray)

Purpose Natrum Muriaticum

6X HPUS excessive moisture, nasal discharge,watery eyes, dryness of the lips, skin or eyes “ HPUS ” is the Homeopathic Pharmacopoeia of the United States

Inactive ingredients benzyl alcohol, cocamidopropyl betaine, disodium EDTA, fragrances, polyquaternium 10, purified water, sodium lauryl sulfate, tea tree oil

Inactive Ingredients aminomethyl propanol, anise oil, carbomer, cocamidopropyl betaine, fragrance, PEG-6 caprylic/capric glycerides, purified water