MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Endogenous cysteine is synthesized from methionine by the enzyme, cystathionase, via the trans-sulfuration pathway, andserves as precursor substrate for both glutathione and taurine. ELCYS provides cysteine to the systemic circulation ofpatients who require PN and cannot synthesize adequate quantities of cysteine due to insufficient or deficientcystathionase activity.

OVERDOSAGE SECTION.

10 OVERDOSAGE In the event of over hydration or solute overload, re-evaluate the patient and institute appropriate corrective measures [see Warnings and Precautions (5.3, 5.4, 5.5, 5.7, 5.8)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL-Vial Label Rx Only NDC 51754-1007-1ELCYS(Cysteine HydrochlorideInjection), USP500 mg/10 mL (50 mg/mL)Must Be DilutedFor Intravenous Use Only After Dilution10 mL Single Dose Sterile Vial-Discard Unused Portion. Vial Label.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information:oPulmonary embolism due to pulmonary vascular precipitates [see Warnings and Precautions (5.1)]oVein damage and thrombosis [see Warnings and Precautions (5.2)]oIncreased BUN [see Warnings and Precautions (5.3)]oAcid-base imbalance [see Warnings and Precautions (5.4)]oHepatobiliary disorders [see Warnings and Precautions (5.5)]oHyperammonemia [see Warnings and Precautions (5.6)]oAluminum toxicity [see Warnings and Precautions (5.7)]Adverse reactions with the use of cysteine hydrochloride injection were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.oLocal infusion site reactions, including warm sensation, erythema, phlebitis and thrombosis at the infusion siteoGeneralized flushing, fever and nausea. oPulmonary embolism due to pulmonary vascular precipitates [see Warnings and Precautions (5.1)]. oVein damage and thrombosis [see Warnings and Precautions (5.2)]. oIncreased BUN [see Warnings and Precautions (5.3)]. oAcid-base imbalance [see Warnings and Precautions (5.4)]. oHepatobiliary disorders [see Warnings and Precautions (5.5)]. oHyperammonemia [see Warnings and Precautions (5.6)]. oAluminum toxicity [see Warnings and Precautions (5.7)]. oLocal infusion site reactions, including warm sensation, erythema, phlebitis and thrombosis at the infusion site. oGeneralized flushing, fever and nausea. Most common adverse reactions are local reactions (warm sensation, erythema, phlebitis and thrombosis at the infusion site), generalized flushing, fever and nausea (6).To report SUSPECTED ADVERSE REACTIONS, contact Exela Pharma Sciences, LLC or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Endogenous cysteine is synthesized from methionine by the enzyme, cystathionase, via the trans-sulfuration pathway, andserves as precursor substrate for both glutathione and taurine. ELCYS provides cysteine to the systemic circulation ofpatients who require PN and cannot synthesize adequate quantities of cysteine due to insufficient or deficientcystathionase activity.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS ELCYS is contraindicated in:oPatients with known hypersensitivity to one or more amino acids.oPatients with inborn errors of amino acid metabolism due to risk of severe metabolic or neurologic complications.oPatients with pulmonary edema or acidosis due to low cardiac output.. oPatients with known hypersensitivity to one or more amino acids.. oPatients with inborn errors of amino acid metabolism due to risk of severe metabolic or neurologic complications.. oPatients with pulmonary edema or acidosis due to low cardiac output.. oHypersensitivity to one or more amino acids (4)oInborn errors of amino acid metabolism (4)oPulmonary edema or acidosis due to low cardiac output (4). oHypersensitivity to one or more amino acids (4). oInborn errors of amino acid metabolism (4). oPulmonary edema or acidosis due to low cardiac output (4).

DESCRIPTION SECTION.

11 DESCRIPTION ELCYS (cysteine hydrochloride injection) is sterile, nonpyrogenic solution for intravenous use. Each 10 mL of ELCYScontains 500 mg of cysteine hydrochloride, USP (equivalent to 345 mg of cysteine) in water for injection. Sodiumhydroxide and/or hydrochloric acid are used as needed to adjust the pH. The pH range is 1.0 to 2.5.The active ingredient is cysteine hydrochloride. Cysteine is sulfur-containing amino acid. The chemical name ofcysteine hydrochloride is L-cysteine hydrochloride monohydrate and is chemically designated as C3H7NO2S HCI H2Ohaving molecular weight of 175.63. Cysteine hydrochloride is white crystalline powder soluble in water. Cysteineaqueous solution is prone to oxidation when exposed to air, and when mixed with amino acids solutions, cysteine mayconvert to insoluble cystine which leads to precipitation over time. It has the following structural formula:ELCYS contains no more than 120 mcg/L of aluminum.. Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oELCYS is for admixing use only. Not for direct intravenous infusion. (2.1)oSee full prescribing information for information on preparation, administration, instructions for use, dosing considerations, including the recommended dosage in pediatric patients and adults. (2.1, 2.2, 2.3, 2.4, 2.5). oELCYS is for admixing use only. Not for direct intravenous infusion. (2.1). oSee full prescribing information for information on preparation, administration, instructions for use, dosing considerations, including the recommended dosage in pediatric patients and adults. (2.1, 2.2, 2.3, 2.4, 2.5). 2.1 Important Administration Information ELCYS is for admixing use only. It is not for direct intravenous infusion. Prior to administration, ELCYS must be diluted and used as an admixture in parenteral nutrition (PN) solutions.The resulting solution is for intravenous infusion into central or peripheral vein. The choice of central or peripheralvenous route should depend on the osmolarity of the final infusate. Solutions with osmolarity of 900 mOsm/L or greatermust be infused through central catheter [see Warnings and Precautions (5.2)].. 2.2 Preparation and Administration Instructions oELCYS is not for direct intravenous infusion. Prior to administration, ELCYS must be diluted and used as anadmixture in PN solutions.oELCYS is to be prepared only in suitable work area such as laminar flow hood (or an equivalent clean air compounding area). The key factor in the preparation is careful aseptic technique to avoid inadvertent touch contamination during mixing of solutions and addition of other nutrients.oELCYS is for addition to amino acid solutions prior to further admixing with dextrose injection using PN container.oUse dedicated line for PN solutions.oIntravenous lipid emulsions can be infused concurrently into the same vein as ELCYS containing amino acid and dextrose solutions by Y-connector located near the infusion site; flow rates of each solution should be controlled separately by infusion pumps.oFor administration without lipid emulsion, use 0.22 micron in-line filter.oTo prevent air embolism, use non-vented infusion set or close the vent on vented set, avoid multiple connections, do not connect flexible containers in series, fully evacuate residual gas in the container prior to administration, do not pressurize the flexible container to increase flow rates, and if administration is controlled by pumping device, turn off pump before the container runs dry.oIf infused with lipid emulsion, do not use administration sets and lines that contain di-2-ethylhexyl phthalate (DEHP). Administration sets that contain polyvinyl chloride (PVC) components have DEHP as plasticizer.oVisually inspect the diluted PN solution containing ELCYS for particulate matter before admixing, after admixing, and prior to administration. The solution should be clear and there should be no precipitates. slight yellow color does not alter the quality and efficacy of this product.. oELCYS is not for direct intravenous infusion. Prior to administration, ELCYS must be diluted and used as anadmixture in PN solutions.. oELCYS is to be prepared only in suitable work area such as laminar flow hood (or an equivalent clean air compounding area). The key factor in the preparation is careful aseptic technique to avoid inadvertent touch contamination during mixing of solutions and addition of other nutrients.. oELCYS is for addition to amino acid solutions prior to further admixing with dextrose injection using PN container.. oUse dedicated line for PN solutions.. oIntravenous lipid emulsions can be infused concurrently into the same vein as ELCYS containing amino acid and dextrose solutions by Y-connector located near the infusion site; flow rates of each solution should be controlled separately by infusion pumps.. oFor administration without lipid emulsion, use 0.22 micron in-line filter.. oTo prevent air embolism, use non-vented infusion set or close the vent on vented set, avoid multiple connections, do not connect flexible containers in series, fully evacuate residual gas in the container prior to administration, do not pressurize the flexible container to increase flow rates, and if administration is controlled by pumping device, turn off pump before the container runs dry.. oIf infused with lipid emulsion, do not use administration sets and lines that contain di-2-ethylhexyl phthalate (DEHP). Administration sets that contain polyvinyl chloride (PVC) components have DEHP as plasticizer.. oVisually inspect the diluted PN solution containing ELCYS for particulate matter before admixing, after admixing, and prior to administration. The solution should be clear and there should be no precipitates. slight yellow color does not alter the quality and efficacy of this product.. 2.3 Preparation Instructions for Admixing Using Parenteral Nutrition (PN) Container oRemove ELCYS vial from the carton and inspect for particulate matter.oTransfer the required amount of ELCYS to an amino acid solution using strict aseptic techniques to avoid microbial contamination.oThe amino acid solution containing ELCYS can then be used to prepare admixtures in the PN container using strict aseptic techniques.oAmino acids solution containing ELCYS may be mixed with dextrose injection. The following proper mixing sequence must be followed to minimize pH related problems:oTransfer dextrose injection to the parental nutrition pooling containeroTransfer phosphate saltoTransfer ELCYS-containing amino acid solutionoTransfer electrolytesoTransfer trace elementsoUse gentle agitation during admixing to minimize localized concentration effects; shake containers gently after each addition.oFor automated compounding, refer to Instructions for Use of the applicable compounder.oBecause additives may be incompatible, evaluate all additions to the PN container for compatibility and stability of the resulting preparation. Consult with pharmacist, if available. Questions about compatibility may be directed to Exela Pharma Sciences, LLC. If it is deemed advisable to introduce additives to the PN container, use aseptic technique.oInspect the final PN solution containing ELCYS to ensure that precipitates have not formed during mixing or addition on additives. Discard if any precipitates are observed.Stability and StorageoFor single use only. Discard used container of ELCYS.oUse of ELCYS for admixing should be limited to up to hours at room temperature (25oC/77oF) after the container closure has been penetrated. Discard any remaining drug.oUse PN solution containing ELCYS promptly after mixing. Any storage of the admixture should be under refrigeration and limited to brief period of time, no longer than 24 hours. After removal from refrigeration, use promptly and complete the infusion within 24 hours. Discard any remaining admixture.oProtect PN solution from light.. oRemove ELCYS vial from the carton and inspect for particulate matter.. oTransfer the required amount of ELCYS to an amino acid solution using strict aseptic techniques to avoid microbial contamination.. oThe amino acid solution containing ELCYS can then be used to prepare admixtures in the PN container using strict aseptic techniques.. oAmino acids solution containing ELCYS may be mixed with dextrose injection. The following proper mixing sequence must be followed to minimize pH related problems:. oTransfer dextrose injection to the parental nutrition pooling container. oTransfer phosphate salt. oTransfer ELCYS-containing amino acid solution. oTransfer electrolytes. oTransfer trace elements. oUse gentle agitation during admixing to minimize localized concentration effects; shake containers gently after each addition.. oFor automated compounding, refer to Instructions for Use of the applicable compounder.. oBecause additives may be incompatible, evaluate all additions to the PN container for compatibility and stability of the resulting preparation. Consult with pharmacist, if available. Questions about compatibility may be directed to Exela Pharma Sciences, LLC. If it is deemed advisable to introduce additives to the PN container, use aseptic technique.. oInspect the final PN solution containing ELCYS to ensure that precipitates have not formed during mixing or addition on additives. Discard if any precipitates are observed.. oFor single use only. Discard used container of ELCYS.. oUse of ELCYS for admixing should be limited to up to hours at room temperature (25oC/77oF) after the container closure has been penetrated. Discard any remaining drug.. oUse PN solution containing ELCYS promptly after mixing. Any storage of the admixture should be under refrigeration and limited to brief period of time, no longer than 24 hours. After removal from refrigeration, use promptly and complete the infusion within 24 hours. Discard any remaining admixture.. oProtect PN solution from light.. 2.4 Dosing Considerations oThe dosage of the final PN solution containing ELCYS must be based on the concentrations of all components in the solution and the recommended nutritional requirements [see Dosage and Administration (2.5)]. Consult the prescribing information of all added components to determine the recommended nutritional requirements for dextrose and lipid emulsion, as applicable.oThe dosage of ELCYS should be individualized based on the patients clinical condition (ability to adequately metabolize amino acids), body weight and nutritional/fluid requirements, as well as additional energy given orally/enterally to the patient. Prior to initiating parenteral nutrition, the following patient information should be reviewed: review of all medications, gastrointestinal function and laboratory data (such as electrolytes (including magnesium, calcium, and phosphorus), glucose, urea/creatinine, liver panel, complete blood count and triglyceride level (if adding lipid emulsion).oPrior to administration of PN solution containing ELCYS, correct severe fluid, electrolyte and acid-base disorders.. oThe dosage of the final PN solution containing ELCYS must be based on the concentrations of all components in the solution and the recommended nutritional requirements [see Dosage and Administration (2.5)]. Consult the prescribing information of all added components to determine the recommended nutritional requirements for dextrose and lipid emulsion, as applicable.. oThe dosage of ELCYS should be individualized based on the patients clinical condition (ability to adequately metabolize amino acids), body weight and nutritional/fluid requirements, as well as additional energy given orally/enterally to the patient. Prior to initiating parenteral nutrition, the following patient information should be reviewed: review of all medications, gastrointestinal function and laboratory data (such as electrolytes (including magnesium, calcium, and phosphorus), glucose, urea/creatinine, liver panel, complete blood count and triglyceride level (if adding lipid emulsion).. oPrior to administration of PN solution containing ELCYS, correct severe fluid, electrolyte and acid-base disorders.. 2.5 Recommended Dosage in Pediatric Patients and Adults The recommended dosage and volume of ELCYS is shown in Table and is based upon the recommended daily protein(amino acids) requirement. For pediatric patients from birth to less than 12 years of age, the recommended dosage ofELCYS is 22 mg/gram of amino acids. For adults and pediatric patients 12 years of age and older, the recommendeddosage of ELCYS is mg/gram of amino acids.Table 1. Recommended Daily Dosage of ELCYS in Pediatric Patients and Adults Age Recommended Proteina Requirement (g AA/kg/day)1 Recommended Dosage (mg ELCYS/g AA) Recommended Volume (mL ELCYS/g AA)Preterm and term infants less than month of age to 22 0.44Pediatric patients month to less than year of age to 22 0.44Pediatric patients year to 11 years of age to 22 0.44Pediatric patients 12 years to 17 years of age 0.8 to 1.5 0.14Adults: Stable Patients 0.8 to 7 0.14Adults: Critically Ill Patientsb 1.5 to 7 0.14AA Amino Acida Protein is provided as amino acids (AA).b Includes patients requiring more than to days in the intensive care unit with organ failure, sepsis or postoperative major surgery. Do not use in patients withconditions that are contraindicated [see Contraindications (4)] ELCYS contains 50 mg/mL of cysteine hydrochloride (equivalent to 34.5 mg/mL of cysteine). Therefore, the ELCYSdosages in Table provide:o15 mg cysteine/gram of amino acids for pediatric patients less than 12 years of ageo5 mg cysteine/gram of amino acids for adults and pediatric patients 12 years of age and older. Age. Recommended Proteina Requirement. (g AA/kg/day)1. Recommended Dosage. (mg ELCYS/g AA). Recommended Volume. (mL ELCYS/g AA). to 4. 22. 0.44. to 3. 22. 0.44. to 2. 22. 0.44. 0.8 to 1.5. 7. 0.14. 0.8 to 1. 7. 0.14. 1.5 to 2. 7. 0.14. o15 mg cysteine/gram of amino acids for pediatric patients less than 12 years of age. o5 mg cysteine/gram of amino acids for adults and pediatric patients 12 years of age and older.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Injection: 500 mg/10 mL (50 mg/mL) cysteine hydrochloride, USP as clear, colorless, sterile solution in 10 mL single-dose vial.. Injection: 500 mg/10 mL (50 mg/mL) cysteine hydrochloride, USP in 10 mL single-dose vial. (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use Clinical studies with ELCYS have not been performed to determine whether patients aged 65 and over respond differentlyfrom younger patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING ELCYS is supplied as follows:500 mg/10 mL (50 mg/mL) of cysteine hydrochloride, USP is clear, colorless, sterile and nonpyrogenic solution in 10mL single-dose vials (51754-1007-1), packaged as 10 per carton (NDC 51754-1007-3)Store at 20C to 25C (68F to 77F). [See USP Controlled Room Temperature]. Avoid excessive heat. Protect fromfreezing. If accidentally frozen, discard the vial.For storage of admixed solution see Dosage and Administration (2.3).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE ELCYS is indicated for use as an additive to amino acid solutions to meet the nutritional requirements of newborn infantsrequiring total parenteral nutrition (TPN) and of adult and pediatric patients with severe liver disease who may haveimpaired enzymatic processes and require TPN. It can also be added to amino acid solutions to provide more completeprofile of amino acids for protein synthesis.. ELCYS is sulfur-containing amino acid indicated to meet the nutritional requirements of newborn infants requiring total parenteral nutrition (TPN); and of adult and pediatric patients with severe liver disease who may have impaired enzymatic processes and require TPN. It can also be added to amino acid solutions to provide more complete profile of amino acids for protein synthesis. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Inform patients, caregivers, or home healthcare providers of the following risks of ELCYS:oPulmonary embolism due to pulmonary vascular precipitates [see Warnings and Precautions (5.1)]oVein damage and thrombosis [see Warnings and Precautions (5.2)]oIncreased BUN [see Warnings and Precautions (5.3)]oAcid base imbalance [see Warnings and Precautions (5.4)]oHepatobiliary disorders [see Warnings and Precautions (5.5)]oHyperammonemia [see Warnings and Precautions (5.6)]oAluminum toxicity [see Warnings and Precautions (5.7)]oMonitoring and laboratory tests [see Warnings and Precautions (5.8)]Manufactured and Distributed by:Exela Pharma Sciences, LLCLenoir, NC 28645 oPulmonary embolism due to pulmonary vascular precipitates [see Warnings and Precautions (5.1)]. oVein damage and thrombosis [see Warnings and Precautions (5.2)]. oIncreased BUN [see Warnings and Precautions (5.3)]. oAcid base imbalance [see Warnings and Precautions (5.4)]. oHepatobiliary disorders [see Warnings and Precautions (5.5)]. oHyperammonemia [see Warnings and Precautions (5.6)]. oAluminum toxicity [see Warnings and Precautions (5.7)]. oMonitoring and laboratory tests [see Warnings and Precautions (5.8)]. Logo.

LACTATION SECTION.

8.2 Lactation Risk SummaryData available on the effects of cysteine hydrochloride on infants, either directly or through breastmilk, do not suggest asignificant risk of adverse events from exposure. Although there are no data on the presence of cysteine hydrochloride inhuman or animal milk or the effects on milk production, appropriate administration of ELCYS is not expected to causeharm to breastfed infant. The development and health benefits of breastfeeding should be considered along with themothers clinical need for ELCYS and any potential adverse effects on the breastfed infant from ELCYS or from theunderlying maternal condition.

PEDIATRIC USE SECTION.

8.4 Pediatric Use ELCYS is approved for use in pediatric patients, from birth to 17 years of age, for use as an additive to amino acidsolutions to meet the nutritional requirements of newborn infants, including preterm infants, requiring total parenteralnutrition (TPN) and pediatric patients with severe liver disease who may have impaired enzymatic processes and requireTPN. The safety profile for ELCYS use in pediatric patients includes risks of acid-base imbalance and hyperammonemia.Acid-base imbalance, including metabolic acidosis, may occur with ELCYS administration in preterm infants. Frequentclinical and laboratory assessments are necessary to monitor and manage fluid balance, electrolyte concentrations, andacid-base balance during parenteral nutrition therapy [see Warnings and Precautions (5.4)].Hyperammonemia is of special significance in infants (birth to two years of age). This reaction appears to be related to adeficiency of the urea cycle amino acids of genetic or product origin. It is essential that blood ammonia be measuredfrequently in infants [see Warnings and Precautions (5.6)]. Because of immature renal function, preterm infants receiving prolonged PN treatment with ELCYS may be at higher riskof aluminum toxicity [see Warnings and Precautions (5.7)].

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryAppropriate administration of ELCYS is not expected to cause major birth defects, miscarriage or adverse maternal orfetal outcomes. Animal reproduction studies have not been conducted with cysteine hydrochloride.The estimated background risk for major birth defects and miscarriage for the indicated populations is unknown. Allpregnancies have background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, theestimated background risk of major birth defect and miscarriage in the clinically recognized pregnancies is to 4% and 15to 20%, respectively.

REFERENCES SECTION.

15 REFERENCES 1. Ayers P. et al. A.S.P.E.N. Parenteral Nutrition Handbook, 2nd ed. 2014 pg. 123 and 124.

SPL UNCLASSIFIED SECTION.

2.1 Important Administration Information ELCYS is for admixing use only. It is not for direct intravenous infusion. Prior to administration, ELCYS must be diluted and used as an admixture in parenteral nutrition (PN) solutions.The resulting solution is for intravenous infusion into central or peripheral vein. The choice of central or peripheralvenous route should depend on the osmolarity of the final infusate. Solutions with osmolarity of 900 mOsm/L or greatermust be infused through central catheter [see Warnings and Precautions (5.2)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk SummaryAppropriate administration of ELCYS is not expected to cause major birth defects, miscarriage or adverse maternal orfetal outcomes. Animal reproduction studies have not been conducted with cysteine hydrochloride.The estimated background risk for major birth defects and miscarriage for the indicated populations is unknown. Allpregnancies have background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, theestimated background risk of major birth defect and miscarriage in the clinically recognized pregnancies is to 4% and 15to 20%, respectively.. 8.2 Lactation Risk SummaryData available on the effects of cysteine hydrochloride on infants, either directly or through breastmilk, do not suggest asignificant risk of adverse events from exposure. Although there are no data on the presence of cysteine hydrochloride inhuman or animal milk or the effects on milk production, appropriate administration of ELCYS is not expected to causeharm to breastfed infant. The development and health benefits of breastfeeding should be considered along with themothers clinical need for ELCYS and any potential adverse effects on the breastfed infant from ELCYS or from theunderlying maternal condition.. 8.4 Pediatric Use ELCYS is approved for use in pediatric patients, from birth to 17 years of age, for use as an additive to amino acidsolutions to meet the nutritional requirements of newborn infants, including preterm infants, requiring total parenteralnutrition (TPN) and pediatric patients with severe liver disease who may have impaired enzymatic processes and requireTPN. The safety profile for ELCYS use in pediatric patients includes risks of acid-base imbalance and hyperammonemia.Acid-base imbalance, including metabolic acidosis, may occur with ELCYS administration in preterm infants. Frequentclinical and laboratory assessments are necessary to monitor and manage fluid balance, electrolyte concentrations, andacid-base balance during parenteral nutrition therapy [see Warnings and Precautions (5.4)].Hyperammonemia is of special significance in infants (birth to two years of age). This reaction appears to be related to adeficiency of the urea cycle amino acids of genetic or product origin. It is essential that blood ammonia be measuredfrequently in infants [see Warnings and Precautions (5.6)]. Because of immature renal function, preterm infants receiving prolonged PN treatment with ELCYS may be at higher riskof aluminum toxicity [see Warnings and Precautions (5.7)]. 8.5 Geriatric Use Clinical studies with ELCYS have not been performed to determine whether patients aged 65 and over respond differentlyfrom younger patients.. 8.6 Renal Impairment Monitor patients with impaired renal function receiving PN solutions containing the recommended dosage of ELCYS withfrequent clinical evaluation and laboratory tests to assess renal function, including serum electrolytes and fluid balance[see Dosage and Administration (2.4), Warnings and Precautions (5.8)].. 8.7 Hepatic Impairment Monitor patients with impaired liver function receiving PN solutions containing the recommended dosage of ELCYS withfrequent clinical evaluation and laboratory tests to assess liver function, such as bilirubin and liver function parameters[see Dosage and Administration (2.4), Warnings and Precautions (5.8)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oPulmonary Embolism due to Pulmonary Vascular Precipitates: If signs of pulmonary distress occur, stop the infusion and initiate medical evaluation. (5.1)oVein Damage and Thrombosis: Solutions with osmolarity of 900 mOsm/L or more must be infused through central catheter. (2.1, 5.2)oIncreased blood urea nitrogen (BUN): Monitor laboratory parameters and discontinue if exceeds normal postprandial limits and continues to increase. (5.3)oAcid-Base Imbalance: Monitor laboratory parameters and supplement with electrolytes as needed. (5.4)oHepatobiliary Disorders: Monitor liver function parameters and ammonia levels. (5.5)oHyperammonemia: Neurocognitive delay possible in infants; monitor blood ammonia levels. (5.6, 8.4)oAluminium Toxicity: Increased risk in patients with renal impairment, including preterm infants. (5.7, 8.4)oMonitoring and Laboratory Tests: Monitor fluid and electrolytes, serum osmolarity, blood glucose, kidney and liver function, blood count and coagulation parameters throughout treatment. (5.8). oPulmonary Embolism due to Pulmonary Vascular Precipitates: If signs of pulmonary distress occur, stop the infusion and initiate medical evaluation. (5.1). oVein Damage and Thrombosis: Solutions with osmolarity of 900 mOsm/L or more must be infused through central catheter. (2.1, 5.2). oIncreased blood urea nitrogen (BUN): Monitor laboratory parameters and discontinue if exceeds normal postprandial limits and continues to increase. (5.3). oAcid-Base Imbalance: Monitor laboratory parameters and supplement with electrolytes as needed. (5.4). oHepatobiliary Disorders: Monitor liver function parameters and ammonia levels. (5.5). oHyperammonemia: Neurocognitive delay possible in infants; monitor blood ammonia levels. (5.6, 8.4). oAluminium Toxicity: Increased risk in patients with renal impairment, including preterm infants. (5.7, 8.4). oMonitoring and Laboratory Tests: Monitor fluid and electrolytes, serum osmolarity, blood glucose, kidney and liver function, blood count and coagulation parameters throughout treatment. (5.8). 5.1 Pulmonary Embolism due to Pulmonary Vascular Precipitates Pulmonary vascular precipitates causing pulmonary vascular emboli and pulmonary distress have been reported inpatients receiving PN. In some fatal cases, pulmonary embolism occurred as result of calcium phosphate precipitates.Precipitation following passage through an in-line filter and suspected in vivo precipitate formation has also beenreported. If signs of pulmonary distress occur, stop the PN infusion and initiate medical evaluation. In addition toinspection of the solution [see Dosage and Administration (2.1, 2.2)], the infusion set and catheter should alsoperiodically be checked for precipitates.. 5.2 Vein Damage and Thrombosis ELCYS must be diluted and used as an admixture in PN solutions. It is not for direct intravenous infusion. Solutions withan osmolarity of 900 mOsm/L or greater must be infused through central catheter [see Dosage and Administration (2.1)]. The infusion of hypertonic nutrient injections into peripheral vein may result in vein irritation, vein damage,and/or thrombosis. The primary complication of peripheral access is venous thrombophlebitis, which manifests as pain,erythema, tenderness or palpable cord. Remove the catheter as soon as possible, if thrombophlebitis develops.. 5.3 Increased Blood Urea Nitrogen (BUN) Intravenous infusion of amino acids may induce rise in blood urea nitrogen (BUN), especially in patients with impairedhepatic or renal function. Appropriate laboratory tests should be performed periodically and infusion discontinued if BUNlevels exceed normal postprandial limits and continue to rise. It should be noted that modest rise in BUN normallyoccurs as result of increased protein intake.Administration of amino acid solutions in the presence of impaired renal function may augment an increasing BUN, asdoes any protein dietary component.. 5.4 Acid-Base Imbalance Administration of ELCYS may result in metabolic acidosis in preterm infants.Administration of amino acid solutions to patient with hepatic impairment may result in serum amino acid imbalances,metabolic alkalosis, prerenal azotemia, hyperammonemia, stupor and coma.Frequent clinical evaluation and laboratory determinations are necessary for proper monitoring of acid-base balanceduring parenteral nutrition therapy. Significant deviations from normal concentrations may require the use of additionalelectrolyte supplements.. 5.5 Hepatobiliary Disorders Hepatobiliary disorders are known to develop in some patients without preexisting liver disease who receive PN,including cholecystitis, cholelithiasis, cholestasis, hepatic steatosis, fibrosis and cirrhosis, possibly leading to hepaticfailure. The etiology of these disorders is thought to be multifactorial and may differ between patients.Monitor liver function parameters and ammonia levels. Patients developing signs of hepatobiliary disorders should beassessed early by clinician knowledgeable in liver diseases in order to identify possible causative and contributoryfactors, and possible therapeutic and prophylactic interventions.. 5.6 Hyperammonemia Hyperammonemia is of special significance in infants, as it can result in neurocognitive delays. Therefore, it is essentialthat blood ammonia levels be measured frequently in infants.Instances of asymptomatic hyperammonemia have been reported in patients without overt liver dysfunction. Themechanisms of this reaction are not clearly defined but may involve genetic defects and immature or subclinicallyimpaired liver function [see Contraindications (4), Use in Specific Populations (8.4)].. 5.7 Aluminum Toxicity ELCYS contains aluminum that may be toxic.Aluminum may reach toxic levels with prolonged parenteral administration in patients with renal impairment. Preterminfants are particularly at risk for aluminum toxicity because their kidneys are immature, and they require large amountsof calcium and phosphate solutions, which also contain aluminum.Patients with renal impairment, including preterm infants, who receive greater than to mcg/kg/day of parenteralaluminum can accumulate aluminum to levels associated with central nervous system and bone toxicity. Tissue loadingmay occur at even lower rates of administration.Exposure to aluminum from ELCYS is not more than 0.21 mcg/kg/day when preterm and term infants less than monthof age are administered the recommended maximum dosage of ELCYS (15 mg cysteine/g of amino acids and g ofamino acids/kg/day) [see Table 1, Dosage and Administration (2.5)]. When prescribing ELCYS for use in PN containingother small volume parenteral products, the total daily patient exposure to aluminum from the admixture should beconsidered and maintained at no more than mcg/kg/day [see Use in Specific Populations (8.4)].. 5.8 Monitoring and Laboratory Tests Monitor fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, blood count andcoagulation parameters throughout treatment [see Dosage and Administration (2.4)].