ELCYS

1 INDICATIONS AND USAGE ELCYS is indicated for use as an additive to amino acid solutions 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 a more complete profile of amino acids for protein synthesis. ELCYS is a 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 a more complete profile of amino acids for protein synthesis. ( 1 )

2 DOSAGE AND ADMINISTRATION • ELCYS is for admixing use only. Not for direct intravenous infusion . ( 2.1 ) • See 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 a central or peripheral vein. The choice of a central or peripheral venous route should depend on the osmolarity of the final infusate. Solutions with osmolarity of 900 mOsm/L or greater must be infused through a central catheter [see Warnings and Precautions ( 5.2 )] . 2.2 Preparation and Administration Instructions • ELCYS is not for direct intravenous infusion . Prior to administration, ELCYS must be diluted and used as anadmixture in PN solutions. • ELCYS is to be prepared only in a suitable work area such as a 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. • ELCYS is for addition to amino acid solutions prior to further admixing with dextrose injection using a PN container. • Use a dedicated line for PN solutions. • Intravenous lipid emulsions can be infused concurrently into the same vein as ELCYS containing amino acid and dextrose solutions by a Y-connector located near the infusion site; flow rates of each solution should be controlled separately by infusion pumps. • For administration without lipid emulsion, use a 0.22 micron in-line filter. • To prevent air embolism, use a non-vented infusion set or close the vent on a 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 a pumping device, turn off pump before the container runs dry. • If 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 a plasticizer. • Visually 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. A slight yellow color does not alter the quality and efficacy of this product. 2.3 Preparation Instructions for Admixing Using a Parenteral Nutrition (PN) Container • Remove ELCYS vial from the carton and inspect for particulate matter. • Transfer the required amount of ELCYS to an amino acid solution using strict aseptic techniques to avoid microbial contamination. • The amino acid solution containing ELCYS can then be used to prepare admixtures in the PN container using strict aseptic techniques. • Amino acids solution containing ELCYS may be mixed with dextrose injection. The following proper mixing sequence must be followed to minimize pH related problems: • Transfer dextrose injection to the parental nutrition pooling container • Transfer phosphate salt • Transfer ELCYS-containing amino acid solution • Transfer electrolytes • Transfer trace elements • Use gentle agitation during admixing to minimize localized concentration effects; shake containers gently after each addition. • For automated compounding, refer to Instructions for Use of the applicable compounder. • Because 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 compatibilit…

5 WARNINGS AND PRECAUTIONS • Pulmonary Embolism due to Pulmonary Vascular Precipitates: If signs of pulmonary distress occur, stop the infusion and initiate a medical evaluation. ( 5.1 ) • Vein Damage and Thrombosis: Solutions with osmolarity of 900 mOsm/L or more must be infused through a central catheter. ( 2.1 , 5.2 ) • Increased blood urea nitrogen (BUN): Monitor laboratory parameters and discontinue if exceeds normal postprandial limits and continues to increase. ( 5.3 ) • Acid-Base Imbalance: Monitor laboratory parameters and supplement with electrolytes as needed. ( 5.4 ) • Hepatobiliary Disorders: Monitor liver function parameters and ammonia levels. ( 5.5 ) • Hyperammonemia: Neurocognitive delay possible in infants; monitor blood ammonia levels. ( 5.6 , 8.4 ) • Aluminium Toxicity: Increased risk in patients with renal impairment, including preterm infants. ( 5.7 , 8.4 ) • Monitoring 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 in patients receiving PN. In some fatal cases, pulmonary embolism occurred as a result of calcium phosphate precipitates. Precipitation following passage through an in-line filter and suspected in vivo precipitate formation has also been reported. If signs of pulmonary distress occur, stop the PN infusion and initiate a medical evaluation. In addition to inspection of the solution [see Dosage and Administration ( 2.1 , 2.2 )] , the infusion set and catheter should also periodically 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 with an osmolarity of 900 mOsm/L or greater must be infused through a central catheter [see Dosage and Administration ( 2.1 )] . The infusion of hypertonic nutrient injections into a 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 a 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 a rise in blood urea nitrogen (BUN), especially in patients with impaired hepatic or renal function. Appropriate laboratory tests should be performed periodically and infusion discontinued if BUN levels exceed normal postprandial limits and continue to rise. It should be noted that a modest rise in BUN normally occurs as a result of increased protein intake. Administration of amino acid solutions in the presence of impaired renal function may augment an increasing BUN, as does 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 a 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 balance during parenteral nutrition therapy. Significant deviations from normal concentrations may require the use of additional electrolyte 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 hepatic failure. 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…

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

8.1 Pregnancy Risk Summary Appropriate administration of ELCYS is not expected to cause major birth defects, miscarriage or adverse maternal or fetal 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. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information: • Pulmonary embolism due to pulmonary vascular precipitates [see Warnings and Precautions ( 5.1 )] • Vein damage and thrombosis [see Warnings and Precautions ( 5.2 )] • Increased BUN [see Warnings and Precautions ( 5.3 )] • Acid-base imbalance [see Warnings and Precautions ( 5.4 )] • Hepatobiliary disorders [see Warnings and Precautions ( 5.5 )] • Hyperammonemia [see Warnings and Precautions ( 5.6 )] • Aluminum 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Local infusion site reactions, including a warm sensation, erythema, phlebitis and thrombosis at the infusion site • Generalized 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.