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 ) • PHARMACY BULK PACKAGE: Dispense single-doses to many patients in a pharmacy admixture program. Use within 4 hours of puncture. ( 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 Prior to administration, ELCYS® must be diluted and used as an admixture in PN solutions. ELCYS® is not for direct intravenous infusion. 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 )] . ELCYS ® is supplied as a pharmacy bulk package, and consists of one pharmacy bulk vial which must be diluted prior to intravenous administration [see Dosage andAdministration ( 2.3 )]. As a pharmacy bulk vial, ELCYS ® is intended for dispensing of single doses to many patients. Dispensing from a pharmacy bulk vial should be completed within 4 hours after the vial is penetrated. Do not administer ELCYS ® as a direct, undiluted intravenous injection. 2.2 Preparation and Administration Instructions Prior to administration, ELCYS® must be diluted and used as an admixture in PN solutions. ELCYS® is not for direct intravenous infusion. • 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 containe …

3 DOSAGE FORMS AND STRENGTHS Injection • Pharmacy Bulk Package: 2500 mg/50mL (50 mg/mL) cysteine hydrochloride, USP in a clear, colorless, sterile solution in a 50 mL vial. Injection • Pharmacy Bulk Package: 2500 mg/50 mL (50 mg/mL) cysteine hydrochloride, USP in a 50 mL vial. ( 3 )

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 )

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.

8 USE IN SPECIFIC POPULATIONS 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. 8.2 Lactation Risk Summary Data available on the effects of cysteine hydrochloride on infants, either directly or through breastmilk, do not suggest a significant risk of adverse events from exposure. Although there are no data on the presence of cysteine hydrochloride in human or animal milk or the effects on milk production, appropriate administration of ELCYS ® is not expected to cause harm to a breastfed infant. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for ELCYS ® and any potential adverse effects on the breastfed infant from ELCYS ® or from the underlying 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 acid solutions to meet the nutritional requirements of newborn infants, including preterm infants, requiring total parenteral nutrition (TPN) and pediatric patients with severe liver disease who may have impaired enzymatic processes and require TPN . 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. Frequent clinical and laboratory assessments are necessary to monitor and manage fluid balance, electrolyte concentrations, and acid-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 a deficiency of the urea cycle amino acids of genetic or product origin. It is essential that blood ammonia be measured frequently in infants [see Warnings and Precautions ( 5.6 )]. Because of immature renal function, preterm infants receiving prolonged parenteral nutrition treatment with ELCYS ® may be at higher risk of 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 differently from younger patients. 8.6 Renal Impairment Monitor patients with impaired renal function receiving PN solutions containing the recommended dosage of ELCYS ® with frequent 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 ® with frequent 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 )].

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

11 DESCRIPTION ELCYS ® (cysteine hydrochloride injection) is a sterile, nonpyrogenic solution for intravenous use. Each 50 mL of ELCYS ® contains 2500 mg of cysteine hydrochloride, USP (equivalent to 345 mg of cysteine) in water for injection. Sodium hydroxide 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 a sulfur-containing amino acid. The chemical name of cysteine hydrochloride is L-cysteine hydrochloride monohydrate and is chemically designated as C 3 H 7 NO 2 S • HCI • H 2 O having a molecular weight of 175.63. Cysteine hydrochloride is a white crystalline powder soluble in water. Cysteine aqueous solution is prone to oxidation when exposed to air, and when mixed with amino acids solutions, cysteine may convert 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

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 )] .

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