CYSTEINE HYDROCHLORIDE

1 INDICATIONS AND USAGE Cysteine hydrochloride injection, USP is indicated for use as an additive to amino acids solutions to meet nutritional requirements of neonates (preterm and term infants less than one month of age) requiring total parenteral nutrition. Cysteine hydrochloride injection, USP is a sulfur-containing amino acid indicated for use as an additive to amino acids solutions to meet nutritional requirements of neonates (preterm and term infants less than one month of age) requiring total parenteral nutrition. ( 1 )

2 DOSAGE AND ADMINISTRATION • Cysteine hydrochloride injection, USP is for intravenous infusion after dilution and admixing only. ( 2.1 ) • See full prescribing information for information on preparation, administration, and instructions for use. ( 2.1 , 2.2 , 2.3 , 2.4 ) • The recommended dosage in neonates is based upon the recommended daily protein (amino acid) requirements: 22 mg cysteine hydrochloride injection, USP/g amino acids. The corresponding volume is 0.44 mL cysteine hydrochloride injection, USP/g amino acids. ( 2.5 ) 2.1 Important Administration Information Cysteine hydrochloride injection, USP is for intravenous infusion after dilution and admixing use only. Prior to administration, cysteine hydrochloride injection, USP must be diluted and used as an admixture in parenteral nutrition 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 Information • Prior to administration, cysteine hydrochloride injection, USP must be diluted and used as an admixture in parenteral nutrition solutions. • Cysteine hydrochloride injection, USP 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. • Cysteine hydrochloride injection, USP is for addition to amino acid solutions prior to further admixing with dextrose injection using a parenteral nutrition container. • Calcium and phosphate ratios must be considered. Excess addition of calcium and phosphate, especially in the form of mineral salts, may result in the formation of calcium phosphate precipitates [see Warnings and Precautions (5.1) ] . • Use a dedicated line for parenteral nutrition solutions. • Intravenous lipid emulsions can be infused concurrently into the same vein as cysteine hydrochloride injection, USP-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, 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. • Visually inspect the diluted parenteral nutrition solution containing cysteine hydrochloride injection, USP for particulate matter and discoloration before admixing, after admixing, after removal from refrigeration, 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 Container • Remove cysteine hydrochloride injection, USP vial from the carton and inspect for particulate matter. • Transfer the required amount of cysteine hydrochloride injection, USP to an amino acid solution using strict aseptic techniques to avoid microbial contamination. • The amino acid solution containing cysteine hydrochloride injection, USP can then be used to prepare admixtures in the parenteral nutrition container using strict aseptic techniques. • Amino acids solution containing cysteine hydrochloride injection, USP may be mixed with dextrose injection. The following proper mixing sequence must be followed to minimize pH related problems: 1. Transfer dextrose injection to the parental nutrition pooling container 2. Transfer phosphate salt 3. Transfer cysteine hydrochloride injection, USP-containing amino acid solution 4. Transfer electrolytes 5. 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 parenteral nutrition container for compatibility and stability of the resulting preparation. Consult with pharmacist, if available. Questions about compatibility may be directed to Baxter Healthcare Corporation. If it is deemed advisable to introduce additives to the parenteral nutrition container, use aseptic technique. • Inspect the final parenteral nutrition solution containing cysteine hydrochloride injection, USP to ensure that precipitates have not formed during mixing or on addition of additives. Discard if any precipitates are observed. Stability and Storage • For single use only. Discard unused portion of the vial of cysteine hydrochloride injection, USP. • Use parenteral nutrition solution containing cysteine hydrochloride injection, USP promptly after mixing. Any storage of the admixture should be under refrigeration at 2ºC to 8ºC (36ºF to 46ºF) and limited to a brief period of time, no longer than 24 hours. After removal from refrigeration, inspect for precipitates, use promptly, and complete the infusion within 24 hours. Discard if any precipitates are observed. • Discard any remaining admixture. • Protect parenteral nutrition solution from light. 2.4 Dosing Considerations The dosage of the final parenteral nutrition solution containing cysteine hydrochloride injection, USP 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. The dosage of cysteine hydrochloride injection, USP should be individualized based on the patient’s 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, and complete blood count. Prior to administration of parenteral nutrition solution containing cysteine hydrochloride injection, USP, correct severe fluid, electrolyte and acid-base disorders. 2.5 Recommended Dosage for Neonates The recommended dosage and volume of cysteine hydrochloride injection, USP is based upon the recommended daily protein (amino acid) requirements. Table 1. Recommended Daily Dosage of cysteine hydrochloride injection, USP in Neonates (Preterm and Term Infants Less Than One Month of Age) Dosage Protein Protein is provided as amino acids. Requirement (g Amino Acids/kg/day) 1 Dosage (mg cysteine hydrochloride injection, USP/g Amino Acids) Volume (mL cysteine hydrochloride injection, USP/g Amino Acids) Neonates 3 to 4 22 0.44 Cysteine hydrochloride injection, USP contains 50 mg/mL of cysteine hydrochloride (equivalent to 34.5 mg/mL of cysteine). Therefore, the recommended dosage of cysteine hydrochloride injection, USP provides 15 mg cysteine/gram of amino acids for neonates.

4 CONTRAINDICATIONS Cysteine hydrochloride injection, USP 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 )

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 BUN 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 : Neurocognitive delay possible in infants; monitor liver function parameters and ammonia levels. ( 5.5 , 8.4 ) • Aluminum Toxicity : Increased risk in patients with renal impairment, including preterm infants. ( 5.6 , 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. ( 5.7 ) 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 parenteral nutrition. 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 parenteral nutrition 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 Cysteine hydrochloride injection, USP must be diluted and used as an admixture in parenteral nutrition solutions. 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 cysteine hydrochloride injection, USP may result in metabolic acidosis in neonates. 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, including neonates, without preexisting liver disease who receive parenteral nutrition, 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. Instances of asymptomatic hyperammonemia have been reported in patients receiving parenteral nutrition without overt liver dysfunction. The mechanisms of this reaction are not clearly defined but may involve genetic defects and immature or subclinically impaired liver function [see Contraindications (4) , Use in Specific Populations (8.4) ] Hyperammonemia is of special significance in infants, as it can result in neurocognitive delays. Monitor liver function parameters and ammonia levels during treatment with cysteine hydrochloride injection, USP. Patients developing signs of hepatobiliary disorders should be assessed early by a clinician knowledgeable in liver diseases in order to identify possible causative and contributory factors, and possible therapeutic and prophylactic interventions. 5.6 Aluminum Toxicity Cysteine hydrochloride injection, USP contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration in patients with renal impairment. Neonates and preterm infants are particularly at risk for aluminum toxicity because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which also contain aluminum. Patients with renal impairment including neonates and preterm infants, who receive greater than 4 to 5 mcg/kg/day of parenteral aluminum can accumulate aluminum to levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration. Exposure to aluminum from cysteine hydrochloride injection, USP is not more than 0.25 mcg/kg/day when preterm and term neonates are administered the recommended maximum dosage of cysteine hydrochloride injection, USP (22 mg cysteine hydrochloride/g of amino acids and 4 g of amino acids/kg/day) [see Dosage and Administration (2.5) ]. When prescribing cysteine hydrochloride injection, USP for use in parenteral nutrition containing other small volume parenteral products, the total daily patient exposure to aluminum from the admixture should be considered and maintained at no more than 5 mcg/kg/day [see Use in Specific Populations (8.4) ]. 5.7 Monitoring and Laboratory Tests Monitor fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, ammonia levels, blood count and coagulation parameters throughout treatment [see Dosage and Administration (2.4) ].

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 Warning and Precautions (5.5) ] • Aluminum toxicity [see Warnings and Precautions (5.6) ] Adverse reactions with the use of cysteine hydrochloride injection were identified in clinical studies or postmarketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. • Metabolic acidosis • 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, nausea, and metabolic acidosis. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8.1 Pregnancy Risk Summary Cysteine hydrochloride injection, USP for use as an additive to amino acid solutions to meet nutritional requirements is not indicated for use in adults. Appropriate administration of cysteine hydrochloride injection, USP 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.