CYSTEINE: 41 Adverse Event Reports & Safety Profile

Cysteine hydrochloride injection, USP (cysteine hydrochloride injection) is a sterile, nonpyrogenic solution for intravenous use supplied as 500 mg/10 mL cysteine hydrochloride, USP in a single-dose vial. Each mL of cysteine hydrochloride injection, USP contains 50 mg of cysteine hydrochloride, (equivalent to 34.5 mg of cysteine), and 0.006 mL of hydrochloric acid (6M) in water for injection. Sodium hydroxide and/or hydrochloric acid are used as needed to adjust the pH. The pH range of cysteine hydrochloride injection, USP is 1.0 to 1.5. The active ingredient is cysteine hydrochloride. The chemical name of cysteine hydrochloride is L-cysteine hydrochloride monohydrate. Its molecular formula is C 3 H 7 NO 2 S

• HCI
• H 2 O and molecular weight is 175.63. The chemical structure of L-cysteine hydrochloride monohydrate is depicted below: Cysteine hydrochloride is a white crystalline powder soluble in water. Cysteine is a sulfur-containing amino acid and is prone to oxidation when exposed to air in aqueous solution, which may convert cysteine to insoluble cystine resulting in precipitation over time. Cysteine hydrochloride injection, USP contains no more than 145 mcg/L of aluminum.

Structural

Formula

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 )

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . ELCYS ® is supplied as a pharmacy bulk package, and consists of one pharmacy bulk vial which must be diluted prior to intravenous administration <span class="opacity-50 text-xs">[see Dosage andAdministration ( 2.3 )]</span>. 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 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 compatibility may be directed to Exela Pharma Sciences, LLC. If it is deemed advisable to introduce additives to the PN container, use aseptic technique.
• Inspect 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 Storage
• Use of ELCYS ® for admixing should be limited to up to 4 hours at room temperature (25ºC/77ºF) after the container closure has been penetrated. Discard any remaining drug.
• Use PN solution containing ELCYS ® promptly after mixing. Any storage of the admixture should be under refrigeration and limited to a 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.
• Protect PN solution from light.

2.4 Dosing Considerations

• The 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.
• The dosage of ELCYS ® 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, complete blood count and triglyceride level (if adding lipid emulsion).
• Prior 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 1 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 of ELCYS ® is 22 mg/gram of amino acids. For adults and pediatric patients 12 years of age and older, the recommended dosage of ELCYS ® is 7 mg/gram of amino acids.

Table

1.

Recommended Daily

Dosage of ELCYS ® in Pediatric Patients and Adults Age Recommended Protein a Requirement (g AA/kg/day) 1 Recommended Dosage (mg ELCYS/g AA)

Recommended

Volume (mL ELCYS/g AA) Preterm and term infants less than 1 month of age 3 to 4 22

0.44 Pediatric patients 1 month to less than 1 year of age 2 to 3 22

0.44 Pediatric patients 1 year to 11 years of age 1 to 2 22

0.44 Pediatric patients 12 years to 17 years of age 0.8 to 1.5 7

0.14 Adults: Stable Patients 0.8 to 1 7

0.14 Adults: Critically Ill Patients b 1.5 to 2 7

0.14 AA = Amino Acid a Protein is provided as amino acids (AA) b Includes patients requiring more than 2 to 3 days in the intensive care unit with organ failure, sepsis or postoperative major surgery. Do not use in patients with conditions that are contraindicated <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> ELCYS ® contains 50 mg/mL of cysteine hydrochloride (equivalent to 34.5 mg/mL of cysteine). Therefore, the ELCYS ® dosages in Table 1 provide:

• 15 mg cysteine/gram of amino acids for pediatric patients less than 12 years of age
• 5 mg cysteine/gram of amino acids for adults and pediatric patients 12 years of age and older

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 )

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.

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1 , 2.2) ]</span>, 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span>. 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 <span class="opacity-50 text-xs">[see Contraindications (4) , Use in Specific Populations (8.4) ]</span> 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) <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span>. 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span>.

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span>.

ACTIVE INGREDIENTS L-Cysteine 4X, 7X, 12X

INACTIVE INGREDIENTS 20% ethanol, purified water.