Cysteine Hydrochloride

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 )

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 )

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 )

• 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 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 Hyperammonemia Hyperammonemia is of special significance in infants, as it can result in neurocognitive delays. Therefore, it is essential that blood ammonia levels be measured frequently in infants. Instances of asymptomatic hyperammonemia have been reported in patients 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 )] .

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. 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 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 ELCYS ® is not more than 0.21 mcg/kg/day when preterm and term infants less than 1 month of age are administered the recommended maximum dosage of ELCYS ® (15 mg cysteine/g of amino acids and 4 g of amino acids/kg/day) [see Table 1, Dosage and Administration ( 2.1 )] . When prescribing ELCYS ® for use in PN 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 )] .

5.8 Monitoring and Laboratory Tests Monitor fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, blood count and coagulation parameters throughout treatment [see Dosage and Administration ( 2.4 )] .

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.

8.1 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 )].

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.