PACKAGE/LABEL PRINCIPAL DISPLAY PANEL-Carton Label

Rx Only NDC 51754-1008-4

ELCYS®

(cysteine hydrochloride injection), USP

2,500 mg/50 mL (50 mg/mL)

Pharmacy Bulk Package - Not for direct infusion.

Must be diluted. For intravenous infusion after dilution and admixing only.*

25 x 50 mL Vials

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.

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.

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

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)].

2 DOSAGE AND ADMINISTRATION

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.

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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:

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Transfer dextrose injection to the parental nutrition pooling container

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Transfer phosphate salt

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Transfer ELCYS®-containing amino acid solution

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Transfer electrolytes

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Transfer trace elements

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Use gentle agitation during admixing to minimize localized concentration effects; shake containers gently after each addition.

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For automated compounding, refer to Instructions for Use of the applicable compounder.

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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)**

3 to 4

22

0.44

2 to 3

22

0.44

1 to 2

22

0.44

0.8 to 1.5

7

0.14

0.8 to 1

7

0.14

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 [see Contraindications (4)]

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

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

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.

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)].

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 C3H7NO2S • HCI • H2O 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 80 mcg/L of aluminum.

15 REFERENCES

1. Ayers P. et al. A.S.P.E.N. Parenteral Nutrition Handbook, 2nd ed. 2014 pg. 123 and 124.

12 CLINICAL PHARMACOLOGY

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

ELCYS® is supplied as follows:

Pharmacy Bulk Package: 2,500 mg/50 mL (50 mg/mL) of cysteine hydrochloride, USP is a clear, colorless, sterile and nonpyrogenic solution in 50 mL vials packaged as 1 per carton (NDC 51754-1008-1), 25 cartons per case (NDC 51754-1008-4)

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).

17 PATIENT COUNSELING INFORMATION

Inform patients, caregivers, or home healthcare providers of the following risks of ELCYS®:

•

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)]

•

Monitoring and laboratory tests [see Warnings and Precautions (5.8)]

Manufactured and Distributed by:

Exela Pharma Sciences, LLC

Lenoir, NC 28645