Multrys

6 ADVERSE REACTIONS The following adverse reactions were identified in clinical studies or post-marketing reports. Given that 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. Adverse reactions with other components of parenteral nutrition solutions: Pulmonary embolism due to pulmonary vascular precipitates [see Warnings and Precautions ( 5.1 )] Vein damage and thrombosis [see Warnings and Precautions ( 5.2 )] Aluminum toxicity [see Warnings and Precautions ( 5.5 )] Adverse reactions with the use of trace elements administered parenterally or by other routes of administration: Neurologic toxicity with manganese [see Warnings and Precautions ( 5.3 )] Hepatic accumulation of copper and manganese [see Warnings and Precautions ( 5.4 )] Hypersensitivity reactions with zinc and copper [see Warnings and Precautions ( 5.7)] This section intentionally left blank. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

4 CONTRAINDICATIONS Multrys is contraindicated in patients with hypersensitivity to zinc or copper [see Warnings and Precautions ( 5.7 )]. Hypersensitivity to zinc or copper ( 4, 5.7 )

11 DESCRIPTION Multrys (trace elements injection 4*, USP) is a sterile, non-pyrogenic, clear, and colorless to slightly blue solution, intended for use as a combination of four trace elements and an additive to intravenous solutions for parenteral nutrition. It contains no preservative. Each single-dose vial contains 1 mL. *Each mL contains zinc 1,000 mcg (equivalent to zinc sulfate 2,470 mcg), copper 60 mcg (equivalent to cupric sulfate 150 mcg), manganese 3 mcg (equivalent to manganese sulfate 8.22 mcg), selenium 6 mcg (equivalent to selenious acid 9.8 mcg), and water for injection. Sulfuric acid may be added to adjust pH between 1.5 and 3.5. Zinc sulfate exists as a heptahydrate. The structural formula is: Molecular formula: ZnSO 4 • 7H 2 O. Molecular weight: 287.54 g/mol. Cupric sulfate exists as a pentahydrate. The structural formula is: Molecular formula: CuSO 4 • 5H 2 O. Molecular weight: 249.69 g/mol. Manganese sulfate exists as a monohydrate. The structural formula is: Molecular formula: MnSO 4 • H 2 O. Molecular weight: 169.02 g/mol. The structural formula of selenious acid is: Molecular formula: H 2 SeO 3 . Molecular weight: 128.97 g/mol. Multrys contains no more than 1,500 mcg/L of aluminum. Zinc Sulfate Structural Formula Cupric Sulfate Structural Formula Manganese Structural Formula Selenious Acid Structural Formula

2 DOSAGE AND ADMINISTRATION Single-dose vial, for admixture use only. ( 2.1 ) See full prescribing information for information on preparation, administration and general dosing considerations. ( 2.1 , 2.2 , 2.3 , 2.4 ) Recommended Dosage Each mL of Multrys provides zinc 1,000 mcg, copper 60 mcg, manganese 3 mcg, and selenium 6 mcg. ( 2.5 ) Multrys is recommended only for pediatric patients who require supplementation with all four of the individual trace elements (i.e., zinc, copper, manganese, and selenium) to meet daily requirements. ( 2.5 ) Pediatric Patients 0.4 kg to 0.59 kg : The total recommended dosage of Multrys is 0.2 mL every other day .Daily supplementation of Zinc Sulfate, Cupric Chloride and Selenious Acid will be needed to meet daily requirements. ( 2.5 ) Pediatric Patients 0.6 kg to 10 kg : The recommended dosage of Multrys is 0.3 mL/kg/day rounded to the nearest 0.1 mL for up to a maximum of 1 mL per day. The recommended volume of Multrys to be added to parenteral nutrition ranges from 0.2 mL per day to 1 mL per day based on body weight. ( 2.5 ) Multrys is not recommended for patients who may require a lower dosage of one or more of the individual trace elements. ( 2.5 ) Monitor trace element concentrations in blood during long-term administration of parenteral nutrition. ( 2.5 ) 2.1 Important Administration Information Multrys is supplied as a single-dose vial for admixture use only. Prior to administration, Multrys must be transferred to a separate parenteral nutrition container , diluted, and used as an admixture in parenteral nutrition solution. The final parenteral nutrition 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 mOsmol/L or greater must be infused through a central catheter [see Warnings and Precautions ( 5.2 )] . 2.2 Preparation and Administration Instructions Multrys is for admixture use only.Prior to administration, Multrys must be prepared and used as an admixture in parenteral nutrition solution. Add Multrys to the parenteral nutrition solution 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. Inspect the parenteral nutrition solution containing Multrys for particulate matter before admixing, after admixing, and prior to administration. 2.3 Preparation Instructions for Admixing Using a Parenteral Nutrition Container Inspect Multrys single-dose vial for particulate matter. Transfer Multrys to the parenteral nutrition container after the admixture of amino acids, dextrose, lipid emulsion (if added), and electrolyte solutions is prepared. Because additives may be incompatible, evaluate all additions to the parenteral nutrition container for compatibility and stability of the resulting preparation.Consult with a pharmacist, if available.For introducing additives to the parenteral nutrition container, use aseptic technique. An interaction may occur between cupric ion and ascorbic acid; therefore, multivitamin additives should be added to the admixed parenteral nutrition solution shortly before infusion. Inspect the final parenteral nutrition solution containing Multrys to ensure that: Precipitates have not formed during mixing or addition of additives. The emulsion has not separated, if lipid emulsion has been added.Separation of the emulsion can be visibly identified by a yellowish streaking or the accumulation of yellowish droplets in the admixed emulsion. Discard if any precipitates are observed. Stability and Storage Single dose vial.Discard any unused portion. Penetrate vial closure only one time with a suitable sterile transfer device or dispensing set that allows measured dispensing of the contents. Transfer Multrys to the parenteral nutrition container promptly after removal from the vial. Discard any remaining drug. Use parenteral nutrition solutions containing Multrys promptly after mixing.Any storage of the admixture should be under refrigeration from 2ºC to 8ºC (36ºF to 46ºF) and limited to a period of no longer than 9 days.After removal from refrigeration, use promptly and complete the infusion within 24 hours. Discard any remaining admixture. Protect the parenteral nutrition solution from light. 2.4 Overview of Dosing Prior to administration of parenteral nutrition solution containing Multrys, correct severe fluid, electrolyte, and acid-base disorders. The dosage of the final parenteral nutrition solution containing Multrys must be based on the concentrations of all components in the solution, the patient’s clinical condition, nutritional requirements, and the contribution of oral or enteral intake. Monitor fluid and electrolyte status during treatment use of Multrys and adjust the parenteral nutrition solution as needed. 2.5 Recommended Dosage in Pediatric Patients and Monitoring Considerations Multrys is a fixed-combination product. Each mL of Multrys provides zinc 1,000 mcg, copper 60 mcg, manganese 3 mcg, and selenium 6 mcg. Recommended Dosage for Pediatric Patients Weighing 0.4 kg to 0.59 kg The total recommended dosage of Multrys is 0.2 mL every other day. Daily supplementation of Zinc, Copper, and Selenium will be needed to meet daily requirements (See Table 2 below). Recommended Dosage f or Pediatric Patients Weighing 0.6 kg to less than 10 kg The recommended dosage of Multrys is 0.3 mL/kg/day rounded to nearest 0.1 mL for up to a maximum of 1 mL per day. The recommended volume of Multrys to be added to parenteral nutrition ranges from 0.2 mL per day to 1 mL per day based on body weight, see Table 1 below. Table 1. Recommended Daily Volume of Multrys and Corresponding Amount of Each Trace Element (mcg) Body Weight Recommended Daily Volume Amount of Trace Element Provided by the Corresponding Multrys Volume Zinc mcg Copper mcg Manganese mcg Selenium mcg 0.6 kg to 0.8 kg 0.2 mL 200 12 0.6 1.2 0.9 kg to 1.1 kg 0.3 mL 300 18 0.9 1.8 1.2 kg to 1.4 kg 0.4 mL 400 24 1.2 2.4 1.5 kg to 1.7 kg 0.5 mL 500 30 1.5 3 1.8 kg to 2 kg 0.6 mL 600 36 1.8 3.6 2.1 kg to 2.3 kg 0.7 mL 700 42 2.1 4.2 2.4 kg to 2.6 kg 0.8 mL 800 48 2.4 4.8 2.7 kg to 2.9 kg 0.9 mL 900 54 2.7 5.4 3 kg to 9.9 kg 1 mL 1,000 60 3 6 Additional Trace Element Supplementation with Multrys Multrys is recommended only for pediatric patients who require supplementation with all four of the individual trace elements (i.e., zinc, copper, manganese and selenium). To determine the additional amount of supplementation that is needed, compare the calculated daily recommended dosage based on the body weight of the patient to the amount of each trace element provided by Multrys and enteral nutrition sources. Table 2: Daily Requirement for Trace Element Supplementation for Pediatric Patients Trace Element Patient Weight (kg) Daily Requirement* Zinc Less than 3 kg 400 mcg/kg/day 3 kg to 5 kg 250 mcg/kg/day 5 to 10 kg 100 mcg/kg/day Copper - 20 mcg/kg/day Selenium - 2 mcg/kg/day Manganese** - 1 mcg/kg/day *Multrys is not recommended for pediatric patients who may require a lower dosage of one or more of these individual trace elements. **Avoid additional manganese supplementation with Multrys use. Accumulation of manganese in the brain can occur with long-term administration with higher than the recommended dosage of 1 mcg/kg/day [see Warnings and Precautions ( 5.3 )]. For pediatric patients weighing less than 3 kg, Multrys does not provide the recommended daily dosage of zinc. Zinc:For patients weighing less than 3 kg, add Zinc Sulfate to provide total daily recommended dose of 400 mcg/kg/day using parenteral and/or enteral routes of administration. For pediatric patients weighing 0.4 kg to 0.59 kg and 4 kg to 9.9 kg, Multrys does not provide the recommended daily dosage of copper or selenium. Copper:For patients weighing 0.4 to 0.59 kg or 4 kg to 9.9 kg, add Cupric Chloride to provide total daily recommended dose of 20 mcg/kg/day using parenteral and/or enteral routes of administration. Selenium: For patients weighing 0.4 to 0.59 kg or 4 kg to 9.9 kg, add Selenious Acid to provide total daily recommended dose of 2 mcg/kg/day using parenteral and/or enteral routes of administration. Monitoring Monitor zinc, copper, and selenium serum concentrations and manganese whole blood concentrations during long-term administration of parenteral nutrition. Trace element concentrations may vary depending on the assay used and the laboratory reference range.The collection, processing, and storage of the blood samples should be performed according to the laboratory’s sample requirements for analysis.

1 INDICATIONS AND USAGE Multrys is indicated in neonatal and pediatric patients weighing less than 10 kg as a source of zinc, copper, manganese, and selenium for parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. Multrys is a combination of trace elements (zinc sulfate, cupric sulfate, manganese sulfate, and selenious acid) indicated in neonatal and pediatric patients weighing less than 10 kg as a source of zinc, copper, manganese, and selenium for parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. ( 1 )

10 OVERDOSAGE There is no information on overdose-related toxicity with a fixed-combination trace element product. However, there are reports on overdosage in the literature for the individual trace elements. Management of overdosage is supportive care based on presenting signs and symptoms. Obtain blood samples for laboratory testing of the individual trace elements and ceruloplasmin for copper. Zinc Acute zinc toxicity was reported in an infant who received an inadvertent 1,000-fold overdose of zinc in parenteral nutrition that led to cardiac failure and death. Zinc toxicity in adult patients receiving 17 to 400-fold the recommended dosage in parenteral nutrition for 2.5 to 60 days reported signs and symptoms including vomiting, diarrhea, hyperamylasemia, thrombocytopenia, and anemia. The zinc serum concentration was 2 to 30-fold the upper end of the reported range in healthy subjects in these cases. Copper Acute copper toxicity was reported in patients with oral, intravenous, or subcutaneous administration. Clinical manifestations included metallic taste, nausea, vomiting, abdominal pain, and multi-organ failure involving kidney, liver, blood, and cardiovascular systems. Chelating agents can be used for treatment of acute toxicity. Long-term administration of parenteral copper above recommended dosage may result in significant accumulation of copper in the liver, brain, and other tissues with possible organ damage [see Warnings and Precautions ( 5.4 )] . Manganese Acute manganese toxicity was reported in adult patients following infusion of manganese more than 10,000-fold the recommended dosage and after use of dialysis fluid contaminated with manganese. Signs and symptoms included skin flushing, acute pancreatitis, elevated whole blood manganese concentrations, and MRI evidence of brain accumulation of manganese. Chronic infusion and oral intake of manganese above recommended dosage have resulted in neuropsychiatric symptoms and MRI evidence of brain accumulation of manganese [see Warnings and Precautions (5.3)] . Selenium Acute selenium toxicity was reported with oral overdosage of greater than 1 g/day. Symptoms included nausea, vomiting, diarrhea, abdominal pain, garlic breath odor, and altered mental status. Death from circulatory collapse was reported after oral ingestion of 5 to 10 g of selenium with blood concentrations ranging 10 to 50-fold the upper end of the reported range in healthy subjects.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Zinc Zinc functions as a cofactor of various enzymes including DNA polymerases, RNA polymerases, alcohol dehydrogenase, and alkaline phosphatases. Zinc is a coordinator of protein structural folding that interacts with a variety of proteins, lipids, and nucleic acids. In addition, zinc is a catalyst of essential biochemical reactions, including activation of substrates of carbonic anhydrase in erythrocyte. Copper Copper is a cofactor for many metalloenzymes acting as an oxidase to achieve reduction of molecular oxygen. Examples of copper metalloenzymes include but are not limited to lysyl oxidase, monoamine oxidase, ferroxidase, cytochrome C oxidase, dopamine beta monooxygenase, tyrosinase, and superoxide dismutase. Manganese Manganese is essential for the normal catalytic activity of several metalloenzymes including manganese superoxide dismutase, arginase, glutamine synthetase, phosphoenolpyruvate decarboxylase, and pyruvate carboxylase. Manganese contributes to the normal function of several other enzyme families including the oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. Selenium Selenious acid is converted in vivo to hydrogen selenide via glutathione-involved electron reductions. Hydrogen selenide acts as a selenium pool to form selenoproteins which include, but are not limited to, glutathione peroxidase, iodothyronine deiodinase, peroxidase, and thioredoxins. 12.2 Pharmacodynamics The exposure-response relationship and the time course of pharmacodynamic response are unknown for zinc, copper, manganese, and selenium. 12.3 Pharmacokinetics Zinc Over 85% of total body zinc is found in skeletal muscle and bone. In blood, zinc is mainly localized within erythrocytes. Approximately 80% of serum zinc is bound to albumin and the remainder to α-2-macroglobulin and amino acids. In adults, zinc is primarily excreted via the gastrointestinal tract and eliminated in the feces. A smaller amount of zinc is excreted via the kidneys in the urine. Urinary zinc excretion rates in very low birth weight preterm infants are relatively high in the neonatal period, and they decline to a level on a body weight basis that is similar to that of normal adults by two months of age. Copper In plasma, about 7% of copper is bound to albumin and amino acids. In the liver, about 93% of copper is bound to ceruloplasmin and released to the serum. Copper is excreted in bile and into the gastrointestinal tract where it is not reabsorbed. Copper is also eliminated through the kidneys. Manganese Manganese is widely distributed in body tissues including liver and specific brain regions such as the basal ganglia. The concentrations of manganese are higher in erythrocytes compared to the plasma or serum concentrations. In human plasma, manganese is bound to albumin and β 1 -globulin. Manganese is found in human bile suggesting biliary excretion. Selenium In humans, 85% of intravenous administered 75 Se-sodium selenite was protein-bound within 4 to 6 hours and 95% by 24 hours.

12.1 Mechanism of Action Zinc Zinc functions as a cofactor of various enzymes including DNA polymerases, RNA polymerases, alcohol dehydrogenase, and alkaline phosphatases. Zinc is a coordinator of protein structural folding that interacts with a variety of proteins, lipids, and nucleic acids. In addition, zinc is a catalyst of essential biochemical reactions, including activation of substrates of carbonic anhydrase in erythrocyte. Copper Copper is a cofactor for many metalloenzymes acting as an oxidase to achieve reduction of molecular oxygen. Examples of copper metalloenzymes include but are not limited to lysyl oxidase, monoamine oxidase, ferroxidase, cytochrome C oxidase, dopamine beta monooxygenase, tyrosinase, and superoxide dismutase. Manganese Manganese is essential for the normal catalytic activity of several metalloenzymes including manganese superoxide dismutase, arginase, glutamine synthetase, phosphoenolpyruvate decarboxylase, and pyruvate carboxylase. Manganese contributes to the normal function of several other enzyme families including the oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. Selenium Selenious acid is converted in vivo to hydrogen selenide via glutathione-involved electron reductions. Hydrogen selenide acts as a selenium pool to form selenoproteins which include, but are not limited to, glutathione peroxidase, iodothyronine deiodinase, peroxidase, and thioredoxins.

12.2 Pharmacodynamics The exposure-response relationship and the time course of pharmacodynamic response are unknown for zinc, copper, manganese, and selenium.

12.3 Pharmacokinetics Zinc Over 85% of total body zinc is found in skeletal muscle and bone. In blood, zinc is mainly localized within erythrocytes. Approximately 80% of serum zinc is bound to albumin and the remainder to α-2-macroglobulin and amino acids. In adults, zinc is primarily excreted via the gastrointestinal tract and eliminated in the feces. A smaller amount of zinc is excreted via the kidneys in the urine. Urinary zinc excretion rates in very low birth weight preterm infants are relatively high in the neonatal period, and they decline to a level on a body weight basis that is similar to that of normal adults by two months of age. Copper In plasma, about 7% of copper is bound to albumin and amino acids. In the liver, about 93% of copper is bound to ceruloplasmin and released to the serum. Copper is excreted in bile and into the gastrointestinal tract where it is not reabsorbed. Copper is also eliminated through the kidneys. Manganese Manganese is widely distributed in body tissues including liver and specific brain regions such as the basal ganglia. The concentrations of manganese are higher in erythrocytes compared to the plasma or serum concentrations. In human plasma, manganese is bound to albumin and β 1 -globulin. Manganese is found in human bile suggesting biliary excretion. Selenium In humans, 85% of intravenous administered 75 Se-sodium selenite was protein-bound within 4 to 6 hours and 95% by 24 hours.

20210601

1

3 DOSAGE FORMS AND STRENGTHS Injection: Each mL of Multrys contains zinc 1,000 mcg, copper 60 mcg, manganese 3 mcg, and selenium 6 mcg in a clear, colorless to slightly blue solution, single-dose vial. Injection: Each mL contains zinc 1,000 mcg, copper 60 mcg, manganese 3 mcg, and selenium 6 mcg in a 1 mL, single-dose vial. (3)

Multrys Trace Elements Injection 4 ZINC SULFATE ZINC CATION CUPRIC SULFATE CUPRIC CATION MANGANESE SULFATE MANGANESE CATION (2+) SELENIOUS ACID SELENIOUS ACID WATER

NDA209376

Multrys

Trace Elements Injection 4

0517-9302

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL - Container Label NDC 0517-9302-01 Rx Only Multrys TM (Trace Elements Injection 4*, USP) *Each mL provides: zinc 1,000 mcg, copper 60 mcg, manganese 3 mcg, and selenium 6 mcg For intravenous infusion after dilution and admixing 1 mL Single-Dose Vial - Discard Unused Portion Container Label

Manufactured by: IN9302 Rev. 6/2021 ARI Logo

17 PATIENT COUNSELING INFORMATION Inform patients, caregivers, and home healthcare providers of the following risks of Multrys: Pulmonary embolism due to pulmonary vascular precipitates [see Warnings and Precautions ( 5.1 )] Vein damage and thrombosis [see Warnings and Precautions ( 5.2 )] Neurologic toxicity with manganese [see Warnings and Precautions ( 5.3 )] Hepatic accumulation of copper and manganese [see Warnings and Precautions ( 5.4)] Aluminum toxicity [see Warnings and Precautions ( 5.5) ] Hypersensitivity reactions with zinc and copper [see Warnings and Precautions ( 5.7 )]

8.4 Pediatric Use Multrys is approved for use in neonatal and pediatric patients weighing less than 10 kg as a source of zinc, copper, manganese, and selenium for parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. Safety and dosing recommendations in pediatric patients less than 10 kg are based on published literature describing controlled studies of products containing zinc, copper, manganese, and selenium [see Dosage and Administration ( 2.5) ] .

8 USE IN SPECIFIC POPULATIONS This section intentionally left blank. ( 8 ) 8.4 Pediatric Use Multrys is approved for use in neonatal and pediatric patients weighing less than 10 kg as a source of zinc, copper, manganese, and selenium for parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. Safety and dosing recommendations in pediatric patients less than 10 kg are based on published literature describing controlled studies of products containing zinc, copper, manganese, and selenium [see Dosage and Administration ( 2.5) ] . 8.6 Hepatic Impairment Copper is primarily excreted in the bile. Excretion is decreased in patients with cholestasis and/or cirrhosis. Manganese is presumed to be excreted in bile [see Clinical Pharmacology ( 12.3 )] . Hepatic accumulation of copper and manganese has been reported with long-term administration of parenteral nutrition at dosages higher than recommended [see Warnings and Precautions ( 5.4)] . For patients with cholestasis or cirrhosis, monitor hepatic and biliary function during long-term administration of Multrys. If a patient develops signs or symptoms of hepatobiliary disease during use of Multrys, obtain serum concentrations of copper and ceruloplasmin as well as manganese whole blood concentrations; consider using individual trace element products in these patients.

16 HOW SUPPLIED Multrys (trace elements injection 4*, USP) is a clear, colorless to slightly blue solution supplied in: 1 mL single-dose vial (NDC 0517-9302-01) and packaged in trays containing 25 vials per tray (NDC 0517-9302-25). *Each mL of Multrys contains zinc 1,000 mcg, copper 60 mcg, manganese 3 mcg, and selenium 6 mcg. Vial closure is not made with natural rubber latex. Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Store admixed solution at 2ºC to 8ºC (36ºF to 46ºF) [see Dosage and Administration ( 2.3 )] .