Trace Elements Injection 4

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 )

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 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.

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 .

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.