Trace Elements Injection 4

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 )

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

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 mOsmol/L or more must be infused through a central catheter. ( 2.1 , 5.2 ) Neurologic Toxicity with Manganese :Monitor for clinical signs and symptoms of neurotoxicity, whole blood manganese concentrations, and liver function tests in patients receiving long-term Multrys.Discontinue Multrys and consider brain magnetic resonance imaging (MRI) if toxicity is suspected. ( 5.3 ) Hepatic Accumulation of Copper and Manganese :Assess for development of hepatic accumulation.Monitor concentrations of copper and manganese in patients with cholestasis or cirrhosis receiving Multrys long-term. ( 5.4 ) Aluminum Toxicity : Increased risk in patients with renal impairment, including preterm infants. ( 5.5 ) Monitoring and Laboratory Tests : Monitor zinc, copper, and selenium serum concentrations, whole blood manganese concentration, fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, blood count, and coagulation parameters. ( 5.6 , 2.4 ) Hypersensitivity Reactions with Zinc and Copper : If reactions occur, discontinue Multrys and initiate appropriate medical 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. The cause of precipitate formation has not been determined in all cases; however, in some fatal cases, pulmonary emboli occurred as a result of calcium phosphate precipitates. Precipitation has occurred following passage through an in-line filter; in vivo precipitate formation may also have occurred. If signs of pulmonary distress occur, stop the parenteral nutrition infusion and initiate a medical evaluation. In addition to inspection of the solution [see Dosage and Administration ( 2.2 , 2.3 )] , the infusion set and catheter should also periodically be checked for precipitates.

5.2 Vein Damage and Thrombosis Multrys must be prepared and used as an admixture in parenteral nutrition solution. It is not for direct intravenous infusion. In addition, consider the osmolarity of the final parenteral nutrition solution in determining peripheral versus central administration. Solution with an osmolarity of 900 mOsmol/L or greater must be infused through a central catheter [see Dosage and Administration ( 2.1 )] . The infusion of hypertonic nutrient solution 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 Neurologic Toxicity with Manganese Pediatric patients on long-term parenteral nutrition receiving manganese at higher than recommended dosages and pediatric patients with cholestatic liver disease have experienced manganese accumulation in the basal ganglia. Some adult patients with brain MRI findings reportedly experienced neuropsychiatric symptoms, including changes in mood or memory, seizures and/or parkinsonian-like tremors, dysarthria, mask-face, and halting gait. Some pediatric patients experienced dystonic movements or seizures. Brain MRI findings and clinical symptoms have also been observed in patients who received manganese at or below the recommended dosage and with normal blood manganese concentrations. Regression of symptoms and brain MRI findings have occurred over weeks to months following discontinuation of manganese in most patients but have not always completely resolved. Monitor patients receiving long-term parenteral nutrition solutions containing Multrys for neurologic signs and symptoms and routinely monitor whole blood manganese concentrations and liver function tests. In case of suspected manganese toxicity or new neuro-psychiatric manifestations, temporarily discontinue Multrys, check manganese whole blood concentrations, and consider brain MRI evaluation. Monitor patients receiving Multrys for cholestasis or other biliary liver disease. Consider individual trace element products as an alternative to Multrys in patients with hepatobiliary disease [see Warnings and Precautions ( 5.4 )] .

5.4 Hepatic Accumulation of Copper and Manganese Copper is primarily eliminated in the bile and excretion is decreased in patients with cholestasis and/or cirrhosis. Hepatic accumulation of copper and manganese have been reported in autopsies of patients receiving long-term parenteral nutrition containing copper and manganese at dosages higher than recommended. Patients with cholestasis and/or cirrhosis receiving parenteral nutrition are at increased risk of manganese brain deposition and neurotoxicity [see Warnings and Precautions ( 5.3) ]. Administration of copper to patients with cholestasis and/or cirrhosis may cause hepatic accumulation of copper. Administration of copper to patients with Wilson disease, an inborn error of copper metabolism with a defect in hepatocellular copper transport, may cause both increased hepatic accumulation of copper and aggravation of the underlying hepatocellular degeneration. If a patient develops signs or symptoms of hepatobiliary disease during the 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 [see Use in Specific Populations ( 8.6 )] .

5.5 Aluminum Toxicity Multrys contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Preterm infants, including preterm neonates, are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including preterm infants and premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration or lower daily amounts. Exposure to aluminum from Multrys is not more than 0.45 mcg/kg/day. When prescribing Multrys 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.

5.6 Monitoring and Laboratory Tests Monitor zinc, copper, and selenium serum concentrations, manganese whole blood concentration, fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, blood count, and coagulation parameters during use of parenteral nutrition containing Multrys [see Dosage and Administration ( 2.4 )] .

5.7 Hypersensitivity Reactions with Zinc and Copper Postmarket safety reporting has identified zinc hypersensitivity in patients receiving zinc-containing insulin products and copper hypersensitivity in women receiving copper-containing intrauterine devices, providing evidence that patients may experience hypersensitivity reactions when exposed to these metals. If hypersensitivity reactions (e.g., pruritis, angioedema, dyspnea, rash, urticaria) occur in patients receiving Multrys in parenteral nutrition, discontinue Multrys, and initiate appropriate medical treatment [see Contraindications ( 4)] .

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 .

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.

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.