CUPRIC: 376 Adverse Event Reports & Safety Profile

Tralement ® (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 and each multiple-dose vial contains 10 mL. *Each mL contains zinc 3 mg (equivalent to zinc sulfate 7.41 mg), copper 0.3 mg (equivalent to cupric sulfate 0.75 mg), manganese 55 mcg (equivalent to manganese sulfate 151 mcg), selenium 60 mcg (equivalent to selenious acid 98 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. Tralement contains no more than 6,000 mcg/L of aluminum.

Zinc Sulfate Structural Formula Cupric

Sulfate Structural Formula Manganese Structural Formula Selenious Acid Structural Formula

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 )

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> .

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.

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

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) ] No adverse reactions related to zinc, copper, selenium, or manganese have been reported in patients receiving intravenously administered parenteral solutions containing these trace elements within the recommended dosage range. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-432-8534 or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch.

AND PRECAUTIONS 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 Tralement.

Discontinue

Tralement and consider brain magnetic resonance imaging (MRI) if toxicity suspected. ( 5. 3)

Hepatic

Accumulation of Copper and Manganese : Assess for development of hepatic or biliary dysfunction. Monitor concentrations of copper and manganese in patients with cholestasis, biliary dysfunction or cirrhosis receiving Tralement long-term. ( 5.4 )

Aluminum

Toxicity : Increased risk in patients with renal impairment, including preterm infants. ( 5.5 , 8.4 ) Monitoring and Laboratory Tests : Monitor blood zinc, copper, manganese, and selenium concentrations, 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 Tralement and initiate appropriate medical treatment. ( 5.7) 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.

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 Tralement 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 Manganese accumulation in the basal ganglia has been reported in adult and pediatric patients on long-term parenteral nutrition receiving manganese at higher than recommended dosages and in association with cholestatic liver disease. 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 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 Tralement 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 Tralement, check manganese whole blood concentrations, and consider brain MRI evaluation. Monitor patients receiving Tralement for cholestasis or other biliary liver disease. Consider individual trace element products as an alternative to Tralement in patients with hepatic and/or biliary dysfunction [ 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 receiving parenteral nutrition with cholestasis and/or cirrhosis are at increased risk of manganese brain deposition and neurotoxicity <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 ) ]</span>. 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 defect in hepatocellular copper transport, may cause both increased hepatic accumulation of copper and aggravation of the underlying hepatocellular degeneration. For patients with cholestasis, biliary dysfunction, or cirrhosis, monitor hepatic and biliary function during long-term administration of Tralement. If a patient develops signs or symptoms of hepatic or biliary dysfunction during the use of Tralement, obtain serum concentrations of copper and ceruloplasmin as well as manganese whole blood concentrations. Consider using individual trace element products in patients with hepatic and/or biliary dysfunction [ see Use in Specific Populations ( 8.6) ] .

5.5 Aluminum Toxicity Tralement 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 Tralement is no more than 0.1 mcg/kg/day. When prescribing Tralement 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4 )]</span> .

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

5.7 Hypersensitivity Reactions with Zinc and Copper Hypersensitivity reactions to subcutaneously administered zinc-containing insulin products and copper-containing intrauterine devices (IUD) were identified in postmarketing case reports. If hypersensitivity reactions occur in patients receiving Tralement in parenteral nutrition, discontinue Tralement, and initiate appropriate medical treatment [ see Contraindications ( 4 )] .

Zinc

For patients prescribed zinc-containing insulin products, reported reactions included injection site induration, erythema, pruritus, papular rash, generalized urticaria, facial swelling, and dyspnea. Patients did not manifest symptoms after changing to zinc-free insulin or another insulin product with a reduced amount of zinc. In some cases, allergy testing confirmed the allergy to the zinc component of the insulin product.

Copper

For women with copper IUD implantation, reported reactions included diffuse eczematous dermatitis, maculopapular skin eruption, urticaria, and angioedema of the eyelids, face, and labia weeks or months after IUD insertion. In most cases, the patch test for copper was positive, and the adverse reactions resolved after IUD removal.

PRECAUTIONS General Do not use unless the solution is clear and the seal is intact. Administration of zinc in the absence of copper may cause a decrease in serum copper levels.

Cupric Chloride

Injection, USP 0.4 mg/mL should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed. It is not recommended to administer copper to a patient with Wilson’s Disease, a genetic disease of copper metabolism.

Drug Interactions

Cupric ion may degrade ascorbic acid in total parenteral nutrition (TPN) solutions. In order to avoid this loss of ascorbate, multivitamin additives should be added to TPN solutions immediately prior to infusion. Alternatively, the multivitamin additive may be added to one container of TPN solution, followed by copper in a subsequent container.

Laboratory Tests

Twice monthly serum assays for copper and/or ceruloplasmin are suggested for monitoring copper concentrations in long-term TPN patients. As ceruloplasmin is a cuproenzyme, ceruloplasmin assays may be depressed secondary to copper deficiency. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies to evaluate the carcinogenic potential of Cupric Chloride Injection, USP 0.4 mg/mL have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Cupric Chloride Injection, USP 0.4 mg/mL is administered to a nursing woman.

Pediatric

Use (See DOSAGE AND ADMINISTRATION section.) There are limited data in infants weighing less than 1,500 grams.

Pregnancy

Animal reproduction studies have not been conducted with cupric chloride. It is also not known whether cupric chloride can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Cupric chloride should be given to a pregnant woman only if clearly indicated.

Geriatric

Use An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Drug Interactions Cupric ion may degrade ascorbic acid in total parenteral nutrition (TPN) solutions. In order to avoid this loss of ascorbate, multivitamin additives should be added to TPN solutions immediately prior to infusion. Alternatively, the multivitamin additive may be added to one container of TPN solution, followed by copper in a subsequent container.

Cuprum oxydatum nigrum 200CK HPUS Active ingredient**: See product name on front panel (**contains 0.443 mg of the active ingredient per pellet).

Inactive Ingredients: White petrolatum, Mineral oil Prepared using rhythmical processes.