CUPRIC Drug Interactions: What You Need to Know

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.

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 )

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.