warnings and cautions
5 WARNINGS 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 ) • Aluminum Toxicity: Increase risk in patients with renal impairment, including preterm infants ( 5.3 , 8.4 ) • Monitoring and Laboratory Tests: Monitor fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, blood count and coagulation parameters throughout treatment. ( 5.4 , 2.4 ) • Copper Deficiency: If signs and symptoms develop, interrupt treatment with zinc sulfate injection and check zinc, copper, and ceruloplasmin levels. ( 5.5 ) • Hypersensitivity Reactions: If reactions occur, discontinue zinc sulfate injection and initiate appropriate medical treatment. ( 5.6 ) 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 Zinc sulfate injection has a low pH and must be prepared and used as an admixture in parenteral nutrition solutions. It is not for direct intravenous infusion. In addition, consider the osmolarity of the final parenteral nutrition solution in determining peripheral versus central administration. Solutions 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 solutions 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 Aluminum Toxicity Zinc sulfate injection contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Preterm infants are particularly at risk for aluminum toxicity because the kidneys are immature, and they require large amounts of calcium and phosphate solutions, which also contain aluminum. Patients with impaired kidney function, including preterm infants, who receive greater than 4 to 5 mcg/kg/day of parenteral aluminum can accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration. Exposure to aluminum from zinc sulfate injection is not more than 0.6 mcg/kg/day. When prescribing zinc sulfate injection 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 [see Use in Specific Populations (8.4) ]. 5.4 Monitoring and Laboratory Tests Monitor zinc concentrations, fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, blood count and coagulation parameters throughout treatment [see Dosage and Administration (2.4) ]. 5.5 Copper Deficiency Several post-marketing cases have reported that high doses of supplemental zinc (approximately 10 times the recommended dosage of 3 mg/day zinc sulfate injection in adults) taken over extended periods of time (i.e., months to years) may result in decreased enteral copper absorption and copper deficiency. The cases reported the following complications of copper deficiency: anemia, leukopenia, thrombocytopenia, myeloneuropathy, and nephrotic-range proteinuria [see Adverse Reactions (6) ]. If a patient develops signs and symptoms of copper deficiency during treatment with zinc sulfate injection, interrupt zinc treatment and check zinc, copper, and ceruloplasmin levels. Copper deficiency should be treated with supplemental copper administration and discontinuation of zinc supplementation. 5.6 Hypersensitivity Reactions Hypersensitivity reactions to subcutaneously administered zinc-containing insulin products were identified in postmarketing case reports. 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. If hypersensitivity reactions occur, discontinue zinc sulfate injection and initiate appropriate medical treatment [see Contraindications (4) ].