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 mOsm/L or more must be infused through a central catheter ( 2.1 , 5.2 ) • Increased Blood Urea Nitrogen (BUN) : Monitor laboratory parameters and discontinue if BUN exceeds normal postprandial limits and continues to increase. ( 5.3 ) • Acid-Base Imbalance : Monitor laboratory parameters and supplement with electrolytes as needed. ( 5.4 ) • Hepatobiliary Disorders : Neurocognitive delay possible in infants; monitor liver function parameters and ammonia levels. ( 5.5 , 8.4 ) • Aluminum Toxicity : Increased risk in patients with renal impairment, including preterm infants. ( 5.6 , 8.4 ) • Monitoring and Laboratory Tests : Monitor fluid and electrolytes, serum osmolarity, blood glucose, kidney and liver function, blood count, and coagulation parameters throughout 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. In some fatal cases, pulmonary embolism occurred as a result of calcium phosphate precipitates. Precipitation following passage through an in-line filter and suspected in vivo precipitate formation has also been reported. 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 (2.1 , 2.2) ], the infusion set and catheter should also periodically be checked for precipitates. 5.2 Vein Damage and Thrombosis Cysteine hydrochloride injection, USP must be diluted and used as an admixture in parenteral nutrition solutions. Solutions with an osmolarity of 900 mOsm/L or greater must be infused through a central catheter [see Dosage and Administration (2.1) ]. The infusion of hypertonic nutrient injections 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 Increased Blood Urea Nitrogen (BUN) Intravenous infusion of amino acids may induce a rise in blood urea nitrogen (BUN), especially in patients with impaired hepatic or renal function. Appropriate laboratory tests should be performed periodically and infusion discontinued if BUN levels exceed normal postprandial limits and continue to rise. It should be noted that a modest rise in BUN normally occurs as a result of increased protein intake. Administration of amino acid solutions in the presence of impaired renal function may augment an increasing BUN, as does any protein dietary component. 5.4 Acid-Base Imbalance Administration of cysteine hydrochloride injection, USP may result in metabolic acidosis in neonates. Administration of amino acid solutions to a patient with hepatic impairment may result in serum amino acid imbalances, metabolic alkalosis, prerenal azotemia, hyperammonemia, stupor and coma. Frequent clinical evaluation and laboratory determinations are necessary for proper monitoring of acid-base balance during parenteral nutrition therapy. Significant deviations from normal concentrations may require the use of additional electrolyte supplements. 5.5 Hepatobiliary Disorders Hepatobiliary disorders are known to develop in some patients, including neonates, without preexisting liver disease who receive parenteral nutrition, including cholecystitis, cholelithiasis, cholestasis, hepatic steatosis, fibrosis and cirrhosis, possibly leading to hepatic failure. The etiology of these disorders is thought to be multifactorial and may differ between patients. Instances of asymptomatic hyperammonemia have been reported in patients receiving parenteral nutrition without overt liver dysfunction. The mechanisms of this reaction are not clearly defined but may involve genetic defects and immature or subclinically impaired liver function [see Contraindications (4) , Use in Specific Populations (8.4) ] Hyperammonemia is of special significance in infants, as it can result in neurocognitive delays. Monitor liver function parameters and ammonia levels during treatment with cysteine hydrochloride injection, USP. Patients developing signs of hepatobiliary disorders should be assessed early by a clinician knowledgeable in liver diseases in order to identify possible causative and contributory factors, and possible therapeutic and prophylactic interventions. 5.6 Aluminum Toxicity Cysteine hydrochloride injection, USP contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration in patients with renal impairment. Neonates and preterm infants are particularly at risk for aluminum toxicity because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which also contain aluminum. Patients with renal impairment including neonates and preterm infants, who receive greater than 4 to 5 mcg/kg/day of parenteral aluminum can accumulate aluminum to levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration. Exposure to aluminum from cysteine hydrochloride injection, USP is not more than 0.25 mcg/kg/day when preterm and term neonates are administered the recommended maximum dosage of cysteine hydrochloride injection, USP (22 mg cysteine hydrochloride/g of amino acids and 4 g of amino acids/kg/day) [see Dosage and Administration (2.5) ]. When prescribing cysteine hydrochloride injection, USP 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) ]. 5.7 Monitoring and Laboratory Tests Monitor fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, ammonia levels, blood count and coagulation parameters throughout treatment [see Dosage and Administration (2.4) ].