warnings and cautions
5 WARNINGS AND PRECAUTIONS • Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsion in Neonates and Infants : Acute respiratory distress, metabolic acidosis, and death after rapid infusion of intravenous lipid emulsions have been reported. ( 5.1 ) • Parenteral Nutrition-Associated Liver Disease : Increased risk in patients who receive parenteral nutrition for greater than 2 weeks. Monitor liver tests; if abnormalities occur, consider discontinuation or dosage reduction. ( 5.2 ) • Pulmonary Embolism and Respiratory Distress due to Pulmonary Vascular Precipitates: If signs of pulmonary distress occur, stop the infusion and initiate a medical evaluation. ( 5.3 ) • Hypersensitivity Reactions : Monitor for signs or symptoms and discontinue infusion if reactions occur. ( 5.4 ) • Precipitation with Ceftriaxone: Do not administer ceftriaxone simultaneously with KABIVEN via a Y-site. ( 4 , 5.5 , 8.4 ) • Infection, fat overload, hyperglycemia and refeeding complications : Monitor for signs and symptoms; monitor laboratory parameters. ( 5.6 , 5.7 , 5.8 , 5.9 , 5.14 ) 5.1 Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsion in Neonates and Infants In the postmarketing setting, serious adverse reactions including acute respiratory distress, metabolic acidosis, and death have been reported in neonates and infants after rapid infusion of intravenous lipid emulsions. Hypertriglyceridemia was commonly reported. Preterm and small for gestational age infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion. 5.2 Parenteral Nutrition-Associated Liver Disease and Other Hepatobiliary Disorders Risk of Parenteral Nutrition-Associated Liver Disease Parenteral nutrition-associated liver disease (PNALD), also referred to as intestinal failure-associated liver disease (IFALD), can present as cholestasis or hepatic steatosis, and may progress to steatohepatitis with fibrosis and cirrhosis (possibly leading to chronic hepatic failure). The etiology of PNALD is multifactorial; however, intravenously administered phytosterols (plant sterols) contained in plant-derived lipid emulsions, such as Intralipid (included in KABIVEN), have been associated with development of PNALD. In a randomized study of neonates and infants expected to be treated with PN for at least 28 days, parenteral nutrition-associated cholestasis (PNAC), a precursor to PNALD, developed more frequently in Intralipid-treated patients than in patients treated with a 4-oil mixed lipid emulsion [see Adverse Reactions ( 6.1 ), Use in Specific Populations ( 8.4 )]. Monitor liver tests in patients treated with KABIVEN and consider discontinuation or dosage reduction if abnormalities occur. Other Hepatobiliary Disorders Hepatobiliary disorders including cholecystitis and cholelithiasis have developed in some PN-treated patients without preexisting liver disease. Monitor liver tests when administering KABIVEN. Patients developing signs of hepatobiliary disorders should be assessed early to determine whether these conditions are related to KABIVEN use. 5.3 Pulmonary Embolism and Respiratory Distress due to Pulmonary Vascular Precipitates Pulmonary vascular precipitates causing pulmonary emboli (including some fatalities) and respiratory distress have been reported in patients receiving parenteral nutrition. Excessive addition of calcium and phosphate increases the risk of the formation of calcium phosphate precipitates; however, precipitates have been reported even in the absence of phosphate salt in the solution. Precipitation following passage through an in-line filter and suspected in vivo precipitate formation has also been reported. Visually inspect the prepared solution, the infusion set, and catheter for precipitates, prior to administration as well as periodically during the administration. If signs of respiratory distress or pulmonary embolism occur, stop the KABIVEN infusion and initiate a medical evaluation. 5.4 Hypersensitivity Reactions KABIVEN contains soybean oil, which may cause hypersensitivity reactions. Cross reactions have been observed between soybean and peanut. In postmarketing experience, anaphylaxis has been reported following KABIVEN administration [see Adverse Reactions ( 6.2 )] . KABIVEN is contraindicated in patients with known hypersensitivity to egg, soybean, peanut or any of the active or inactive ingredients in KABIVEN [see Contraindications ( 4 )] . If a hypersensitivity reaction occurs, stop infusion of KABIVEN immediately and initiate appropriate treatment and supportive measures. 5.5 Precipitation with Ceftriaxone Precipitation of ceftriaxone-calcium can occur when ceftriaxone is mixed with calcium-containing parenteral nutrition solutions, such as KABIVEN in the same intravenous administration line. Do not administer ceftriaxone simultaneously with KABIVEN via a Y-site. However, in patients other than neonates, ceftriaxone and KABIVEN may be administered sequentially if the infusion lines are thoroughly flushed between infusions with a compatible fluid [ s ee Dosage and Administration ( 2.1 )] . Deaths have occurred in neonates (28 days of age or younger) who received concomitant intravenous calcium-containing solutions with ceftriaxone resulting from calcium-ceftriaxone precipitates in the lungs and kidneys, even when separate infusion lines were used [see Contraindications ( 4 ), Pediatric Use ( 8.4 )]. 5.6 Infections Parenteral nutrition, such as KABIVEN, can support microbial growth and is an independent risk factor for the development of catheter-related bloodstream infections. To decrease the risk of infectious complications, ensure aseptic techniques are used for catheter placement, catheter maintenance, and preparation and administration of KABIVEN. Monitor for signs and symptoms of infection including fever and chills, as well as laboratory test results that might indicate infection (including leukocytosis and hyperglycemia). Perform frequent checks of the intravenous catheter insertion site for edema, redness, and discharge. 5.7 Fat Overload Syndrome Fat overload syndrome is a rare condition that has been reported with intravenous lipid formulations and is characterized by a sudden deterioration in the patient's condition (e.g., fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, hepatomegaly, deteriorating liver function, and central nervous system manifestations such as coma). A reduced or limited ability to metabolize lipids, accompanied by prolonged plasma clearance (resulting in higher lipid levels), may result in this syndrome. Although fat overload syndrome has been most frequently observed when the recommended lipid dose or infusion rate was exceeded, cases have also been described when the lipid formulation was administered according to instructions. If signs or symptoms of fat overload syndrome occur, stop KABIVEN. The syndrome is usually reversible when the infusion including the lipid emulsion is stopped. 5.8 Refeeding Syndrome Administering PN to severely malnourished patients may result in refeeding syndrome, characterized by the intracellular shift of potassium, phosphorus, and magnesium as patients become anabolic. Thiamine deficiency and fluid retention may also develop. To prevent these complications, closely monitor severely undernourished patients and slowly increase their nutrient intake. 5.9 Diabetes and Hyperglycemia Administration of dextrose at a rate exceeding the patient's utilization rate may lead to hyperglycemia, hyperosmolar coma, and death. Monitor blood glucose levels and treat hyperglycemia to maintain optimal glucose levels while infusing KABIVEN. Insulin may be administered or adjusted to maintain optimal blood glucose levels during KABIVEN administration. 5.10 Hypertriglyceridemia The use of KABIVEN is contraindicated in patients with hypertriglyceridemia with serum triglyceride concentrations >1,000 mg/dL. Patients with conditions such as inherited lipid disorders, obesity, diabetes mellitus, or metabolic syndromes have a higher risk of developing hypertriglyceridemia with the use of KABIVEN. In addition, patients with hypertriglyceridemia may have worsening of their hypertriglyceridemia with administration of KABIVEN. Excessive dextrose administration may further increase such risk. Evaluate patients' capacity to eliminate and metabolize the infused lipid emulsion by measuring serum triglycerides before the start of infusion (baseline value), with each increase in dosage, and regularly throughout treatment. If triglyceride levels are above 400 mg/dL in adults, stop the KABIVEN infusion and monitor serum triglyceride levels to avoid clinical consequences of hypertriglyceridemia such as pancreatitis. To minimize the risk of new or worsening of hypertriglyceridemia, assess high-risk patients for their overall energy intake including other sources of lipid and dextrose, as well as concomitant drugs that may affect lipid and dextrose metabolism. 5.11 Vein Damage and Thrombosis The infusion of hypertonic nutrient injections into a peripheral vein may result in vein irritation, vein damage, and/or thrombosis. KABIVEN is only approved for administration into a central vein, such as the superior vena cava [see Dosage and Administration ( 2.1 )]. Remove the catheter as soon as possible if thrombophlebitis develops. 5.12 Electrolyte Imbalance and Fluid Overload in Patients with Decreased Renal Function Patients with decreased renal function, including those with pre-renal azotemia, renal obstruction, or intrinsic renal disease, may be at increased risk of electrolyte and fluid volume imbalance when receiving PN, including KABIVEN. In patients with decreased renal function with electrolyte imbalance or fluid overload, the KABIVEN dosage (e.g., fluid, protein, and electrolyte content) may require adjustment. Monitor renal function parameters. Patients developing signs of decreased renal function should be assessed early by a clinician knowledgeable in renal disease in order to determine the appropriate KABIVEN dosage. 5.13 Aluminum Toxicity KABIVEN contains no more than 25 mcg/L of aluminum. The aluminum contained in KABIVEN may reach toxic levels with prolonged parenteral administration in patients with impaired kidney function. Preterm infants are at greater risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions that contain aluminum. Patients with impaired kidney function, including preterm infants, 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 of total parenteral nutrition products. 5.14 Monitoring/Laboratory Tests Monitor fluid status closely in patients with pulmonary edema or heart failure. Throughout treatment, monitor serum triglycerides [see Warnings and Precautions ( 5.13 )] , fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, blood count (including platelets), and coagulation parameters. KABIVEN contains Vitamin K that may counteract anticoagulant activity [see Drug Interactions ( 7 )] . The lipids contained in KABIVEN may interfere with some laboratory tests (e.g., hemoglobin, triglycerides, lactate dehydrogenase, bilirubin and oxygen saturation) if blood is sampled before the lipids have cleared from the bloodstream. Conduct these tests at least 6 hours after stopping the infusion.