I.v. Fat Emulsion

Intralipid ® is indicated as a source of calories and essential fatty acids for adult and pediatric patients requiring parenteral nutrition (PN) and as a source of essential fatty acids for prevention of essential fatty acid deficiency (EFAD). Intralipid is indicated as a source of calories and essential fatty acids for adult and pediatric patients requiring parenteral nutrition (PN) and as a source of essential fatty acids for prevention of essential fatty acid deficiency (EFAD).

Intralipid 20% is a sterile, homogenous, milky, white lipid injectable emulsion in Flexible Containers supplied as:

• 20 g/100 mL (0.2 g/mL) of lipid in 100 mL single-dose Flexible Container
• 50 g /250 mL (0.2 g/mL) of lipid in 250 mL single-dose Flexible Container
• 100 g/500 mL (0.2 g/mL) of lipid in 500 mL single-dose Flexible Container
• 200 g /1,000 mL (0.2 g/mL) of lipid in 1,000 mL Pharmacy Bulk Package 20% Injectable emulsion:
• 20 g/100 mL (0.2 g/mL) of lipid in 100 mL single-dose flexible container ( 3 )
• 50 g/250 mL (0.2 g/mL) of lipid in 250 mL single-dose flexible container ( 3 )
• 100 g/500 mL (0.2 g/mL) of lipid in 500 mL single-dose flexible container ( 3 )
• 200 g/1,000 mL (0.2 g/mL) of lipid in 1,000 mL Pharmacy Bulk Package ( 3 )

• Known hypersensitivity to egg, soybean, peanut, or any of the active or inactive ingredients in Intralipid [see Warnings and Precautions ( 5.3 )]
• Severe disorders of lipid metabolism characterized by hypertriglyceridemia (serum triglyceride > 1,000 mg/dL) [see Warnings and Precautions ( 5.7 )]
• Known hypersensitivity to egg, soybean, or peanut, or any of the active ingredients or excipients. ( 4 , 5.3 )
• Severe disorders of lipid metabolism characterized by hypertriglyceridemia (serum triglyceride > 1,000 mg/dL). ( 4 , 5.7 )

• Risk of 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 , 8.4 )
• Risk of Parenteral Nutrition-Associated Liver Disease (PNALD): Increased risk in patients who receive PN for extended periods of time, especially preterm neonates. Monitor liver function tests; if abnormalities occur consider discontinuation or dosage reduction. ( 5.2 , 6.1 , 8.4 )
• Hypersensitivity Reactions: Monitor for signs or symptoms. Discontinue infusion if reactions occur. ( 5.3 )
• Risk of Infections, Fat Overload Syndrome, Refeeding Syndrome, and Hypertriglyceridemia: Monitor for signs and symptoms; monitor laboratory parameters. ( 5.4 , 5.5 , 5.6 , 5.7 )
• Aluminum Toxicity: Increased risk in patients with renal impairment, including preterm neonates. ( 5.8 , 8.4 )

5.1 Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsions 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. Strictly adhere to the recommended total daily dosage; the hourly infusion rate should not exceed 0.75 mL/kg/hour [see Dosage and Administration ( 2.3 )]. 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. Carefully monitor the infant's ability to eliminate the infused lipids from the circulation (e.g., measure serum triglycerides and/or plasma free fatty acid levels). If signs or poor clearance of lipids from the circulation occur, stop the infusion and initiate a medical evaluation [see Warnings and Precautions ( 5.5 , 5.7 ) and Overdosage ( 10 )].

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, including Intralipid, 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 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 Intralipid 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 Intralipid. Patients developing signs of hepatobiliary disorders should be assessed early to determine whether these conditions are related to Intralipid use.

5.3 Hypersensitivity Reactions Intralipid contains soybean oil and egg phospholipids, which may cause hypersensitivity reactions. Cross reactions have been observed between soybean and peanut. In postmarketing experience, anaphylaxis has been reported following Intralipid administration [see Adverse Reactions ( 6.2 )] . Intralipid is contraindicated in patients with known hypersensitivity to egg, soybean, peanut or any of the active or inactive ingredients in Intralipid [see Contraindications ( 4 )] . If a hypersensitivity reaction occurs, stop infusion of Intralipid immediately and initiate appropriate treatment and supportive measures.

5.4 Infections Parenteral nutrition, such as Intralipid, 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 Intralipid. 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.

5.5 Fat Overload Syndrome Fat overload syndrome is a rare condition that has been reported with intravenous lipid injectable emulsions 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 the infusion of Intralipid. The syndrome is usually reversible when the infusion of the lipid emulsion is stopped.

5.6 Refeeding Syndrome Administering PN to severely malnourished patients may result in refeeding syndrome, which is 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 malnourished patients and slowly increase their nutrient intake.

5.7 Hypertriglyceridemia The use of Intralipid 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 Intralipid. In addition, patients with hypertriglyceridemia may have worsening of their hypertriglyceridemia with administration of Intralipid. Excessive dextrose administration may further increase such risk. Evaluate patients' capacity to metabolize and eliminate the infused lipid emulsion by measuring serum triglycerides before the start of infusion (baseline value) and regularly throughout treatment. If triglyceride levels are above 400 mg/dL in adults, stop the Intralipid infusion and monitor serum triglyceride levels to avoid clinical consequences of hypertriglyceridemia such as pancreatitis. In pediatric patients with hypertriglyceridemia, lower triglyceride levels (i.e., below 400 mg/dL) may be associated with adverse reactions. Monitor serum triglyceride levels to avoid potential complications with hypertriglyceridemia such as pancreatitis, lipid pneumonitis, and neurologic changes, including kernicterus. To minimize the risk of new or worsening of hypertriglyceridemia, assess high-risk patients for their overall energy intake including other sources of lipids and dextrose, as well as concomitant drugs that may affect lipid and dextrose metabolism.

5.8 Aluminum Toxicity Intralipid contains no more than 25 mcg/L of aluminum. Prolonged PN administration in patients with renal impairment may result in aluminum reaching toxic levels. […]

Adverse reactions described elsewhere in this Prescribing Information are:

• Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsion in Neonates and Infants [see Warnings and Precautions ( 5.1 )]
• Parenteral Nutrition-Associated Liver Disease and Other Hepatobiliary Disorders [see Warnings and Precautions ( 5.2 )]
• Hypersensitivity Reactions [see Warnings and Precautions ( 5.3 )]
• Infections [see Warnings and Precautions ( 5.4 )]
• Fat Overload Syndrome [see Warnings and Precautions ( 5.5 )]
• Refeeding Syndrome [see Warnings and Precautions ( 5.6 )]
• Hypertriglyceridemia [see Warnings and Precautions ( 5.7 )]
• Aluminum Toxicity [see Warnings and Precautions ( 5.8 )] Most common adverse drug reactions (≥5%) from clinical trials in adults were nausea, vomiting, and pyrexia. Most common adverse drug reactions (≥5%) from clinical trials in pediatric patients were anemia, vomiting, increased gamma-glutamyltransferase, and cholestasis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Intralipid or equivalent soybean oil lipid emulsions functioned as the comparator in trials of the 4-oil mixed lipid emulsion [see Clinical Studies ( 14 )]. The adverse reactions from these studies are included to present the clinical experience with Intralipid. The safety database for Intralipid or equivalent soybean oil lipid emulsion exposure in these studies includes 393 patients (230 adults; 163 pediatric) in 9 clinical trials. Adult patients were exposed for 5 days to 4 weeks in 5 clinical trials. Intralipid or equivalent soybean oil lipid emulsion was used as a component of PN which also included dextrose, amino acids, vitamins, and trace elements. Two of the 5 studies in adults were performed with Intralipid as a component of PN delivered in a 3-chamber bag. Table 2: Adverse Reactions in >1% of Adult Patients Treated with Intralipid/Soybean oil emulsion Adverse Reaction Number of Patients in Soybean Oil Lipid Emulsion Group (N=230) Number of Patients in 4-Oil Mixed Lipid Emulsion Comparator Group (N=229) Nausea 26 (11%) 20 (9%) Vomiting 12 (5%) 15 (7%) Pyrexia 11 (5%) 9 (4%) Hypertension 9 (4%) 6 (3%) Headache 7 (3%) 3 (1%) Hyperglycemia 5 (2%) 12 (5%) Abdominal pain 5 (2%) 8 (4%) Flatulence 4 (2%) 10 (4%) Blood triglycerides increased 4 (2%) 6 (3%) Sepsis 4 (2%) 5 (2%) Diarrhea 4 (2%) 3 (1%) Pneumonia 4 (2%) 3 (1%) Pruritus 4 (2%) 3 (1%) Gamma-glutamyltransferase increased 4 (2%) 2 (1%) Less common adverse reactions occurring in ≤1% of adult patients who received Intralipid or equivalent soybean oil lipid emulsion were dyspepsia, urinary tract infection, anemia, infection, dyspnea, cholestasis, dysgeusia, increased blood alkaline phosphatase, tachycardia, liver function test abnormalities, dizziness, rash, and thrombophlebitis. The 163 patients treated with Intralipid in four pediatric trials consisted of 147 patients <28 days of age, 9 patients 28 days to <2 years of age, and 7 patients 2 to 7 years of age; the duration of exposure was 7 to 84 days. Fifty-six percent of the pediatric patients were female, and 85% were Caucasian. Most pediatric patients were preterm neonates with feeding intolerance or other conditions requiring short-term (<29 days) PN. Table 3: Adverse Reactions in >1% of Pediatric Patients Treated with Intralipid Adverse Reaction Number of Patients in Intralipid Group (N=163) Number of Patients in 4-Oil Mixed Lipid Emulsion Comparator Group (N=170) Anemia 33 (20%) 30 (18%) Vomiting 16 (10%) 16 (9%) Gamma-glutamyltransferase increased 12 (7%) 10 (6%) Cholestasis 10 (6%) 7 (4%) Pyrexia 7 (4%) 7 (4%) C-reactive protein increased 7 (4%) 6 (4%) Hyperbilirubinemia 7 (4%) 5 (3%) Bilirubin conjugated increased 7 (4%) 3 (2%) Nosocomial infection 6 (4%) 10 (6%) Blood alkaline phosphatase increased 6 (4%) 1 (1%) Abdominal pain 5 (3%) 4 (2%) Hematocrit decreased 5 (3%) 2 (1%) Metabolic acidosis 5 (3%) 2 (1%) Diarrhea 4 (3%) 3 (2%) Tachycardia 4 (3%) 3 (2%) Thrombocytopenia 4 (3%) 3 (2%) Alanine aminotransferase increased 3 (2%) 1 (1%) Aspartate aminotransferase increased 3 (2%) 0 (0%) Parenteral nutrition-associated liver disease 3 (2%) 0 (0%) Less common adverse reactions occurring in ≤1% of pediatric patients who received Intralipid were hyperglycemia, sepsis, increased blood triglycerides, infection, fluid overload, hypertension, hypertriglyceridemia, rash, and hyperlipidemia. In a randomized active-controlled, double-blind, parallel-group, multi-center study that included 152 neonates and 9 patients ranging in age from 29 to 153 days who were expected to require PN for at least 28 days, PNAC, a precursor to PNALD, developed more frequently in Intralipid-treated patients than in patients treated with a comparator 4-oil mixed lipid emulsion. PNAC (defined as direct bilirubin >2 mg/dL with a second confirmed elevation >2 mg/dL at least 7 days later) occurred in 11.5% (9/78) in Intralipid-treated patients and 2.4% (2/83) of patients treated with a 4-oil mixed lipid emulsion. Most PNAC events occurred in patients who were treated for longer than 28 days. The estimated cumulative incidence of PNAC is shown in the Kaplan-Meier cumulative incidence curve in Figure 1 [see Pediatric Clinical Studies ( 14.2 )] . Figure 1: Cumulative Incidence Curve of Time to Parenteral Nutrition-Associated Cholestasis (PNAC) with Standard Error Bars intra-img-06.jpg

6.2 Postmarketing Experience The following adverse reactions from voluntary reports have been reported with Intralipid. Because many 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. Cardiac disorders: palpitations Gastrointestinal disorders: vomiting, nausea General disorders and administration site conditions: chills, chest discomfort, pyrexia Nervous system disorders: dizziness Respiratory, thoracic, and mediastinal disorders : dyspnea Immune system disorders: hypersensitivity reactions, including anaphylaxis [see Contraindications ( 4 ), Warnings and Precautions ( 5.3 )] Vascular disorders : phlebitis Blood and lymphatic system disorders: hypercoagulability

Soybean oil in Intralipid contains vitamin K 1 which may counteract the anticoagulant activity of vitamin K antagonists such as warfarin. In patients who receive concomitant Intralipid and warfarin, increase monitoring of laboratory parameters for anticoagulant activity. Vitamin K Antagonists (e.g., warfarin) : Anticoagulant activity may be counteracted; increase monitoring of coagulation parameters. ( 7 )

8.1 Pregnancy Risk Summary Administration of the recommended dose of Intralipid is not expected to cause major birth defects, miscarriage, or other adverse maternal or fetal outcomes. No animal reproduction studies have been conducted with Intralipid. There are risks to the fetus associated with severe malnutrition during pregnancy (see Clinical Considerations ) . The background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Severe malnutrition in pregnant women is associated with preterm delivery, low birth weight, intrauterine growth restriction, congenital malformations, and perinatal mortality. Parenteral nutrition should be considered if the pregnant woman's nutritional requirements cannot be fulfilled by oral or enteral intake.

8.2 Lactation Risk Summary Administration of the recommended dose of Intralipid is not expected to cause harm to a breastfed infant. There are no data on the presence of Intralipid in human or animal milk or its effects on milk production. Available published literature includes fewer than five reported cases of breastfed infants exposed to various lipid emulsions via lactation, and these cases did not report adverse events. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Intralipid and any potential adverse effects of Intralipid on the breastfed infant, or from the underlying maternal condition.

8.4 Pediatric Use Intralipid is contraindicated in pediatric patients with severe disorders of lipid metabolism [ (see Contraindications ( 4 )]. The safety and effectiveness of Intralipid have been established as a source of calories and essential fatty acids for PN in pediatric patients, including term and preterm neonates. Use of Intralipid in neonates is supported by evidence from short-term (i.e., 1- to 4- week) studies, and one study following neonates beyond 4 weeks [see Clinical Studies ( 14.2 )] . Use of Intralipid in older pediatric patients is supported by evidence from short-term (i.e., <28 days) studies in pediatric patients 28 days to 12 years of age and additional evidence from studies in adults [see Clinical Studies ( 14 )] . The most common adverse reactions in Intralipid-treated pediatric patients were anemia, vomiting, gamma-glutamyltransferase increased, and cholestasis. PNAC, a precursor to PNALD, developed more frequently in Intralipid-treated patients than in patients treated with a comparator 4-oil mixed lipid emulsion [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 )]. In the postmarketing setting, clinical decompensation with rapid infusion of intravenous lipid emulsion in neonates and infants, sometimes fatal, has been reported [see Warnings and Precautions ( 5.1 )] . Because of immature renal function, preterm neonates receiving prolonged treatment with Intralipid may be at risk for aluminum toxicity [see Warnings and Precautions ( 5.8 )] .

8.5 Geriatric Use Reported clinical experience has not identified differences in responses between the 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 drug therapy.

Intralipid provides a biologically utilizable source of calories and essential fatty acids. Fatty acids serve as an important substrate for energy production. The most common mechanism of action for energy production derived from fatty acid metabolism is beta oxidation. Fatty acids are also important for membrane structure and function, as precursors for bioactive molecules (such as prostaglandins), and as regulators of gene expression.