Intralipid

1 INDICATIONS AND USAGE Intralipid ® is indicated as a source of calories and essential fatty acids for adult and pediatric patients requiring parenteral nutrition 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).

2 DOSAGE AND ADMINISTRATION • Intralipid 30% Pharmacy Bulk Package is for admixing only and is not intended for direct intravenous infusion. ( 2.1 ) • Admixtures containing Intralipid 30% are prepared by a healthcare provider. ( 2.1 ) • Intralipid 30% must be combined with other PN fluids so that the resulting admixture has a final lipid concentration of no more than 20% (0.2 g lipid per mL of admixture). ( 2.1 , 2.2 ) • Protect the admixed PN solution from light. ( 2.2 , 16 ) • Recommended dosage depends on age, energy expenditure, clinical status, body weight, tolerance, ability to metabolize and eliminate lipids, and consideration of additional energy given to the patient. ( 2.3 ) Age Nutritional Requirements Recommended Initial Dosage and Maximum Dosage Birth to 2 years of age (including preterm and term neonates) Initial 0.5 g/kg/day not to exceed 3 g/kg/day Pediatric patients 2 to <12 years of age Initial 1 to 2 g/kg/day not to exceed 2.5 g/kg/day Pediatric patients 12 to 17 years of age Initial 1 g/kg/day not to exceed 2 g/kg/day Adults 1 g/kg/day (stable) ≤1 g/kg/day (critically ill) not to exceed 2.5 g/kg/day 2.1 Important Preparation and Administration Instructions • Intralipid 30% Pharmacy Bulk Package is for admixing use only and is not intended for direct intravenous administration. • Admixtures containing Intralipid 30% are prepared and administered by a healthcare provider in the inpatient setting [see Dosage and Administration ( 2.2 )]. • Patients and caregivers may administer admixtures containing Intralipid for home use after appropriate training by a trained healthcare provider [see Patient Counseling Information ( 17 )]. • Intralipid 30% must be combined with other PN fluids so that the resulting admixture has a final lipid concentration of no more than 20% (0.2 g lipid per mL of admixture). Refer to Admixture Preparation Instructions [ see Dosage and Administration ( 2.2 ) ]. • When Intralipid 30% is diluted to 20%, strictly adhere to the recommended total daily dosage; the hourly infusion rate should not exceed 0.125 g/kg/hour for neonates and infants [see Warnings and Precautions ( 5.1 )]. • Intralipid admixtures with osmolarity o Greater than or equal to 900 mOsm/L must be infused through a central vein. o Less than 900 mOsm/L may be administered either through a central or peripheral vein. • Use a 1.2 micron in-line filter during admixture administration. • PN admixtures should use a dedicated infusion line without any connections. Do not connect multiple medications in series. • To prevent air embolism, use a non-vented infusion set or close the vent on a vented set and fully evacuate residual gas in the bag prior to admixture administration. • The flow rate of the admixture should be controlled with an infusion pump. Do not pressurize the flexible bag to increase flow rates, and if administration is controlled by a pumping device, turn off the pump before the bag runs dry. • Do not use infusion sets and lines that contain di-2-ethylhexyl phthalate (DEHP), including infusion sets that contain polyvinyl chloride (PVC) components, because they contain DEHP as a plasticizer. • After connecting the infusion set, start infusion of PN admixture with Intralipid immediately. Complete the infusion within 24 hours. 2.2 Admixture Preparation Instructions Use the following instructions to prepare the Intralipid 30% Pharmacy Bulk Package for transfer to a compounding bag: 1. Inspect Bag • Inspect the integrity indicator (Oxalert ® ) (A) before removing the overpouch. • Discard the product if the indicator is black, overpouch is opened or damaged, emulsion color is not white, or seals of bag are broken. 2. Remove Overpouch • Place the bag on a clean, flat surface. • Tear the overpouch at notch and pull down. • Discard the Oxalert sachet (A) and the oxygen absorber (B). • Visually inspect the bag and contents for particulate matter and discoloration prior to administration. The lipid emulsion should be a homogenous …

5 WARNINGS AND PRECAUTIONS • 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. When Intralipid 30% is diluted to 20%, strictly adhere to the recommended total daily dosage; the hourly infusion rate should not exceed 0.125 g/kg/hour for neonates and infants. ( 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. Intralipid 30% Pharmacy Bulk Package is not intended for direct infusion. When it is diluted to 20%, strictly adhere to the recommended total daily dosage; the hourly infusion rate should not exceed 0.125 g/kg/hour. 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 admixtures containing 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 admixtures containing 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. …

4 CONTRAINDICATIONS • 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 )

7 DRUG INTERACTIONS 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.

6 ADVERSE REACTIONS 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 20% 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 because Intralipid 30% is to be diluted down to 20% or lower for PN admixture. The safety database for Intralipid or equivalent soybean oil lipid emulsion exposure in these studies include 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-glutamyltran…