Intralipid

Boxed Warning (Removed) 5/2023 Dosage and Administration ( 2.3 ) 5/2023 Contraindications ( 4 ) 5/2023 Warnings and Precautions ( 5.1 ) 5/2023

1 INDICATIONS AND USAGE 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).

2 DOSAGE AND ADMINISTRATION For intravenous infusion into a peripheral or central vein. ( 2.1 ) Intralipid Pharmacy Bulk Package is only indicated for use in pharmacy admixture program for the preparation of three-in-one or total nutrition admixtures (TNAs). ( 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 Initial Recommended Dosage Maximum Dosage Birth to 2 years of age (including preterm and term neonates) 0.5 g/kg/day 3 g/kg/day Pediatric patients 2 to <12 years of age 1 to 2 g/kg/day 2.5 g/kg/day Pediatric patients 12 to 17 years of age 1 g/kg/day 2 g/kg/day Adults 1 g/kg/day (stable) ≤1 g/kg/day (critically ill) 2.5 g/kg/day 2.1 Important Administration Instructions Intralipid is prepared and administered by a healthcare provider in the inpatient setting. Patients and caregivers may prepare and administer Intralipid for home use after appropriate training by a trained healthcare provider. Intralipid is for intravenous infusion into a central or peripheral vein. Do not exceed the recommended maximum infusion rate in Table 1 [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.1 )]. Intralipid admixtures with osmolarity Greater than or equal to 900 mOsm/L must be infused through a central vein. Less than 900 mOsm/L may be administered either through a central or peripheral vein. Use a 1.2 micron in-line filter during administration. 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 administration. 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. Intralipid can be infused concurrently into the same vein as dextrose-amino acid solutions (as part of PN) by a Y-connector located near the infusion site; flow rates of each solution should be controlled separately by infusion pumps. After connecting the infusion set, start infusion of Intralipid immediately. Complete the infusion within 12 hours when using a Y-connector and within 24 hours when used as part of an admixture. 2.2 Preparation Instructions Use the following instructions to prepare single-dose 100 mL, 250 mL, and 500 mL Flexible containers for administration: 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 liquid with a milky white appearance. If the mixture is not white or the emulsion has separated (noted by discoloration, phase separation, or oily droplets), or if particulates and/or leakage are observed, discard the bag. 3. Spike Bag Identify the infusion port ( blue cap with the arrow pointing away from the bag). Immediately before inserting the infusion set, break off the blue infusion port cap. Use infusion sets according to ISO Number 8536-4 with an external spike diameter of 5.5 to 5.7 mm and use a non-vented infusion set or close the air-inlet on a vented set. Use a 1.2 micron in-line filter for administration. Hold …

3 DOSAGE FORMS AND STRENGTHS 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 )

CONTRAINDICATIONS Intralipid is contraindicated in patients with: Disturbances of normal fat metabolism such as pathologic hyperlipemia, lipoid nephrosis or acute pancreatitis if accompanied by hyperlipidemia. Known hypersensitivity to egg, soybean, peanut protein, or to any of the active ingredients or excipients in Intralipid 30%. INTRALIPID 30% PHARMACY BULK PACKAGE IS NOT INTENDED FOR DIRECT INTRAVENOUS ADMINISTRATION. DILUTING INTRALIPID 30% TO A 10% OR 20% CONCENTRATION WITH AN INTRAVENOUS FLUID SUCH AS NORMAL SALINE OR OTHER DILUENT DOES NOT PRODUCE A DILUTION THAT IS EQUIVALENT IN COMPOSITION TO INTRALIPID 10% OR 20% I.V. FAT EMULSIONS, AND SUCH A DILUTION SHOULD NOT BE GIVEN BY DIRECT INTRAVENOUS ADMINISTRATION (FOR EXAMPLE, THROUGH A Y‐CONNECTOR).

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 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 …

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 USE IN SPECIFIC POPULATIONS 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.

12.1 Mechanism of Action 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.

DESCRIPTION Intralipid ® 20% (A 20% I.V. Fat Emulsion) Pharmacy Bulk Package is a sterile, non-pyrogenic fat emulsion intended as a source of calories and essential fatty acids for use in a pharmacy admixture program. It is made up of 20% Soybean Oil, 1.2% Egg Yolk Phospholipids, 2.25% Glycerin, and Water for Injection. In addition, sodium hydroxide has been added to adjust the pH so that the final product pH is 8. pH range is 6 to 8.9. Intralipid ® 20% Pharmacy Bulk Package is not intended for direct infusion. It is a sterile dosage form which contains several single doses for use in the preparation of three-in-one or total nutrient admixtures (TNAs) in a pharmacy admixture program. The soybean oil is a refined natural product consisting of a mixture of neutral triglycerides of predominantly unsaturated fatty acids with the following structure: where are saturated and unsaturated fatty acid residues. The major component fatty acids are linoleic (44-62%), oleic (19-30%), palmitic (7-14%), linolenic (4-11%) and stearic (1.4-5.5%) 1 . These fatty acids have the following chemical and structural formulas: Linoleic acid C 18 H 32 O 2 Oleic acid C 18 H 34 O 2 Palmitic acid C 16 H 32 O 2 Linolenic acid C 18 H 30 O 2 Stearic acid C 18 H 36 O 2 Purified egg phosphatides are a mixture of naturally occurring phospholipids which are isolated from the egg yolk. These phospholipids have the following general structure: contain saturated and unsaturated fatty acids that abound in neutral fats. R 3 is primarily either the choline or ethanolamine ester of phosphoric acid. Phosphatidylcholine Phosphatidylethanolamine Glycerin is chemically designated C 3 H 8 O 3 and is a clear colorless, hygroscopic syrupy liquid. It has the following structural formula: Intralipid ® 20% (A 20% I.V. Fat Emulsion) has an osmolality of approximately 350 mOsmol/kg water (which represents 260 mOsmol/liter of emulsion) and contains emulsified fat particles of approximately 0.5 micron size. The total caloric value, including fat, phospholipid and glycerin, is 2.0 kcal per mL of Intralipid ® 20%. The phospholipids present contribute 47 milligrams or approximately 1.5 mmol of phosphorus per 100 mL of the emulsion. The primary container is manufactured from Excel ® film, a polypropylene based material comprised of three co-extruded layers. The plastic container is made from multilayered film specifically designed for parenteral drugs. It contains no plasticizers and exhibits virtually no leachables. The solution contact layer is a rubberized copolymer of ethylene and propylene. The container is nontoxic and biologically inert. The container-solution unit is a closed system and is not dependent upon entry of external air during administration. The container is overwrapped to provide protection from the physical environment and to provide an additional moisture barrier when necessary. structure r1c r2c r3c structure structure structure structure structure structure structure figure stuct

10 OVERDOSAGE In the event of an overdose, serious adverse reactions may result [see Warnings and Precautions ( 5.1 , 5.5 )] . Stop the infusion of admixtures containing Intralipid until triglyceride levels have normalized and symptoms have abated. The effects are usually reversible by stopping the lipid infusion. If medically appropriate, further intervention may be indicated. Lipids are not dialyzable from plasma.

16 HOW SUPPLIED/STORAGE AND HANDLING Intralipid 20% (lipid injectable emulsion, USP) is a sterile, homogeneous, milky, white lipid emulsion supplied in Flexible Containers as follows: Product Code Unit of Use Unit of Sale 831800311 NDC 65219-531-01 One 100 mL free flex ® bag NDC 65219-531-10 Package of 10 free flex ® bags 831818311 NDC 65219-533-01 One 250 mL free flex ® bag NDC 65219-533-25 Package of 10 free flex ® bags 831826311 NDC 65219-535-01 One 500 mL free flex ® bag NDC 65219-535-50 Package of 12 free flex ® bags 831842311 NDC 65219-539-01 One 1000 mL Pharmacy Bulk Package free flex ® bag NDC 65219-539-10 Package of 6 free flex ® bags Store below 25°C (77°F). Avoid excessive heat. Do not freeze. If accidentally frozen, discard container. Store in the overpouch until ready for use. Intralipid 100 mL, 250 mL and 500 mL single-dose Flexible Containers After removing the overpouch, infuse immediately. If not used immediately, the product should be stored at 2°C to 8°C (36°F to 46°F) for no longer than 24 hours. After removal from storage, infuse within 12 hours when using a Y-connector or within 24 hours if used as part of an admixture [see Dosage and Administration ( 2.2 )]. Intralipid 1,000 mL Pharmacy Bulk Package Use the Pharmacy Bulk Package immediately for admixing after removal from the overpouch. If not used immediately, the product should be stored for no longer than 24 hours at 2°C to 8°C (36°F to 46°F). After removal from storage, and once the closure is penetrated, use Pharmacy Bulk Package contents within 4 hours [see Dosage and Administration ( 2.2 )]. Admixtures Infuse admixtures containing Intralipid immediately. If not used immediately, admixtures should be stored at 2°C to 8°C (36°F to 46°F) for no longer than 24 hours. After removal from storage, infuse within 24 hours [see Dosage and Administration ( 2.2 )] . Protect the admixed PN solution from light [see Dosage and Administration ( 2.2 )].