Intralipid

ADVERSE REACTIONS The adverse reactions observed can be separated into two classes: Those more frequently encountered are due either to a) contamination of the intravenous catheter and result in sepsis, or to b) vein irritation by concurrently infused hypertonic solutions and may result in thrombophlebitis. These adverse reactions are inseparable from the hyperalimentation procedure with or without Intralipid. Less frequent reactions more directly related to Intralipid are: a) immediate or early adverse reactions, each of which has been reported to occur in clinical trials, in an incidence of less than 1%; dyspnea, cyanosis, allergic reactions, hyperlipemia, hypercoagulability, nausea, vomiting, headache, flushing, increase in temperature, sweating, sleepiness, pain in the chest and back, slight pressure over the eyes, dizziness, and irritation at the site of infusion, and, rarely, thrombocytopenia in neonates; b) delayed adverse reactions such as hepatomegaly, jaundice due to central lobular cholestasis, splenomegaly, thrombocytopenia, leukopenia, transient increases in liver tests, and overloading syndrome (focal seizures, fever, leukocytosis, hepatomegaly, splenomegaly and shock). The deposition of a brown pigmentation in the reticuloendothelial system, the so-called “intravenous fat pigment,” has been reported in patients infused with Intralipid. The causes and significance of this phenomenon are unknown.

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, or 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).

DESCRIPTION Intralipid ® 30% (A 30% 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 30% Soybean Oil, 1.2% Egg Yolk Phospholipids, 1.7% 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 30% 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 acid (44-62%), oleic acid (19-30%), palmitic acid (7-14%), α-linolenic acid (4-11%) and stearic acid (1.4-5.5%) 1 . These fatty acids have the following chemical and structural formulas: 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. 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 30% (A 30% I.V. Fat Emulsion) has an osmolality of approximately 310 mOsmol/kg water (which represents 200 mOsmol/L of emulsion) and contains emulsified fat particles of approximately 0.5 micron size. The total caloric value, including fat, phospholipid and glycerin, is 3.0 kcal per mL of Intralipid 30%. The phospholipids present contribute 47 milligrams or approximately 1.5 mmol of phosphorus per 100 mL of the emulsion. The primary plastic container (Biofine TM ) is made from multilayered film specifically designed for parenteral nutrition drug products. The film is polypropylene based comprising three co-extruded layers. It contains no plasticizers and exhibits virtually no leachables. The container does not contain DEHP (di(2-ethylhexyl) phthalate) or PVC. This product is not made with natural rubber latex. The container is nontoxic and biologically inert. The container-emulsion 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. Figure Figure Figure Figure Figure Figure Figure

DOSAGE AND ADMINISTRATION Intralipid 30% (A 30% I.V. Fat Emulsion) Pharmacy Bulk Package should be administered only as a part of a three-in-one or total nutrient admixture via peripheral vein or by central venous infusion. The recommended nutritional requirements of fat and recommended dosages of Intralipid to be administered to meet those requirements for adults and pediatric patients are provided below, along with recommendations for the initial and maximum infusion rates. Do not exceed the recommended maximum infusion rate. Directions For Proper Use of Pharmacy Bulk Package INTRALIPID 30% (A 30% I.V. Fat Emulsion) PHARMACY BULK PACKAGE IS NOT INTENDED FOR DIRECT INFUSION. The container closure may be penetrated only once using a suitable sterile transfer device or dispensing set which allows measured dispensing of the contents. The Pharmacy Bulk Package is to be used only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area). Once the closure is penetrated, the contents should be dispensed as soon as possible; the transfer of contents to suitable TPN admixture containers must be completed within 4 hours of closure penetration. The bag should be stored below 25°C (77°F) after the closure has been entered. Admixtures made using Intralipid 30% should be used promptly. See MIXING GUIDELINES AND LIMITATIONS section for admixture storage recommendations. Adult Patients The initial infusion rate of the nutrient admixture in adults should be the equivalent of 0.1 g fat/minute for the first 15 to 30 minutes of infusion. If no untoward reactions occur (see ADVERSE REACTIONS section), the infusion rate of the nutrient admixture can be increased to be equivalent to 0.2 g fat/minute. For adults, the admixture should not contain more than 330 mL of Intralipid 30% on the first day of therapy. If the patient has no untoward reactions, the dose can be increased on the following day. The daily dosage should not exceed 2.5 g of fat/kg of body weight (8.3 mL of Intralipid 30% per kg). Intralipid 30% should make up no more than 60% of the total caloric input to the patient. Maximum infusion rate should not exceed 0.1 g/kg/hr. Carbohydrate and a source of amino acids should comprise the remaining caloric input. Maximum infusion rate should not exceed 0.1 g/kg/hr. Pediatric Patients The dosage for premature infants starts at 0.5 g fat/kg body weight/24 hours (1.7 mL) Intralipid 30% and may be increased in relation to the infant's ability to eliminate fat. The maximum recommended dosage is 3 g fat/kg/24 hours. Pediatric patients may be at risk for parenteral nutrition-associated liver disease (PNALD), also known as intestinal failure-associated liver disease (see WARNINGS section) when receiving Intralipid for durations exceeding two weeks. During intravenous administration of Intralipid 30%, perform liver tests to monitor for PNALD. The initial rate of infusion of the nutrient admixture in older pediatric patients should be no more than 0.01 g fat/minute for the first 10 to 15 minutes. If no untoward reactions occur, the rate can be changed to permit infusion of 0.1 g of fat/kg/hour. The daily dosage should not exceed 3 g of fat/kg of body weight 3 . Intralipid (equivalent to 0.125 g/kg/hour) should make up no more than 60% of the total caloric input to the patient. Carbohydrate and a source of amino acids should comprise the remaining caloric input. Essential Fatty Acid Deficiency When Intralipid 30% is administered to correct essential fatty acid deficiency, eight to ten percent of the caloric input should be supplied by Intralipid 30% in order to provide adequate amounts of linoleic and linolenic acids. When EFAD occurs together with stress, the amount of Intralipid 30% needed to correct the deficiency may be increased. Administration See MIXING GUIDELINES AND LIMITATIONS section for information regarding mixing this fat emulsion with other parenteral fluids. INTRALIPID 30% (A 30% I.V. Fat Emulsion) is not for direct infusion. It must be infused as part of an admixture into a central or peripheral vein. The flow rate of the admixture should be controlled with an infusion pump. Use a 1.2-micron filter with admixtures containing Intralipid 30%. Filters of less than 1.2-micron pore size must not be used. Conventional administration sets and TPN pooling bags contain polyvinyl chloride (PVC) components that have DEHP (di(2-ethylhexyl) phthalate) as a plasticizer. Fat‑containing fluids such as Intralipid extract DEHP from these PVC components. Therefore, it may be advisable to use a non‑DEHP administration set for infusing admixtures which contain Intralipid. Do not use any bag in which there appears to be an oiling out on the surface of the emulsion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

INDICATIONS AND USAGE Intralipid ® 30% Pharmacy Bulk Package is indicated for use in a pharmacy admixture program for the preparation of three-in-one or total nutrient admixtures (TNAs) to provide a source of calories and essential fatty acids for patients requiring parenteral nutrition for extended periods of time (usually for more than 5 days) and as a source of essential fatty acids for prevention of EFAD.

WARNINGS 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 0.5 mL/kg/hour. (see DOSAGE AND ADMINISTRATION section) 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 PRECAUTIONS and OVERDOSAGE sections) 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 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, 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. PNAC (defined as direct bilirubin >2mg/dl with a second confirmed elevation >2mg/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 . Figure 1: Cumulative Incidence Curve of Time to Parenteral Nutrition-Associated Cholestasis (PNAC) with Standard Error Bars 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. Figure 1 Aluminum Toxicity This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, 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.

OVERDOSAGE In the event of overdose, serious adverse reactions may result. Stop the infusion containing Intralipid 30% (A 30% I.V. Fat Emulsion) until visual inspection of the plasma, determination of triglyceride concentrations, or measurement of plasma light-scattering activity by nephelometry indicates the lipid has cleared. Re-evaluate the patient and institute appropriate corrective measures. See WARNINGS and PRECAUTIONS . 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.

CLINICAL PHARMACOLOGY Intralipid is metabolized and utilized as a source of energy causing an increase in heat production, decrease in respiratory quotient and increase in oxygen consumption. The infused fat particles are cleared from the blood stream in a manner thought to be comparable to the clearing of chylomicrons. Intralipid will prevent the biochemical lesions of essential fatty acid deficiency (EFAD) and correct the clinical manifestations of the EFAD syndrome.

20230816

2

Intralipid I.V. Fat Emulsion EGG PHOSPHOLIPIDS GLYCERIN SODIUM HYDROXIDE WATER SOYBEAN OIL SOYBEAN OIL

Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with Intralipid have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

NDA019942

Intralipid

I.V. Fat Emulsion

65219-537

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE LABEL - PRINCIPAL DISPLAY - Intralipid 500 mL Bag Label NDC 65219-537-01 Intrapilid ® 30% 500 ml A 30% I.V. Fat Emulsion 500 mL Pharmacy Bulk Package Not For Direct Infusion For Intravenous Use Rx only PACKAGE LABEL - PRINCIPAL DISPLAY - Intralipid 500 mL Container Label

Pharmacy Bulk Package Not for Direct Infusion

Instruction for Use - Intralipid 30% Pharmacy Bulk Package Container 1. 1. The integrity indicator (Oxalert™) A should be inspected before removing the overwrap. If the indicator is black the overwrap is damaged and the product should be discarded. 2. 2. Remove the overwrap by tearing at the notch and pulling down along the container. The Oxalert sachet (A) and the oxygen absorber (B) should be discarded. Place the bag on a clean, flat surface or hang on a support hook. 3. 3. Break off the tamper-evident arrow flag from the blue infusion port. Use a compounding set with a diameter of 5.6 +/- 0.1 mm. Follow the instructions for use for the compounding set. 4. 4. Hold the base of the infusion port firmly and insert the spike straight through the center of the septum by rotating the wrist slightly if needed. NOTE: Assure that the spike is inserted straight into the port and not at an angle. Inspect the bag and contents for particulate matter in a well-lit environment prior to use. Discard the bag if there are any signs of discoloration or particulates. 5. 5. Hang the bag in the hanger cut and start transfer to the compounding bag Figure Figure Figure Figure Figure

REFERENCES Padley FB: “Major Vegetable Fats”, The Lipid Handbook (Gunstone FD, Harwood JL, Padley FB, eds.), Chapman and Hall Ltd., Cambridge, UK (1986), pp. 88-9. Levene MI, Wigglesworth JS, Desai R: Pulmonary fat accumulation after Intralipid infusion in the preterm infant. Lancet 1980; 2(8199):815-8. American Academy of Pediatrics: Use of intravenous fat emulsion in pediatric patients. Pediatrics 1981; 68:5(Nov) 738-43. Manufactured By: Uppsala, Sweden Intralipid ® is a registered trademark of Fresenius Kabi AB. www.fresenius-kabi.com/us 451715B Revised: June 2023 Fresenius Kabi Logo

Nursing Mothers: Caution should be exercised when Intralipid is administered to a nursing woman.

Pediatric Use: See DOSAGE AND ADMINISTRATION .

Pregnancy: Animal reproduction studies have not been conducted with Intralipid. It is also not known whether Intralipid can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Intralipid should be given to a pregnant woman only if clearly needed.

HOW SUPPLIED Intralipld 30% (A 30% I.V. Fat Emulsion) is supplied as a sterile emulsion in a Pharmacy Bulk Package in the following fill size: Product Code Unit of Use Unit of Sale 831834311 NDC 65219-537-01 One 500 mL free flex ® bag NDC 65219-537-50 Package of 12 free flex ® bags

STORAGE Intralipid 30% should not be stored above 25°C (77°F). Do not freeze Intralipid 30%. If accidentally frozen, discard the bag.

PRECAUTIONS When Intralipid 30% is administered, the patient's capacity to eliminate the infused fat from the circulation must be monitored by use of an appropriate laboratory determination of serum triglycerides. Overdosage must be avoided. During intravenous administration with Intralipid 30%, perform liver tests to monitor for PNALD. If patients develop liver test abnormalities, consider discontinuation of Intralipid or dosage reduction. (See WARNINGS section) Frequent platelet counts should be done in neonatal patients receiving parenteral nutrition with Intralipid 30%. Drug product contains no more than 25 mcg/L of aluminum. Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with Intralipid have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Animal reproduction studies have not been conducted with Intralipid. It is also not known whether Intralipid can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Intralipid should be given to a pregnant woman only if clearly needed. Nursing Mothers: Caution should be exercised when Intralipid is administered to a nursing woman. Pediatric Use: See DOSAGE AND ADMINISTRATION .