INTRALIPID

Intralipid is a sterile, non-pyrogenic, white, homogenous lipid emulsion for intravenous infusion as a source of calories and essential fatty acids for use in a pharmacy admixture program. The lipid content of Intralipid 30% Pharmacy Bulk Package is 0.3 g/mL and comprises soybean oil. The phosphate content is 15 mmol/L. The total energy content, including fat, phospholipids, and glycerin is 3,000 kcal/L. Each 100 mL of Intralipid contains approximately 30 g soybean oil, 1.2 g egg yolk phospholipids, 1.7 g glycerin, water for injection, and sodium hydroxide for pH adjustment (pH 6 to 8.9). Intralipid has an osmolality of approximately 310 mOsm/kg water (which represents an osmolarity of 200 mOsm/L). 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 in Intralipid are linoleic acid (44% to 62%), oleic acid (19% to 30%), palmitic acid (7% to 14%), alpha-linolenic acid (4% to 11%), and stearic acid (1.4% to 5.5%). 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 α-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. Glycerin is chemically designated C 3 H 8 O 3 and is a clear colorless, hygroscopic syrupy liquid. It has the following structural formula: 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 oxygen and moisture barrier when necessary. Intralipid contains no more than 25 mcg/L of aluminum. The container is not made with natural rubber latex, PVC, or DEHP. intra-struc-01.jpg intra-struc-02.jpg intra-struc-03.jpg intra-struc-04.jpg intra-struc-05.jpg intra-struc-06.jpg intra-struc-07.jpg intra-struc-08.jpg intra-struc-09.jpg intra-struc-10.jpg intra-struc-11.jpg

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).

• 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 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 compounding set, break off the blue infusion port cap. • Use a suitable sterile transfer device or dispensing set with an external spike diameter of 5.5 to 5.7 mm. • Hold the base of the infusion port. • Insert the spike through the infusion port by rotating your wrist slightly until the spike is inserted. • Do not pierce the infusion port more than once. 4. Transfer to the Compounding Bag • Hang the bag using the hanger cut and start transfer to the compounding bag. • Discard unused portion. • Use the Intralipid 30% immediately for admixing after removal from the overpouch. If not used immediately, the product can 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. • 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% intravenous lipid emulsions. Therefore, diluents other than dextrose and amino acids should not be used to prepare admixtures for direct intravenous administration. Admixing Instructions • Prepare the admixture in PN containers using strict aseptic techniques to avoid microbial contamination. • Do not add Intralipid 30% Pharmacy Bulk Package to the PN container first; destabilization of the lipid may occur. The prime destabilizers of emulsions are excessive acidity (such as a pH <5) and inappropriate electrolyte content. Amino acid solutions exert buffering effects that protect the emulsion from destabilization. Give careful consideration to the addition of divalent cations (Ca++ and Mg++), which have been shown to cause emulsion instability. • Do not inject additives directly into Intralipid. • Intralipid 30% may be mixed with amino acid and dextrose injections to produce “all-in-one” PN admixtures. The mixing sequence below must be followed for manual compounding to minimize pH-related problems by ensuring that typically acidic dextrose injections are not mixed with lipid emulsions alone; shake bags gently after each addition. o Transfer dextrose injection to the PN container. o Transfer amino acid injection. o Transfer Intralipid 30%. • Simultaneous transfer of amino acid injection, dextrose injection, and Intralipid to the PN container is also permitted; follow automated compounding device instructions as indicated. Use gentle agitation during admixing to minimize localized concentration effects. • Additions to the PN admixtures should be evaluated by a pharmacist for compatibility. Questions about compatibility may be directed to Fresenius Kabi. • Inspect the admixture to ensure that precipitates have not formed during preparation of the admixture and the emulsion has not separated. Discard the admixture if any of the above are observed. • Infuse admixtures containing Intralipid immediately. If not used immediately, store admixtures under refrigeration at 2°C to 8°C (36°F to 46°F) for no longer than 24 hours. Infusion must be complete within 24 hours after removal from refrigeration. Discard any remaining admixture. • Protect the admixed PN solution from light. intra-img-01.jpg intra-img-02.jpg intra-img-03.jpg intra-img-04.jpg 2.3 Recommended Dosage and Administration • The recommended nutritional requirements of lipid and recommended dosages of Intralipid to be administered to meet those requirements for adults and pediatric patients are provided in Table 1 . • The dosing of Intralipid depends on the patient's individual energy requirements influenced by age, body weight, tolerance, clinical status, and the ability to metabolize and eliminate lipids. • When determining dose, energy supplied by dextrose and amino acids from PN, as well as energy from oral or enteral nutrition, has to be taken into account. Energy and lipid provided from lipid-based medications should also be taken into account (e.g., propofol). • Prior to administration of admixtures with Intralipid, correct severe fluid and electrolyte disorders and measure serum triglyceride levels to establish a baseline value. In patients with elevated triglyceride levels, initiate Intralipid at a lower dosage and titrate in smaller increments, monitoring the triglyceride levels with each adjustment [see Warnings and Precautions ( 5.7 )] . Table 1: Recommended Pediatric and Adult Dosage for Intralipid Concentrations of 20% or less in an Admixture * The neonatal period is defined as including term, post-term, and preterm neonates. The neonatal period for term and post-term neonates is the day of birth plus 27 days. For preterm neonates, the neonatal period is defined as the day of birth through the expected age of delivery plus 27 days (i.e., 44 weeks post-menstrual age). ** Daily dosage should also not exceed a maximum of 60% of total energy requirements [see Overdosage ( 10 )]. Age Nutritional Requirements Recommended Initial Dosage and Maximum Dosage Birth to 2 years of age (including preterm and term neonates*) [see Warnings and Precautions ( 5.1 )] 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 in stable patients ≤1 g/kg/day in critically ill patients not to exceed 2.5 g/kg/day** Dosage Modifications in Patients with Essential Fatty Acid Deficiency When admixtures with Intralipid are administered to correct essential fatty acid deficiency (EFAD), supply 8% to 10% of caloric input from Intralipid in order to provide adequate amounts of linoleic and linolenic acids.

• 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 )

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-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-graph-01.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 )