Smoflipid

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 )] Essential Fatty Acid Deficiency [see Warnings and Precautions ( 5.9 )] Most common adverse drug reactions (≥5%) from clinical trials in adults were nausea, vomiting, and hyperglycemia. Most common adverse drug reactions (≥5%) from clinical trials in pediatric patients were anemia, vomiting, increased gamma-glutamyltransferase, and nosocomial infection. ( 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. The safety database for SMOFlipid includes exposure in 399 patients (229 adults; 170 pediatric) in 9 clinical trials. Adult patients were exposed for 5 days to 4 weeks in 5 clinical trials. The pooled population exposed to SMOFlipid was adult patients up to 89 years old (20 to 89 years of age), 43% female and 99% Caucasian. The most frequently reported medical histories in the SMOFlipid group were surgical and medical procedures (84%), neoplasms (57%), gastrointestinal disorders (53%), vascular disorders (37%), and infections and infestations (20%). SMOFlipid 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 SMOFlipid as a component of PN delivered in a 3- chamber bag. Table 2: Adverse Reactions in >1% of Adult Patients Treated with SMOFlipid Adverse Reaction Number of Patients in SMOFlipid Group (N=229) Number of Patients in Soybean Oil lipid emulsion Comparator Group (N=230) Nausea 20 (9%) 26 (11%) Vomiting 15 (7%) 12 (5%) Hyperglycemia 12 (5%) 5 (2%) Flatulence 10 (4%) 4 (2%) Pyrexia 9 (4%) 11 (5%) Abdominal pain 8 (4%) 5 (2%) Blood triglycerides increased 6 (3%) 4 (2%) Hypertension 6 (3%) 9 (4%) Sepsis 5 (2%) 4 (2%) Dyspepsia 5 (2%) 1 (0%) Urinary tract infection 4 (2%) 3 (1%) Anemia 4 (2%) 2 (1%) Device related infection 4 (2%) 2 (1%) Less common adverse reactions occurring in ≤1% of adult patients who received SMOFlipid were dyspnea, leukocytosis, diarrhea, pneumonia, cholestasis, dysgeusia, increased blood alkaline phosphatase, increased gamma-glutamyltransferase, increased C-reactive protein, tachycardia, liver function test abnormalities, headache, pruritus, dizziness, rash and thrombophlebitis. The 170 patients treated with SMOFlipid in four pediatric trials consisted of 149 patients <28 days of age, 13 patients 28 days to <2 years of age, and 8 patients 2 to 7 years of age; the duration of exposure was 7 to 84 days. Forty five percent of the pediatric patients were female, and 89% 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 SMOFlipid Adverse Reaction Number of Patients in SMOFlipid Group (N=170) Number of Patients in Soybean Oil lipid emulsion Comparator Group (N=163) Anemia 30 (18%) 33 (20%) Vomiting 16 (9%) 16 (10%) Gamma-glutamyltransferase increased 10 (6%) 12 (7%) Nosocomial infection 10 (6%) 6 (4%) Cholestasis 7 (4%) 10 (6%) Pyrexia 7 (4%) 7 (4%) C-reactive protein increased 6 (4%) 7 (4%) Hyperbilirubinemia 5 (3%) 7 (4%) Abdominal pain 4 (2%) 5 (3%) Bilirubin conjugated increased 3 (2%) 7 (4%) Diarrhea 3 (2%) 4 (3%) Tachycardia 3 (2%) 4 (3%) Thrombocytopenia 3 (2%) 4 (3%) Hyperglycemia 3 (2%) 2 (1%) Sepsis 3 (2%) 2 (1%) Less common adverse reactions occurring in ≤1% of pediatric patients who received SMOFlipid were decreased hematocrit, metabolic acidosis, increased blood triglycerides, infection, increased blood alkaline phosphatase, increased alanine aminotransferase, fluid overload, hypertension, hypertriglyceridemia, and rash. The hepatic safety of SMOFlipid was evaluated in Pediatric Study 1, 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 (defined as direct bilirubin >2mg/dl with a second confirmed elevation >2mg/dl at least 7 days later) occurred in 2.4% (2/83) of SMOFlipid-treated patients and 11.5% (9/78) in soybean oil lipid emulsion-treated patients. 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 Clinical Trials ( 14 )] . Figure 1 Cumulative Incidence Curve of Time to Parenteral Nutrition-Associated Cholestasis (PNAC) with Standard Error Bars In the same trial, EFAD was determined by calculating the Holman index (the triene [Mead acid] to tetraene [arachidonic acid] ratio; T:T ratio). At the end of the first 28 days of treatment, 2.4% (2/83) SMOFlipid-treated patients and 2.6% (2/78) soybean oil lipid emulsion-treated patients had suspected EFAD (T:T ratio >0.05), and there were no cases of moderate (T:T ratio >0.2) or severe (T:T ratio >0.4) EFAD. There are insufficient data from this trial to determine the incidence of EFAD with duration of SMOFlipid treatment greater than 28 days because of substantial patient discontinuation from PN during the first 28 days. Figure 1 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of SMOFlipid in countries where it is registered. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. Cardiac disorders: palpitations General disorders and administration site conditions: chills, chest pain, malaise Hepatobiliary disorders: cholestasis Infections and infestations: infection Metabolism and nutrition disorders: fatty acid deficiency Respiratory, thoracic and mediastinal disorders : dyspnea Skin and subcutaneous tissue disorders: hyperhidrosis Vascular disorders : phlebitis

4 CONTRAINDICATIONS Use of SMOFlipid is contraindicated in patients with: Known hypersensitivity to fish, egg, soybean, peanut or any of the active or inactive ingredients in SMOFlipid [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 fish, egg, soybean, peanut or any of the active or inactive ingredients. ( 4 ) Severe disorders of lipid metabolism characterized by hypertriglyceridemia (serum triglycerides >1,000 mg/dL). ( 4 , 5.7 )

11 DESCRIPTION SMOFlipid is a sterile, nonpyrogenic, white, homogenous lipid emulsion for intravenous infusion. The lipid content of SMOFlipid is 0.2 g/mL, and comprises a mixture of soybean oil, MCTs, olive oil, and fish oil. The mean concentration of linoleic acid (an omega-6 essential fatty acid) is 35 mg/mL (range of 28 to 50 mg/mL), and alpha-linolenic acid (an omega-3 essential fatty acid) is 4.5 mg/mL (range of 3 to 7 mg/mL). The phosphate content is 15 mmol/L. The total energy content, including fat, phospholipids, and glycerol is 2,000 kcal/L. Each 100 mL of SMOFlipid contains approximately 6 g soybean oil, 6 g MCT, 5 g olive oil, 3 g fish oil, 1.2 g egg phospholipids, 2.5 g glycerin, 16.3 to 22.5 mg all-rac-alpha-tocopherol, 0.03 g sodium oleate, water for injection, and sodium hydroxide for pH adjustment (pH 6 to 9). SMOFlipid has an osmolality of approximately 380 mOsm/kg water (which represents an osmolarity of 270 mOsm/L). The oils included in SMOFlipid consist of a mixture of triglycerides of predominantly unsaturated fatty acids with the following structure: where , , and are saturated and unsaturated fatty acid residues. The major components of the fatty acids in SMOFlipid are oleic acid (23% to 35%), linoleic acid (14% to 25%), caprylic acid (13% to 24%), palmitic acid (7% to 12%), capric acid (5% to 15%), stearic acid (1.5% to 4%), alpha-linolenic acid (1.5% to 3.5%), eicosapentaenoic acid (EPA; 1% to 3.5%), and docosahexaenoic acid (DHA; 1% to 3.5%). Oleic Acid C 18 H 34 O 2 Linoleic Acid C 18 H 32 O 2 Caprylic Acid C 8 H 16 O 2 Capric Acid C 10 H 20 O 2 Stearic Acid C 18 H 36 O 2 Palmitic Acid C 16 H 32 O 2 Linolenic Acid C 18 H 30 O 2 EPA C 20 H 30 O 2 DHA C 22 H 32 O 2 SMOFlipid contains no more than 25 mcg/L of aluminum. The container is not made with natural rubber latex, PVC, or DEHP. Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure

2 DOSAGE AND ADMINISTRATION For intravenous infusion into a central or peripheral vein. ( 2.1 ) SMOFlipid Pharmacy Bulk Package is only indicated for use in pharmacy admixture programs for the preparation of three-in-one or total nutrition admixtures. ( 2.2 ) Protect the admixed PN solution from light. ( 2.2 ) 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 ) For information on the age-appropriate infusion rate, see the full prescribing information ( 2.3 , 5.1 ) Age Nutritional Requirements Initial Recommended Dosage Maximum Dosage Birth to 2 years of age (including preterm and term neonates) 0.5 to 1 g/kg/day 3 g/kg/day Pediatric patients 2 to <12 years of age 1 to 2 g/kg/day 3 g/kg/day Pediatric patients 12 to 17 years of age 1 g/kg/day 2.5 g/kg/day Adults 1 to 2 g/kg/day 2.5 g/kg/day 2.1 Important Administration Instructions SMOFlipid is prepared and administered by a healthcare provider in the inpatient setting. Patients and caregivers may prepare and administer SMOFlipid for home use after appropriate training by a trained healthcare provider. SMOFlipid 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 )]. SMOFlipid 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 nonvented 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. SMOFlipid 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 SMOFlipid 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 SMOFlipid 100 mL, 250 mL, and 500 mL Flexible Containers for administration: 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. Remove Overpouch Place the bag on a clean, flat surface. Tear 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. 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 nonvented infusion set or close the air-inlet on a vented set. Use a 1.2 micron in-line filter for administration. 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. Hang the bag On the hanger cut and start infusion. Discard unused portion. SMOFlipid 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 and within 24 hours when used as part of an admixture. SMOFlipid 1000 mL Pharmacy Bulk Package For admixing use only and not for direct intravenous infusion . Prior to administration, transfer to a separate PN container for individual patient use. Transfer the contents through the blue infusion port using a suitable sterile transfer device or dispensing set. Discard any unused contents. Use the Pharmacy Bulk Package immediately for admixing after removal from 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. Admixing Instructions Prepare the admixture in PN containers using strict aseptic techniques to avoid microbial contamination. Do not add SMOFlipid 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 SMOFlipid. SMOFlipid 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. Transfer dextrose injection to the PN container. Transfer amino acid injection. Transfer SMOFlipid. Simultaneous transfer of amino acid injection, dextrose injection, and SMOFlipid 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 USA, LLC. 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 SMOFlipid 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. Figure Figure Figure Figure Figure 2.3 Recommended Dosage and Administration The recommended nutritional requirements of lipid and recommended dosages of SMOFlipid to be administered to meet those requirements for pediatric and adult patients are provided in Table 1, along with recommendations for the initial and maximum infusion rates. The recommended duration of infusion for SMOFlipid will vary depending on the clinical situation. Adjust the administration flow rate by taking into account the dose being administered, the daily volume/intake, and the duration of the infusion [see Overdosage ( 10 )]. 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 SMOFlipid, correct severe fluid and electrolyte disorders and measure serum triglyceride levels to establish a baseline value. In patients with elevated triglyceride levels, initiate SMOFlipid at a lower dosage and titrate in smaller increments, monitoring the triglyceride levels with each adjustment [see Warnings and Precautions ( 5.7 )] . SMOFlipid contains 0.162 to 0.225 mg/mL of all-rac-alpha-tocopherol. Take into account the amount of all-rac-alpha-tocopherol in SMOFlipid when determining the need for additional supplementation. Table 1: Recommended Pediatric and Adult Dosage and Infusion Rate *The neonatal period is defined as including term, post-term, and preterm newborn infants. The neonatal period for term and post-term infants is the day of birth plus 27 days. For preterm infants, 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 Direct Infusion Rate Recommended Initial Dosage and Maximum Dosage Initial Maximum Birth to 2 years of age (including preterm and term neonates*) [see Warnings and Precautions ( 5.1 )] Initial 0.5 to 1 g/kg/day not to exceed 3 g/kg/day** 0.1 to 0.2 mL/kg/hour for the first 15 to 30 minutes; gradually increase to the required rate after 30 minutes 0.75 mL/kg/hour Pediatric patients 2 to <12 years of age Initial 1 to 2 g/kg/day not to exceed 3 g/kg/day** 0.2 to 0.4 mL/kg/hour for the first 15 to 30 minutes; gradually increase to the required rate after 30 minutes 0.75 mL/kg/hour Pediatric patients 12 to 17 years of age Initial 1 g/kg/day not to exceed 2.5 g/kg/day** 0.2 to 0.4 mL/kg/hour for the first 15 to 30 minutes; gradually increase to the required rate after 30 minutes 0.75 mL/kg/hour Adults 1 to 2 g/kg/day not to exceed 2.5 g/kg/day** 0.2 mL/kg/hour for the first 15 to 30 minutes; gradually increase to the required rate after 30 minutes 0.5 mL/kg/hour

1 INDICATIONS AND USAGE SMOFlipid is indicated in adult and pediatric patients, including term and preterm neonates, as a source of calories and essential fatty acids for parenteral nutrition (PN) when oral or enteral nutrition is not possible, insufficient, or contraindicated. SMOFlipid is indicated in adult and pediatric patients, including term and preterm neonates, as a source of calories and essential fatty acids for parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. ( 1 )

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 SMOFlipid 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.

7 DRUG INTERACTIONS Soybean and olive oils in SMOFlipid contain vitamin K 1 which may counteract the anticoagulant activity of vitamin K antagonists such as warfarin. In patients who receive concomitant SMOFlipid 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 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action SMOFlipid 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. 12.2 Pharmacodynamics The pharmacodynamic effects of SMOFlipid have not been fully characterized. 12.3 Pharmacokinetics SMOFlipid provides fatty acids in the form of triglycerides which are hydrolyzed by lipoprotein lipase to release free fatty acids. Alpha-linolenic acid and linoleic acid are metabolized within a common biochemical pathway through a series of desaturation and elongation steps. Downstream products of alpha-linolenic acid are EPA and DHA, and linoleic acid is converted to arachidonic acid.

12.1 Mechanism of Action SMOFlipid 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.

12.2 Pharmacodynamics The pharmacodynamic effects of SMOFlipid have not been fully characterized.

12.3 Pharmacokinetics SMOFlipid provides fatty acids in the form of triglycerides which are hydrolyzed by lipoprotein lipase to release free fatty acids. Alpha-linolenic acid and linoleic acid are metabolized within a common biochemical pathway through a series of desaturation and elongation steps. Downstream products of alpha-linolenic acid are EPA and DHA, and linoleic acid is converted to arachidonic acid.

20230714

10

3 DOSAGE FORMS AND STRENGTHS SMOFlipid is a sterile, homogenous lipid injectable emulsion in Flexible Containers supplied as: 20 g of lipid/100 mL in 100 mL single-dose Flexible Container 50 g of lipid/250 mL in 250 mL single-dose Flexible Container 100 g of lipid/500 mL in 500 mL single-dose Flexible Container 200 g of lipid/1000 mL in 1000 mL Pharmacy Bulk Package SMOFlipid is a sterile, homogenous lipid injectable emulsion supplied as 20 g of lipid/100 mL in 100 mL single-dose Flexible Container, 50 g of lipid/250 mL in 250 mL single-dose Flexible Container, 100 g of lipid/500 mL in 500 mL single-dose Flexible Container, and 200 g of lipid/1000 mL in 1000 mL Pharmacy Bulk Package. ( 3 )

Smoflipid Smoflipid GLYCERIN EGG PHOSPHOLIPIDS .ALPHA.-TOCOPHEROL, DL- WATER SODIUM OLEATE SODIUM HYDROXIDE SOYBEAN OIL SOYBEAN OIL MEDIUM-CHAIN TRIGLYCERIDES MEDIUM-CHAIN TRIGLYCERIDES OLIVE OIL OLIVE OIL FISH OIL FISH OIL

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with SMOFlipid have not been performed to evaluate the carcinogenic potential or effects on fertility. No mutagenic effects were observed in the following in vitro studies with SMOFlipid: bacterial gene mutation assay in Salmonella typhimurium , chromosomal aberration assay in human lymphocytes, and hypoxanthine phosphoribosyl transferase (HPRT) gene mutation assay in V79 cells. In an in vivo bone marrow cytogenic study in rats, no mutagenic effect was observed.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with SMOFlipid have not been performed to evaluate the carcinogenic potential or effects on fertility. No mutagenic effects were observed in the following in vitro studies with SMOFlipid: bacterial gene mutation assay in Salmonella typhimurium , chromosomal aberration assay in human lymphocytes, and hypoxanthine phosphoribosyl transferase (HPRT) gene mutation assay in V79 cells. In an in vivo bone marrow cytogenic study in rats, no mutagenic effect was observed.

NDA207648

Smoflipid

Smoflipid

63323-820

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE LABEL - PRINCIPAL DISPLAY – SMOFlipid ® 100 mL Bag Label SMOFlipid ® (lipid injectable emulsion, USP), 20% 20 grams/100 mL (0.2 grams/mL) For intravenous use. 100 mL Energy: 200 kcal per 100 mL Rx only NDC 63323-820-01 PACKAGE LABEL - PRINCIPAL DISPLAY – SMOFlipid

Dosage and Administration ( 2.1 , 2.3 ) 5/2023 Warnings and Precautions ( 5.1 ) 5/2023

17 PATIENT COUNSELING INFORMATION When initiating SMOFlipid administration, discuss the following information: Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsion in Neonates and Infants Inform caregivers that acute respiratory distress and death may occur in neonates and infants after rapid infusion of intravenous lipid emulsions. If SMOFlipid is infused at home, instruct caregivers not to exceed the maximum infusion rate [see Warnings and Precautions ( 5.1 )]. Parenteral Nutrition-Associated Liver Disease and Other Hepatobiliary Disorders Inform patients and caregivers that use of parenteral nutrition may result in parenteral nutrition- associated liver disease and/or other hepatobiliary disorders [see Warnings and Precautions ( 5.2 )]. Hypersensitivity Reactions Inform patients and caregivers that SMOFlipid may cause hypersensitivity reactions. If SMOFlipid is infused at home, instruct patients or caregivers to stop the infusion of SMOFlipid immediately and seek medical attention if a hypersensitivity reaction occurs [see Warnings and Precautions ( 5.3 )]. Infections Inform patients and caregivers that patients who receive SMOFlipid are at risk of infection. If SMOFlipid is infused at home, instruct patients or caregivers to ensure aseptic techniques are used for the preparation and administration of SMOFlipid and to monitor for signs and symptoms of infection [see Warnings and Precautions ( 5.4 )] . Fat Overload Syndrome Inform patients and caregivers that fat overload syndrome has been reported with the use of intravenous lipid emulsions. If SMOFlipid is infused at home, instruct patients or caregivers to stop SMOFlipid if signs or symptoms of fat overload syndrome occur [see Warnings and Precautions ( 5.5 )] . Refeeding Syndrome If the patient is severely malnourished, inform patients and caregivers that administering parenteral nutrition including SMOFlipid may result in refeeding syndrome. [see Warnings and Precautions ( 5.6 )] . Hypertriglyceridemia Inform patients and caregivers about the risks of hypertriglyceridemia with SMOFlipid use [see Warnings and Precautions ( 5.7 )] . Aluminum Toxicity Inform patients and caregivers that prolonged PN administration in patients with renal impairment, including preterm neonates, may result in aluminum reaching toxic levels associated with central nervous system and bone toxicity [see Warnings and Precautions ( 5.8 )] . Essential Fatty Acid Deficiency Inform patients and caregivers that cases of EFAD with the use of SMOFlipid have been reported in adults and pediatric patients in the postmarketing period [see Warnings and Precautions ( 5.9 )] . Preparation and Administration Instructions If it is acceptable for a patient or caregiver to administer SMOFlipid at home, then provide recommendations on how to prepare, add compatible additives (when appropriate), administer, and store SMOFlipid [see Dosage and Administration ( 2.1 , 2.2 )]. Manufactured by: Uppsala, Sweden Fresenius Kabi, Oxalert, and SMOFlipid are registered trademarks of Fresenius Kabi, www.fresenius-kabi.com/us 451418E Fresenius Kabi Logo

14 CLINICAL STUDIES 14.1 Adult Clinical Studies The efficacy of SMOFlipid compared to soybean oil lipid emulsions was evaluated in 3 clinical studies in adult patients. Nutritional efficacy in adult studies was assessed by changes in anthropometric indices (body weight, height, and body mass index [BMI]), changes in lipid and protein metabolism (albumin), and fatty acid parameters. Of the 354 adult patients (176 SMOFlipid; 178 comparator), 62% were male, 99% were Caucasian, and ages ranged from 19 to 96 years. All patients received SMOFlipid or the comparator as part of a PN regimen. Although Adult Study 1, Adult Study 2, and Adult Study 3 were not adequately designed to demonstrate the noninferiority of SMOFlipid to the soybean oil comparator, they support SMOFlipid as a source of calories and essential fatty acids in adults. The lipid dosage was variable in these studies and adjusted to the patient's nutritional requirements. Adult Study 1 was a double-blind, randomized, active-controlled, parallel-group, multicenter study in patients who required PN for at least 28 days. Seventy-five patients were enrolled, and 73 patients were treated with either SMOFlipid or a soybean oil lipid emulsion. Changes in mean triglyceride levels from baseline values to Week 4 were similar in both the SMOFlipid and comparator groups. Mean albumin levels demonstrated a comparable decrease in both groups. Mean changes in body weight (kg) and BMI (kg/m 2 ) were similar in both the SMOFlipid and comparator group. Adult Study 2 was a phase 3, randomized, double-blind, active-controlled, multicenter study. A total of 249 postoperative adult patients were randomized to receive either SMOFlipid or a soybean oil intravenous lipid emulsion for at least 5 days as part of their total parenteral nutrition (TPN) regimen. From baseline to Day 6, mean triglyceride levels increased similarly in both the SMOFlipid and comparator groups. Adult Study 3 was a double-blind randomized, active-controlled, parallel-group, single-center study in 32 adult patients who required TPN for 10 to 14 days. Patients were treated with either SMOFlipid or a soybean oil lipid emulsion. The increase in mean triglyceride levels from baseline to the final assessment was similar in both the SMOFlipid and comparator groups. 14.2 Pediatric Clinical Studies The efficacy of SMOFlipid compared to soybean oil lipid emulsions in pediatric patients of all age groups, including term and preterm neonates, was evaluated in 333 pediatric patients in 4 randomized active-controlled, double-blind, parallel-group controlled clinical studies. Although Pediatric Studies 1, 2, 3, and 4 were not adequately designed to demonstrate the noninferiority of SMOFlipid to the soybean oil comparator, they support SMOFlipid as a source of calories and essential fatty acids in pediatric patients. The 333 pediatric patients (170 SMOFlipid; 163 comparator) consisted of 296 patients who were <28 days old, 22 patients 29 days to <2 years old, and 15 patients 2 to <12 years old. Fifty percent of the pediatric patients were male and 87% were Caucasian. All patients received SMOFlipid or the comparator as part of a PN regimen. Nutritional efficacy in neonates was assessed by changes in anthropometric indices (body weight, height, head circumference). Nutritional efficacy in pediatric patients, 28 days to 12 years of age, was assessed by changes in triglyceride concentrations and fatty acid parameters. Pediatric Study 1 enrolled 152 preterm and term neonates (birth up to 28 days) and 9 patients ranging in age from 29 to 153 days. Patients were treated with either SMOFlipid (n=83) or a soybean oil lipid emulsion (n=78). A total of 119 patients (61 SMOFlipid; 58 comparator) received study treatment for ≥14 days. A total of 25 patients received SMOFlipid for ≥29 days; 5 patients received SMOFlipid for the maximum study duration of 78-84 days. Pediatric Studies 2 and 3 enrolled 60 and 84 preterm neonates, respectively, who were treated with either SMOFlipid or a soybean oil lipid emulsion (72 neonates in each group). The median treatment duration for SMOFlipid group was 12 days in Pediatric Study 2 and 7 days in Pediatric Study 3. Pediatric Study 4 enrolled 13 patients 5 months to <2 years of age and 15 patients 2 to 11.5 years of age. Patients were treated with either SMOFlipid (n=15) or a soybean oil lipid emulsion (n=13) with a median treatment duration of 27 days. In Pediatric Studies 1, 2 and 3, which enrolled neonates, SMOFlipid-treated patients showed increases in the median body weight, height/length, and head circumference (which was measured in Studies 1 and 3) comparable to the soybean oil lipid emulsion-treated patients. Mean triglyceride levels from baseline to the final assessment in Pediatric Studies 1, 2, and 3 were variable in these neonates, but overall differences between groups were not considered clinically relevant. Mean triglyceride levels in Pediatric Study 4 were variable, but remained within the normal range.

8.5 Geriatric Use Energy expenditure and requirements may be lower for older adults than younger patients. Of the 354 adult patients in clinical studies of SMOFlipid, 35% were >65 years of age and 10% were >75 years of age. No overall differences in the safety and efficacy of SMOFlipid were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity in some older patients cannot be ruled out.

8.4 Pediatric Use The safety and effectiveness of SMOFlipid have been established as a source of calories and essential fatty acids for PN when oral or enteral nutrition is not possible, insufficient, or contraindicated in pediatric patients, including term and preterm neonates. Use of SMOFlipid 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 SMOFlipid in older pediatric patients is supported by evidence from a short-term (i.e., <28 days) study 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 SMOFlipid-treated pediatric patients were anemia, vomiting, gamma-glutamyltransferase increased, and nosocomial infection [see Adverse Reactions ( 6.1 )]. PNALD, also referred to as IFALD, has been reported in pediatric patients who received SMOFlipid for more than 2 weeks. PNAC (a precursor to PNALD) was reported less frequently in SMOFlipid- treated patients compared to soybean oil lipid emulsion-treated patients in Pediatric Study 1 [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )]. Although clinically significant cases of EFAD were not observed during short-term use in pediatric clinical studies, cases of EFAD have been reported with the use of SMOFlipid in the postmarketing setting [ see Warnings and Precautions ( 5.9 ), Adverse Reactions ( 6.1 )]. Monitor pediatric patients for laboratory evidence of EFAD because they may be particularly vulnerable to neurologic complications if adequate amounts of essential fatty acids are not provided [see Warnings and Precautions ( 5.9 )]. 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 infants receiving prolonged treatment with SMOFlipid may be at risk for aluminum toxicity [see Warnings and Precautions ( 5.8 )].

8.1 Pregnancy Risk Summary Administration of the recommended dose of SMOFlipid is not expected to cause major birth defects, miscarriage, or other adverse maternal or fetal outcomes. No animal reproduction studies have been conducted with SMOFlipid. There are risks to the fetus associated with severe malnutrition during pregnancy ( see Clinical Considerations ) . The estimated 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Administration of the recommended dose of SMOFlipid is not expected to cause major birth defects, miscarriage, or other adverse maternal or fetal outcomes. No animal reproduction studies have been conducted with SMOFlipid. There are risks to the fetus associated with severe malnutrition during pregnancy ( see Clinical Considerations ) . The estimated 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 SMOFlipid is not expected to cause harm to a breastfed infant. There are no data on the presence of SMOFlipid 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 SMOFlipid and any potential adverse effects of SMOFlipid on the breastfed infant, or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of SMOFlipid have been established as a source of calories and essential fatty acids for PN when oral or enteral nutrition is not possible, insufficient, or contraindicated in pediatric patients, including term and preterm neonates. Use of SMOFlipid 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 SMOFlipid in older pediatric patients is supported by evidence from a short-term (i.e., <28 days) study 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 SMOFlipid-treated pediatric patients were anemia, vomiting, gamma-glutamyltransferase increased, and nosocomial infection [see Adverse Reactions ( 6.1 )]. PNALD, also referred to as IFALD, has been reported in pediatric patients who received SMOFlipid for more than 2 weeks. PNAC (a precursor to PNALD) was reported less frequently in SMOFlipid- treated patients compared to soybean oil lipid emulsion-treated patients in Pediatric Study 1 [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )]. Although clinically significant cases of EFAD were not observed during short-term use in pediatric clinical studies, cases of EFAD have been reported with the use of SMOFlipid in the postmarketing setting [ see Warnings and Precautions ( 5.9 ), Adverse Reactions ( 6.1 )]. Monitor pediatric patients for laboratory evidence of EFAD because they may be particularly vulnerable to neurologic complications if adequate amounts of essential fatty acids are not provided [see Warnings and Precautions ( 5.9 )]. 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 infants receiving prolonged treatment with SMOFlipid may be at risk for aluminum toxicity [see Warnings and Precautions ( 5.8 )]. 8.5 Geriatric Use Energy expenditure and requirements may be lower for older adults than younger patients. Of the 354 adult patients in clinical studies of SMOFlipid, 35% were >65 years of age and 10% were >75 years of age. No overall differences in the safety and efficacy of SMOFlipid were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity in some older patients cannot be ruled out.

16 HOW SUPPLIED/STORAGE AND HANDLING SMOFlipid is a sterile lipid injectable emulsion with a lipid content of 0.2 gram/mL available in Flexible Containers in the following sizes: Product Code Unit of Sale Strength Each 830307310 NDC 63323-820-00 Unit of 10 20 grams/100 mL (0.2 grams/mL) NDC 63323-820-01 100 mL single-dose Bag 830307312 NDC 63323-820-12 Unit of 20 20 grams/100 mL (0.2 grams/mL) NDC 63323-820-02 100 mL single-dose Bag 830570310 NDC 63323-820-74 Unit of 10 50 grams/250 mL (0.2 grams/mL) NDC 63323-820-04 250 mL single-dose Bag 830820310 NDC 63323-820-50 Unit of 12 100 grams/500 mL (0.2 grams/mL) NDC 63323-820-03 500 mL single-dose Bag 830920310 NDC 63323-820-10 Unit of 6 200 grams/1000 mL (0.2 grams/mL) NDC 63323-820-05 1000 mL Pharmacy Bulk Package Bag Store below 25°C (77°F). Avoid excessive heat. Do not freeze. If accidentally frozen, discard container. Store in overpouch until ready for use. SMOFlipid 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 )] . SMOFlipid 1000 mL Pharmacy Bulk Package Use the Pharmacy Bulk Package immediately for admixing after removal from 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 SMOFlipid 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 )].