NutriLipid I.V. Fat Emulsion

1 INDICATIONS AND USAGE Nutrilipid ® 20% is indicated as a source of calories and essential fatty acids for parenteral nutrition and as a source of essential fatty acids when a deficiency occurs when oral or enteral nutrition is not possible, insufficient, or contraindicated. Nutrilipid 20% is indicated as a source of calories and essential fatty acids for parenteral nutrition and as a source of essential fatty acids when a deficiency occurs when oral or enteral nutrition is not possible, insufficient, or contraindicated. ( 1 )

2 DOSAGE AND ADMINISTRATION Nutrilipid 20% Pharmacy Bulk Package is not intended for direct intravenous administration. ( 2.1 ) For intravenous infusion through a peripheral or central line ( 2.1 ) Recommended dosage depends on age, energy expenditure, clinical status, body weight, tolerance, ability to metabolize and consideration of additional energy given to the patient. ( 2.4 ) For information on the age-appropriate infusion rate, see the full prescribing information. ( 2.4 , 5.1 ) Age Nutritional Requirements Initial Recommended Dosage Maximum Dosage Preterm and term infants (<1 year) 1 to 2 g/kg/day 3 g/kg/day Pediatric patients 1 to 10 years Pediatric patients 11 to <17 years 1 g/kg/day 2.5 g/kg/day Adults 1 to 1.5 g/kg/day 2.5 g/kg/day 2.1 Administration Instructions Nutrilipid 20% Pharmacy Bulk Package is not intended for direct intravenous administration. Nutrilipid 20% is for intravenous infusion through a peripheral or central line. When administered with dextrose and amino acids, the choice of a central or peripheral venous route should depend on the osmolarity of the final infusate. Do not exceed the recommended maximum infusion rate in Table 1 [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ]. Use a non-vented infusion set or close the air vent on a vented set. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Use a dedicated line without any connections. Multiple connections could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Use a 1.2 micron in-line filter. Nutrilipid 20% can be infused concurrently into the same vein as carbohydrate-amino acid solutions by means of a Y-connector located near the infusion site; flow rates of each solution should be controlled separately by infusion pumps. Do not use administration sets and lines that contain di-2-ethylhexyl phthalate (DEHP). Conventional administration sets contain polyvinyl chloride (PVC) components that have DEHP as a plasticizer. 2.2 Preparation Instructions for Nutrilipid 20% Bags for Direct Infusion Caution: Nutrilipid 20% Pharmacy Bulk Package is not intended for direct intravenous administration. Step 1: Inspect infusion bag overwrap and primary bag and do not use if damaged. Inspect oxygen indicator and do not use if oxygen indicator is pink or dark pink. Use only if container and seals are intact. Step 2: To open, tear overwrap starting from the tear notches (Figure 1). Remove Nutrilipid 20% bag from overwrap and discard oxygen indicator, oxygen absorber and overwrap. Step 3: Inspect Nutrilipid 20% bag visually (Figure 2). Nutrilipid 20% is a homogenous white and milky, sterile, nonpyrogenic lipid injectable emulsion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect Nutrilipid 20% to ensure that the emulsion has not separated. Discard the bag if any particulates or discoloration are observed. Step 4: Remove aluminum foil of outlet port at the bottom of the bag (Figure 3a) and attach administration set (Figure 3b). Do not use/penetrate blocked port. Step 5: Hang bag on IV Pole (Figure 4). If infusion pumps are used, flow rates of each parenteral fluid should be controlled with a separate pump. Do not connect flexible bags in series to avoid air embolism due to possible residual gas contained in the primary bag. Air embolism can result if residual gas in the bag is not fully evacuated prior to administration if the flexible bag is pressurized to increase flow rates. If administration is controlled by a pumping device, discontinue pumping action before the bag runs dry to avoid air embolism. Overwrap Illustration Figure 1 Tear Overwrap Figure 2 Inspect Bag Blocked port illustration Figure 3a and 3b Peel Foil and Insert Spike Do not use blocked port illustration Figure 4 Hang Bag 2.3 Preparation Instructions for Admixing Using Total Parenteral Nutrition Pooling Bags Prepare the admixture into pooling bags using strict aseptic techniques to avoid microbial contamination. Do not add additives directly to Nutrilipid 20% Pharmacy Bulk Package. Some additives may be incompatible and should not be used. If it is deemed advisable to introduce additives, prepare the admixture using strict aseptic techniques to avoid microbial contamination. Additions to the pooling bag should be evaluated by a pharmacist for compatibility. Questions about compatibility may be directed to B. Braun Medical Inc., Medical Affairs. Do not add Nutrilipid 20% to the pooling bag first; destabilization of the lipid may occur from such an admixture. The following proper mixing sequence must be followed to minimize pH related problems by ensuring that typically acidic Dextrose Injections are not mixed with lipid emulsions alone: Manual Admixing Manually transfer Dextrose Injection to the Total Parental Nutrition Admixture Container Manually transfer Amino Acid Injection Manually transfer Nutrilipid 20% Use gentle agitation during admixing to minimize localized concentration effects; shake bags gently after each addition. Automated Device Admixing When admixing parenteral nutrition using an automated device, the Nutrilipid 20% must be separated from the dextrose product by an amino acid product or other non-acidic products. The prime destabilizers of emulsions are excessive acidity (such as pH below 5) and inappropriate electrolyte content. Give careful consideration to additions of divalent cations (Ca ++ and Mg ++ ), which have been shown to cause emulsion instability. Amino acid solutions exert buffering effects that protect the emulsion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect Nutrilipid 20% to ensure that: precipitates have not formed during the mixing or addition of additives and the emulsion has not separated. Separation of the emulsion can be visibly identified by a yellowish streaking or the accumulation of yellowish droplets in the admixed emulsion. Discard the admixture if any of the above are observed. If using an Automated Device, follow the manufacturer instructions. Use of the Pharmacy Bulk Package for admixing should be limited to up to four hours after opening. Admixtures should be used promptly with storage under refrigeration [2°C to 8°C (36°F to 46°F)] not to exceed 24 hours and must be completely used within 24 hours after removal from refrigeration. Do not connect flexible bags in series to avoid air embolism due to possible residual gas contained in the primary bag. Air embolism can result if residual gas in the bag is not fully evacuated prior to administration if the flexible bag is pressurized to increase flow rates. If administration is controlled by a pumping device, discontinue pumping action before the bag runs dry to avoid air embolism. Protect the admixed parenteral nutrition solution from light. 2.4 Dosing Considerations The dosing of Nutrilipid 20% depends on the patient’s individual energy requirements, influenced by body weight, tolerance, clinical status, age-related growth rate in pediatric patients and the ability to eliminate and metabolize fat. For partial parenteral nutrition, energy supply by oral or enteral nutrition has to be taken into account. For complete parenteral nutrition, concomitant supplementation with amino acids, carbohydrates, electrolytes, vitamins, and trace elements is necessary. Prior to administration of Nutrilipid 20%, correct severe water and electrolyte disorders, severe fluid overload states, and severe metabolic disorders. Before starting the infusion, obtain serum triglyceride levels to establish the baseline value. Recommended Adult and Pediatric Dosing The recommended nutritional requirements of lipid and recommended dosages of Nutrilipid 20% to be administered to meet those requirements for adults and pediatric patients are provided in Table 1, along with recommendations for the initial and maximum infusion rates. The recommended duration of infusion for Nutrilipid 20% is between 12 and 24 hours, 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) ]. Treatment with parenteral nutrition may be continued for as long as is required by the patient’s condition. In patients with elevated triglyceride levels, initiate Nutrilipid 20% injection at a lower dose, and advance in smaller increments, monitoring the triglyceride levels with each adjustment [ see Warnings and Precautions (5.7) and (5.9) ] . When Nutrilipid 20% is administered to correct essential fatty acid deficiency, 8% to 10% of the caloric input should be supplied by Nutrilipid 20% in order to provide adequate amounts of linoleic and linolenic acids. Table 1: Recommended Pediatric and Adult Dosage and Infusion Rate Age Nutritional Requirements Direct Infusion Rate Nutrilipid 20% Pharmacy Bulk Package is not intended for direct intravenous administration. Recommended Initial Dosage and Maximum Dosage Initial Maximum Preterm and term infants (less than 1 year of age) [see Warnings and Precautions (5.1) ] Initial 1 to 2 g/kg/day not to exceed 3 g/kg/day Daily dosage should also not exceed a maximum of 60% of total energy requirements [see Overdosage (10)]. 0.05 mL/min for the first 10 to 15 minutes; gradually increase to the required rate after 15 minutes 0.75 mL/kg/hour Pediatric patients 1 to 10 years of age Initial 1 to 2 g/kg/day not to exceed 3 g/kg/day 0.75 mL/kg/hour Pediatric patients 11 to <17 years of age Initial 1 g/kg/day not to exceed 2.5 g/kg/day 0.5 mL/kg/hour Adults 1 to 1.5 g/kg/day not to exceed 2.5 g/kg/day 0.5 mL/min for the first 15 to 30 minutes; gradually increase to the required rate after 30 minutes 0.5 mL/kg/hour

4 CONTRAINDICATIONS Nutrilipid 20% injection is contraindicated in patients who have: Known hypersensitivity to egg, soybean, peanut, or any of the active or inactive ingredients in Nutrilipid 20% [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, 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 )

5 WARNINGS AND PRECAUTIONS Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsion in Neonates and Infants : Acute respiratory distress, metabolic acidosis, and death after rapid infusion of intravenous lipid emulsions have been reported. ( 5.1, 8.4 ) Parenteral Nutrition-Associated Liver Disease : Increased risk in patients who receive parenteral nutrition for greater than 2 weeks, especially preterm neonates. Monitor liver tests; if abnormalities occur, consider discontinuation or dosage reduction. ( 5.2, 8.4 ) Hypersensitivity reactions: Monitor for signs or symptoms. Discontinue infusion if reactions occur. ( 5.3 ) Infections, Fat Overload Syndrome, and Refeeding Syndrome, Hypertriglyceridemia: Monitor for signs and symptoms; monitor laboratory parameters. ( 5.4 , 5.5 , 5.6, 5.7 ) Aluminum Toxicity : Increased risk in patients with renal impairment, including preterm neonates. ( 5.8, 8.4 ) 5.1 Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsion 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 0.75 mL/kg/hour [see Dosage and Administration (2.4) ]. 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 of poor clearance of lipids from the circulation occur, stop the infusion and initiate a medical evaluation [see Warnings and Precautions (5.5, 5.7) and Overdosage (10) ]. 5.2 Parenteral Nutrition-Associated Liver Disease and Other Hepatobiliary Disorders Risk of Parenteral Nutrition-Associated Liver Disease Parenteral nutrition-associated liver disease (PNALD), also referred to as intestinal failure-associated liver disease (IFALD), can present as cholestasis or hepatic steatosis, and may progress to steatohepatitis with fibrosis and cirrhosis (possibly leading to chronic hepatic failure). The etiology of PNALD is multifactorial; however, intravenously administered phytosterols (plant sterols) contained in plant-derived lipid emulsions, including Nutrilipid 20%, have been associated with development of PNALD. Monitor liver tests in patients treated with Nutrilipid 20% 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 Nutrilipid 20%. Patients developing signs of hepatobiliary disorders should be assessed early to determine whether these conditions are related to Nutrilipid 20% use. 5.3 Hypersensitivity Reactions Nutrilipid 20% contains soybean oil and egg phospholipids which may cause hypersensitivity reactions. Cross reactions have been observed between soybean and peanut. In postmarketing experience, anaphylaxis has been reported following Nutrilipid administration [see Adverse Reactions (6.2) ]. Nutrilipid 20% is contraindicated in patients with known hypersensitivity to egg, soybean, peanut, or any of the active or inactive ingredients in Nutrilipid 20% [see Contraindications (4)] . If a hypersensitivity reaction occurs, stop infusion of Nutrilipid 20% immediately and initiate appropriate treatment and supportive measures. 5.4 Infections Lipid emulsions, such as Nutrilipid 20%, can support microbial growth and are an independent risk factor for the development of catheter-related bloodstream infections. To decrease the risk of infectious complications, ensure aseptic techniques are used for catheter placement, catheter maintenance, and preparation and administration of Nutrilipid 20%. Monitor for signs and symptoms of infection, including fever and chills, as well as including laboratory test results (including leukocytosis and hyperglycemia). Perform frequent checks of the intravenous catheter insertion site for edema, redness, and discharge. 5.5 Fat Overload Syndrome Fat overload syndrome is a rare condition that has been reported with intravenous lipid formulations and is characterized by a sudden deterioration in the patient's condition (e.g., fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, hepatomegaly, deteriorating liver function, and central nervous system manifestations such as coma). A reduced or limited ability to metabolize lipids, accompanied by prolonged plasma clearance (resulting in higher lipid levels), may result in this syndrome. Although fat overload syndrome has been most frequently observed when the recommended lipid dose or infusion rate was exceeded, cases have also been described when the lipid formulation was administered according to instructions. If signs or symptoms of fat overload syndrome occur, stop Nutrilipid 20%. The syndrome is usually reversible when the infusion of the lipid emulsion is stopped. 5.6 Refeeding Syndrome Administering PN to severely malnourished patients may result in the refeeding syndrome, which is characterized by the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop. To prevent these complications, closely monitor severely malnourished patients and slowly increase their nutrient intake. 5.7 Hypertriglyceridemia The use of Nutrilipid 20% is contraindicated in patients with hypertriglyceridemia with serum triglyceride concentrations >1,000 mg/dL. Patients with conditions such as inherited lipid disorders, obesity, diabetes mellitus, or metabolic syndromes have a higher risk of developing hypertriglyceridemia with the use of Nutrilipid 20%. In addition, patients with hypertriglyceridemia may have worsening of their hypertriglyceridemia with administration of Nutrilipid 20%. Excessive dextrose administration may further increase such risk. Evaluate patients’ capacity to metabolize and eliminate the infused lipid emulsion by measuring serum triglycerides before the start of infusion (baseline value) and regularly throughout treatment. If triglyceride levels are above 400 mg/dL in adults, stop the Nutrilipid 20% infusion and monitor serum triglyceride levels to avoid clinical consequences of hypertriglyceridemia such as pancreatitis. In pediatric patients with hypertriglyceridemia, lower triglyceride levels (i.e., below 400 mg/dL) may be associated with adverse reactions. Monitor serum triglyceride levels to avoid potential complications with hypertriglyceridemia such as pancreatitis, lipid pneumonitis, and neurologic changes, including kernicterus. To minimize the risk of new or worsening of hypertriglyceridemia, assess high-risk patients for their overall energy intake including other sources of lipids and dextrose, as well as concomitant drugs that may affect lipid and dextrose metabolism. 5.8 Aluminum Toxicity Nutrilipid 20% contains no more than 25 mcg/L of aluminum. Prolonged parenteral nutrition administration in patients with renal impairment may result in aluminum reaching toxic levels. Preterm infants are at greater risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions that contain aluminum. Patients with impaired kidney function, including preterm infants, 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 of total parenteral nutrition products. 5.9 Monitoring / Laboratory Tests Monitor fluid status closely in patients with pulmonary edema or heart failure. Throughout treatment, monitor serum triglycerides [see Warnings and Precautions (5.7) ] , fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, blood count (including platelets), and coagulation parameters. The lipids contained in Nutrilipid may interfere with some laboratory tests (e.g., hemoglobin, lactate dehydrogenase, bilirubin, oxygen saturation) if blood is sampled before the lipids have cleared from the bloodstream. Conduct these tests at least 6 hours after stopping the infusion. Nutrilipid contains Vitamin K that may counteract anticoagulant activity [see Drug Interactions (7) ].

7 DRUG INTERACTIONS Coumarin and coumarin derivatives, including warfarin: Anticoagulant activity may be counteracted; monitor laboratory parameters (7.1) 7.1 Coumarin and Coumarin Derivatives The soybean oil in Nutrilipid 20% contains vitamin K1. Vitamin K can reverse the anticoagulant activity of coumarin and coumarin derivatives, including warfarin, which work by blocking recycling of vitamin K. Monitor laboratory parameters for anticoagulant activity in patients who are on both Nutrilipid 20% and coumarin or coumarin derivatives.

6 ADVERSE REACTIONS Adverse Reactions described elsewhere in labeling: Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsion in Neonates and Infants [see Warnings and Precautions (5.1) ] Risk of Parenteral Nutrition Associated Liver Disease [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) ] Adverse reactions include administration site reactions (e.g., erythema, extravasation, pain, phlebitis, pruritus, swelling), hyperlipidemia, hypercoagulability, thrombophlebitis, thrombocytopenia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact B. Braun Medical Inc. at 1-833-425-1464 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 directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions reported with other intravenous lipid emulsions include hyperlipidemia, hypercoagulability, thrombophlebitis, and thrombocytopenia. Adverse reactions reported in long-term use with other intravenous lipid emulsions include hepatomegaly, jaundice due to central lobular cholestasis, splenomegaly, thrombocytopenia, leukopenia, abnormalities in liver function tests, brown pigmentation of the liver and overloading syndrome (focal seizures, fever, leukocytosis, hepatomegaly, splenomegaly and shock). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Nutrilipid 20%. 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 drug exposure. General disorders and administration site conditions: extravasation, infusion site erythema, infusion site pain, infusion site phlebitis, infusion site pruritus, and infusion site swelling. Immune system disorders: hypersensitivity reactions, including anaphylaxis [see Contraindications (4) , Warnings and Precautions (5.3) ].

8.1 Pregnancy Risk Summary There are no adequate or well controlled studies with Nutrilipid 20% in pregnant women. Additionally, animal reproduction studies have not been conducted with Nutrilipid 20%. It is not known whether Nutrilipid 20% can cause fetal harm when administered to a pregnant woman. Nutrilipid 20% should be given to a pregnant woman only if clearly needed.