Clinolipid

1 INDICATIONS AND USAGE CLINOLIPID is indicated in adults 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. CLINOLIPID is indicated in adults 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. ( 1 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • 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 (≥5%) adverse drug reactions from clinical trials in adults were nausea and vomiting, hyperlipidemia, hyperglycemia, hypoproteinemia, and abnormal liver function tests. Most common (≥5%) adverse reactions from clinical trials in pediatric patients were hyperbilirubinemia, patent ductus arteriosus, anemia, gastroesophageal reflux disease, bradycardia, feeding intolerance, neonatal intraventricular hemorrhage, increased alkaline phosphatase, atrial septal defect, hyponatremia, sepsis, and infantile apnea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472 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. The CLINOLIPID trials had small sample sizes and patients had a variety of underlying medical conditions both between different trials and within the individual trials. Patients had gastrointestinal diseases/dysfunction or were recovering from gastrointestinal or other surgeries, trauma, burns, or were afflicted by other chronic illness. Adult Trials Commonly observed adverse reactions in 261 adult patients who received CLINOLIPID were nausea and vomiting, hyperlipidemia, hyperglycemia, hypoproteinemia, and abnormal liver function tests and occurred in 2 to 10 % of patients. The largest clinical trial in adult patients (Study 1) enrolled 48 subjects with different underlying diagnoses. Study 2 was a randomized, open label multicenter study that enrolled 22 subjects, aged 32-81 years, who required long-term parenteral nutrition. The most common adverse reactions in Study 1 and Study 2 were infectious complications (urinary tract infection, septicemia, and fever of unknown origin), treatment emergent abnormalities on liver/gallbladder ultrasound and abnormalities of serum chemistries, principally, hepatic function tests. 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). Pediatric Trials The safety of CLINOLIPID in pediatric patients was evaluated in Studies 3, 4, 5, and 6 [see Clinical Studies (14.2) ] . In Study 3, EFAD was defined by calculating the Holman index (the triene [Mead acid] to tetraene [arachidonic acid] ratio; T:T ratio > 0.4). Although no patient developed EFAD, one CLINOLIPID-treated patient who had a T:T ratio that increased from < 0.2 at baseline to > 0.2 at end of study treatment was considered at risk for EFAD. This patient’s arachidonic and linoleic acid levels remained within the normal range. No soybean oil lipid emulsion-treated patients had a T:T ratio ≥ 0.2. In Studies 3, 4, 5, and 6, adverse reactions occurred at similar rates in subjects treated with CLINOLIPID and the 100% soybean oil comparator. Adverse reactions that occurred in ≥5% of patients included hyperbilirubinemia, patent ductus arteriosus, anemia, gastroesophageal reflux disease, bradycardia, feeding intolerance, neonatal intraventricular hemorrhage, increased alkaline phosphatase, atrial septal defect, hyponatremia, sepsis, and infantile apnea. 6.2 Postmarketing Experience The following adverse reactions have been identified during use of CLINOLIPID. 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. Gastrointestinal Disorders : Diarrhea Skin and Subcutaneous Tissue Disorders : Pruritus Immune System Disorders : Hypersensitivity with the manifestations of rash and dyspnea Investigations : International normalized ratio (INR) decreased in anticoagulated patients [see Drug Interactions (7) ] Hepatobiliary disorders: cholestasis

4 CONTRAINDICATIONS The use of CLINOLIPID is contraindicated in patients with the following: • Known hypersensitivity to egg, soybean, peanut or to any of the active or inactive ingredients in CLINOLIPID [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 )

11 DESCRIPTION CLINOLIPID lipid injectable emulsion, USP is a sterile, non-pyrogenic, homogenous, white, milky lipid emulsion for intravenous infusion. The lipid content of CLINOLIPID is 0.2 g/mL and comprises a mixture of refined olive oil and refined soybean oil in an approximate ratio of 4:1 (olive:soy). The mean concentration of linoleic acid (an omega-6 essential fatty acid) is 35.8 mg/mL (range 27.6 to 44.0 mg/mL) and α-linolenic acid (an omega-3 essential fatty acid) is 4.7 mg/mL (range 1.0 to 8.4 mg/mL). The phospholipids provide 470 milligrams or 15 mmol of phosphorus per liter. The total energy content, including fat, phospholipids and glycerin is 2000 kcal/L. Each 100 mL of CLINOLIPID 20% contains approximately 16 g of Olive Oil NF and 4 g of Soybean Oil USP, 1.2 g Egg Phospholipids NF, 2.25 g Glycerin USP, 0.03 g Sodium Oleate, and Water for Injection USP. Sodium Hydroxide NF for pH adjustment, pH: 6.0 to 9.0. The olive and soybean oils are refined natural products consisting of a mixture of neutral triglycerides of predominantly unsaturated fatty acids with the following structure: The major component fatty acids are linoleic (13.8 to 22.0%), oleic (44.3 to 79.5%), palmitic (7.6 to 19.3%), linolenic (0.5 to 4.2%), palmitoleic (0.0 to 3.2%) and stearic (0.7 to 5.0%). These fatty acids have the following chemical and structural formulas: CLINOLIPID has an osmolality of approximately 340 mOsmol/kg water (which represents an osmolarity of 260 mOsmol/liter of emulsion). CLINOLIPID contains no more than 25 mcg/L of aluminum. Structural Formula 1 Structural Formula 2

2 DOSAGE AND ADMINISTRATION • Use a 1.2 micron in-line filter when administering to a patient. ( 2.1 ) • For infusion into a central or peripheral vein. ( 2.2 ) • See full prescribing information for administration and admixing instructions. ( 2.2 , 2.3 ) • CLINOLIPID 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 parenteral solution from light. ( 2.3 ) • 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. ( 2.4 ) • For information on the age-appropriate infusion rate, see the full prescribing information. ( 2.4 , 5.1 ) Age Initial Dose Maximum Dose 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 less than 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 3 g/kg/day Adults 1 to 1.5 g/kg/day 2.5 g/kg/day 2.1 Use of an Inline Filter When Administering CLINOLIPID to a Patient Fragments of the administration port membrane could be dislodged into the bag after spiking. Use a 1.2 micron in-line filter during administration of CLINOLIPID (alone or as part of an admixture) to remove particulate matter or micro-precipitate contamination during administration of a lipid injection (alone or as part of an admixture). Particulate matter greater than 5 microns has the capability of obstructing blood flow through capillaries, which could lead to embolism and vascular occlusion. Do not use filters of less than 1.2 micron pore size with lipid emulsions. 2.2 Important Administration Instructions Before opening the overwrap, check the color of the oxygen indicator. Compare the color of the indicator to the reference color printed next to the OK symbol depicted in the printed area of the indicator label. Do not use the product if the color of the oxygen absorber/indicator does not correspond to the reference color printed next to the OK symbol. After opening the bag, use the contents immediately and discard unused portion. Visually inspect that the emulsion is a homogeneous liquid with a milky appearance. Inspect for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not exceed the recommended maximum infusion rate (0.75 mL/kg/hour for pediatric patients and 0.5 mL/kg/hour for adults) [see Dosage and Administration (2.4 ) and Warnings and Precautions (5.1) ] . When Administering CLINOLIPID to a Patient : 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. Do not use vented administration sets with the vent in the open position. This can result in air embolism. If CLINOLIPID is mixed with dextrose and/or amino acid solutions, check the compatibility before administration by inspecting the mixture closely for the presence of precipitates. Formation of precipitates could result in vascular occlusion. CLINOLIPID can be administered via central or peripheral vein. 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 use administration sets and lines that contain di-2-ethylhexy phthalate (DEHP). Use only a 1.2 micron pore size in-line filter to administer CLINOLIPID. DO NOT use any size less than 1.2 micron pore size in-line filter [see Dosage and Administration (2.1) ] . CLINOLIPID 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 for no longer than 24 hours at no more than 25°C (77°F). CLINOLIPID 1,000 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 infusion port using a suitable sterile transfer device or dispensing set. Discard any unused contents. Discard any unused portion. • 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 no more than 25°C (77°F). • Once the closure is penetrated use Pharmacy Bulk Package contents within 4 hours. 2.3 Admixing Guidelines When Admixing CLINOLIPID in the Pharmacy: Prepare the admixture using strict aseptic techniques to avoid microbial contamination. Do not add additives directly to CLINOLIPID. Do not add CLINOLIPID to the total parenteral nutrition container first; destabilization of the lipid may occur from such an admixture. Do not use the EXACTAMIX Inlet REF 173 (H938173) with an EXACTAMIX compounder to transfer CLINOLIPID. This inlet spike has been associated with dislodgement of the administration port membrane into the CLINOLIPID bag. Use of EXACTAMIX Inlet REF 174 (H938174) is recommended. 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: 1. Transfer Dextrose Injection to the Total Parenteral Nutrition Admixture Container 2. Transfer Amino Acid Injection 3. Transfer Lipid Emulsion Amino Acid Injection, Dextrose Injection and Lipid Emulsions may be simultaneously transferred to the admixture container. Use gentle agitation during admixing to minimize localized concentration effects; shake bags gently after each addition. The prime destabilizers of emulsions are excessive acidity (such as a 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. Inspect the admixture closely for separation of the emulsion. This can be visibly identified by a yellowish streaking or the accumulation of yellowish droplets in the admixed emulsion. The admixture should also be examined for particulates. Discard the admixture if any of the above is observed. Protect the admixed parenteral nutrition solution from light. 2.4 Dosing Considerations The recommended nutritional requirements of lipid and recommended dosages of CLINOLIPID 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. For complete parenteral nutrition, concomitant supplementation with amino acids, carbohydrates, electrolytes, vitamins, and trace elements is necessary. Prior to administration of CLINOLIPID, 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. In patients with elevated triglyceride levels, initiate CLINOLIPID injection at a lower dose, and advance in smaller increments, checking the triglyceride levels prior to each adjustment. Adjust the infusion rate by taking into account the dose being administered, the daily volume intake, and the duration of the infusion. Do not exceed the maximum infusion rates in Table 1 [see Warnings and Precautions (5.1) and see Overdosage (10) ] . The recommended duration of infusion for a parenteral nutrition bag is between 12 and 24 hours, depending on the clinical situation. For preterm and term neonates, the recommended duration of infusion is 20 to 24 hours. Treatment with parenteral nutrition may be continued for as long as required by the patient’s condition. The maximum daily dosage of CLINOLIPID should be based on individual total nutritional requirements and patient tolerance ( Table 1 ). Table 1: Recommended Pediatric and Adult Dosage and Infusion Rate Age Nutritional Requirements Direct Infusion Rate CLINOLIPID Pharmacy Bulk Package is not intended for direct intravenous administration. Recommended Initial Dosage and Maximum Dosage Initial Maximum Birth to 2 years of age (including preterm and term neonates 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). ) [see Warnings and Precautions (5.1) ] Initial 0.5 to 1g/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) ] . 0.1 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 less than 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 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 Adults 1 to 1.5 g/kg/day not to exceed 2.5 g/kg/day 0.2 mL/kg/hour for the first 15 to 30 minutes; if tolerated, gradually increase to the required rate after 30 minutes 0.5 mL/kg/hour

10 OVERDOSAGE In the event of overdose, serious adverse reactions may result [see Warnings and Precautions (5.1 , 5.5 )] . Stop the infusion to allow lipids to clear from serum. The effects are usually reversible after the lipid infusion is stopped. If medically appropriate, further intervention may be indicated. The lipid administered and fatty acids produced are not dialyzable.

7 DRUG INTERACTIONS No drug interaction studies have been performed with CLINOLIPID. Olive and soybean oils have a natural content of Vitamin K 1 that may counteract the anticoagulant activity of coumadin derivatives, including warfarin. The anticoagulant activity of coumadin derivatives, including warfarin, may be counteracted. ( 7 )

12 CLINICAL PHARMACOLOGY CLINOLIPID administered intravenously provides biologically utilizable source of calories and essential fatty acids. 12.1 Mechanism of Action 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 important for membrane structure and function, precursors for bioactive molecules (such as prostaglandins), and as regulators of gene expression. 12.2 Pharmacodynamics Infused essential fatty acids are synthesized into higher derivative fatty acids. Olive oil contains significant amounts of alpha-tocopherol that contributes to Vitamin E status. 12.3 Pharmacokinetics Metabolism and Excretion The fatty acids, phospholipids, and glycerol found in lipid emulsions are metabolized by cells to carbon dioxide and water. The metabolism of these substances results in the generation of energy in the form of adenosine triphosphate (ATP). Some fatty acids are stored in the body in fat tissue, cell membranes, or as intracellular triglycerides. There is constant turn-over of these tissues, with the result that the lipid components are eventually metabolized to carbon dioxide and water. Carbon dioxide is expired through the lungs. Water is excreted through the kidneys or lost through evaporation/expiration through the skin, lungs, and other tissue surfaces. Some lipids (i.e., phospholipids, cholesterol, and bile acids) are excreted through the biliary system.

12.1 Mechanism of Action 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 important for membrane structure and function, precursors for bioactive molecules (such as prostaglandins), and as regulators of gene expression.

12.2 Pharmacodynamics Infused essential fatty acids are synthesized into higher derivative fatty acids. Olive oil contains significant amounts of alpha-tocopherol that contributes to Vitamin E status.

12.3 Pharmacokinetics Metabolism and Excretion The fatty acids, phospholipids, and glycerol found in lipid emulsions are metabolized by cells to carbon dioxide and water. The metabolism of these substances results in the generation of energy in the form of adenosine triphosphate (ATP). Some fatty acids are stored in the body in fat tissue, cell membranes, or as intracellular triglycerides. There is constant turn-over of these tissues, with the result that the lipid components are eventually metabolized to carbon dioxide and water. Carbon dioxide is expired through the lungs. Water is excreted through the kidneys or lost through evaporation/expiration through the skin, lungs, and other tissue surfaces. Some lipids (i.e., phospholipids, cholesterol, and bile acids) are excreted through the biliary system.

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3 DOSAGE FORMS AND STRENGTHS CLINOLIPID is a sterile, homogenous, white, milky, lipid injectable emulsion supplied as: • 20% (20 g/100 mL)(0.2g/mL) of lipid in 100 mL single-dose Flexible Container • 20% (50 g/250 mL)(0.2g/mL) of lipid in 250 mL single-dose Flexible Container • 20% (100 g/500 mL)(0.2g/mL) of lipid in 500 mL single-dose Flexible Container • 20% (200 g/1,000 mL)(0.2g/mL) of lipid in 1,000 mL Pharmacy Bulk Package Injectable emulsion: • 20% (20 g/100 mL) (0.2 g/mL) of lipid in 100 mL single-dose flexible container ( 3 ) • 20% (50 g/250 mL) (0.2 g/mL) of lipid in 250 mL single-dose flexible container ( 3 ) • 20% (100 g/500 mL) (0.2 g/mL) of lipid in 500 mL single-dose flexible container ( 3 ) • 20% (200 g/1,000 mL) (0.2 g/mL) of lipid in 1,000 mL Pharmacy Bulk Package ( 3 )

Clinolipid Olive Oil and Soybean Oil OLIVE OIL OLIVE OIL SOYBEAN OIL SOYBEAN OIL EGG PHOSPHOLIPIDS GLYCERIN SODIUM OLEATE

13.2 Animal Toxicology and/or Pharmacology CLINOLIPID was evaluated in toxicity studies conducted in rats and dogs for up to 3 months. The principal signs of toxicity noted in the 3-month studies were: • Slight hemolytic anemia at 12 g/kg/day in rats and at 6 g/kg/day in dogs. These doses in rats and dogs are 4 and 2 times higher, respectively, than the maximum recommended pediatric dose (3 g/kg/day) of CLINOLIPID. • Dose-dependent decrease in urea levels in rats at 6 and 12 g/kg/day dose levels and in dogs at 3, 4.5 and 6 g/kg/day dose levels associated with decreased feed consumption. • Hypercholesterolemia in dogs at 3, 4.5 and 6 g/kg/day dose levels. • Hepatic pathology of lipid and pigmentary overload in male and female rats at 3, 6 and 12 g/kg/day dose levels and brownish-yellow pigmentation in vacuolated Kupffer cells in male and female dogs at 3, 4.5 and 6 g/kg/day dose levels with hepatocyte vacuolation in male dogs at 6 g/kg/day and female dogs at 4.5 and 6 g/kg/day dose levels. • Splenic pigmentation and vacuolization in rats at 3, 6 and 12 g/kg/day dose levels, and dogs in 4.5 and 6 g/kg/day dose levels. At doses of 3 g/kg/day, slight lipid and pigmentary overload of the liver and vacuolization of Kupffer cells were observed in rats and dogs. At a dose of 12 g/kg/day in rats, hepatocellular vacuolation, granulomatous inflammation of the liver, hepatocellular necrosis and hemosiderosis of the liver and lipid deposits and splenic hemosiderosis, were observed. In dogs, at a dose of 6 g/kg/day, brownish-yellow pigmentation in the Kupffer cells of liver and spleen, hyperplasia of vacuolated Kupffer cells, hepatocyte vacuolization, a slight increase in the number of lipid storage cells (Ito cells) in the liver and macrophage vacuolization of the spleen were observed.

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

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with CLINOLIPID have not been performed to evaluate the carcinogenic potential, mutagenic potential, or effects on fertility. 13.2 Animal Toxicology and/or Pharmacology CLINOLIPID was evaluated in toxicity studies conducted in rats and dogs for up to 3 months. The principal signs of toxicity noted in the 3-month studies were: • Slight hemolytic anemia at 12 g/kg/day in rats and at 6 g/kg/day in dogs. These doses in rats and dogs are 4 and 2 times higher, respectively, than the maximum recommended pediatric dose (3 g/kg/day) of CLINOLIPID. • Dose-dependent decrease in urea levels in rats at 6 and 12 g/kg/day dose levels and in dogs at 3, 4.5 and 6 g/kg/day dose levels associated with decreased feed consumption. • Hypercholesterolemia in dogs at 3, 4.5 and 6 g/kg/day dose levels. • Hepatic pathology of lipid and pigmentary overload in male and female rats at 3, 6 and 12 g/kg/day dose levels and brownish-yellow pigmentation in vacuolated Kupffer cells in male and female dogs at 3, 4.5 and 6 g/kg/day dose levels with hepatocyte vacuolation in male dogs at 6 g/kg/day and female dogs at 4.5 and 6 g/kg/day dose levels. • Splenic pigmentation and vacuolization in rats at 3, 6 and 12 g/kg/day dose levels, and dogs in 4.5 and 6 g/kg/day dose levels. At doses of 3 g/kg/day, slight lipid and pigmentary overload of the liver and vacuolization of Kupffer cells were observed in rats and dogs. At a dose of 12 g/kg/day in rats, hepatocellular vacuolation, granulomatous inflammation of the liver, hepatocellular necrosis and hemosiderosis of the liver and lipid deposits and splenic hemosiderosis, were observed. In dogs, at a dose of 6 g/kg/day, brownish-yellow pigmentation in the Kupffer cells of liver and spleen, hyperplasia of vacuolated Kupffer cells, hepatocyte vacuolization, a slight increase in the number of lipid storage cells (Ito cells) in the liver and macrophage vacuolization of the spleen were observed.

NDA204508

Clinolipid

Olive Oil and Soybean Oil

0338-9540

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Container Label 1000 mL EADB9524 NDC 0338-9540-04 Baxter Logo Clinolipid (Lipid Injectable Emulsion, USP) 20% 200 g/1000 mL (0.2 g/mL) Pharmacy Bulk Package Not For Direct Infusion Intravenous use only 1000 mL Energy Content 2000 kcal/L Each 100 mL contains approximately 16 g of Olive Oil NF and 4 g of Soybean Oil USP, 1.2 g Egg Phospholipids NF, 2.25 g Glycerin USP, 0.03 g Sodium Oleate, Water for Injection USP and Sodium Hydroxide NF for pH adjustment pH 6.0–9.0 Osmolarity 260 mOsmol/L (calc) Cautions Use only if the color of the oxygen indicator is within allowable range Do not use unless emulsion has homogeneous milky appearance Once container closure has been penetrated withdrawal of contents should be completed without delay. Dispense contents within 4 hours after initial entry. See prescribing information for proper use of Pharmacy Bulk Package. Store at 20 to 25 °C (68 to 77 °F) See USP Controlled Room Temperature Protect from freezing Rx Only Bar code appears here, and is printed on line during production. Baxter Healthcare Corporation BE-35-04-865 EXP YYY-MM LOT 1000 750 500 250 100 Clinolipid Representative Container Label 0338-9540-04.jpg

Boxed Warning (Removed) 5/2023 Indications and Usage ( 1 ) 4/2024 Dosage and Administration ( 2.4 ) 4/2024 Contraindication ( 4 ) 5/2023 Warnings and Precautions ( 5.1 ) 5/2023 Warnings and Precautions ( 5.9 ) 4/2024

Baxter Healthcare Corporation Deerfield, IL 60015 USA Baxter, Clarity, Clinolipid and Exactamix are trademarks of Baxter International Inc.

17 PATIENT COUNSELING INFORMATION When initiating CLINOLIPID administration, discuss the following information with the patient or caregiver: 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 CLINOLIPID may cause hypersensitivity reactions. If CLINOLIPID is infused at home, instruct patients or caregivers to stop the infusion of CLINOLIPID 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 CLINOLIPID are at risk of infection. If CLINOLIPID is infused at home, instruct patients or caregivers to ensure aseptic techniques are used for the preparation and administration of CLINOLIPID 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 CLINOLIPID is infused at home, instruct patients or caregivers to stop CLINOLIPID 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 CLINOLIPID may result in refeeding syndrome [see Warnings and Precautions (5.6) ]. Hypertriglyceridemia Inform patients and caregivers about the risks of hypertriglyceridemia with CLINOLIPID 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) ]. Preparation and Administration Instructions If it is acceptable for a patient or caregiver to administer CLINOLIPID at home, then provide recommendations on how to prepare, add compatible additives (when appropriate), administer, and store CLINOLIPID [see Dosage and Administration (2.1 , 2.2 )].

14 CLINICAL STUDIES 14.1 Adult Clinical Studies Two clinical trials (Study 1 and Study 2) in adults compared CLINOLIPID to soybean oil-based intravenous lipid emulsion. Although Study 1 and Study 2 were not adequately designed to demonstrate noninferiority of CLINOLIPID to the soybean oil comparator, they support CLINOLIPID as a source of calories and essential fatty acids in adults. The lipid dosage was variable in Studies 1 and 2 and adjusted to the patient’s nutritional requirements. Study 1 was a randomized, open-label, multicenter study. Forty-eight patients, aged 17 to 75 years, requiring total parenteral nutrition (TPN) for ≥15 days (mean 22 days) were enrolled and randomized to either CLINOLIPID or a 100% soybean oil-based intravenous lipid emulsion. Nutritional efficacy was assessed by anthropometric indices (body weight, arm circumference, skin-fold thickness), biomarkers of protein metabolism (total protein, albumin) and lipid metabolism. Anthropometric criteria (body weight, arm circumference, and skin fold thickness) were comparable for both groups. Mean total serum protein and albumin increased similarly in both groups. Study 2 was a randomized, open label multicenter study that enrolled 22 patients aged 32-81 years who required long-term parenteral nutrition. Twelve patients received CLINOLIPID for a mean of 202 days (range 24 to 408 days) and 10 patients received the comparator lipid for a mean of 145 days (range 29-394 days). The two groups had similar outcomes for weight, weight loss, mid-arm circumference and triceps skinfold thickness. 14.2 Pediatric Clinical Studies The efficacy of CLINOLIPID compared to soybean oil-based lipid emulsions was evaluated in 179 pediatric patients in four randomized, active-controlled, parallel-group clinical studies. Three studies (161 patients) were double-blinded. Although the four pediatric clinical studies were not adequately designed to demonstrate the noninferiority of CLINOLIPID to the soybean oil comparator, they support CLINOLIPID as a source of calories and essential fatty acids in pediatric patients, including term and preterm neonates. The 179 pediatric patients (89 treated with CLINOLIPID; 90 with comparator) consisted of 140 patients who were less than 1 month of age, 23 patients one month to less than two years old, and 16 patients two to less than 18 years old. Nutritional efficacy in pediatric patients, including preterm infants, was assessed by evaluating growth parameters, protein biomarkers, changes in triglyceride and cholesterol concentrations, and fatty acid parameters. Study 3 (NCT 04555044) randomized 102 patients (101 analyzed) to receive either CLINOLIPID (n = 50) or a soybean oil-based lipid emulsion (n = 51) as part of PN in the hospital setting. Baseline characteristics and outcomes during the study were similar in the two groups. The majority of study patients (n=94, 93%) were preterm neonates born at less than 37 weeks of gestation. The median age at enrollment in this study was day one of life and the median gestational age of neonates was 29 weeks. Eighty-five patients (84%) were very low birth weight, including 53 patients (52%) with a birth weight of 1000-1499 grams and 32 patients (32%) with a birthweight of less than 1000 g. Forty-one patients (41%) were Black, 42 (42%) were White, and 8 (8%) were Hispanic or Latino. In both study groups, the mean daily dose administered was approximately 2.3 g/kg/day (SD 0.8 g/kg/day), and the median duration of treatment was 8 days (range: 3 – 60 days; interquartile range [IQR]: 8 – 10 days). The primary endpoint was at risk of developing EFAD, defined as triene:tetraene (T:T) ratio >0.4, which did not occur during the study in either treatment group. Secondary endpoints included incidence of parenteral nutrition-associated cholestasis (PNAC) defined as direct bilirubin ≥2 mg/dL with no other etiology identified. One patient in the CLINOLIPID group (2%) and two patients in the comparator group (3.9%) developed PNAC during the study. Median increases in body weight, length/height, and head circumference were similar between CLINOLIPID and the soybean oil comparator group. Study 4 randomized 45 preterm neonates of which 42 were treated and analyzed for safety; 33 (n=18 on CLINOLIPID and n=15 on soybean oil lipid emulsion) completed the 7-day treatment period and were analyzed for efficacy. The study evaluated weight, fatty acid profiles, triglyceride and cholesterol levels, and protein biomarkers. Two (6%) of patients had birth weight less than 1000 grams and 14 patients (42%) weighed between 1000 and 1500 grams at birth. The mean (range) daily dose of Clinolipid was 1.5 g/kg/day (0.7 – 1.7), and median (range) treatment duration period was 7 (2 – 7) days. Complete blood counts, total bilirubin, cholesterol, triglycerides, and weight of CLINOLIPID-treated patients were similar to those treated with soybean oil lipid emulsion. Study 5 randomized 18 pediatric patients (16 analyzed) between two and 57 months of age (median 6.3 months) who were treated with either CLINOLIPID (n = 7) or soybean oil lipid emulsion (n = 9). In both groups, the mean (SD) daily dose of lipid emulsion was 2.9 (0.4) g/kg/day and median treatment duration was 15 days (range: 1 – 29 days, IQR: 15 – 17 days). There were no meaningful differences between the groups at day 15 in weight gain, complete blood count, total bilirubin, total protein, cholesterol, or triglycerides. No patient in the study had evidence of biochemical EFAD (T:T ratio >0.4). Study 6 evaluated the long-term safety and efficacy of CLINOLIPID in 18 pediatric patients between one and nine years of age (median, 2.5 years) who had been treated with 50% medium-chain triglycerides/50% soybean oil lipid emulsion for 30 days, and were randomized to either CLINOLIPID (n = 9) or a soybean oil lipid emulsion (n = 9) three to five days per week. Patients had received PN for a mean of 34 months prior to study entry and treatment groups had comparable fatty acid profiles, lipids, albumin, total bilirubin, and parenteral nutrition intake during the run-in period. The average daily lipid dose in the treatment period was 1.9 g/kg/day (range: 1.4 – 3 g/kg/day) in CLINOLIPID group and 1.7 g/kg/day (range: 0.9 – 2.3 g/kg/day) for the soybean oil group. The median treatment duration for CLINOLIPID was 56 days (range: 56 – 63 days; IQR: 56 – 61 days). There were no meaningful differences between treatment groups in height, weight, and albumin levels. No patient in the study had evidence of biochemical EFAD (T:T ratio > 0.4).

8.5 Geriatric Use Of the total number of subjects in clinical studies of CLINOLIPID, 21% were 65 and over, while 10% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.4 Pediatric Use The safety and effectiveness of CLINOLIPID have been established as a source of calories and essential fatty acids for PN in pediatric patients, including term and preterm neonates, when oral or enteral nutrition is not possible, insufficient, or contraindicated. Use of CLINOLIPID in pediatric patients is supported by evidence from four studies that enrolled pediatric patients, including preterm and term neonates, and additional evidence from clinical studies in adults. Use of CLINOLIPID in older pediatric patients is supported by evidence from two studies in pediatric patients up to 9 years of age treated for a median of 15 and 56 days, respectively, with additional evidence from clinical studies in adults [see Clinical Studies (14.2) ] . No clinically significant cases of EFAD were observed in short term pediatric clinical studies. However, one premature neonate in study 3 became at risk for EFAD after 14 days of treatment based on a Holman Index increase above 0.2. This patient’s arachidonic and linoleic acid levels remained within the normal range [see Adverse Reactions (6.1) ] . Monitor pediatric patients for laboratory evidence of EFAD, including fatty acid profile (i.e., arachidonic acid) 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 CLINOLIPID may be at risk for aluminum toxicity [see Warnings and Precautions (5.8) ] .

8.1 Pregnancy Risk Summary Administration of the recommended dose of CLINOLIPID is not expected to cause major defects, miscarriage, or other adverse maternal or fetal outcomes. No animal reproduction studies have been conducted with lipid injectable emulsion. There are clinical considerations if CLINOLIPID is used in pregnant women [see Clinical Considerations ] . The estimated background risk of major birth defects and miscarriage for the indicated population are 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 a pregnant woman is associated with preterm delivery, low birth weight, intrauterine growth restriction, congenital malformations and perinatal mortality. Parenteral nutrition should be considered if a pregnant woman’s nutritional requirements cannot be fulfilled by oral or enteral intake. It is not known whether the administration of CLINOLIPID to pregnant women provides adequate essential fatty acids to the developing fetus.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Administration of the recommended dose of CLINOLIPID is not expected to cause major defects, miscarriage, or other adverse maternal or fetal outcomes. No animal reproduction studies have been conducted with lipid injectable emulsion. There are clinical considerations if CLINOLIPID is used in pregnant women [see Clinical Considerations ] . The estimated background risk of major birth defects and miscarriage for the indicated population are 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 a pregnant woman is associated with preterm delivery, low birth weight, intrauterine growth restriction, congenital malformations and perinatal mortality. Parenteral nutrition should be considered if a pregnant woman’s nutritional requirements cannot be fulfilled by oral or enteral intake. It is not known whether the administration of CLINOLIPID to pregnant women provides adequate essential fatty acids to the developing fetus. 8.2 Lactation Risk Summary There are no data available to assess the presence of CLINOLIPID and/or its active metabolite(s) in human milk, the effects on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CLINOLIPID and any potential adverse effects on the breastfed child from CLINOLIPID or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of CLINOLIPID have been established as a source of calories and essential fatty acids for PN in pediatric patients, including term and preterm neonates, when oral or enteral nutrition is not possible, insufficient, or contraindicated. Use of CLINOLIPID in pediatric patients is supported by evidence from four studies that enrolled pediatric patients, including preterm and term neonates, and additional evidence from clinical studies in adults. Use of CLINOLIPID in older pediatric patients is supported by evidence from two studies in pediatric patients up to 9 years of age treated for a median of 15 and 56 days, respectively, with additional evidence from clinical studies in adults [see Clinical Studies (14.2) ] . No clinically significant cases of EFAD were observed in short term pediatric clinical studies. However, one premature neonate in study 3 became at risk for EFAD after 14 days of treatment based on a Holman Index increase above 0.2. This patient’s arachidonic and linoleic acid levels remained within the normal range [see Adverse Reactions (6.1) ] . Monitor pediatric patients for laboratory evidence of EFAD, including fatty acid profile (i.e., arachidonic acid) 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 CLINOLIPID may be at risk for aluminum toxicity [see Warnings and Precautions (5.8) ] . 8.5 Geriatric Use Of the total number of subjects in clinical studies of CLINOLIPID, 21% were 65 and over, while 10% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

16 HOW SUPPLIED/STORAGE AND HANDLING CLINOLIPID is a sterile, white, milky homogenous lipid injectable emulsion supplied in CLARITY polyolefin Flexible Containers as follows: Strengths Container Size Product Code NDC Number (1 Bag) NDC Number (Shelf Pack) 20% (20 g/100 mL) (0.2 g/mL) 100 mL EADB9520 0338-9540-01 (single-dose Flexible Container) 0338-9540-05 (15 pack) 20% (50 g/250 mL) (0.2 g/mL) 250 mL EADB9521 0338-9540-02 (single-dose Flexible Container) 0338-9540-06 (10 pack) 20% (100 g/500 mL) (0.2 g/mL) 500 mL EADB9523 0338-9540-03 (single-dose Flexible Container) 0338-9540-07 (12 pack) 20% (200 g/1,000 mL) (0.2 g/mL) 1,000 mL EADB9524 0338-9540-04 (Pharmacy Bulk Package bag) 0338-9540-08 (6 pack) The CLARITY Container is a lipid-compatible plastic container (PL 2401-1). The bag is packaged in an oxygen barrier overpouch, which contains an oxygen absorber / oxygen indicator sachet. CLINOLIPID should be stored at 20°C to 25°C (68°F to 77°F). Excursion permitted between 15°C to 30 °C (59°F to 86°F). See USP Controlled Room Temperature. Protect from freezing. Avoid excessive heat. Store in overpouch until ready to use. CLINOLIPID 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 for no longer than 24 hours at not more than 25°C (77°F) [ See Dosage and Administration (2.2) ]. CLINOLIPID 1,000 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 not more than 25°C (77°F) [ see Dosage and Administration (2.2) ].