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 )

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-ethylhexyl 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 …

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 ) • Risk of Infections, Fat Overload Syndrome, Refeeding Syndrome, Hypertriglyceridemia, and Essential Fatty Acid Deficiency : Monitor for signs and symptoms; monitor laboratory parameters. ( 5.4 , 5.5 , 5.6 , 5.7 , 5.9 ) • 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. The risk due to poor lipid clearance should be considered when administering intravenous lipid emulsions. 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 CLINOLIPID, have been associated with development of PNALD. Monitor liver tests in patients treated with CLINOLIPID 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 CLINOLIPID. Patients developing signs of hepatobiliary disorders should be assessed early to determine whether these conditions are related to CLINOLIPID use. 5.3 Hypersensitivity Reactions CLINOLIPID 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 CLINOLIPID administration [see Adverse Reactions (6.2 )] . CLINOLIPID is contraindicated in patients with known hypersensitivity to egg, soybean, peanut, or any of the active or inactive ingredients in CLINOLIPID [see Contraindications (4)]. If a hypersensitivity reaction occurs, stop infusion of CLINOLIPID immediately and initiate appropriate treatment and supportive measures. 5.4 Infections Lipid emulsions, such as CLINOLIPID, can support microb…

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 )

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 coumarin derivatives, including warfarin, may be counteracted. ( 7 )

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.

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 emulsio…