Omegaven

1 INDICATIONS AND USAGE Omegaven is indicated as a source of calories and fatty acids in pediatric patients with parenteral nutrition-associated cholestasis (PNAC). Limitations of Use: • Omegaven is not indicated for the prevention of PNAC. It has not been demonstrated that Omegaven prevents PNAC in parenteral nutrition (PN)-dependent patients [see Clinical Studies ( 14 )]. • It has not been demonstrated that the clinical outcomes observed in patients treated with Omegaven are a result of the omega-6: omega-3 fatty acid ratio of the product [see Clinical Studies ( 14 )]. Omegaven is indicated as a source of calories and fatty acids in pediatric patients with parenteral nutrition-associated cholestasis (PNAC). ( 1 ) Limitations of Use: • Omegaven is not indicated for the prevention of PNAC. It has not been demonstrated that Omegaven prevents PNAC in parenteral nutrition (PN)-dependent patients. ( 1 ) • It has not been demonstrated that the clinical outcomes observed in patients treated with Omegaven are a result of the omega-6:omega-3 fatty acid ratio of the product. ( 1 )

2 DOSAGE AND ADMINISTRATION • For infusion into a central or peripheral vein. ( 2.1 ) • See full prescribing information for administration and admixing instructions. ( 2.1 , 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 consideration of additional energy sources given to the patient. The recommended daily dose (and the maximum dose) in pediatric patients is 1 g/kg/day. ( 2.3 ) • For information on infusion rate when initiating dosing and in patients with elevated triglyceride levels, see the full prescribing information. ( 2.3 , 5.1 , 5.6 ) • The recommended duration for infusion is between 8 and 24 hours, depending on the clinical situation. ( 2.3 ) 2.1 Administration Instructions • Omegaven can be administered alone or as part of a PN admixture. • Omegaven is for central or peripheral intravenous infusion. 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. Solutions with osmolarity of 900 mOsm/L or greater must be infused through a central vein. • 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 1.2 micron in-line filter during administration. • Use a dedicated line for PN. Omegaven should be infused concurrently into the same vein as dextrose-amino acid solutions (as part of PN) by a Y-connector located closest to the infusion site; flow rates of each solution should be controlled separately by infusion pumps. Avoid multiple connections; do not connect multiple medications in series. Turn off the pump before the bottle runs dry. • Use a vented infusion set when Omegaven is infused from the bottle. • Do not use infusion sets and lines that contain di-2-ethylhexyl phthalate (DEHP). Infusion sets that contain polyvinyl chloride (PVC) components have DEHP as a plasticizer. • Prior to infusion, visually inspect Omegaven for particulate matter and discoloration. Discard the bottle if any particulates or discoloration are observed. • Gently invert the bottle before use. Use Omegaven only if the emulsion is homogeneous and the container is undamaged. • Strict aseptic techniques must be followed. • Hang the bottle using the attached hanger and start infusion. • After connecting the infusion set, start infusion of Omegaven immediately. Complete the infusion within 12 hours when using a Y-connector and within 24 hours when used as part of an admixture. • For single use only. Discard unused portion. 2.2 Admixing Instructions If Omegaven is administered as part of a PN admixture, follow the instructions below. • Prepare the admixture in PN containers using strict aseptic techniques to avoid microbial contamination. • Do not add Omegaven directly to the empty PN container; destabilization of the lipid emulsion may occur. • When Omegaven is administered with other infusion solutions (e.g., amino acids, dextrose), the compatibility of the solutions used must be ensured. Questions related to compatibility may be directed to Fresenius Kabi USA, LLC, at 1-800-551-7176. • The following proper mixing sequence must be followed to minimize pH-related problems by ensuring that typically acidic dextrose solutions are not mixed with lipid emulsions alone: 1. Transfer dextrose solution to the PN container. 2. Transfer amino acid solution to the PN container. 3. Transfer Omegaven to the PN container. Simultaneous transfer of amino acid solution, dextrose solution, and Omegaven using an automated compounding device is also permitted; follow automated compounding device instructions as indicated. Use gentle agitation during admixing to minimize localized concentration effects; shake container gently after each addition. • The prime destabilizers of emulsions are excessive acidity (such as a pH less than 5) and inappropriate electrolyte content. Care should be taken if adding divalent cations (e.g., Ca ++ and Mg ++ ), which have been shown to cause emulsion instability. Amino acid solutions exert buffering effects that can protect the emulsion from destabilization. • Inspect the admixture to ensure that precipitates have not formed during preparation of the admixture 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 admixture. Discard the admixture if any of these are observed. Stability and Storage • Protect the admixed PN solution from light. • Start infusion of admixtures containing Omegaven immediately. If not used immediately, admixtures may be stored for up to 6 hours at room temperature or up to 24 hours under refrigeration. Complete the infusion within 24 hours after removal from storage. • Any remaining contents of a partly used PN container must be discarded. • Follow the instructions of each product included in the admixture. 2.3 Dosing Information Dosing Considerations • Prior to administration of Omegaven, correct severe fluid and electrolyte disorders and measure serum triglycerides to establish a baseline level. • Initiate Omegaven dosing as soon as direct or conjugated bilirubin (DBil) levels are 2 mg/dL or greater in pediatric patients who are expected to be PN-dependent for at least 2 weeks. • The dosing of Omegaven depends on each patient's energy requirements, which may be influenced by age, body weight, tolerance, clinical status, and ability to metabolize and eliminate lipids. • When determining dose, take into account the energy supplied by dextrose and amino acids from PN, as well as energy from oral or enteral nutrition. Energy provided from lipid-based medications must also be taken into account (e.g., propofol). • Omegaven contains 0.15 to 0.30 mg/mL of dl-alpha-tocopherol. Take into account the amount of alpha-tocopherol in Omegaven when determining the need for additional supplementation of vitamin E. Recommended Pediatric Dosing • The recommended nutritional requirements of fat and recommended dosage of Omegaven to meet those requirements for pediatric patients are provided in Table 1 , along with recommendations for the initial and maximum infusion rates. • If hypertriglyceridemia (triglycerides greater than 250 mg/dL in neonates and infants or greater than 400 mg/dL in older children) develops once Omegaven has been initiated at the recommended dosage, consider stopping the administration of Omegaven for 4 hours and obtain a repeat serum triglyceride level. Resume Omegaven based on new result as indicated. • In patients with elevated triglyceride levels, consider other reasons for hypertriglyceridemia (e.g., renal disease, other drugs). If triglycerides remain at elevated levels, consider a reduced dose of 0.5 g to 0.75 g/kg/day with an incremental increase to 1 g/kg/day. • Monitor triglyceride levels during treatment [see Warnings and Precautions ( 5.6 , 5.8 )]. • The recommended duration for infusion of Omegaven is between 8 and 24 hours, depending on the clinical situation. • Administer Omegaven until DBil levels are less than 2 mg/dL or until the patient no longer requires PN. Table 1: Recommended Pediatric Dosage and Infusion Rate Nutritional Requirements Direct Infusion Rate Recommended Initial Dosage and Maximum Dosage Initial Maximum 1 g/kg/day; this is also the maximum daily dose 0.2 mL/kg/hour for the first 15 to 30 minutes; gradually increase to the required rate after 30 minutes 1.5 mL/kg/hour

4 CONTRAINDICATIONS Use of Omegaven is contraindicated in patients with: • Known hypersensitivity to fish or egg protein or to any of the active ingredients or excipients [see Warnings and Precautions ( 5.2 )]. • Severe hemorrhagic disorders due to a potential effect on platelet aggregation. • Severe disorders of lipid metabolism characterized by hypertriglyceridemia (serum triglyceride concentrations greater than 1,000 mg/dL) [see Warnings and Precautions ( 5.6 )]. • Known hypersensitivity to fish or egg protein or to any of the active ingredients or excipients. ( 4 ) • Severe hemorrhagic disorders. ( 4 ) • Severe disorders of lipid metabolism characterized by hypertriglyceridemia (with serum triglycerides greater than 1,000 mg/dL). ( 4 , 5.6 )

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 ) • Hypersensitivity Reactions: Monitor for signs or symptoms. Discontinue infusion if reaction occurs. ( 5.2 ) • Risk of Infections, Fat Overload Syndrome, Refeeding Syndrome, and Hypertriglyceridemia : Monitor for signs and symptoms; monitor laboratory parameters. ( 5.3 , 5.4 , 5.5 , 5.6 ) • Aluminum Toxicity : Increased risk in patients with renal impairment, including preterm infants. ( 5.7 ) • Monitoring and Laboratory Tests : Routine laboratory monitoring is recommended, including monitoring for essential fatty acid deficiency. ( 5.8 ) 5.1 Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsion in Neonates and Infants In the postmarket 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 1.5 mL/kg/hour [see Dosage and Administration ( 2.3 )]. 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 ( 5.4 , 5.6 ) and Overdosage ( 10 )]. 5.2 Hypersensitivity Reactions Omegaven contains fish oil and egg phospholipids, which may cause hypersensitivity reactions. In postmarketing experience, anaphylaxis has been reported following Omegaven administration [see Adverse Reactions ( 6.2 )] . Omegaven is contraindicated in patients with known hypersensitivity to fish or egg protein or to any of the active or inactive ingredients in Omegaven [see Contraindications ( 4 )] . If a hypersensitivity reaction occurs, stop infusion of Omegaven immediately and initiate appropriate treatment and supportive measures. 5.3 Infections Lipid emulsions, such as Omegaven, can support microbial growth and are an independent risk factor for the development of bloodstream infections. The risk of infection is increased in patients with malnutrition-associated immunosuppression, long-term use and poor maintenance of intravenous catheters, or immunosuppressive effects of other conditions or concomitant drugs. To decrease the risk of infectious complications, ensure aseptic technique in catheter placement and maintenance, as well as in the preparation and administration of Omegaven. Monitor for signs and symptoms of early infections including fever and chills, laboratory test results that might indicate infection (including leukocytosis and hyperglycemia), and frequently inspect the intravenous catheter insertion site for edema, redness, and discharge. 5.4 Fat Overload Syndrome Fat overload syndrome is a rare condition that has been reported with intravenous lipid emulsions. A reduced or limited ability to metabolize lipids accompanied by prolonged plasma clearance may result in this syndrome, which is characterized by a sudden deterioration in the patient's condition including fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, hepatomegaly, deteriorating liver function, and central nervous system manifestations (e.g., coma). The cause of fat overload syndrome is unclear. Although it has been most frequently observed when the recommended lipid dose was exceeded, cases have also been described where the formulation was administered according to instructions. The syndrome is usually reversible when the infusion of the lipid emulsion is stopped. 5.5 Refeeding Syndrome Administering PN to severely malnourished patients may result in 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. 5.6 Hypertriglyceridemia Impaired lipid metabolism with hypertriglyceridemia may occur in conditions such as inherited lipid disorders, obesity, diabetes mellitus, and metabolic syndrome. Serum triglyceride levels greater than 1,000 mg/dL have been associated with an increased risk of pancreatitis [see Contraindications ( 4 )] . To evaluate the patient's capacity to metabolize and eliminate the infused lipid emulsion, measure serum triglycerides before the start of infusion (baseline value), and regularly throughout treatment. If hypertriglyceridemia (triglycerides greater than 250 mg/dL in neonates and infants or greater than 400 mg/dL in older children) develops, consider stopping the administration of Omegaven for 4 hours and obtain a repeat serum triglyceride level. Resume Omegaven based on new result as indicated [see Dosage and Administration ( 2.3 )] . 5.7 Aluminum Toxicity Omegaven contains no more than 25 mcg/L of aluminum. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Preterm infants are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which 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. 5.8 Monitoring/Laboratory Tests Routine Monitoring 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 Omegaven may interfere with the results of some laboratory tests (e.g., hemoglobin, lactate dehydrogenase, bilirubin, oxygen saturation) if the blood is sampled before the lipids have cleared from the bloodstream. Conduct these tests at least 6 hours after stopping the infusion. Omegaven contains Vitamin K that may counteract anticoagulant activity [see Drug Interactions ( 7 )]. Essential Fatty Acids Monitoring patients for signs and symptoms of essential fatty acid deficiency (EFAD) is recommended. Laboratory tests are available to determine serum fatty acids levels. Reference values should be consulted to help determine adequacy of essential fatty acid status. Increasing essential fatty acid intake (enterally or parenterally) is effective in treating and preventing EFAD.

7 DRUG INTERACTIONS Antiplatelet Agents and Anticoagulants : Prolonged bleeding time has been reported in patients taking antiplatelet agents or anticoagulants and oral omega-3 fatty acids. Periodically monitor bleeding time in patients receiving Omegaven and concomitant antiplatelet agents or anticoagulants. ( 7.1 ) 7.1 Antiplatelet Agents and Anticoagulants Some published studies have demonstrated prolongation of bleeding time in patients taking antiplatelet agents or anticoagulants and oral omega-3 fatty acids. The prolongation of bleeding times reported in those studies did not exceed normal limits and there were no clinically significant bleeding episodes. Nonetheless, it is recommended to periodically monitor bleeding time in patients receiving Omegaven and concomitant antiplatelet agents or anticoagulants.

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 )] • Hypersensitivity reactions [see Warnings and Precautions ( 5.2 )] • Infections [see Warnings and Precautions ( 5.3 )] • Fat overload syndrome [see Warnings and Precautions ( 5.4 )] • Refeeding syndrome [see Warnings and Precautions ( 5.5 )] • Hypertriglyceridemia [see Warnings and Precautions ( 5.6 )] • Aluminum toxicity [see Warnings and Precautions ( 5.7 )] Most common adverse drug reactions (>15%) are: vomiting, agitation, bradycardia, apnea and viral 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 directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety database for Omegaven reflects exposure in 189 pediatric patients (19 days to 15 years of age) treated for a median of 14 weeks (3 days to 8 years) in two clinical trials. Omegaven was administered at a maximum dose of 1 g/kg/day as the lipid component of a PN regimen which also included dextrose, amino acids, vitamins, and trace elements; 158 (84%) of these patients received concurrent lipids from enteral nutrition [see Clinical Studies ( 14 )] . Adverse reactions that occurred in more than 5% of patients who received Omegaven and with a higher incidence than the comparator group are shown in Table 2 . Patients had a complicated medical and surgical history prior to receiving Omegaven treatment and the mortality was 13%. Underlying clinical conditions prior to the initiation of Omegaven therapy included prematurity, low birth weight, necrotizing enterocolitis, short bowel syndrome, ventilator dependence, coagulopathy, intraventricular hemorrhage, and sepsis. Table 2: Adverse Reactions in Greater Than 5% of Omegaven-Treated Pediatric Patients with PNAC Adverse Reaction Omegaven (N=189) n (%) Vomiting 87 (46) Agitation 67 (35) Bradycardia 66 (35) Apnea 38 (20) Viral Infection 30 (16) Erythema 23 (12) Rash 15 (8) Abscess 14 (7) Neutropenia 13 (7) Hypertonia 11 (6) Incision site erythema 11 (6) Twelve (6%) Omegaven-treated patients were listed for liver transplantation (1 patient was listed 18 days before treatment, and 11 patients after a median of 42 days [range: 2 days to 8 months] of treatment); 9 (5%) received a transplant after a median of 121 days (range: 25 days to 6 months) of treatment, and 3 (2%) were taken off the waiting list because cholestasis resolved. One hundred thirteen (60%) Omegaven-treated patients reached DBil levels less than 2 mg/dL and AST or ALT levels less than 3 times the upper limit of normal, with median AST and ALT levels for Omegaven-treated patients at 89 and 65 U/L, respectively, by the end of the study. Median hemoglobin levels and platelet counts for Omegaven-treated patients at baseline were 10.2 g/dL and 173 × 10 9 /L, and by the end of the study these levels were 10.5 g/dL and 217 × 10 9 /L, respectively. Adverse reactions associated with bleeding were experienced by 74 (39%) of Omegaven-treated patients. Median glucose levels at baseline and the end of the study were 86 and 87 mg/dL for Omegaven-treated patients, respectively. Hyperglycemia was experienced by 13 (7%) Omegaven-treated patients. Median triglyceride levels at baseline and the end of the study were 121 mg/dL and 72 mg/dL for Omegaven-treated patients respectively. Hypertriglyceridemia was experienced by 5 (3%) Omegaven-treated patients. The triene:tetraene (Mead acid:arachidonic acid) ratio was used to monitor essential fatty acid status in Omegaven-treated patients only in Study 1 (n = 123) [see Warnings and Precautions ( 5.8 )] . The median triene:tetraene ratio was 0.02 (interquartile range: 0.01 to 0.03) at both baseline and the end of the study. Blood samples for analysis may have been drawn while the lipid emulsion was being infused and patients received enteral or oral nutrition. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Omegaven. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hematologic system disorders: hemorrhage Immune system disorders: hypersensitivity reactions, including anaphylaxis [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )]

8.1 Pregnancy Risk Summary There are no available data on Omegaven use in pregnant women to establish a drug- associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with fish oil triglycerides. The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US 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.