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 inap…

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…

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 )

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.

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.

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 onl…