Omegaven Drug Information

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. • 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.

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.

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. • 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

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. 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. 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. 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.

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).

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.

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

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.

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 respectively.

Pediatric Use The effectiveness of Omegaven was established in two open-label clinical trials of 82 pediatric patients, 3 to 42 weeks of age, including preterm neonates with estimated gestational age of greater than 24 weeks at birth. Patients administered Omegaven attained and maintained growth through at least 108 weeks of treatment. The safety of Omegaven was established in 189 pediatric patients (19 days to 15 years of age).

The most common adverse reactions in Omegaven-treated patients were vomiting, agitation, and bradycardia. In the postmarketing setting, clinical decompensation with rapid infusion of intravenous lipid emulsion in neonates and infants, sometimes fatal has been reported. Preterm neonates and infants who receive treatment with Omegaven may be at risk of aluminum toxicity and other metabolic abnormalities.

• Use of Omegaven is contraindicated in patients with:
• Known hypersensitivity to fish or egg protein or to any of the active ingredients or excipients.
• 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).
• Severe hemorrhagic disorders.
• Severe disorders of lipid metabolism characterized by hypertriglyceridemia (with serum triglycerides greater than 1,000 mg/dL).

In the event of an overdose, serious adverse reactions may occur. Stop the infusion of Omegaven until triglyceride levels have normalized and any symptoms have abated. The effects are usually reversible by stopping the lipid infusion.

If medically appropriate, further intervention may be indicated. Lipids are not dialyzable from serum.