FISH OIL: 1,170 Adverse Event Reports & Safety Profile

Omegaven (fish oil triglycerides) is a sterile, nonpyrogenic, white, homogenous emulsion for intravenous infusion as a supply of calories in patients with PNAC. Each mL of Omegaven contains 0.1 g of fish oil, 0.012 g egg phospholipids, 0.025 g glycerin, 0.15 to 0.3 mg dl-alpha-tocopherol, 0.3 mg sodium oleate, water for injection, and sodium hydroxide for pH adjustment (pH 6 to 9). The phosphate content is 0.015 mmol/mL. The fish oil included in Omegaven is a triglyceride mixture consisting of esters of long-chain saturated fatty acids and unsaturated fatty acids with the following structure: where , , and are long chain acyl groups. Because triglycerides often contain different long chain fatty acids at each position, possible structures can have molecular weights ranging from 700 to 1000 g/mol. The main fatty acid components of the fish oil in Omegaven are EPA (13% to 26%) and DHA (14% to 27%). The fish oil also contains palmitic acid (4% to 12%), oleic acid (4% to 11%), palmitoleic acid (4% to 10%), myristic acid (2% to 7%), and arachidonic acid (0.2% to 2.0%). Additionally, the mean contents of linoleic acid and alpha-linolenic acid are 1.5% and 1.1%, respectively. The fish oil component has a total omega-3 fatty acid content of 40% to 54%. The empirical formula, molecular weight, and chemical structure of the main fatty acid components are: EPA C 20 H 30 O 2

302.45 DHA C 22 H 32 O 2

328.49 Palmitic acid C 16 H 32 O 2

256.43 Oleic acid C 18 H 34 O 2

282.47 Palmitoleic acid C 16 H 30 O 2

254.41 Linoleic acid C 18 H 32 O 2

280.45 Myristic acid C 14 H 28 O 2

228.38 Arachidonic acid C 20 H 32 O 2

304.47 Alpha-linolenic acid C 18 H 30 O 2

278.44 Omegaven 5 g/50 mL contains 5 grams of fish oil and 0.6 g egg phospholipids, 1.25 g glycerin, 7.5 to 15 mg dl-alpha-tocopherol, 0.015 g sodium oleate, water for injection, and sodium hydroxide for pH adjustment (pH 6 to 9) packaged in a single-dose 50-mL glass bottle enclosed with a rubber stopper. The phosphate content of the drug product is 0.75 mmol. The mean content of the two major fatty acid components in 50 mL are 1.0 g EPA (range: 0.6 to 1.5 g) and 0.96 g DHA (range: 0.7 to 1.7 g). Additionally, the mean content of linoleic acid, alphalinolenic acid, and arachidonic acid per 50 mL are 0.16 g, 0.07 g, and 0.13 g, respectively.

Omegaven

10 g/100 mL contains 10 grams of fish oil and 1.2 g egg phospholipids, 2.5 g glycerin, 15 to 30 mg dl-alpha-tocopherol, 0.03 g sodium oleate, water for injection, and sodium hydroxide for pH adjustment (pH 6 to 9) packaged in a single-dose 100-mL glass bottle enclosed with rubber stopper. The phosphate content of the drug product is 1.5 mmol. The mean content of the two major fatty acid components in 100 mL are 2.0 g EPA (range: 1.2 to 3.0 g) and 1.9 g DHA (range: 1.3 to 3.3 g). Additionally, the mean content of linoleic acid, alpha-linolenic acid, and arachidonic acid per 100 mL are 0.31g, 0.13 g, and 0.25 g; respectively. The total energy content of Omegaven is 112 kcal/100 mL (1.12 kcal/mL), including lipids, phospholipids, and glycerol. Omegaven has an osmolality of approximately 342 mOsm/kg water (which represents an osmolarity of 273 mOsm/L). Omegaven contains no more than 25 mcg/L of aluminum.

Structural Formula Figure Figure Figure

Figure Figure Figure Figure Figure Figure Figure Figure Figure

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 )

AND ADMINISTRATION

• For intravenous infusion into a central or peripheral vein. ( 2.1 )
• SMOFlipid 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 PN solution from light. ( 2.2 )
• 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. ( 2.3 )
• For information on the age-appropriate infusion rate, see the full prescribing information ( 2.3 , 5.1 )

Age Nutritional Requirements Initial Recommended

Dosage Maximum Dosage 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 <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 2.5 g/kg/day Adults 1 to 2 g/kg/day 2.5 g/kg/day

2.1 Important Administration Instructions

• SMOFlipid is prepared and administered by a healthcare provider in the inpatient setting. Patients and caregivers may prepare and administer SMOFlipid for home use after appropriate training by a trained healthcare provider.
• SMOFlipid is for intravenous infusion into a central or peripheral vein.
• Do not exceed the recommended maximum infusion rate in Table 1 [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.1 )].
• SMOFlipid admixtures with osmolarity ͦ Greater than or equal to 900 mOsm/L must be infused through a central vein. ͦ Less than 900 mOsm/L may be administered either through a central or peripheral vein.
• Use a 1.2 micron in-line filter during administration.
• Use a dedicated infusion line without any connections. Do not connect multiple medications in series.
• To prevent air embolism, use a nonvented infusion set or close the vent on a vented set and fully evacuate residual gas in the bag prior to administration.
• Do not pressurize the flexible bag to increase flow rates, and if administration is controlled by a pumping device, turn off the pump before the bag runs dry.
• Do not use infusion sets and lines that contain di-2-ethylhexyl phthalate (DEHP), including infusion sets that contain polyvinyl chloride (PVC) components, because they contain DEHP as a plasticizer.
• SMOFlipid can be infused concurrently into the same vein as dextrose-amino acid solutions (as part of PN) by a Y-connector located near the infusion site; flow rates of each solution should be controlled separately by infusion pumps.
• After connecting the infusion set, start infusion of SMOFlipid immediately. Complete the infusion within 12 hours when using a Y-connector and within 24 hours when used as part of an admixture.

2.2 Preparation Instructions Use the following instructions to prepare single-dose SMOFlipid 100 mL, 250 mL, and 500 mL Flexible Containers for administration: 1.

Inspect

Bag

• Inspect the integrity indicator (Oxalert ® ) (A) before removing the overpouch.
• Discard the product if the indicator is black, overpouch is opened or damaged, emulsion color is not white, or seals of bag are broken. 2.

Remove

Overpouch

• Place the bag on a clean, flat surface.
• Tear overpouch at notch and pull down.
• Discard the Oxalert sachet (A) and the oxygen absorber (B).
• Visually inspect the bag and contents for particulate matter and discoloration prior to administration. The lipid emulsion should be a homogenous liquid with a milky white appearance. If the mixture is not white or the emulsion has separated (noted by discoloration, phase separation, or oily droplets), or if particulates and/or leakage are observed, discard the bag. 3.

Spike

Bag

• Identify the infusion port ( blue cap with the arrow pointing away from the bag).
• Immediately before inserting the infusion set, break off the blue infusion port cap.
• Use infusion sets according to ISO Number 8536-4 with an external spike diameter of 5.5 to 5.7 mm and use a nonvented infusion set or close the air-inlet on a vented set.
• Use a 1.2 micron in-line filter for administration.
• Hold the base of the infusion port.
• Insert the spike through the infusion port by rotating your wrist slightly until the spike is inserted.
• Do not pierce the infusion port more than once. 4. Hang the bag
• On the hanger cut and start infusion.
• Discard unused portion. SMOFlipid 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 at 2°C to 8°C (36°F to 46°F) for no longer than 24 hours. After removal from storage, infuse within 12 hours when using a Y-connector and within 24 hours when used as part of an admixture. SMOFlipid 1000 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 blue infusion port using a suitable sterile transfer device or dispensing set. Discard any unused contents.
• Use the Pharmacy Bulk Package immediately for admixing after removal from overpouch. If not used immediately, the product can be stored for no longer than 24 hours at 2°C to 8°C (36°F to 46°F). After removal from storage, and once the closure is penetrated, use Pharmacy Bulk Package contents within 4 hours.

Admixing

Instructions

• Prepare the admixture in PN containers using strict aseptic techniques to avoid microbial contamination.
• Do not add SMOFlipid to the PN container first; destabilization of the lipid may occur. The prime destabilizers of emulsions are excessive acidity (such as a pH <5) and inappropriate electrolyte content. Amino acid solutions exert buffering effects that protect the emulsion from destabilization. Give careful consideration to the addition of divalent cations (Ca ++ and Mg ++ ), which have been shown to cause emulsion instability.
• Do not inject additives directly into SMOFlipid.
• SMOFlipid may be mixed with amino acid and dextrose injections to produce “all-in-one” PN admixtures. The mixing sequence below must be followed for manual compounding to minimize pH-related problems by ensuring that typically acidic dextrose injections are not mixed with lipid emulsions alone; shake bags gently after each addition. ͦ Transfer dextrose injection to the PN container. ͦ Transfer amino acid injection. ͦ Transfer SMOFlipid.
• Simultaneous transfer of amino acid injection, dextrose injection, and SMOFlipid to the PN container is also permitted; follow automated compounding device instructions as indicated. Use gentle agitation during admixing to minimize localized concentration effects.
• Additions to the PN admixtures should be evaluated by a pharmacist for compatibility. Questions about compatibility may be directed to Fresenius Kabi USA, LLC.
• Inspect the admixture to ensure that precipitates have not formed during preparation of the admixture and the emulsion has not separated. Discard the admixture if any of the above are observed.
• Infuse admixtures containing SMOFlipid immediately. If not used immediately, store admixtures under refrigeration at 2°C to 8°C (36°F to 46°F) for no longer than 24 hours. Infusion must be complete within 24 hours after removal from refrigeration. Discard any remaining admixture.
• Protect the admixed PN solution from light. smofl-img-01.jpg smofl-img-02.jpg smofl-img-03.jpg smofl-img-04.jpg smofl-img-05.jpg

2.3 Recommended Dosage and Administration

• The recommended nutritional requirements of lipid and recommended dosages of SMOFlipid 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.
• The recommended duration of infusion for SMOFlipid will vary depending on the clinical situation. Adjust the administration flow rate by taking into account the dose being administered, the daily volume/intake, and the duration of the infusion [see Overdosage ( 10 )].
• When determining dose, energy supplied by dextrose and amino acids from PN, as well as energy from oral or enteral nutrition, has to be taken into account. Energy and lipid provided from lipid-based medications should also be taken into account (e.g., propofol).
• Prior to administration of SMOFlipid, correct severe fluid and electrolyte disorders and measure serum triglyceride levels to establish a baseline value. In patients with elevated triglyceride levels, initiate SMOFlipid at a lower dosage and titrate in smaller increments, monitoring the triglyceride levels with each adjustment [see Warnings and Precautions ( 5.7 )] .
• SMOFlipid contains 0.162 to 0.225 mg/mL of all-rac-alpha-tocopherol. Take into account the amount of all-rac-alpha-tocopherol in SMOFlipid when determining the need for additional supplementation.

Table

1: Recommended Pediatric and Adult Dosage and Infusion Rate *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). ** Daily dosage should also not exceed a maximum of 60% of total energy requirements [see Overdosage ( 10 )].

Age Nutritional Requirements Direct Infusion

Rate Recommended Initial Dosage and Maximum Dosage Initial Maximum Birth to 2 years of age (including preterm and term neonates*) [see Warnings and Precautions ( 5.1 )]

Initial

0.5 to 1 g/kg/day not to exceed 3 g/kg/day** 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 <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 2.5 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 2 g/kg/day not to exceed 2.5 g/kg/day** 0.2 mL/kg/hour for the first 15 to 30 minutes; gradually increase to the required rate after 30 minutes 0.5 mL/kg/hour

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 )

REACTIONS Adverse reactions described elsewhere in this Prescribing Information are:

• 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 adverse drug reactions (≥5%) from clinical trials in adults were nausea, vomiting, and hyperglycemia. Most common adverse drug reactions (≥5%) from clinical trials in pediatric patients were anemia, vomiting, increased gamma-glutamyltransferase, and nosocomial 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 compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety database for SMOFlipid includes exposure in 399 patients (229 adults; 170 pediatric) in 9 clinical trials. Adult patients were exposed for 5 days to 4 weeks in 5 clinical trials. The pooled population exposed to SMOFlipid was adult patients up to 89 years old (20 to 89 years of age), 43% female and 99% Caucasian. The most frequently reported medical histories in the SMOFlipid group were surgical and medical procedures (84%), neoplasms (57%), gastrointestinal disorders (53%), vascular disorders (37%), and infections and infestations (20%). SMOFlipid was used as a component of PN which also included dextrose, amino acids, vitamins, and trace elements. Two of the 5 studies in adults were performed with SMOFlipid as a component of PN delivered in a 3- chamber bag.

Table

2: Adverse Reactions in >1% of Adult Patients Treated with SMOFlipid Adverse Reaction Number of Patients in SMOFlipid Group (N=229) Number of Patients in Soybean Oil lipid emulsion Comparator Group (N=230)

Nausea

20 (9%) 26 (11%)

Vomiting

15 (7%) 12 (5%)

Hyperglycemia

12 (5%) 5 (2%)

Flatulence

10 (4%) 4 (2%)

Pyrexia

9 (4%) 11 (5%) Abdominal pain 8 (4%) 5 (2%) Blood triglycerides increased 6 (3%) 4 (2%)

Hypertension

6 (3%) 9 (4%)

Sepsis

5 (2%) 4 (2%)

Dyspepsia

5 (2%) 1 (0%) Urinary tract infection 4 (2%) 3 (1%)

Anemia

4 (2%) 2 (1%) Device related infection 4 (2%) 2 (1%) Less common adverse reactions occurring in ≤1% of adult patients who received SMOFlipid were dyspnea, leukocytosis, diarrhea, pneumonia, cholestasis, dysgeusia, increased blood alkaline phosphatase, increased gamma-glutamyltransferase, increased C-reactive protein, tachycardia, liver function test abnormalities, headache, pruritus, dizziness, rash and thrombophlebitis.

The

170 patients treated with SMOFlipid in four pediatric trials consisted of 149 patients <28 days of age, 13 patients 28 days to <2 years of age, and 8 patients 2 to 7 years of age; the duration of exposure was 7 to 84 days. Forty five percent of the pediatric patients were female, and 89% were Caucasian. Most pediatric patients were preterm neonates with feeding intolerance or other conditions requiring short-term (<29 days) PN.

Table

3: Adverse Reactions in >1% of Pediatric Patients Treated with SMOFlipid Adverse Reaction Number of Patients in SMOFlipid Group (N=170) Number of Patients in Soybean Oil lipid emulsion Comparator Group (N=163)

Anemia

30 (18%) 33 (20%)

Vomiting

16 (9%) 16 (10%) Gamma-glutamyltransferase increased 10 (6%) 12 (7%) Nosocomial infection 10 (6%) 6 (4%)

Cholestasis

7 (4%) 10 (6%)

Pyrexia

7 (4%) 7 (4%) C-reactive protein increased 6 (4%) 7 (4%)

Hyperbilirubinemia

5 (3%) 7 (4%) Abdominal pain 4 (2%) 5 (3%) Bilirubin conjugated increased 3 (2%) 7 (4%)

Diarrhea

3 (2%) 4 (3%)

Tachycardia

3 (2%) 4 (3%)

Thrombocytopenia

3 (2%) 4 (3%)

Hyperglycemia

3 (2%) 2 (1%)

Sepsis

3 (2%) 2 (1%) Less common adverse reactions occurring in ≤1% of pediatric patients who received SMOFlipid were decreased hematocrit, metabolic acidosis, increased blood triglycerides, infection, increased blood alkaline phosphatase, increased alanine aminotransferase, fluid overload, hypertension, hypertriglyceridemia, and rash. The hepatic safety of SMOFlipid was evaluated in Pediatric Study 1, a randomized, active- controlled, double-blind, parallel-group, multi-center study that included 152 neonates and 9 patients ranging in age from 29 to 153 days who were expected to require PN for at least 28 days. PNAC (defined as direct bilirubin >2mg/dl with a second confirmed elevation >2mg/dl at least 7 days later) occurred in 2.4% (2/83) of SMOFlipid-treated patients and 11.5% (9/78) in soybean oil lipid emulsion-treated patients. Most PNAC events occurred in patients who were treated for longer than 28 days. The estimated cumulative incidence of PNAC is shown in the Kaplan-Meier cumulative incidence curve in Figure 1 [see Clinical Trials ( 14 )] .

Figure

1 Cumulative Incidence Curve of Time to Parenteral Nutrition-Associated Cholestasis (PNAC) with Standard Error Bars In the same trial, EFAD was determined by calculating the Holman index (the triene [Mead acid] to tetraene [arachidonic acid] ratio; T:T ratio). At the end of the first 28 days of treatment, 2.4% (2/83) SMOFlipid-treated patients and 2.6% (2/78) soybean oil lipid emulsion-treated patients had suspected EFAD (T:T ratio >0.05), and there were no cases of moderate (T:T ratio >0.2) or severe (T:T ratio >0.4) EFAD. There are insufficient data from this trial to determine the incidence of EFAD with duration of SMOFlipid treatment greater than 28 days because of substantial patient discontinuation from PN during the first 28 days. smofl-img-06.jpg

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of SMOFlipid in countries where it is registered. 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 product exposure. Cardiac disorders: palpitations General disorders and administration site conditions: chills, chest pain, malaise Hepatobiliary disorders: cholestasis Infections and infestations: infection Metabolism and nutrition disorders: fatty acid deficiency Respiratory, thoracic and mediastinal disorders: dyspnea Immune system disorders: hypersensitivity reactions, including anaphylaxis <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Warnings and Precautions ( 5.3 )]</span> Skin and subcutaneous tissue disorders: hyperhidrosis Vascular disorders: phlebitis

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 , 6.1 , 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span>. 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&apos;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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 , 5.7 ) and Overdosage ( 10 )]</span>.

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 SMOFlipid, have been associated with development of PNALD. In a randomized study of neonates and infants expected to be treated with PN for at least 28 days, parenteral nutrition-associated cholestasis (PNAC), a precursor to PNALD, developed less frequently in SMOFlipid-treated patients than in 100% soybean oil lipid emulsion-treated patients <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 ), Use in Specific Populations ( 8.4 )]</span> . Monitor liver tests in patients treated with SMOFlipid 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 SMOFlipid. Patients developing signs of hepatobiliary disorders should be assessed early to determine whether these conditions are related to SMOFlipid use.

5.3 Hypersensitivity Reactions SMOFlipid contains soybean oil, fish 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 SMOFlipid administration <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . SMOFlipid is contraindicated in patients with known hypersensitivity to fish, egg, soybean, peanut or any of the active or inactive ingredients in SMOFlipid <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . If a hypersensitivity reaction occurs, stop infusion of SMOFlipid immediately and initiate appropriate treatment and supportive measures.

5.4 Infections Lipid emulsions, such as SMOFlipid, can support microbial growth and are an independent risk factor for the development of catheter-related bloodstream infections. To decrease the risk of infectious complications, ensure aseptic techniques are used for catheter placement, catheter maintenance, and preparation and administration of SMOFlipid. Monitor for signs and symptoms of infection including fever and chills, as well as laboratory test results that might indicate infection (including leukocytosis and hyperglycemia). Perform frequent checks of the intravenous catheter insertion site for edema, redness, and discharge.

5.5 Fat Overload Syndrome Fat overload syndrome is a rare condition that has been reported with intravenous lipid injectable emulsions and is characterized by a sudden deterioration in the patient&apos;s condition (e.g., fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, hepatomegaly, deteriorating liver function, and central nervous system manifestations such as coma). A reduced or limited ability to metabolize lipids, accompanied by prolonged plasma clearance (resulting in higher lipid levels), may result in this syndrome. Although fat overload syndrome has been most frequently observed when the recommended lipid dose or infusion rate was exceeded, cases have also been described when the lipid formulation was administered according to instructions. If signs or symptoms of fat overload syndrome occur, stop SMOFlipid. The syndrome is usually reversible when the infusion of the lipid emulsion is stopped.

5.6 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 patients become anabolic. Thiamine deficiency and fluid retention may also develop. To prevent these complications, closely monitor severely malnourished patients and slowly increase their nutrient intake.

5.7 Hypertriglyceridemia The use of SMOFlipid is contraindicated in patients with hypertriglyceridemia with serum triglyceride concentrations &gt;1,000 mg/dL. Patients with conditions such as inherited lipid disorders, obesity, diabetes mellitus, or metabolic syndromes have a higher risk of developing hypertriglyceridemia with the use of SMOFlipid. In addition, patients with hypertriglyceridemia may have worsening of their hypertriglyceridemia with administration of SMOFlipid. Excessive dextrose administration may further increase such risk. Evaluate patients&apos; capacity to metabolize and eliminate the infused lipid emulsion by measuring serum triglycerides before the start of infusion (baseline value) and regularly throughout treatment. If triglyceride levels are above 400 mg/dL in adults, stop the SMOFlipid infusion and monitor serum triglyceride levels to avoid clinical consequences of hypertriglyceridemia such as pancreatitis. In pediatric patients with hypertriglyceridemia, lower triglyceride levels (i.e., below 400 mg/dL) may be associated with adverse reactions. Monitor serum triglyceride levels to avoid potential complications with hypertriglyceridemia such as pancreatitis, lipid pneumonitis, and neurologic changes, including kernicterus. To minimize the risk of new or worsening of hypertriglyceridemia, assess high-risk patients for their overall energy intake including other sources of lipids and dextrose, as well as concomitant drugs that may affect lipid and dextrose metabolism.

5.8 Aluminum Toxicity SMOFlipid contains no more than 25 mcg/L of aluminum. Prolonged PN administration in patients with renal impairment may result in aluminum reaching toxic levels. Preterm neonates are at greater risk because their kidneys are immature and they require large amounts of calcium and phosphate solutions that contain aluminum. Patients with impaired kidney function, including preterm neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day can accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading in these patients may occur at even lower rates of administration.

5.9 Essential Fatty Acid Deficiency Treatment-emergent cases of moderate or severe essential fatty acid deficiency (EFAD) (defined as the triene [Mead acid] to tetraene [arachidonic acid] ratio &gt;0.2 and &gt;0.4, respectively) were not observed in pediatric clinical trials of SMOFlipid up to 28 days <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . However, cases of EFAD have been reported in adult and pediatric patients in the postmarketing period with the use of SMOFlipid. The median time to onset was greater than 28 days among cases that reported time to onset. Monitor patients for laboratory evidence (e.g., abnormal fatty acid levels) and clinical symptoms of EFAD (e.g., skin manifestations, poor growth). Laboratory testing using the triene to tetraene ratio may not be adequate to diagnose EFAD, and assessment of individual fatty acid levels may be needed. Ensure patients are receiving recommended dosages of SMOFlipid to prevent EFAD <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 ), Description ( 11 )]</span> .

5.10 Monitoring/Laboratory Tests Throughout treatment, monitor serum triglycerides <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.7 )]</span> , fluid and electrolyte status, blood glucose, liver and kidney function, coagulation parameters, and complete blood count including platelets. The lipids contained in SMOFlipid may interfere with some laboratory blood tests (e.g., hemoglobin, lactate dehydrogenase, bilirubin, oxygen saturation) if blood is sampled before lipids have cleared from the bloodstream. Conduct these blood tests at least 6 hours after stopping the infusion. SMOFlipid contains vitamin K that may counteract anticoagulant activity <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> .

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.