ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information.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)] Diabetes/Hyperglycemia [see Warnings and Precautions (5.6)] Thrombophlebitis [see Warnings and Precautions (5.8)] Hepatobiliary Disorders [see Warnings and Precautions (5.10, 5.15 ] Electrolyte Imbalance and Fluid Overload in Renal Impairment [see Warnings and Precautions (5.11)] Hypertriglyceridemia [see Warnings and Precautions (5.12)] Aluminum Toxicity [see Warnings and Precautions (5.13)] 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)] Diabetes/Hyperglycemia [see Warnings and Precautions (5.6)] Thrombophlebitis [see Warnings and Precautions (5.8)] Hepatobiliary Disorders [see Warnings and Precautions (5.10, 5.15 ] Electrolyte Imbalance and Fluid Overload in Renal Impairment [see Warnings and Precautions (5.11)] Hypertriglyceridemia [see Warnings and Precautions (5.12)] Aluminum Toxicity [see Warnings and Precautions (5.13)] The most common adverse reactions (>=3%) are hyperglycemia, hypokalemia, pyrexia, and increased blood triglycerides. 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 Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The clinical data described for PERIKABIVEN (R) reflects exposure in 93 patients exposed for to days in active-controlled trials. The pooled population exposed to PERIKABIVEN (R) was 18 to 87 years old, 48% female, 73% Caucasian. The enrolled patients had varied underlying conditions such as gastrointestinal disorders (55%), vascular disorders (30%), metabolism and nutrition disorders (28%), respiratory, thoracic, and mediastinal disorders (22%), and psychiatric disorders (20%). Most patients received peripheral intravenous infusion doses of >=80% of their target mean daily exposure. Adverse reactions occurring in at least 2% of patients who received PERIKABIVEN (R) are shown in Table 3. Table 3: Adverse Reactions in >2% of Patients Treated with PERIKABIVEN (R) Adverse reaction PERIKABIVEN (R) N=93 (%)Hyperglycemia (5) Hypokalemia (4) Pyrexia (4) Blood triglycerides increased (3) Phlebitis (2) Nausea (2) Pruritus (2) Gamma-glutamyltransferase increased (2) Blood alkaline phosphatase increased (2) Alanine aminotransferase increased (2) Blood glucose increased (2) C-reactive protein increased (2) Blood urea increased (2) Hypoalbuminemia (2) Terms as reported in clinical studiesLess common adverse reactions in <=1% of patients who received PERIKABIVEN (R) were hyperkalemia, hypomagnesaemia, hypernatremia, tachycardia, hypertension, thrombophlebitis, vomiting, jaundice, rash and increased blood bilirubin. 6.2 Post-Marketing Experience. The following additional adverse reactions have been identified during post-approval use of PERIKABIVEN (R) in countries where it is registered. Because these reactions are reported voluntarily post-approval from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to product exposure. Gastrointestinal disorders: abdominal distension, abdominal pain General disorders and administration site conditions: chest tightness Hepatobiliary disorders: cholestasis Immune system disorders: allergic reaction, anaphylaxisInfections and infestations: infectionVascular disorders: flushed face Gastrointestinal disorders: abdominal distension, abdominal pain General disorders and administration site conditions: chest tightness Hepatobiliary disorders: cholestasis Immune system disorders: allergic reaction, anaphylaxis. Infections and infestations: infection. Vascular disorders: flushed face.

BOXED WARNING SECTION.

WARNING: DEATH IN PRETERM INFANTS. Deaths in preterm infants after infusion of intravenous lipid emulsions have been reported in the medical literature.Autopsy findings included intravascular fat accumulation in the lungs.Preterm infants and low birth weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion. [See Warnings and Precautions (5.1) and Use in Specific Populations (8.4)]. Deaths in preterm infants after infusion of intravenous lipid emulsions have been reported in the medical literature.. Autopsy findings included intravascular fat accumulation in the lungs.. Preterm infants and low birth weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion. WARNING: DEATH IN PRETERM INFANTSSee full prescribing information for complete boxed warningDeaths in preterm infants have been reported in literature. 5.1, 8.4) Autopsy findings included intravascular fat accumulation in the lungs. 5.1, 8.4) Preterm and low birth weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion. 5.1, 8.4) Deaths in preterm infants have been reported in literature. 5.1, 8.4) Autopsy findings included intravascular fat accumulation in the lungs. 5.1, 8.4) Preterm and low birth weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion. 5.1, 8.4).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies have not been conducted to evaluate carcinogenic potential of PERIKABIVEN (R) or its effect on fertility. Genotoxicity studies have not been conducted with PERIKABIVEN (R) to assess its mutagenic potential.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. PERIKABIVEN (R) is used as supplement or as the sole source of nutrition in patients, providing macronutrients (amino acids, dextrose and lipids) and micronutrients (electrolytes) parenterally. The amino acids provide the structural units that make up proteins and are used to synthesize proteins and other biomolecules or are oxidized to urea and carbon dioxide as source of energy. The administered dextrose is oxidized to carbon dioxide and water, yielding energy.Intravenously administered lipids provide biologically utilizable source of calories and essential fatty acids. Fatty acids serve as an important substrate for energy production. The most common mechanism of action for energy derived from fatty acid metabolism is beta- oxidation. Fatty acids are important for membrane structure and function, precursors for bioactive molecules (such as prostaglandins), and as regulators of gene expression.. 12.3 Pharmacokinetics. The infused lipid particles provided by PERIKABIVEN (R) are expected to be cleared from the blood stream in manner thought to be comparable to the clearing of chylomicrons. In healthy volunteers, the maximum clearance rate of the triglycerides after fasting overnight has been found to be 3.8 +- 1.5 g/kg per 24 hours. Both elimination and oxidation rates are dependent on the patients clinical condition; elimination is faster and utilization is increased in postoperative patients, in sepsis, burns and trauma, while patients with renal impairment and hypertriglyceridemia may show lower utilization of exogenous lipid emulsions. Due to differences in elimination, patients with these conditions should be closely monitored during PERIKABIVEN (R) administration [see Warnings and Precautions (5.3, 5.11)] The disposition of infused amino acids, dextrose and electrolytes are essentially the same as those supplied by ordinary food. clinical study in healthy volunteers employing high intravenous doses (80 mmol) of either sodium glycerophosphate used in PERIKABIVEN (R) or reference, inorganic sodium phosphate demonstrated that both compounds resulted in comparable serum inorganic phosphate concentrations after single intravenous dose. Changes from baseline in the serum levels of sodium, potassium and total calcium were comparable across the two phosphate sources in this study.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. The use of PERIKABIVEN (R) is contraindicated in patients with the following: Known hypersensitivity to egg, soybean proteins, peanut proteins, corn or corn products or to any of the active substances or excipients Severe hyperlipidemia or severe disorders of lipid metabolism characterized by hypertriglyceridemia (serum triglyceride concentration >1,000 g/dL) [see Warnings and Precautions (5.12)] Inborn error of amino acid metabolismCardiopulmonary instability (including pulmonary edema, cardiac insufficiency, myocardial infarction, acidosis and hemodynamic instability requiring significant vasopressor support)Hemophagocytic syndrome. Known hypersensitivity to egg, soybean proteins, peanut proteins, corn or corn products or to any of the active substances or excipients Severe hyperlipidemia or severe disorders of lipid metabolism characterized by hypertriglyceridemia (serum triglyceride concentration >1,000 g/dL) [see Warnings and Precautions (5.12)] Inborn error of amino acid metabolism. Cardiopulmonary instability (including pulmonary edema, cardiac insufficiency, myocardial infarction, acidosis and hemodynamic instability requiring significant vasopressor support). Hemophagocytic syndrome. Known hypersensitivity to egg, soybean proteins, peanut proteins, corn or corn products, or to any of the active substances or excipients. 4) Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides >1,000 mg/dL. 4, 5.12) Inborn errors of amino acid metabolism. 4) Cardiopulmonary instability. 4) Hemophagocytic syndrome. 4) Known hypersensitivity to egg, soybean proteins, peanut proteins, corn or corn products, or to any of the active substances or excipients. 4) Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides >1,000 mg/dL. 4, 5.12) Inborn errors of amino acid metabolism. 4) Cardiopulmonary instability. 4) Hemophagocytic syndrome. 4).

DESCRIPTION SECTION.

11 DESCRIPTION. PERIKABIVEN (R) is sterile, hypertonic emulsion, for peripheral or central venous administration, in Three Chamber Bag. The product contains no added sulfites. Chamber contains Dextrose solution for fluid replenishment and caloric supply. Chamber contains the Amino Acid solution with Electrolytes, which comprises essential and nonessential amino acids provided with electrolytes. Chamber contains Intralipid (R) 20% (a 20% Lipid Injectable Emulsion), prepared for intravenous administration as source of calories and essential fatty acids. See below for formulations of each chamber and Table for strength, pH, osmolarity, ionic concentration and caloric content of PERIKABIVEN (R) when all the chambers are mixed together. Chamber 1: Contains sterile, hypertonic solution of Dextrose, USP in water for injection with pH range of 3.5 to 5.5. Dextrose, USP is chemically designated D-glucose, monohydrate (C 6H 12O o 2O) and has the following structure: Chamber 2: Contains sterile solution of amino acids and electrolytes in water for injection. In addition, glacial acetic acid has been added to adjust the pH so that the final solution pH is 5.4 to 5.8. The formulas for the individual electrolytes and amino acids are as follows: ElectrolytesSodium Acetate Trihydrate, USP CH 3COONax3H 2O Potassium Chloride, USP KCl Sodium Glycerophosphate 3H 5(OH) 2PO 4Na 2xH 2O Magnesium Sulfate Heptahydrate, USP MgSO 4x7H 2O Calcium Chloride Dihydrate, USP CaCl 2x2H 2O Essential Amino AcidsLysine (added as the hydrochloride salt) 2N(CH 2) 4CH(NH 2)COOH.HCl Phenylalanine Leucine (CH 3) 2CHCH 2CH(NH 2)COOH Valine (CH 3) 2CHCH(NH 2)COOH Threonine CH 3CH(OH)CH(NH 2)COOH Methionine CH 3S(CH 2) 2CH(NH 2)COOH Isoleucine CH 3CH 2CH(CH 3)CH(NH 2)COOH Tryptophan Nonessential Amino AcidsAlanine CH 3CH(NH 2)COOH Arginine 2NC(NH)NH(CH 2) 3CH(NH 2)COOH Glycine 2NCH 2COOH Proline Histidine Glutamic Acid HOOC(CH 2) 2CH(NH 2)COOH Serine HOCH 2CH(NH 2)COOH Aspartic Acid HOOCCH 2CH(NH 2)COOH Tyrosine Chamber 3: Contains 20% Lipid Injectable Emulsion (Intralipid (R) 20%) which is made up of 20% Soybean Oil, 1.2% Egg Yolk Phospholipids, 2.25% Glycerin, and water for injection. In addition, sodium hydroxide has been added to adjust the pH. The final product pH range is to 9. The soybean oil is refined natural product consisting of mixture of neutral triglycerides of predominantly unsaturated fatty acids with the following structure: where are saturated and unsaturated fatty acid residues. The major component fatty acids are linoleic (48 to 58 %), oleic (17 to 30%), palmitic (9 to 13%), linolenic (5 to 11%) and stearic acid (2.5 to 5%). These fatty acids have the following chemical and structural formulas: Linoleic acid 18H 32O Oleic acid 18H 34O Palmitic acid 16H 32O Linolenic acid 18H 30O Stearic acid 18H 36O Purified egg phosphatides are mixture of naturally occurring phospholipids which are isolated from the egg yolk. These phospholipids have the following general structure: contain saturated and unsaturated fatty acids that abound in neutral fats. R3 is primarily either the choline or ethanolamine ester of phosphoric acid. Glycerin is chemically designated 3H 8O and is clear colorless, hygroscopic syrupy liquid. It has the following structural formula: The container-solution unit is closed system and is not dependent upon entry of external air during administration. The container is overwrapped to provide protection from the physical environment and to provide an additional oxygen and moisture barrier when necessary. An oxygen absorber is placed between the inner bag and the overpouch.The container is not made with natural rubber latex or polyvinyl chloride (PVC). PERIKABIVEN (R) contains no more than 25 mcg/L of aluminum. structure. phenyl. tryp. pro. his. tyro. soybean. r123. linoleic. oleic. palmitic. linolenic. stearic. phosphatides. r2. structure phospha. glycerine.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For intravenous infusion into peripheral or central vein. 2.1, 5.8) Recommended dosage depends on clinical status, body weight and nutritional requirements. 2.4) Adult dosage: 27 to 40 mL/kg/day (0.64 to 0.94 g/kg/day of protein, 1.83 to 2.71 g/kg/day of dextrose, 0.95 to 1.4 g/kg/day of lipid) 2.4) The maximum infusion rate is 3.7 mL/kg/hour (corresponding to 0.09 g/kg/hour of amino acids, 0.25 g/kg/hour of dextrose, the limiting factor, and 0.13 g/kg/hour of lipid). The recommended infusion period is 12 to 24 hours. 2.4) For intravenous infusion into peripheral or central vein. 2.1, 5.8) Recommended dosage depends on clinical status, body weight and nutritional requirements. 2.4) Adult dosage: 27 to 40 mL/kg/day (0.64 to 0.94 g/kg/day of protein, 1.83 to 2.71 g/kg/day of dextrose, 0.95 to 1.4 g/kg/day of lipid) 2.4) The maximum infusion rate is 3.7 mL/kg/hour (corresponding to 0.09 g/kg/hour of amino acids, 0.25 g/kg/hour of dextrose, the limiting factor, and 0.13 g/kg/hour of lipid). The recommended infusion period is 12 to 24 hours. 2.4) 2.1 Administration. PERIKABIVEN (R) is for intravenous infusion into peripheral or central vein [see Warnings and Precautions (5.8)]. Use 1.2 micron in-line filter.Use of vented intravenous administration set with the vent in the open position could result in air embolism.Use dedicated line without any connections. Multiple connections could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Ceftriaxone must not be administered simultaneously with calcium-containing intravenous solutions such as PERIKABIVEN (R) via Y-site due to precipitation. However, ceftriaxone and PERIKABIVEN (R) may be administered sequentially if the infusion lines are thoroughly flushed between infusions with compatible fluid [see Warnings and Precautions (5.9)] Do not use administration sets and lines that contain di-2-ethylhexyl phthalate (DEHP). Administration sets that contain polyvinyl chloride (PVC) components have DEHP as plasticizer. PERIKABIVEN (R) is for intravenous infusion into peripheral or central vein [see Warnings and Precautions (5.8)]. Use 1.2 micron in-line filter.. Use of vented intravenous administration set with the vent in the open position could result in air embolism.. Use dedicated line without any connections. Multiple connections could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Ceftriaxone must not be administered simultaneously with calcium-containing intravenous solutions such as PERIKABIVEN (R) via Y-site due to precipitation. However, ceftriaxone and PERIKABIVEN (R) may be administered sequentially if the infusion lines are thoroughly flushed between infusions with compatible fluid [see Warnings and Precautions (5.9)] . Do not use administration sets and lines that contain di-2-ethylhexyl phthalate (DEHP). Administration sets that contain polyvinyl chloride (PVC) components have DEHP as plasticizer. 2.2 Important Preparation Instructions. Inspect the bag prior to activation. Discard the bag in the following situations: Evidence of damage to the bagMore than one chamber is whiteSolution is yellowAny seal is already broken Activate the bag [s ee Dosage and Administration (2.3) ]. Once the bag is activated, ensure the vertical seals between chambers are broken at least from the bend in the seals and down to the ports. The upper sections of the vertical seals above the bend and the horizontal seal may remain closed.It is recommended to mix the contents thoroughly by inverting the bag upside down to ensure homogenous admixture.Ensure the vertical seals between chambers are broken and the contents of all three chambers are mixed together prior to infusion [s ee Dosage and Administration (2.3) For total parenteral nutrition add multivitamins and trace elements via the additive port. Any other additions to the bag should be evaluated by pharmacist for compatibility. Questions about compatibility may be directed to Fresenius Kabi USA, LLC. When introducing additives, it is recommended to use 18 to 23 gauge needles with maximum length of 1.5 inches (40 mm) and to mix thoroughly after each addition, use aseptic technique and add after the vertical seals have been broken (i.e. bag has been activated) and the three components are mixed [see Dosage and Administration (2.3)]. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect PERIKABIVEN (R) to ensure: Precipitates have not formed during the mixing or addition of additives. The emulsion has not separated. Separation of the emulsion can be visibly identified by yellowish streaking or the accumulation of yellowish droplets in the mixed emulsion. Discard the admixture if any of the above are observed.PERIKABIVEN (R) should be used immediately after mixing and the introduction of additives. If not used immediately, the storage time and conditions prior to use should not be longer than 24 hours at to 8C (36 to 46F). After removal from storage at to 8C (36 to 46F), the admixture should be infused within 24 hours. Any mixture remaining must be discarded. Inspect the bag prior to activation. Discard the bag in the following situations: Evidence of damage to the bagMore than one chamber is whiteSolution is yellowAny seal is already broken Evidence of damage to the bag. More than one chamber is white. Solution is yellow. Any seal is already broken Activate the bag [s ee Dosage and Administration (2.3) ]. Once the bag is activated, ensure the vertical seals between chambers are broken at least from the bend in the seals and down to the ports. The upper sections of the vertical seals above the bend and the horizontal seal may remain closed.. It is recommended to mix the contents thoroughly by inverting the bag upside down to ensure homogenous admixture.. Ensure the vertical seals between chambers are broken and the contents of all three chambers are mixed together prior to infusion [s ee Dosage and Administration (2.3) . For total parenteral nutrition add multivitamins and trace elements via the additive port. Any other additions to the bag should be evaluated by pharmacist for compatibility. Questions about compatibility may be directed to Fresenius Kabi USA, LLC. When introducing additives, it is recommended to use 18 to 23 gauge needles with maximum length of 1.5 inches (40 mm) and to mix thoroughly after each addition, use aseptic technique and add after the vertical seals have been broken (i.e. bag has been activated) and the three components are mixed [see Dosage and Administration (2.3)]. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect PERIKABIVEN (R) to ensure: Precipitates have not formed during the mixing or addition of additives. The emulsion has not separated. Separation of the emulsion can be visibly identified by yellowish streaking or the accumulation of yellowish droplets in the mixed emulsion. Precipitates have not formed during the mixing or addition of additives. The emulsion has not separated. Separation of the emulsion can be visibly identified by yellowish streaking or the accumulation of yellowish droplets in the mixed emulsion. PERIKABIVEN (R) should be used immediately after mixing and the introduction of additives. If not used immediately, the storage time and conditions prior to use should not be longer than 24 hours at to 8C (36 to 46F). After removal from storage at to 8C (36 to 46F), the admixture should be infused within 24 hours. Any mixture remaining must be discarded. 2.3 Instructions for Use. image 1. instruct. image 3. image 4. instruction. 2.4 Dosing Considerations. The dosage of PERIKABIVEN (R) should be individualized based on the patients clinical condition (ability to adequately metabolize amino acids, dextrose and lipids), body weight and nutritional/fluid requirements, as well as additional energy given orally/enterally to the patient. PERIKABIVEN (R) is combination of amino acids, electrolytes, dextrose, and lipids in fixed volume and concentration. The dosage selection is based upon fluid requirements which can be used in conjunction with the nutritional requirements to determine final dosage [see Table 1]. PERIKABIVEN (R) meets the total nutritional requirements for protein, dextrose and lipids in stable patients, and can be individualized to meet specific needs with the addition of nutrients. The maximum infusion rate is based upon the dextrose component. Prior to administration of PERIKABIVEN (R), correct severe fluid, electrolyte and acid-base disorders. Before starting the infusion, obtain serum triglyceride levels to establish the baseline value. Recommended Adult DosageThe recommended dosage of PERIKABIVEN (R) in adults is 27 to 40 mL/kg/day. The recommended daily nutritional requirements for protein, dextrose and lipids compared to the amount of nutrition provided by PERIKABIVEN (R) are shown in Table 1. The maximum daily dosage of PERIKABIVEN (R) in adults should not exceed 40 mL/kg/day. In patients with serum triglyceride concentrations above 400 mg/dL, stop the PERIKABIVEN (R) infusion and monitor serum triglyceride levels. Once the triglycerides are <400 mg/dL, restart PERIKABIVEN (R) at lower infusion rate and advance rate in smaller increments towards target dosage, checking the triglyceride levels prior to each adjustment [see Contraindications (4) and Warnings and Precautions (5.12)] Table 1: Nutritional Comparison Nutrition Provided by PERIKABIVEN (R) recommended dosage Recommended Nutritional Requirements Stable Patients Critically Ill Patients Fluid mL/kg/day 27 to 40 30 to 40 Minimum needed to deliver adequate macronutrients Protein g/kg/day Nitrogen g/kg/day 0.64 to 0.94 0.1 to 0.15 0.8 to 1.0 0.13 to 0.16 1.5 to 0.24 to 0.3 Dextrose g/kg/day 1.8 to 2.7 <=10 <=5.8 Lipids g/kg/day 0.95 to 1.4 <=1 Total Energy Requirement kcal/kg/day 18 to 27 20 to 30 25 to 30 Do not use in patients with conditions that are contraindicated [see Contraindications (4)]. Protein is provided as amino acids. When infused intravenously amino acids are metabolized and utilized as the building blocks of protein. Treatment with PERIKABIVEN (R) may be continued for as long as is required by the patients condition. Dosing in Renal ImpairmentIn patients with renal impairment, the dosage of PERIKABIVEN (R) should be the recommended adult dosage (see above). Prior to administration, correct severe fluid or electrolyte imbalances. Closely monitor serum electrolyte levels and adjust the volume of PERIKABIVEN (R) administered as required [see Warnings and Precautions (5.11)] Renal patients not needing dialysis require 0.6 to 0.8 of protein/kg/day. Patients on dialysis or continuous renal replacement therapy should receive 1.2 to 1.8 of protein/kg/day up to maximum of 2.5 of protein/kg/day based on nutritional status and estimated protein losses 2. The PERIKABIVEN (R) dosage can be adjusted based on the treatment for the renal impairment, supplementing protein as indicated. Additional protein may be added to PERIKABIVEN (R) bag or infused separately. If required, additional amino acids may be added to the PERIKABIVEN (R) bag or infused separately. Compatibility of additions should be evaluated by pharmacist and questions may be directed to Fresenius Kabi USA, LLC. Infusion Duration and RateThe recommended duration of infusion for PERIKABIVEN (R) is between 12 and 24 hours, depending on the clinical situation. The maximum infusion rate of PERIKABIVEN (R) is 3.7 mL/kg/hour. This corresponds to 0.09 g/kg/hour of amino acids, 0.25 g/kg/hour of dextrose (the rate limiting factor) and 0.13 g/kg/hour of lipid. Dosing InstructionsDetermine the fluid requirements (27 to 40 mL/kg/day) and the patients nutritional requirements (see Table 1) to be delivered, then select the corresponding PERIKABIVEN (R) bag. Determine the preferred duration of infusion (12 to 24 hours).Ensure that the rate of infusion (PERIKABIVEN (R) dosage in mL/kg/day divided by the preferred duration of infusion (hours)) does not exceed the maximum infusion rate for the patient (i.e., 3.7 mL/kg/hour). The infusion rate may need to be reduced and duration of infusion increased in order not to exceed the maximum infusion rate. Once the infusion rate in mL/kg/hour has been selected, calculate the infusion rate (mL/hour) using the patients weight.Compare the patients nutrient requirements with the amount supplied by PERIKABIVEN (R). Discuss with pharmacist any additions that may be required. Determine the fluid requirements (27 to 40 mL/kg/day) and the patients nutritional requirements (see Table 1) to be delivered, then select the corresponding PERIKABIVEN (R) bag. Determine the preferred duration of infusion (12 to 24 hours).. Ensure that the rate of infusion (PERIKABIVEN (R) dosage in mL/kg/day divided by the preferred duration of infusion (hours)) does not exceed the maximum infusion rate for the patient (i.e., 3.7 mL/kg/hour). The infusion rate may need to be reduced and duration of infusion increased in order not to exceed the maximum infusion rate. Once the infusion rate in mL/kg/hour has been selected, calculate the infusion rate (mL/hour) using the patients weight.. Compare the patients nutrient requirements with the amount supplied by PERIKABIVEN (R). Discuss with pharmacist any additions that may be required.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. PERIKABIVEN (R) is sterile, hypertonic emulsion in three chamber container. The individual chambers contain one of the following respectively: amino acids and electrolytes, dextrose, or lipid injectable emulsion. Table describes the individual components of PERIKABIVEN (R). Table 2: Contents of PERIKABIVEN (R) when mixed How Supplied 1,440 mL 1,920 mL 2,400 mL Composition of PERIKABIVEN (R) Soybean Oil, USP (g/100 mL) 3.5 Dextrose Anhydrous, USP (g/100 mL) 6.8 Amino Acids, USP (g/100 mL) 2.36 Total Nitrogen (mg/100 mL) 375 Essential amino acids (mg/100 mL) Lysine, USP (added as the hydrochloride salt) 187 Phenylalanine, USP 164 Leucine, USP 164 Valine, USP 152 Threonine, USP 116 Methionine, USP 116 Isoleucine, USP 116 Tryptophan, USP 40 Nonessential amino acids (mg/100 mL) Alanine, USP 333 Arginine, USP 235 Glycine, USP 164 Proline, USP 141 Histidine, USP 141 Glutamic Acid 116 Serine, USP 94 Aspartic Acid, USP 71 Tyrosine, USP 4.8 Electrolytes (mg/100 mL) Sodium Acetate Trihydrate, USP 170 Potassium Chloride, USP 124 Sodium Glycerophosphate Anhydrous 105 Magnesium Sulfate Heptahydrate, USP 68 Calcium Chloride Dihydrate, USP 20 Electrolyte Profile (mEq/L) Sodium 22 (22 mmol/L) Potassium 17 (17 mmol/L) Magnesium 5.6 (2.8 mmol/L) Calcium 2.8 (1.4 mmol/L) Phosphorous N.A. (7.5 mmol/L) Acetate 27 (27 mmol/L) Chloride 32 (32 mmol/L) Sulfate 5.6 (2.8 mmol/L) Calorie Content (kcal/L) From Dextrose 230 From Lipid 350 From Amino Acids 95 Total 675 pH 5.6 Osmolarity (mOsm/L) 750 Balanced by ions from amino acidsContributed by sodium glycerophosphate and sodium acetateContributed by sodium glycerophosphate and phospholipids Derived from sodium acetate and glacial acetic acid (for pH adjustment)Contributed by calcium chloride, lysine hydrochloride, and potassium chlorideDerived from magnesium sulfateTotal caloric value including lipid, phospholipid and glycerinpH of amino acid with electrolyte solution was adjusted with glacial acetic acid, USP and pH of lipid emulsion was adjusted with sodium hydroxide, USP. Balanced by ions from amino acids. Contributed by sodium glycerophosphate and sodium acetate. Contributed by sodium glycerophosphate and phospholipids Derived from sodium acetate and glacial acetic acid (for pH adjustment). Contributed by calcium chloride, lysine hydrochloride, and potassium chloride. Derived from magnesium sulfate. Total caloric value including lipid, phospholipid and glycerin. pH of amino acid with electrolyte solution was adjusted with glacial acetic acid, USP and pH of lipid emulsion was adjusted with sodium hydroxide, USP. PERIKABIVEN (R) is sterile, hypertonic emulsion in three chamber container. The individual chambers contain one of the following respectively: amino acids and electrolytes, dextrose, or lipid injectable emulsion. 3) PERIKABIVEN (R) is available in three sizes 2,400 mL, 1,920 mL, and 1,440 mL. 3) PERIKABIVEN (R) is sterile, hypertonic emulsion in three chamber container. The individual chambers contain one of the following respectively: amino acids and electrolytes, dextrose, or lipid injectable emulsion. 3) PERIKABIVEN (R) is available in three sizes 2,400 mL, 1,920 mL, and 1,440 mL. 3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Coumarin and coumarin derivatives, including warfarin: Anticoagulant activity may be counteracted; monitor laboratory parameters. 7.1) 7.1 Coumarin and Coumarin Derivatives. The soybean oil present in PERIKABIVEN (R) has vitamin 1. Vitamin 1 can reverse the anticoagulant activity of coumarin and coumarin derivatives, which work by blocking recycling of vitamin 1. Monitoring for anticoagulant activity is recommended in patients who are on both PERIKABIVEN (R) and coumarin or coumarin derivatives.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of PERIKABIVEN (R) did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from other younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. PERIKABIVEN (R) is sterile emulsion available in the following sizes: NDC Volume 63323-714-24 2,400 mL63323-714-19 1,920 mL63323-714-14 1,440 mLExposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. If accidentally frozen, discard the bag. It is recommended that the product be stored at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature] Do not remove container from overpouch until intended for use. After breaking the vertical seals, chemical and physical in-use stability of the mixed three chamber bag has been demonstrated for 24 hours at 25C (77F). The product should be used immediately after the introduction of additives. If not used immediately, the storage time and conditions prior to use should not be longer than 24 hours at to 8C (36 to 46F). After removal from storage at to 8C (36 to 46F), the admixture should be infused within 24 hours. Any mixture remaining must be discarded.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. PERIKABIVEN (R) is indicated as source of calories, protein, electrolytes and essential fatty acids for adult patients requiring parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. PERIKABIVEN (R) may be used to prevent essential fatty acid deficiency or treat negative nitrogen balance in adult patients. Limitations of Use:PERIKABIVEN (R) is not recommended for use in pediatric patients under the age of years, including preterm infants because the fixed content of the formulation does not meet the nutritional requirements of this age group [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)] . PERIKABIVEN (R) is indicated as source of calories, protein, electrolytes and essential fatty acids for adult patients requiring parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. PERIKABIVEN (R) may be used to prevent essential fatty acid deficiency or treat negative nitrogen balance in adult patients. 1) Limitations of Use: Not recommended for use in pediatric patients 2 years including preterm infants because the fixed content of the formulation does not meet nutritional requirements in this age group. 1, 5.1, 8.4).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. To ensure the safe and effective use of PERIKABIVEN (R), this information should be discussed with the patient. Inform patients of the following:PERIKABIVEN (R) is given by infusion through peripheral or central vein catheter. Allergic reactions to PERIKABIVEN (R) may occur. There is risk of infection and sepsis associated with formulations administered intravenously.PERIKABIVEN (R) may cause adverse reactions such as nausea and vomiting, excess fat (lipids) in the blood, high blood sugar, abnormally increased transaminase and bilirubin, or abnormally high or low blood electrolyte levels. Contact their healthcare provider if they develop symptoms of an allergic reaction, infection, high blood sugar, low blood sugar, nausea, vomiting, or fluid retention occurs. Have periodic laboratory tests and routinely follow-up with their healthcare provider. Inform their healthcare provider about any changes in prescription or over the counter medications and supplements to avoid potential drug interactions and side effects. When patients self-administer PERIKABIVEN(R) injection at home, inform patients of the following:Patients and/or caregiver must be trained in how to inspect, activate and administer PERIKABIVEN (R). Follow the PERIKABIVEN (R) inspection, activation and administration instructions provided by their home care provider, and Prescribing Information [see Dosage and Administration (2.1, 2.2 and 2.3)]. Do not deviate from the administration instructions given by the healthcare provider.Inspect PERIKABIVEN (R) before using for evidence of damage, particulate matter, and/or discoloration. Discard the bag in the following situations: Evidence of damage to the bagMore than one chamber is whiteSolution is yellowAny seal is already broken Prior to activation, store PERIKABIVEN (R) between 20 to 25C (68 to 77F). Activate bag just prior to use or refrigerate activated bag at to 8C (36 to 46F) for up to 24 hours. Discard any unused portion.After activation and prior to administration carefully inspect bag for separation of the lipid emulsion, which can be visibly identified by yellowish streaking or the accumulation of yellowish droplets in the mixed emulsion. Discard the bag if this occurs.Additional information is available at www.KabivenUSA.com.. PERIKABIVEN (R) is given by infusion through peripheral or central vein catheter. Allergic reactions to PERIKABIVEN (R) may occur. There is risk of infection and sepsis associated with formulations administered intravenously.. PERIKABIVEN (R) may cause adverse reactions such as nausea and vomiting, excess fat (lipids) in the blood, high blood sugar, abnormally increased transaminase and bilirubin, or abnormally high or low blood electrolyte levels. Contact their healthcare provider if they develop symptoms of an allergic reaction, infection, high blood sugar, low blood sugar, nausea, vomiting, or fluid retention occurs. Have periodic laboratory tests and routinely follow-up with their healthcare provider. Inform their healthcare provider about any changes in prescription or over the counter medications and supplements to avoid potential drug interactions and side effects. Patients and/or caregiver must be trained in how to inspect, activate and administer PERIKABIVEN (R). Follow the PERIKABIVEN (R) inspection, activation and administration instructions provided by their home care provider, and Prescribing Information [see Dosage and Administration (2.1, 2.2 and 2.3)]. Do not deviate from the administration instructions given by the healthcare provider.. Inspect PERIKABIVEN (R) before using for evidence of damage, particulate matter, and/or discoloration. Discard the bag in the following situations: Evidence of damage to the bagMore than one chamber is whiteSolution is yellowAny seal is already broken Evidence of damage to the bag. More than one chamber is white. Solution is yellow. Any seal is already broken Prior to activation, store PERIKABIVEN (R) between 20 to 25C (68 to 77F). Activate bag just prior to use or refrigerate activated bag at to 8C (36 to 46F) for up to 24 hours. Discard any unused portion.. After activation and prior to administration carefully inspect bag for separation of the lipid emulsion, which can be visibly identified by yellowish streaking or the accumulation of yellowish droplets in the mixed emulsion. Discard the bag if this occurs.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data available to assess the presence of PERIKABIVEN (R) and/or its active metabolite(s) in human milk, the effects on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for PERIKABIVEN (R), and any potential adverse effects of PERIKABIVEN (R) on the breastfed child or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. PERIKABIVEN (R) is used as supplement or as the sole source of nutrition in patients, providing macronutrients (amino acids, dextrose and lipids) and micronutrients (electrolytes) parenterally. The amino acids provide the structural units that make up proteins and are used to synthesize proteins and other biomolecules or are oxidized to urea and carbon dioxide as source of energy. The administered dextrose is oxidized to carbon dioxide and water, yielding energy.Intravenously administered lipids provide biologically utilizable source of calories and essential fatty acids. Fatty acids serve as an important substrate for energy production. The most common mechanism of action for energy derived from fatty acid metabolism is beta- oxidation. Fatty acids are important for membrane structure and function, precursors for bioactive molecules (such as prostaglandins), and as regulators of gene expression.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies have not been conducted to evaluate carcinogenic potential of PERIKABIVEN (R) or its effect on fertility. Genotoxicity studies have not been conducted with PERIKABIVEN (R) to assess its mutagenic potential.

OVERDOSAGE SECTION.

10 OVERDOSAGE. In the event of overdose, fat overload syndrome may result [see Warnings and Precautions (5.4)] Stop the infusion of PERIKABIVEN (R) to allow lipids to clear from serum. The effects are usually reversible after the lipid infusion is stopped. If medically appropriate, further intervention may be indicated. The lipid administered and fatty acids produced are not dialyzable.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL PRINCIPAL DISPLAY PERIKABIVEN (R) 1440 mL Bag Label NDC 63323-714-14 PERIKABIVEN (R) 1440 mL Amino Acids, Electrolytes, Dextrose, and Lipid Injectable Emulsion, for intravenous use(2.4%, 0.5%, 6.8% and 3.5%), No sulfites added PERIPHERAL INFUSION bag.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of PERIKABIVEN (R) in pediatric patients has not been established. Deaths in preterm infants after infusion of intravenous lipid emulsion have been reported [see Warnings and Precautions (5.1) ]. Patients, particularly preterm infants, are at risk for aluminum toxicity [see Warnings and Precautions (5.13)] PERIKABIVEN (R) is not recommended for use in pediatric patients under the age of two years, including preterm infants, as the fixed content of the formulation does not meet the nutritional requirements of this age group due to the following reasons: Calcium and dextrose needs are not met and lipids, protein and magnesium exceed requirements. The product does not contain the amino acids cysteine and taurine, considered conditionally essential for neonates and infants. Patients, including pediatric patients, may be at risk for PNALD [see Warnings and Precautions (5.15)] Newborns especially those born premature and with low birth weight are at increased risk of developing hypo or hyperglycemia and therefore need close monitoring during treatment with intravenous dextrose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Calcium and dextrose needs are not met and lipids, protein and magnesium exceed requirements. The product does not contain the amino acids cysteine and taurine, considered conditionally essential for neonates and infants.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The infused lipid particles provided by PERIKABIVEN (R) are expected to be cleared from the blood stream in manner thought to be comparable to the clearing of chylomicrons. In healthy volunteers, the maximum clearance rate of the triglycerides after fasting overnight has been found to be 3.8 +- 1.5 g/kg per 24 hours. Both elimination and oxidation rates are dependent on the patients clinical condition; elimination is faster and utilization is increased in postoperative patients, in sepsis, burns and trauma, while patients with renal impairment and hypertriglyceridemia may show lower utilization of exogenous lipid emulsions. Due to differences in elimination, patients with these conditions should be closely monitored during PERIKABIVEN (R) administration [see Warnings and Precautions (5.3, 5.11)] The disposition of infused amino acids, dextrose and electrolytes are essentially the same as those supplied by ordinary food. clinical study in healthy volunteers employing high intravenous doses (80 mmol) of either sodium glycerophosphate used in PERIKABIVEN (R) or reference, inorganic sodium phosphate demonstrated that both compounds resulted in comparable serum inorganic phosphate concentrations after single intravenous dose. Changes from baseline in the serum levels of sodium, potassium and total calcium were comparable across the two phosphate sources in this study.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary The limited available data on the use of PERIKABIVEN (R) in pregnant women are not sufficient to inform drug-associated risk. However, there are clinical considerations if PERIKABIVEN (R) is used in pregnant women [see Clinical Considerations]. Animal reproduction studies have not been conducted with PERIKABIVEN (R). The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. Clinical ConsiderationsDisease-Associated Maternal and/or Embryofetal RiskSevere malnutrition in pregnant woman is associated with preterm delivery, low birth weight, intrauterine growth restriction, congenital malformations and perinatal mortality. Parenteral nutrition should be considered if pregnant womans nutritional requirements cannot be fulfilled by oral or enteral intake.

REFERENCES SECTION.

15 REFERENCES. Ayers P. et al. A.S.P.E.N. Parenteral Nutrition Handbook, 2nd ed. 2014 pg. 123.Mueller CM ed. The A.S.P.E.N. Nutrition Support Core Curriculum 2nd ed. 2012. Chapter 29 Wolk R, Foulks C. Renal Disease., pg. 500. Ayers P. et al. A.S.P.E.N. Parenteral Nutrition Handbook, 2nd ed. 2014 pg. 123.. Mueller CM ed. The A.S.P.E.N. Nutrition Support Core Curriculum 2nd ed. 2012. Chapter 29 Wolk R, Foulks C. Renal Disease., pg. 500.

SPL UNCLASSIFIED SECTION.

The brand names mentioned in this document are the trademarks of their respective owners.Manufactured by: Uppsala, Sweden www.fresenius-kabi.us 451207C logo.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Renal Impairment: Patients on dialysis or continuous renal replacement therapy may require additional protein supplementation to meet nutritional requirements. If required, adjust the volume of PERIKABIVEN (R) administered based on serum electrolyte levels and fluid balance. 2.4, 8.7) 8.1 Pregnancy. Risk Summary The limited available data on the use of PERIKABIVEN (R) in pregnant women are not sufficient to inform drug-associated risk. However, there are clinical considerations if PERIKABIVEN (R) is used in pregnant women [see Clinical Considerations]. Animal reproduction studies have not been conducted with PERIKABIVEN (R). The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. Clinical ConsiderationsDisease-Associated Maternal and/or Embryofetal RiskSevere malnutrition in pregnant woman is associated with preterm delivery, low birth weight, intrauterine growth restriction, congenital malformations and perinatal mortality. Parenteral nutrition should be considered if pregnant womans nutritional requirements cannot be fulfilled by oral or enteral intake. 8.2 Lactation. Risk SummaryThere are no data available to assess the presence of PERIKABIVEN (R) and/or its active metabolite(s) in human milk, the effects on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for PERIKABIVEN (R), and any potential adverse effects of PERIKABIVEN (R) on the breastfed child or from the underlying maternal condition. 8.4 Pediatric Use. The safety and effectiveness of PERIKABIVEN (R) in pediatric patients has not been established. Deaths in preterm infants after infusion of intravenous lipid emulsion have been reported [see Warnings and Precautions (5.1) ]. Patients, particularly preterm infants, are at risk for aluminum toxicity [see Warnings and Precautions (5.13)] PERIKABIVEN (R) is not recommended for use in pediatric patients under the age of two years, including preterm infants, as the fixed content of the formulation does not meet the nutritional requirements of this age group due to the following reasons: Calcium and dextrose needs are not met and lipids, protein and magnesium exceed requirements. The product does not contain the amino acids cysteine and taurine, considered conditionally essential for neonates and infants. Patients, including pediatric patients, may be at risk for PNALD [see Warnings and Precautions (5.15)] Newborns especially those born premature and with low birth weight are at increased risk of developing hypo or hyperglycemia and therefore need close monitoring during treatment with intravenous dextrose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Calcium and dextrose needs are not met and lipids, protein and magnesium exceed requirements. The product does not contain the amino acids cysteine and taurine, considered conditionally essential for neonates and infants. 8.5 Geriatric Use. Clinical studies of PERIKABIVEN (R) did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from other younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. 8.6 Hepatic Impairment. In patients with impaired liver function PERIKABIVEN (R) should be administered with caution. Frequent clinical evaluation and laboratory tests to monitor liver function such as bilirubin and liver function parameters should be conducted [s ee Warnings and Precautions (5.10)] . 8.7 Renal Impairment. In patients with impaired renal function, PERIKABIVEN (R) should be administered with caution. Frequent clinical evaluation and laboratory tests to monitor renal function such as serum electrolytes (especially phosphate and potassium) and fluid balance should be conducted [see Dosage and Administration (2.4) and Warnings and Precautions (5.11)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity reactions: Monitor for signs or symptoms and discontinue infusion if reactions occur. 5.2) Infection, fat overload, hyperglycemia and refeeding complications: Monitor for signs and symptoms; monitor laboratory parameters. 5.3, 5.4, 5.5, 5.6, 5.7) Hypersensitivity reactions: Monitor for signs or symptoms and discontinue infusion if reactions occur. 5.2) Infection, fat overload, hyperglycemia and refeeding complications: Monitor for signs and symptoms; monitor laboratory parameters. 5.3, 5.4, 5.5, 5.6, 5.7) 5.1 Death in Preterm Infants. Deaths in preterm infants after infusion of intravenous lipid emulsions have been reported. Autopsy findings included intravascular lipid accumulation in the lungs. 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 safe and effective use of PERIKABIVEN (R) injection in pediatric patients, including preterm infants, has not been established. PERIKABIVEN (R) is not recommended for use in pediatric patients under the age of years including preterm infants. 5.2 Hypersensitivity Reactions. Stop infusion immediately and treat patient accordingly if signs or symptoms of hypersensitivity or allergic reaction develop. Signs or symptoms may include: tachypnea, dyspnea, hypoxia, bronchospasm, tachycardia, hypotension, cyanosis, vomiting, nausea, headache, sweating, dizziness, altered mentation, flushing, rash, urticaria, erythema, pyrexia and chills.. 5.3 Infections. Patients who require parenteral nutrition are at high risk of infections due to malnutrition and their underlying disease state. Infection and sepsis may occur as result of the use of intravenous catheters to administer parenteral nutrition, poor maintenance of catheters, or immunosuppressive effects of illness, drugs, and parenteral formulations. Decrease the risk of septic complications with heightened emphasis on aseptic technique in catheter placement and maintenance, as well as aseptic technique in the preparation of the nutritional formula. Monitor for signs and symptoms (including fever and chills) of early infections, including laboratory test results (including leukocytosis and hyperglycemia) and frequent checks of the parenteral access device. 5.4 Fat Overload Syndrome. Fat overload syndrome is rare condition that has been reported with intravenous lipid formulations. reduced or limited ability to metabolize the lipid contained in PERIKABIVEN (R) accompanied by prolonged plasma clearance may result in syndrome characterized by sudden deterioration in the patients condition accompanied by fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, liver fatty infiltration (hepatomegaly), deteriorating liver function, and central nervous system manifestations (e.g., coma). The cause of the fat overload syndrome is unclear. The syndrome is usually reversible when the infusion of the lipid emulsion is stopped. Although it has been most frequently observed when the recommended lipid dosage was exceeded, cases have also been described where the lipid formulation was administered according to instructions. 5.5 Refeeding Syndrome. Refeeding severely undernourished patients with parenteral nutrition may result in the refeeding syndrome, characterized by the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop. Carefully monitor severely undernourished patients and slowly increase their nutrient intakes, while avoiding overfeeding, to prevent these complications.. 5.6 Diabetes/Hyperglycemia. PERIKABIVEN (R) should be used with caution in patients with diabetes mellitus or hyperglycemia. With the administration of PERIKABIVEN (R), hyperglycemia and hyperosmolar syndrome may result. Administration of dextrose at rate exceeding the patients utilization rate may lead to hyperglycemia, coma and death. Monitor blood glucose levels and treat hyperglycemia to maintain optimum levels while infusing PERIKABIVEN (R). Insulin may be administered or adjusted to maintain optimal blood glucose levels during PERIKABIVEN (R) administration. 5.7 Monitoring/Laboratory Tests. Routine MonitoringFrequent clinical evaluation and laboratory determinations are necessary for proper monitoring during administration.Monitor fluid status closely in patients with heart failure or pulmonary edema.Monitor serum triglycerides, fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, and blood count, including platelet and coagulation parameters, throughout treatment. In situations of severely elevated electrolyte levels stop PERIKABIVEN (R) until levels have been corrected. Essential Fatty AcidsMonitoring 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.In PERIKABIVEN (R), the mean composition of linoleic acid (an omega-6 essential fatty acid) is 19 mg/mL (range 17 to 20 mg/mL) and alpha-linolenic acid (an omega-3 essential fatty acid) is 2.3 mg/mL (range 1.8 to 3.8 mg/mL). There are insufficient long-term data to determine whether PERIKABIVEN (R) can supply essential fatty acids in adequate amounts in patients who may have increased requirements. Frequent clinical evaluation and laboratory determinations are necessary for proper monitoring during administration.. Monitor fluid status closely in patients with heart failure or pulmonary edema.. Monitor serum triglycerides, fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, and blood count, including platelet and coagulation parameters, throughout treatment. In situations of severely elevated electrolyte levels stop PERIKABIVEN (R) until levels have been corrected. 5.8 Thrombophlebitis. PERIKABIVEN (R) is indicated for peripheral administration, or may be infused into central vein. Peripheral catheters should not be used for solutions with osmolarity of >= 900 mOsm/L. The primary complication of peripheral access is venous thrombophlebitis, which manifests as pain, erythema, tenderness or palpable cord. The catheter should be removed as soon as thrombophlebitis develops. 5.9 Precipitation with Ceftriaxone. Precipitation of ceftriaxone-calcium can occur when ceftriaxone is mixed with calcium-containing parenteral nutrition solutions, such as PERIKABIVEN (R) in the same intravenous administration line. Ceftriaxone must not be administered simultaneously with PERIKABIVEN (R) via Y-site. However, ceftriaxone and PERIKABIVEN (R) may be administered sequentially if the infusion lines are thoroughly flushed between infusions with compatible fluid [s ee Dosage and Administration (2.1)] . 5.10 Hepatobiliary Disorders. Hepatobiliary disorders are known to develop in some patients without preexisting liver disease who receive parenteral nutrition, including cholecystitis, cholelithiasis, cholestasis, hepatic steatosis, fibrosis and cirrhosis, possibly leading to hepatic failure. The etiology of these disorders is thought to be multifactorial and may differ between patients. Increase of blood ammonia levels and hyperammonemia may occur in patients receiving amino acid solutions. In some patients this may indicate hepatic insufficiency or the presence of an inborn error of amino acid metabolism [see Contraindications (4)] or hepatic insufficiency. Monitor liver function parameters and ammonia. Patients developing signs of hepatobiliary disorders should be assessed early by clinician knowledgeable in liver diseases in order to identify causative and contributory factors, and possible therapeutic and prophylactic interventions.. 5.11 Electrolyte Imbalance and Fluid Overload in Renal Impairment. Patients with renal impairment, such as pre-renal azotemia, renal obstruction and protein-losing nephropathy may be at increased risk of electrolyte and fluid volume imbalance. PERIKABIVEN (R) should be used with caution in patients with renal impairment. PERIKABIVEN (R) dosage may require adjustment with specific attention to fluid, protein and electrolyte content in these patients. Monitor renal function parameters. Patients developing signs of renal impairment should be assessed early by clinician knowledgeable in renal disease in order to determine the appropriate PERIKABIVEN (R) dosage and other treatment options. 5.12 Hypertriglyceridemia. To evaluate the patients capacity to eliminate and metabolize the infused lipid emulsion, measure serum triglycerides before the start of infusion (baseline value), with each increase in dosage, and regularly throughout treatment.Reduce dose of PERIKABIVEN (R) and monitor serum triglyceride levels in patients with serum triglyceride concentrations above 400 mg/dL to avoid the clinical consequences associated with hypertriglyceridemia. Serum triglyceride levels above 1,000 mg/dL have been associated with an increased risk of pancreatitis. Impaired lipid metabolism with hypertriglyceridemia may occur in conditions such as inherited lipid disorders, obesity, diabetes mellitus, and metabolic syndrome. In these cases, increased triglycerides can also be increased by dextrose and/or overfeeding. Monitor overall energy intake and other sources of lipid and dextrose, as well as drugs that may interfere with lipid and dextrose metabolism.. 5.13 Aluminum Toxicity. PERIKABIVEN (R) contains no more than 25 mcg/L of aluminum. The aluminum contained in PERIKABIVEN (R) may reach toxic levels with prolonged parenteral administration in patients with impaired kidney function. Preterm infants 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 infants, who receive parenteral levels of aluminum at greater than to 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 of total parenteral nutrition products. 5.14 Interference with Laboratory Tests. High levels of lipids in plasma may interfere with some laboratory blood tests such as hemoglobin, triglycerides, bilirubin, LDH, and oxygen saturation, if blood is sampled before lipid has been cleared from the bloodstream. Lipids are normally cleared after lipid-free interval of to hours in most patients. PERIKABIVEN (R) contains Vitamin 1 which may interfere with anticoagulant activity [see Drug Interactions (7.1)] . 5.15 Risk of Parenteral Nutrition Associated Liver Disease. Parenteral Nutrition Associated Liver Disease (PNALD) has been reported in patients who receive parenteral nutrition for extended periods of time, especially preterm infants, and can present as cholestasis or steatohepatitis. The exact etiology is unknown and is likely multifactorial. Intravenously administered phytosterols (plant sterols) contained in plant-derived lipid formulations have been associated with development of PNALD although causal relationship has not been established. If PERIKABIVEN (R) treated patients develop liver test abnormalities consider discontinuation or dosage reduction.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The clinical data described for PERIKABIVEN reflects exposure in 93 patients exposed for to days in active-controlled trials. The pooled population exposed to PERIKABIVEN was 18 to 87 years old, 48% female, 73% Caucasian. The enrolled patients had varied underlying conditions such as gastrointestinal disorders (55%), vascular disorders (30%), metabolism and nutrition disorders (28%), respiratory, thoracic, and mediastinal disorders (22%), and psychiatric disorders (20%). Most patients received peripheral intravenous infusion doses of >=80% of their target mean daily exposure.Adverse reactions occurring in at least 2% of patients who received PERIKABIVEN are shown in Table 3.Table 3: Adverse Reactions in >2% of Patients Treated with PERIKABIVEN Terms as reported in clinical studiesAdverse reactionPERIKABIVEN N=93 (%)Hyperglycemia5 (5)Hypokalemia4 (4)Pyrexia4 (4)Blood triglycerides increased3 (3)Phlebitis2 (2)Nausea2 (2)Pruritus2 (2)Gamma-glutamyltransferase increased2 (2)Blood alkaline phosphatase increased2 (2)Alanine aminotransferase increased2 (2)Blood glucose increased2 (2)C-reactive protein increased2 (2)Blood urea increased2 (2)Hypoalbuminemia2 (2)Less common adverse reactions in <=1% of patients who received PERIKABIVEN were hyperkalemia, hypomagnesaemia, hypernatremia, tachycardia, hypertension, thrombophlebitis, vomiting, jaundice, rash and increased blood bilirubin.In randomized active-controlled, double-blind, parallel-group, multi-center study that included 152 neonates and patients ranging in age from 29 to 153 days who were expected to require PN for at least 28 days, parenteral nutrition-associated cholestasis (PNAC), precursor to PNALD, developed more frequently in Intralipid-treated patients than in patients treated with 4-oil mixed lipid emulsion. Intralipid is the lipid emulsion component of PERIKABIVEN.PNAC (defined as direct bilirubin >2mg/dl with second confirmed elevation >2mg/dl at least days later) occurred in 11.5% (9/78) of Intralipid-treated patients and 2.4% (2/83) of patients treated with 4-oil mixed lipid emulsion. 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.Figure 1: Cumulative Incidence Curve of Time to Parenteral Nutrition-Associated Cholestasis (PNAC) with Standard Error BarsMonitor liver tests in patients treated with PERIKABIVEN and consider discontinuation or dosage reduction if abnormalities occur.. Figure 1.

LABORATORY TESTS SECTION.

5.14 Monitoring/Laboratory Tests. Monitor fluid status closely in patients with pulmonary edema or heart failure.Throughout treatment, monitor serum triglycerides [see Warnings and Precautions (5.13)], fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, blood count (including platelets), and coagulation parameters.PERIKABIVEN contains Vitamin that may counteract anticoagulant activity [see Drug Interactions (7)]. The lipids contained in PERIKABIVEN may interfere with some laboratory tests (e.g., hemoglobin, triglycerides, lactate dehydrogenase, bilirubin, and oxygen saturation) if blood is sampled before the lipids in PERIKABIVEN have cleared from the bloodstream. Conduct these tests at least hours after stopping the infusion.

RECENT MAJOR CHANGES SECTION.

Boxed Warning (Removed)5/2023Dosage and Administration (2.1)5/2023Warnings and Precautions (5.1)5/2023.