新类型肠外营养药Kabiven(氨基酸，电解质，葡萄糖和脂质注射用乳剂)是一种由重要营养素组成的治疗混合物，用于混合或完全的肠外（静脉）营养患者的最佳组合剂型。 批准日期：2014年8月25日；公司：Fresenius Kabi USA KABIVEN(氨基酸，电解质，葡萄糖和脂质注射用乳剂)为静脉使用 美国初次批准：TBD 作用机制 KABIVEN®是在患者被用作为补充剂或作为营养的唯一来源，肠外地提供大量化学养料(氨基酸，葡萄糖和脂质)和微量营养素(电解质)。 氨基酸提供制造蛋白结构单元和被用于合成蛋白和其他生物分子或被氧化至尿素和二氧化碳作为能量来源。 给予的葡萄糖被氧化至二氧化碳和水，产生能量。 静脉给予脂质提供生物学上可利用的热量和必需脂肪酸来源。脂肪酸作为对能量生成的重要底物。对能量最常见的作用机制衍生自脂肪酸代谢是β-氧化。脂肪酸对膜结构和功能，对生物活性分子(例如前列腺素)前体和作为基因表达的调节物很重要。 适应证和用途 KABIVEN® 是适用为当口服或肠外营养是不可能，不充分，或禁忌时对成年患者需要肠外营养热量，蛋白，电解质和必需脂肪酸的来源。KABIVEN®可能被用于在成年患者中预防必需脂肪酸不足或治疗氮负平衡。 使用限制：不推荐在<2岁儿童患者包括早产儿中使用因为在这个年龄组中制剂的固定内容不符合营养要求。 剂量和给药方法 ⑴ 只为静脉输注至一中心静脉。 ⑵ 推荐剂量依赖于临床状态，体重和营养需求。 ⑶ 成年剂量：19至38 mL/kg/day (0.63至1.26 g/kg/day蛋白，1.85至3.71 g/kg/day葡萄糖，0.74至1.48 g/kg/day of 脂质) ⑷最大输注速率是2.6 mL/kg/hour(相当于0.09 g/kg/hour氨基酸，0.25 g/kg/hour葡萄糖，限制因子，和0.1g/kg/hour脂质)。推荐的输注时间是12至24小时。 剂型和规格 ⑴KABIVEN®是一种无菌，在一个三腔容器中高渗乳液。各个腔分别含以下之一：氨基酸和电解质，葡萄糖，或脂质注射用乳剂。 ⑵可得到四种2,566mL，2,053mL，1,540mL和1,026mL大小KABIVEN®。 禁忌证 ⑴已知对蛋，大豆蛋白，花生蛋白，玉米或玉米产品，或对任何活性物质或赋形剂超敏性。 ⑵严重高脂质血症或严重脂质代谢有血清甘油三酯 >1,000 mg/dL的疾病。 ⑶氨基酸代谢的先天性障碍。 ⑷心肺不稳定.  ⑸噬血细胞综合征. 警告和注意事项 ⑴超敏性反应：监视体征或症状和终止输注如发生反应。 ⑵感染，脂肪超载，高血糖和投喂并发症：监视体征和症状；监视实验室参数。 不良反应 最常见不良反应(≥3%)是恶心，发热，高血压，呕吐，血红蛋白减低，总蛋白减低，低钾血症，钾减低，和γ-谷氨酰转移酶增加。 药物相互作用 香豆素和香豆素衍生物，包括华法林：抗凝活性可能被抵消；监视实验室参数。 在特殊人群中使用 肾受损：用透析患者或连续肾取代治疗可能需要另外蛋白补充以符合营养需求。如需要，根据血清电解质水平和液体平衡调整给予KABIVEN®容积。 包装供应/贮存和处置 KABIVEN®是一种无菌 乳液可得到以下4种规格： 药品对热的暴露应最小。避免过热。保护避免冻结。如意外被冻结，遗弃袋。建议产品贮存在20º至25°C (68º至77°F)[见USP控制室温]。 意向使用前不要从袋中取出容器。 垂直密封破坏后，曾显示在25°C (77°F)24小时时混合三腔袋化学和物理在用稳定性。 产品在混合和引人添加剂后应立即使用。如不立即使用，使用前在2°至8°C (36º在46°F)贮存时间和条件不应长于24小时。从2°至8°C (36º至46°F)贮存取出后混合物应在24小时内输注。任何保留的混合物必须遗弃。 1）：http://kabivenusa.com/ 2）：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=afeb4837-a759-4484-a76e-e04611c459e7 3）：http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/200656s000lbl.pdf Kabiven/Perikabiven(amino acids, electrolytes, dextrose and lipid) Generic Name: Date of Approval: August 25, 2014 Company: Fresenius Kabi USA Treatment for: Parenteral Nutrition 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)] 1. DESCRIPTION  KABIVEN is a sterile, hypertonic emulsion, for central venous administration, in a Three Chamber Bag. The product contains no added sulfites. Chamber 1 contains Dextrose solution for fluid replenishment and caloric supply. Chamber 2 contains the Amino Acid solution with Electrolytes, which comprises essential and nonessential amino acids provided with electrolytes. Chamber 3 contains Intralipid® 20% (a 20% Lipid Injectable Emulsion), prepared for intravenous administration as a source of calories and essential fatty acids. See below for formulations of each chamber and Table 2 for strength, pH, osmolarity, ionic concentration and caloric content of KABIVEN when all the chambers are mixed together. Chamber 1: Contains sterile, hypertonic solution of Dextrose, USP in water for injection with a pH range of 3.5 to 5.5. Dextrose, USP is chemically designated D-glucose, monohydrate (C6H12O6•H2O) and has the following structure: Chamber 2: Contains a 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: Chamber 3: Contains a 20% Lipid Injectable Emulsion (Intralipid® 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 6 to 9. The soybean oil is a refined natural product consisting of a 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: Purified egg phosphatides are a 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 C3H8O3 and is a clear colorless, hygroscopic syrupy liquid. It has the following structural formula: The container-solution unit is a 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. This container is not made with natural rubber latex or polyvinyl chloride (PVC). 2. INDICATIONS AND USAGE  KABIVEN is indicated as a 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. KABIVEN may be used to prevent essential fatty acid deficiency or treat negative nitrogen balance in adult patients. Limitation of Use: KABIVEN is not recommended for use in pediatric patients under the age of 2 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)]. 3. DOSAGE AND ADMINISTRATION  3.1 Administration • KABIVEN is for intravenous infusion only into a central vein [see Warnings and Precautions (5.8)]. • Use a 1.2 micron in-line filter. • Use of a vented intravenous administration set with the vent in the open position could result in air embolism. • Use a 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 KABIVEN via a Y-site due to precipitation. However, ceftriaxone and KABIVEN may be administered sequentially if the infusion lines are thoroughly flushed between infusions with a 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 a plasticizer. 3.2 Important Preparation Instructions • Inspect the bag prior to activation. Discard the bag in the following situations: o Evidence of damage to the bag o More than one chamber is white o Solution is yellow o Any seal is already broken • Activate the bag [see Dosage and Administration (3.3)]. • 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 a homogenous admixture. • Ensure the vertical seals between chambers are broken and the contents of all three chambers are mixed together prior to infusion [see Dosage and Administration (3.3)]. • For total parenteral nutrition add multivitamins and trace elements via the additive port. Any other additions to the bag should be evaluated by a pharmacist for compatibility. Questions about compatibility may be directed to Fresenius Kabi USA, LLC Vigilance and Medical Affairs. • When introducing additives, it is recommended to use 18 to 23 gauge needles with a 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 (3.3)]. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect KABIVEN to ensure: o Precipitates have not formed during the mixing or addition of additives. o The emulsion has not separated. Separation of the emulsion can be visibly identified by a yellowish streaking or the accumulation of yellowish droplets in the mixed emulsion. Discard the admixture if any of the above are observed. • KABIVEN 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 2° to 8°C (36° to 46°F). After removal from storage at 2° to 8°C (36° to 46°F), the admixture should be infused within 24 hours. Any mixture remaining must be discarded. 3.3 Instructions for Use 1. Overpouch Notch 2. Handle 3. Hole (For hanging the bag) 4. Vertical Seals (Must break to activate) 5. Bends in Vertical Seals 6. Horizontal Seal (May remain unopened) 7. Blind Port (NEVER use this port) 8. WHITE Additive Port 9. BLUE Infusion Port 10. Oxygen Absorber (Present between bag and inside overpouch-position may vary) An instructional video is available at www.KabivenUSA.com. 1. INSPECT BAG PRIOR TO ACTIVATION. • KABIVEN is a 3 chambered bag: - One chamber is WHITE. - Two chambers are CLEAR. a) Discard bag if: - Overpouch is OPENED OR DAMAGED. - More than one chamber is WHITE. - Solution is YELLOW. - Seals are already BROKEN. 2. REMOVE OVERPOUCH. a) Place bag on a clean, flat surface. b) Tear from Overpouch Notch, located close to the ports. c) Tear long sides open to access the inner bag. d) Discard Overpouch and Oxygen Absorber. 3. ACTIVATE BAG. a) Place bag on a clean, flat surface with text side up and ports pointing away from you. b) Roll tightly from top of bag down toward ports. c) Apply pressure until both Vertical Seals break and entire contents are white. It may take up to 5 seconds of continued pressure to break Vertical Seals. NOTE: Both Vertical Seals must be broken from bends to ports. Upper section of Vertical Seals and Horizontal Seal may remain unbroken. d) After both Vertical Seals are broken, mix contents thoroughly by inverting the bag at least three times to ensure a homogenous mixture. 4. INSPECT BAG TO CONFIRM ACTIVATION. • An activated bag has both Vertical Seals broken from bends to ports and entire contents are white. 5. IDENTIFY CORRECT PORT. • Additive port is WHITE with arrow pointing toward bag. • Infusion port is BLUE with arrow pointing away from bag. 6. MAKE ADDITIONS (if prescribed). WARNING: Ensure additives are compatible. a) Immediately before injecting additives, break off WHITE Additive Port cap with the arrow pointing toward the bag. b) Hold base of Additive Port horizontally. c) Insert needle horizontally through the center of Additive Port’s septum and inject additives. d) Repeat as necessary using aseptic technique. e) Mix thoroughly after each addition. NOTE: The membrane of Additive Port is sterile at first use. Use aseptic technique for subsequent additions. The septum can be pierced up to 10 times with the recommended needle size 18 – 23 G 1½ inches (40mm). 7. SPIKE AND HANG BAG. a) Immediately before inserting the infusion set, break off BLUE Infusion Port cap with the arrow pointing away from the bag. b) Use a non-vented infusion set or close the air inlet on a vented set. It is recommended to use 1.2 μm in-line filter. c) Close the roller clamp of the infusion set. d) Hold the base of Infusion Port. e) Insert spike through Infusion Port by rotating your wrist slightly until the spike is inserted. f) Lift and hold the bag with both hands. g) Hang the bag by Hole below Handle. NOTE: The membrane of Infusion Port is sterile at first use. Use infusion sets (according to ISO Number 8536-4) with an external spike diameter of 5.5 to 5.7 mm. 8. FOR SINGLE USE ONLY • Discard unused portion. 3.4 Dosing Considerations The dosage of KABIVEN should be individualized based on the patient’s 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. KABIVEN is a combination of amino acids, electrolytes, dextrose, and lipids in a 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]. KABIVEN 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 KABIVEN, correct severe fluid electrolyte and acid-base disorders. Before starting the infusion, obtain serum triglyceride levels to establish the baseline value. Recommended Adult Dosage The recommended dosage of KABIVEN in adults is 19 to 38 mL/kg/day. The recommended daily nutritional requirements for protein, dextrose and lipids compared to the amount of nutrition provided by KABIVEN are shown in Table 1. The maximum daily dosage of KABIVEN in adults should not exceed 40 mL/kg/day. In patients with serum triglyceride concentrations above 400 mg/dL, stop the KABIVEN infusion and monitor serum triglyceride levels. Once the triglycerides are <400 mg/dL, restart KABIVEN at a 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 * 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 KABIVEN may be continued for as long as is required by the patient’s condition. Dosing in Renal Impairment In patients with renal impairment, the dosage of KABIVEN 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 KABIVEN administered as required [see Warnings and Precautions (5.11)]. Renal patients not needing dialysis require 0.6 to 0.8 g of protein/kg/day. Serum electrolyte levels should be closely monitored. Patients on hemodialysis or continuous renal replacement therapy should receive 1.2 to 1.8 g of protein/kg/day up to a maximum of 2.5 g of protein/kg/day based on nutritional status and estimated protein losses. The KABIVEN dosage can be adjusted based on the treatment for the renal impairment, supplementing protein as indicated. If required, additional amino acids may be added to the KABIVEN bag or infused separately. Compatibility of additions should be evaluated by a pharmacist and questions may be directed to Fresenius Kabi USA, LLC Vigilance and Medical Affairs. Infusion Duration and Rate The recommended duration of infusion for KABIVEN is between 12 and 24 hours, depending on the clinical situation. The maximum infusion rate of KABIVEN is 2.6 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 0.1 g/kg/hour of lipids. Dosing Instructions 1. Determine the fluid requirements (19 to 38 mL/kg/day) and the patient’s nutritional requirements (see Table 1) to be delivered, and then select the corresponding KABIVEN bag. 2. Determine the preferred duration of infusion (12 to 24 hours). 3. Ensure that the rate of infusion (KABIVEN 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., 2.6 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. 4. Once the infusion rate in mL/kg/hour has selected, calculate the infusion rate (mL/hour) using the patient’s weight. 5. Compare the patient’s nutrient requirements with the amount supplied by KABIVEN. Discuss with a pharmacist any additions that may be required. Table 2 describes the individual components of KABIVEN . Table 2: Contents of KABIVEN when mixed 1. Balanced by ions from amino acids 2. Contributed by sodium glycerophosphate and sodium acetate 3. Contributed by sodium glycerophosphate and phospholipids 4. Derived from sodium acetate and glacial acetic acid (for pH adjustment) 5. Contributed by calcium chloride, lysine hydrochloride, and potassium chloride 6. Derived from magnesium sulfate 7. Total caloric value including lipid, phospholipid and glycerin 8. 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 4. CONTRAINDICATIONS  The use of KABIVEN 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 metabolism • Cardiopulmonary instability (including pulmonary edema, cardiac insufficiency, myocardial infarction, acidosis and hemodynamic instability requiring significant vasopressor support) • Hemophagocytic syndrome 5. WARNINGS AND PRECAUTIONS  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 KABIVEN injection in pediatric patients, including preterm infants, has not been established. KABIVEN is not recommended for use in pediatric patients under the age of 2 years including preterm infants. 5.2 Hypersensitivity Reactions Stop infusion immediately and treat patient accordingly if signs or symptoms of a 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 a 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 a rare condition that has been reported with intravenous lipid formulations. A reduced or limited ability to metabolize the lipid contained in KABIVEN accompanied by prolonged plasma clearance may result in a syndrome characterized by a sudden deterioration in the patient's 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 KABIVEN should be used with caution in patients with diabetes mellitus or hyperglycemia. With the administration of KABIVEN, hyperglycemia, and hyperosmolar syndrome may result. Administration of dextrose at a rate exceeding the patient’s utilization rate may lead to hyperglycemia, coma and death. Monitor blood glucose levels and treat hyperglycemia to maintain optimum levels while infusing KABIVEN. Insulin may be administered or adjusted to maintain optimal blood glucose levels during KABIVEN administration. 5.7 Monitoring/Laboratory Tests Routine Monitoring • Frequent clinical evaluation and laboratory determinations are necessary for proper 13 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 KABIVEN until levels have been corrected. Essential Fatty Acids Monitoring patients for signs and symptoms of essential fatty acid deficiency (EFAD) is recommended. Laboratory tests are available to determine serum fatty acids levels. Reference values should be consulted to help determine adequacy of essential fatty acid status. Increasing essential fatty acid intake (enterally or parenterally) is effective in treating and preventing EFAD. In KABIVEN, the mean composition of linoleic acid (an omega-6 essential fatty acid) is 21 mg/mL (range 19 to 23 mg/mL) and alpha-linolenic acid (an omega-3 essential fatty acid) is 2.6 mg/mL (range 2.0 to 4.3 mg/mL). There are insufficient long-term data to determine whether KABIVEN can supply essential fatty acids in adequate amounts in patients who may have increased requirements. 5.8 Vein Damage and Thrombosis KABIVEN is indicated for administration into a central vein only, such as the superior vena cava. The infusion of hypertonic nutrient injections into a peripheral vein may result in vein irritation, vein damage, and/or thrombosis. 5.9 Precipitation with Ceftriaxone Precipitation of ceftriaxone-calcium can occur when ceftriaxone is mixed with calcium-containing parenteral nutrition solutions, such as KABIVEN in the same intravenous administration line. Ceftriaxone must not be administered simultaneously with KABIVEN via a Y-site. However, ceftriaxone and KABIVEN may be administered sequentially if the infusion lines are thoroughly flushed between infusions with a compatible fluid [see Dosing and Administration (3.1)]. 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 a 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. KABIVEN should be used with caution in patients with renal impairment. KABIVEN 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 a clinician knowledgeable in renal disease in order to determine the appropriate KABIVEN dosage and other treatment options. 5.12 Hypertriglyceridemia To evaluate the patient’s 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 KABIVEN 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 KABIVEN contains no more than 25 mcg/L of aluminum. The aluminum contained in KABIVEN 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 4 to 5 mcg/kg/day, accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration 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 a lipid-free interval of 5 to 6 hours in most patients. KABIVEN contains Vitamin K1 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 a causal relationship has not been established. If KABIVEN treated patients develop liver test abnormalities consider discontinuation or dosage reduction. 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)] • Vein damage and thrombosis [see Warnings and Precautions (5.8)] • Hepatobiliary disorders [see Warnings and Precautions (5.10, 5.15)] • Renal impairment [see Warnings and Precautions (5.11)] • Hypertriglyceridemia [see Warnings and Precautions (5.12)] • Aluminum toxicity [see Warnings and Precautions (5.13)] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The clinical data described for KABIVEN reflects exposure in 145 patients exposed for 7 days to 4 weeks in 7 active-controlled trials. The pooled population exposed to KABIVEN was 25 to 87 years old, 35% female, 99% Caucasian. The enrolled patients had varied underlying conditions such as gastrointestinal disorders (41%) neoplasms (48%), vascular disorders (35%) and other surgical procedures (21%). Most patients received central intravenous infusion doses of ≥80% of their target mean daily exposure. Adverse reactions occurring in at least 1% of patients who received KABIVEN are shown in Table 3. Table 3: Adverse Reactions in >1% of Patients Treated with KABIVEN * Terms as reported in clinical studies Less common adverse reactions in ≤1% of patients who received KABIVEN were hyperkalemia, hypertriglyceridemia, headache, dizziness, dysgeusia, rash, eczema, blood glucose increased, and increase in blood triglycerides. 6.2 Post-Marketing Experience The following additional adverse reactions have been identified during post-approval use of KABIVEN 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. • Hepatobiliary disorders: cholestasis • Infections and infestations: infection • Nervous system disorders: subependymal hemorrhage 7. DRUG INTERACTIONS  7.1 Coumarin and Coumarin Derivatives The soybean oil present in KABIVEN has vitamin K1. Vitamin K1 can reverse the anticoagulant activity of coumarin and coumarin derivatives, including warfarin, which works by blocking recycling of vitamin K1. Monitor laboratory parameters for anticoagulant activity in patients who are on both KABIVEN and coumarin or coumarin derivatives. 8. USE IN SPECIFIC POPULATIONS  8.1 Usage in Pregnancy Pregnancy Category C Risk Summary There are no adequate or well-controlled studies in pregnant women with KABIVEN. Additionally, animal reproduction studies have not been conducted with lipid injectable emulsion with amino acids and electrolytes and dextrose. It is not known whether KABIVEN can cause fetal harm when administered to a pregnant woman. KABIVEN should be given to a pregnant woman only if clearly needed. Clinical Considerations Based on clinical practice guidelines, parenteral nutrition should be considered in cases of severe maternal malnutrition where nutritional requirements cannot be fulfilled by oral food intake because of the risks to the fetus associated with severe malnutrition, such as preterm delivery, low birth weight, intrauterine growth restriction, congenital malformations and perinatal mortality. 8.3 Nursing Mothers It is not known whether KABIVEN is present in human milk. Because many drugs are present in human milk, caution should be exercised when KABIVEN is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of KABIVEN 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)]. KABIVEN 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: 1. Calcium and dextrose needs are not met and lipids, protein and magnesium exceed requirements. 2. 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. 8.5 Geriatric Use Clinical studies of KABIVEN 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 KABIVEN should be administrated with caution. Frequent clinical evaluation and laboratory tests to monitor liver function such as bilirubin and liver function parameters should be conducted [see Warnings and Precautions (5.10)]. 8.7 Renal Impairment In patients with impaired renal function, KABIVEN 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 (3.4) and Warnings and Precautions (5.11)]. 9. OVERDOSAGE  In the event of overdose, fat overload syndrome may result [see Warnings and Precautions 5.4]. Stop the infusion of KABIVEN 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. 10. MECHANISM OF ACTION  KABIVEN is used as a 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 a 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. 11. PHARMACOKINETICS   The infused lipid particles provided by KABIVEN are expected to be cleared from the blood stream in a 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 patient’s 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 KABIVEN 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. A clinical study in healthy volunteers employing high intravenous doses (80 mmol) of either sodium glycerophosphate used in KABIVEN or reference, inorganic sodium phosphate demonstrated that both compounds resulted in comparable serum inorganic phosphate concentrations after a 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. 12. HOW SUPPLIED/STORAGE AND HANDLING  1) How Available: a) Brand name: KABIVEN, by Fresenius Kabi. b) Generic drugs: None. 2) How Supplied: KABIVEN is a sterile emulsion available in the following 4 sizes: NDC 63323-712-25 2566 mL NDC 63323-712-20 2053 mL NDC 63323-712-15 1540 mL NDC 63323-712-10 1026 mL 3) Storage and Handling: Exposure 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 20º to 25°C (68º to 77°F) [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 25°C (77°F). The product 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 2° to 8°C (36º to 46°F). After removal from storage at 2° to 8°C (36º to 46°F), the admixture should be infused within 24 hours. Any mixture remaining must be discarded.