ALANINE: 18 Adverse Event Reports & Safety Profile

PERIKABIVEN is a sterile, hypertonic emulsion, for peripheral or central venous administration, in a Three Chamber Bag. The product contains no added sulfites.

Chamber

1 contains Dextrose monohydrate 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 PERIKABIVEN 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 (C 6 H 12 O 6

• H 2 O) and has the following structure: Dextrose is derived from corn.

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: Electrolytes Sodium Acetate Trihydrate, USP CH 3 COONax3H 2 O Potassium Chloride, USP KCl Sodium Glycerophosphate C 3 H 5 (OH) 2 PO 4 Na 2 xH 2 O Magnesium Sulfate Heptahydrate, USP MgSO 4 x7H 2 O Calcium Chloride Dihydrate, USP CaCl 2 x2H 2 O Essential Amino Acids Lysine (added as the hydrochloride salt) H 2 N(CH 2 ) 4 CH(NH 2 )COOH.HCl Phenylalanine CH 2 CH(NH 2 )COOH Leucine (CH 3 ) 2 CHCH 2 CH(NH 2 )COOH Valine (CH 3 ) 2 CHCH(NH 2 )COOH Histidine CH 2 CH(NH 2 )COOH Threonine CH 3 CH(OH)CH(NH 2 )COOH Methionine CH 3 S(CH 2 ) 2 CH(NH 2 )COOH Isoleucine CH 3 CH 2 CH(CH 3 )CH(NH 2 )COOH Tryptophan CH 2 CH(NH 2 )COOH Nonessential Amino Acids Alanine CH 3 CH(NH 2 )COOH Arginine H 2 NC(NH)NH(CH 2 ) 3 CH(NH 2 )COOH Glycine H 2 NCH 2 COOH Proline Glutamic Acid HOOC(CH 2 ) 2 CH(NH 2 )COOH Serine HOCH 2 CH(NH 2 )COOH Aspartic Acid HOOCCH 2 CH(NH 2 )COOH Tyrosine 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: Linoleic acid C 18 H 32 O 2 Oleic acid C 18 H 34 O 2 Palmitic acid C 16 H 32 O 2 Linolenic acid C 18 H 30 O 2 Stearic acid C 18 H 36 O 2 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 C 3 H 8 O 3 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. The container is not made with natural rubber latex or polyvinyl chloride (PVC). PERIKABIVEN contains no more than 25 mcg/L of aluminum.

Figure Figure Figure Figure Figure

Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure

INDICATIONS AND USAGE Aminosyn-PF 10%, Sulfite-Free, (an amino acid injection — pediatric formula) is indicated for the nutritional support of infants (including those of low birth weight) and young children requiring TPN via either central or peripheral infusion routes. Parenteral nutrition with Aminosyn-PF 10% is indicated to prevent nitrogen and weight loss or treat negative nitrogen balance in infants and young children where (1) the alimentary tract by the oral gastrostomy, or jejunostomy route, cannot or should not be used or adequate protein intake is not feasible by these routes; (2) gastrointestinal absorption of protein is impaired; or (3) protein requirements are substantially increased as with extensive burns. Dosage, route of administration, and concomitant infusion of non-protein calories are dependent on various factors, such as nutritional and metabolic status of the patient, anticipated duration of parenteral nutrition support, and vein tolerance. See DOSAGE AND ADMINISTRATION for additional information.

Central Venous Infusion

Central venous infusion should be considered when amino acid solutions are to be admixed with hypertonic dextrose to promote protein synthesis in hypercatabolic or severely depleted infants or those requiring long-term parenteral nutrition.

Peripheral Parenteral Nutrition

For moderately catabolic or depleted patients in whom the central venous route is not indicated, diluted amino acid solutions mixed with 5 to 10% dextrose solutions may be infused by peripheral vein, supplemented, if desired, with fat emulsion.

AND ADMINISTRATION See full prescribing information for information on preparation, administration, instructions for use, dosing considerations, including the recommended dosage in adults and pediatrics, and dosage modifications in patients with kidney disease. ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 )

2.1 Preparation Prior to Administration

• CLINIMIX E is available in a three port container configuration and a two port container configuration.
• Three Port Container: the ports consist of one medication port, one additive port and one outlet port. Additives can be introduced to the container through the medication port and lipids through the additive port on the three port container.
• Two Port Container: the ports consist of one medication port and one outlet port. Additives, including lipids, can be introduced to the container through the medication port on the two port container.
• Tear protective overwrap at slit and remove solution container. Small amounts of moisture may be found on the solution container from water permeating from inside the container. The amount of permeated water is insufficient to affect the solution significantly. If larger amounts of water are found, the container should be checked for tears or leaks.
• Inspect the container prior to activation. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Evaluate the following:
• If the outlet or additive port protectors are damaged, detached, or not present, discard container as solution path sterility may be impaired.
• Check to ensure seal between chambers is intact, solutions are contained in separate chambers, and the content of the individual chambers is clear, colorless or slightly yellow. Discard if the seal is broken or if the solution is bright yellow or yellowish brown.
• Check for minute leaks by separately squeezing each chamber. If external leaks or leakage between the chambers are found, discard solution as sterility or stability may be impaired.
• Lipids and/or additives can be introduced to the container after opening seal between chambers. Because additives may be incompatible, evaluate all additions to the plastic container for compatibility. Activate chambers of container prior to introduction of additives. Mix thoroughly when additives have been introduced. Supplemental medication may be added with a 19 to 22 gauge needle through the medication port.
• Calcium and phosphate ratios must be considered. Excess addition of calcium and phosphate, especially in the form of mineral salts, may result in the formation of calcium phosphate precipitates [see Warnings and Precautions (5.1) ].
• Inspect the container to ensure precipitates have not formed during the mixing or addition of additives. A slight yellow color does not alter the quality and efficacy of this product. If lipid has been added, ensure 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.

2.2 Important Administration Instructions

• Set the vent to the closed position on a vented intravenous administration set to prevent air embolism.
• Use a dedicated line without any connections to avoid air embolism.
• CLINIMIX E is for intravenous infusion only into a central or peripheral vein. The choice of a central or peripheral venous route should depend on the osmolarity of the final infusate. Solutions with osmolarity of 900 mOsm/L or greater must be infused through a central catheter [see Warnings and Precautions (5.7) ].
• For central vein infusion only: CLINIMIX E 4.25/10, 5/15, 5/20, 8/10, 8/14
• For central or peripheral vein infusion: CLINIMIX E 2.75/5 and 4.25/5
• The solution should be inspected for precipitates before admixing, after admixing, and again before administration.
• Use a 0.22 micron filter for administration of CLINIMIX E. If a lipid is also administered, use a 1.2 micron filter.
• If lipid emulsion is added, 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.
• Ceftriaxone must not be administered simultaneously with calcium-containing intravenous solutions such as CLINIMIX E via a Y-site. However, in patients other than neonates, ceftriaxone and CLINIMIX E may be administered sequentially if the infusion lines are thoroughly flushed between infusions with a compatible fluid [see Contraindications (4) , Warnings and Precautions (5.2) ] .

2.3 Instructions for Use 1. Open by tearing protective overwrap at slit and remove solution container. The two port container includes an oxygen-absorbing sachet. Discard the oxygen-absorbing sachet after removal from the overwrap. 2. To proceed with activation, the container should be at room temperature. Lay the room temperature container onto a flat surface. Grasp the container firmly on each side of the top of the container ( Figure 1 ). 3. Starting from the top, using some pressure, slowly roll the container to open seal between chambers as shown in Figure 2 . Do not pull or rip the seal apart. The seal must be completely opened towards the port side of the container. The upper section of the seal towards the hanger side can remain unbroken. 4. Mix the contents thoroughly by inverting the container upside down to ensure a homogenous admixture ( Figure 3 ). 5. Once the container is mixed, check for leaks. 6. Make additions (if prescribed). Because additives may be incompatible, evaluate all additions to the container for compatibility and stability of the resulting preparation. Consult with pharmacist, if available. Questions about compatibility may be directed to Baxter. If it is deemed advisable to introduce additives, use aseptic technique. For information on adding lipid emulsions see Dosage and Administration (2.4) . a. Prepare medication port. b. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. c. Mix solution and medication thoroughly ( Figure 3 ). For high density medication (high specific gravity), such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. 7. Inspect final solution for discoloration and particulate matter. Check for leaks. 8. Spike and hang container. a. Suspend container from eyelet support. b. Twist off protector from outlet port at bottom of container ( Figure 4 ). c. Attach administration set. Refer to complete directions accompanying set. For single dose only. Discard unused portion.

Figures

1 – 4 (Three Port Container): Figures 1 – 4 (Two Port Container): Instructions on Storage Storage After Removal of Overwrap: Once removed from the protective overwrap, mixed (peel seal activated) or unmixed (peel seal intact), CLINIMIX E solutions may be stored under refrigeration for up to 9 days.

Storage

Once any Additive is Added: Use promptly after mixing. Any storage with additives should be under refrigeration and limited to a brief period of time, less than 24 hours. After removal from refrigeration, use promptly and complete the infusion within 24 hours. Any remaining mixture must be discarded. Protect the activated parenteral nutrition solution from light.

Figure

1-4 Clinimix E Figures 1-4 - (Two Port Container)

2.4 Preparation and Addition of Lipid Emulsion Three Port Container 1. Prior to adding lipid emulsion, mix amino acid and dextrose injection as shown in Figures 1-3 . 2. Prepare lipid emulsion transfer set following instructions provided. 3. Attach transfer set to lipid emulsion container using aseptic technique. 4. Twist off protector on the additive port of the container. 5. Attach the transfer set to the exposed additive port. 6. Open clamp on transfer set. 7. After completing transfer, use appropriate plastic clamp or metal ferrule to seal off additive port tube. 8. Remove transfer set. 9. Mix contents of container thoroughly. Inspect final solution for discoloration and particulate matter. Check for leaks.

Two Port Container

1. Prior to adding lipid emulsion, mix amino acid and dextrose injection as shown in Figures 1-3. 2. Prepare lipid emulsion transfer set following instructions provided. 3. Attach transfer set to lipid emulsion container using aseptic technique. 4. Prepare medication port. 5. Using a 19 to 22 gauge needle, puncture resealable medication port. 6. Open clamp on transfer set and transfer lipid emulsion. 7. Remove needle. 8. Mix contents of container thoroughly. Inspect final solution for discoloration and particulate matter. Check for leaks.

Storage Once

Lipids are Added: Use promptly after mixing. Any storage with additives should be under refrigeration and limited to a brief period of time, no longer than 24 hours. After removal from refrigeration, use promptly and complete the infusion within 24 hours. Any mixture remaining must be discarded.

2.5 Dosing Considerations

• The dosage of CLINIMIX E should be individualized based on the patient’s clinical condition (ability to adequately metabolize amino acids and dextrose), body weight and nutritional/fluid requirements, as well as additional energy given orally/enterally to the patient. Prior to initiating CLINIMIX E the following patient information should be reviewed: all concomitant medications, gastrointestinal function and laboratory data such as electrolytes (including magnesium, calcium, and phosphorus), glucose, urea/creatinine, liver panel, complete blood count and triglyceride level (if adding lipid emulsion). Refer to the complete prescribing information of lipid emulsion for dosing information.
• CLINIMIX E formulations have varying concentrations of protein, carbohydrate and a standard concentration of electrolytes; thus infusion rates to achieve requirements will vary. Protein, caloric, fluid and electrolyte requirements all need to be taken into consideration when determining individual patient dosage needs.
• The dosage selection is based only on the recommended protein requirements. The maximum dextrose infusion rates and calorie and fluid requirements must also be considered when determining the clinically appropriate infusion rate for patients.
• CLINIMIX E meets the total nutritional requirements for protein and dextrose in stable patients, and can be individualized to meet specific needs with the addition of nutrients.
• Total daily fluid requirements can be met beyond the volume of amino acids solution by supplementing with non-carbohydrate or carbohydrate-containing electrolyte solutions. In many patients, provision of adequate calories in the form of hypertonic dextrose may require the administration of exogenous insulin to prevent hyperglycemia and glycosuria.
• Prior to administration of CLINIMIX E correct severe fluid, electrolyte and acid-base disorders.
• Monitor levels of serum potassium during therapy. It may be necessary to add additional potassium to the CLINIMIX E admixture.
• Lipid emulsion administration should be considered with prolonged use (more than 5 days) of CLINIMIX E in order to prevent essential fatty acid deficiency (EFAD). Serum lipids should be monitored for evidence of EFAD in patients maintained on fat-free parenteral nutrition. See prescribing information of lipid emulsion.
• The flow rate should be increased gradually. The flow rate must be adjusted taking into account the dose being administered, the daily volume intake, and the duration of the infusion.

2.6 Recommended Dosage in Adults The recommended daily nutritional requirements for protein and dextrose compared to the amount of nutrition provided by CLINIMIX E are shown in Table 1 . As indicated on an individual basis, maintenance vitamins, additional electrolytes, trace elements and other components (including lipids) should be administered as required to prevent deficiencies and complications from developing. The maximum infusion rates in adult patients are show in Table 2 . In addition to meeting protein needs, the administration rate should be governed, especially during the first few day of therapy, by the patient’s tolerance to dextrose. Daily intake of amino acids and dextrose should be increased gradually to the maximum required dose as indicated by frequent determinations of blood glucose levels.

Table

1: Nutritional Comparison – Adult Patients Recommended CLINIMIX E Adult Dosage CLINIMIX E 2.75/5 CLINIMIX E 4.25/5 CLINIMIX E 4.25/10 CLINIMIX E 5/15 CLINIMIX E 5/20 CLINIMIX E 8/10 CLINIMIX E 8/14 Fluid (mL/kg/day) 29 to 40 19 to 40 19 to 40 16 to 40 16 to 40 10 to 25 10 to 25 Protein Protein is provided as amino acids. When infused intravenously amino acids are metabolized and utilized as the building blocks of protein. (g/kg/day) (Nitrogen g/kg/day) 0.8 to 1.1 (0.13 to 0.18) 0.8 to 1.7 (0.13 to 0.27) 0.8 to 1.7 (0.13 to 0.27) 0.8 to 2 (0.13 to 0.32) 0.8 to 2 (0.13 to 0.32) 0.8 to 2 (0.13 to 0.32) 0.8 to 2 (0.13 to 0.32) Dextrose (g/kg/day) 1.45 to 2 0.95 to 2 1.9 to 4 2.4 to 6 3.2 to 8 1 to 2.5 1.4 to

3.5 Table 2: Maximum Infusion Rate in Adult Patients Maximum Infusion Rates in Adults Patients CLINIMIX E 2.75/5 CLINIMIX E 4.25/5 CLINIMIX E 4.25/10 CLINIMIX E 5/15 CLINIMIX E 5/20 CLINIMIX E 8/10 CLINIMIX E 8/14 Maximum Infusion Rate (mL/kg/hour) 3.6 2.4 2.4 1.67 1.25 1.3

1.3 Corresponding infusion rate Amino Acid (g/kg/hour)

0.1 Rate limiting factor 0.1 0.1 0.08 0.06 0.1

0.1 Dextrose (g/kg/hour) 0.18 0.12 0.24 0.25 0.25 0.13 0.18

2.7 Dosage Modifications in Patients with Kidney Disease Prior to administration, correct severe fluid or electrolyte imbalances. Closely monitor serum electrolyte levels and adjust the volume of CLINIMIX E administered as required <span class="opacity-50 text-xs">[see Warnings and Precautions (5.11) ]</span> . Chronic kidney disease patients with less than nephrotic range proteinuria require 0.8 g of protein/kg/day. Chronic kidney disease patients with nephrotic range proteinuria require 0.8 g of protein/kg/day plus 1 g of protein for each gram of proteinuria. Patients needing dialysis should receive from 1.2 g of protein/kg/day up to a maximum of 2.5 g of protein/kg/day depending on the nutritional status and the dialysis modality. Serum electrolyte levels should be closely monitored. The CLINIMIX E dosage can be adjusted based on the severity of kidney disease, supplementing protein as indicated. If required, additional amino acids may be added to the CLINIMIX E container or infused separately. Compatibility of additions should be evaluated by a pharmacist and questions may be directed to Baxter.

2.8 Recommended Dosage in Pediatric Patients The dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span> . Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. The infusion rate and volume should be determined by the consulting physician experienced in pediatric intravenous fluid therapy. In pediatric patients, CLINIMIX E is dosed on the basis of protein provided as amino acids. The recommended dosage, by age group is provided in Tables 3 - 6 . Infusion rates are based on protein and do not take carbohydrates, fluid or electrolytes into consideration. This product does not contain the amino acids cysteine and taurine, considered conditionally essential for neonates and infants. If possible, these amino acids should be added to this product if used in this pediatric population.

Table

3: Preterm and Term Infants Less than 1 Month of Age Recommended CLINIMIX E Dosage in Preterm and Term Infants Less than 1 Month of Age CLINIMIX E 2.75/5 CLINIMIX E 4.25/5 CLINIMIX E 4.25/10 CLINIMIX E 5/15 CLINIMIX E 5/20 CLINIMIX E 8/10 CLINIMIX E 8/14 Infusion Rate Range (mL/kg/hr) 4.5 to 6 2.9 to 3.9 2.9 to 3.9 2.5 to 3.3 2.5 to 3.3 1.6 to 2.1 1.6 to

2.1 Fluid (mL/kg/day) 108 to 144 70 to 94 70 to 94 60 to 79 60 to 79 38.4 to 50 38.4 to 50 Protein Protein is provided as amino acids. When infused intravenously amino acids are metabolized and utilized as the building blocks of protein. (g/kg/day) (Nitrogen g/kg/day) 3 to 4 (0.48 to 0.64) 3 to 4 (0.48 to 0.64) 3 to 4 (0.48 to 0.64) 3 to 4 (0.48 to 0.64) 3 to 4 (0.48 to 0.64) 3 to 4 (0.48 to 0.64) 3 to 4 (0.48 to 0.64) Dextrose (g/kg/day) 5.4 to 7.2 3.5 to 4.7 7 to 9.4 9 to 11.9 12 to 15.8 3.8 to 5 5.4 to 7 Table 4: Pediatric Patients 1 Month to Less than 1 Year of Age Recommended CLINIMIX E Dosage in Pediatric Patients 1 Month to Less than 1 Year of Age CLINIMIX E 2.75/5 CLINIMIX E 4.25/5 CLINIMIX E 4.25/10 CLINIMIX E 5/15 CLINIMIX E 5/20 CLINIMIX E 8/10 CLINIMIX E 8/14 Infusion Rate Range (mL/kg/hr) 3 to 4.5 2 to 2.9 2 to 2.9 1.7 to 2.5 1.7 to 2.5 1 to 1.6 1 to

1.6 Fluid (mL/kg/day) 72 to 108 48 to 70 48 to 70 41 to 60 41 to 60 24 to 38.4 24 to

38.4 Protein Protein is provided as amino acids. When infused intravenously amino acids are metabolized and utilized as the building blocks of protein. (g/kg/day) (Nitrogen g/kg/day) 2 to 3 (0.32 to 0.48) 2 to 3 (0.32 to 0.48) 2 to 3 (0.32 to 0.48) 2 to 3 (0.32 to 0.48) 2 to 3 (0.32 to 0.48) 2 to 3 (0.32 to 0.48) 2 to 3 (0.32 to 0.48) Dextrose (g/kg/day) 3.6 to 5.4 2.4 to 3.5 4.8 to 7 6.1 to 9 8.2 to 12 2.4 to 3.8 3.4 to

5.4 Table 5: Pediatric Patients 1 Year to Less than 11 Years of Age Recommended CLINIMIX E Dosage in Pediatric Patients 1 Year to Less than 11 Years of Age CLINIMIX E 2.75/5 CLINIMIX E 4.25/5 CLINIMIX E 4.25/10 CLINIMIX E 5/15 CLINIMIX E 5/20 CLINIMIX E 8/10 CLINIMIX E 8/14 Infusion Rate Range (mL/kg/hr) 1.5 to 3 1 to 2 1 to 2 0.8 to 1.7 0.8 to 1.7 0.5 to 1 0.5 to 1 Fluid (mL/kg/day) 36 to 72 24 to 48 24 to 48 19 to 41 19 to 41 12 to 24 12 to 24 Protein Protein is provided as amino acids. When infused intravenously amino acids are metabolized and utilized as the building blocks of protein. (g/kg/day) (Nitrogen g/kg/day) 1 to 2 (0.16 to 0.32) 1 to 2 (0.16 to 0.32) 1 to 2 (0.16 to 0.32) 1 to 2 (0.16 to 0.32) 1 to 2 (0.16 to 0.32) 1 to 2 (0.16 to 0.32) 1 to 2 (0.16 to 0.32) Dextrose (g/kg/day) 1.8 to 3.6 1.2 to 2.4 2.4 to 4.8 2.9 to 6.1 3.8 to 8.2 1.2 to 2.4 1.7 to

3.4 Table 6: Pediatric Patients 11 Years to 17 Years of Age Recommended CLINIMIX E Dosage in Pediatric Patients 11 Years to 17 Years of Age CLINIMIX E 2.75/5 CLINIMIX E 4.25/5 CLINIMIX E 4.25/10 CLINIMIX E 5/15 CLINIMIX E 5/20 CLINIMIX E 8/10 CLINIMIX E 8/14 Infusion Rate Range (mL/kg/hr) 1.2 to 2.3 0.8 to 1.5 0.8 to 1.5 0.7 to 1.3 0.7 to 1.3 0.4 to 0.8 0.4 to

0.8 Fluid (mL/kg/day) 29 to 55 19 to 36 19 to 36 17 to 31 17 to 31 9.6 to 19.2 9.6 to

19.2 Protein Protein is provided as amino acids. When infused intravenously amino acids are metabolized and utilized as the building blocks of protein. (g/kg/day) (Nitrogen g/kg/day) 0.8 to 1.5 (0.13 to 0.24) 0.8 to 1.5 (0.13 to 0.24) 0.8 to 1.5 (0.13 to 0.24) 0.8 to 1.5 (0.13 to 0.24) 0.8 to 1.5 (0.13 to 0.24) 0.8 to 1.5 (0.13 to 0.24) 0.8 to 1.5 (0.13 to 0.24) Dextrose (g/kg/day) 1.4 to 2.8 1 to 1.8 1.9 to 3.6 2.5 to 4.7 3.4 to 6.2 1 to 1.9 1.4 to 2.7

2.9 Discontinuation of CLINIMIX E injection To reduce the risk of hypoglycemia after discontinuation, a gradual decrease in flow rate in the last hour of infusion should be considered.

The use of PERIKABIVEN is contraindicated in:

• Neonates (28 days of age or younger) receiving concomitant treatment with ceftriaxone, even if separate infusion lines are used, due to the risk of fatal ceftriaxone calcium salt precipitation in the neonate's bloodstream [see Limitations of Use ( 1 ), Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.4 )].
• Patients with known hypersensitivity to egg, soybean, peanut or any of the active or inactive ingredients in PERIKABIVEN [see Warnings and Precautions ( 5.4 )] ;
• Patients with severe disorders of lipid metabolism characterized by hypertriglyceridemia (serum triglyceride concentration >1,000 mg/dL) [see Warnings and Precautions ( 5.10 )].
• Patients with inborn errors of amino acid metabolism
• Patients with cardiopulmonary instability (including pulmonary edema, cardiac insufficiency, myocardial infarction, acidosis and hemodynamic instability requiring significant vasopressor support)
• Patients with hemophagocytic syndrome
• Concomitant treatment with ceftriaxone in neonates (28 days of age or younger). ( 4 )
• Known hypersensitivity to egg, soybean, peanut or any of the active ingredients or excipients. ( 4 )
• Severe disorders of lipid metabolism characterized by hypertriglyceridemia (serum triglycerides >1,000 mg/dL). ( 4 , 5.10 )
• Inborn errors of amino acid metabolism. ( 4 )
• Cardiopulmonary instability. ( 4 )
• Hemophagocytic syndrome. ( 4 )

REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information.

• Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsion in Neonates and Infants [see Warnings and Precautions ( 5.1 )].
• Parenteral Nutrition-Associated Liver Disease and Other Hepatobiliary Disorders [see Warnings and Precautions ( 5.2 )].
• Pulmonary Embolism and Respiratory Distress due to Pulmonary Vascular Precipitates [see Warnings and Precautions ( 5.3 )].
• Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )].
• Precipitation with Ceftriaxone [see Warnings and Precautions ( 5.5 )].
• Infections [see Warnings and Precautions ( 5.6 )].
• Fat Overload Syndrome [see Warnings and Precautions ( 5.7 )].
• Refeeding Syndrome [see Warnings and Precautions ( 5.8 )].
• Diabetes and Hyperglycemia [see Warnings and Precautions ( 5.9 )].
• Hypertriglyceridemia [see Warnings and Precautions ( 5.10 )].
• Vein Damage and Thrombosis [see Warnings and Precautions ( 5.11 )].
• Electrolyte Imbalance and Fluid Overload in Patients with Decreased Renal Function [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 Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The clinical data described for PERIKABIVEN reflects exposure in 93 patients exposed for 5 to 7 days in 4 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 studies Adverse reaction PERIKABIVEN N=93 (%) Hyperglycemia* 5 (5)

Hypokalemia

4 (4)

Pyrexia

4 (4) Blood triglycerides increased 3 (3)

Phlebitis

2 (2)

Nausea

2 (2)

Pruritus

2 (2) Gamma-glutamyltransferase increased 2 (2) Blood alkaline phosphatase increased 2 (2) Alanine aminotransferase increased 2 (2) Blood glucose increased* 2 (2) C-reactive protein increased 2 (2) Blood urea increased 2 (2)

Hypoalbuminemia

2 (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 a randomized active-controlled, double-blind, parallel-group, multi-center study that included 152 neonates and 9 patients ranging in age from 29 to 153 days who were expected to require PN for at least 28 days, parenteral nutrition-associated cholestasis (PNAC), a precursor to PNALD, developed more frequently in Intralipid-treated patients than in patients treated with a 4-oil mixed lipid emulsion. Intralipid is the lipid emulsion component of PERIKABIVEN. PNAC (defined as direct bilirubin >2mg/dl with a second confirmed elevation >2mg/dl at least 7 days later) occurred in 11.5% (9/78) of Intralipid-treated patients and 2.4% (2/83) of patients treated with a 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 Bars Monitor liver tests in patients treated with PERIKABIVEN and consider discontinuation or dosage reduction if abnormalities occur.

Figure

1

6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of PERIKABIVEN in countries where it is registered. Because these reactions are reported voluntarily post-approval from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a 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: hypersensitivity reactions including anaphylaxis [see Contraindications ( 4 ), Warnings and Precautions ( 5.4 )]
• Infections and infestations: infection
• Vascular disorders: flushed face

AND PRECAUTIONS

• Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsion in Neonates and Infants : Acute respiratory distress, metabolic acidosis, and death after rapid infusion of intravenous lipid emulsions have been reported. ( 5.1 )
• Parenteral Nutrition-Associated Liver Disease : Increased risk in patients who receive parenteral nutrition for greater than 2 weeks. Monitor liver tests; if abnormalities occur, consider discontinuation or dosage reduction. ( 5.2 )
• Pulmonary Embolism and Respiratory Distress due to Pulmonary Vascular Precipitates : If signs of pulmonary distress occur, stop the infusion and initiate a medical evaluation. ( 5.3 )
• Hypersensitivity Reactions: Monitor for signs or symptoms and discontinue infusion if reactions occur. ( 5.4 )
• Precipitation with Ceftriaxone: Do not administer ceftriaxone simultaneously with PERIKABIVEN via a Y-Site ( 4 , 5.5 , 8.4 )
• Infection, fat overload, hyperglycemia and refeeding complications: Monitor for signs and symptoms; monitor laboratory parameters. ( 5.6 , 5.7 , 5.8 , 5.9 , 5.14 )

5.1 Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsion in Neonates and Infants In the postmarketing setting, serious adverse reactions including acute respiratory distress, metabolic acidosis, and death have been reported in neonates and infants after rapid infusion of intravenous lipid emulsions. Hypertriglyceridemia was commonly reported. 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.

5.2 Parenteral Nutrition-Associated Liver Disease and Other Hepatobiliary Disorders Risk of Parenteral Nutrition-Associated Liver Disease Parenteral nutrition-associated liver disease (PNALD), also referred to as intestinal failure-associated liver disease (IFALD), can present as cholestasis or hepatic steatosis, and may progress to steatohepatitis with fibrosis and cirrhosis (possibly leading to chronic hepatic failure). The etiology of PNALD is multifactorial; however, intravenously administered phytosterols (plant sterols) contained in plant-derived lipid emulsions, such as Intralipid (included in PERIKABIVEN), have been associated with development of PNALD. In a randomized study of neonates and infants expected to be treated with PN for at least 28 days, parenteral nutrition-associated cholestasis (PNAC), a precursor to PNALD, developed more frequently in Intralipid-treated patients than in patients treated with a 4-oil mixed lipid emulsion <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 ), Use in Specific Populations ( 8.4 )]</span>. Monitor liver tests in patients treated with PERIKABIVEN and consider discontinuation or dosage reduction if abnormalities occur.

Other Hepatobiliary Disorders

Hepatobiliary disorders including cholecystitis and cholelithiasis have developed in some PN-treated patients without preexisting liver disease. Monitor liver tests when administering PERIKABIVEN. Patients developing signs of hepatobiliary disorders should be assessed early to determine whether these conditions are related to PERIKABIVEN use.

5.3 Pulmonary Embolism and Respiratory Distress due to Pulmonary Vascular Precipitates Pulmonary vascular precipitates causing pulmonary emboli (including some fatalities) and respiratory distress have been reported in patients receiving parenteral nutrition. Excessive addition of calcium and phosphate increases the risk of the formation of calcium phosphate precipitates; however, precipitates have been reported even in the absence of phosphate salt in the solution. Precipitation following passage through an in-line filter and suspected in vivo precipitate formation has also been reported. Visually inspect the prepared solution, the infusion set, and catheter for precipitates, prior to administration as well as periodically during the administration. If signs of respiratory distress or pulmonary embolism occur, stop the PERIKABIVEN infusion and initiate a medical evaluation.

5.4 Hypersensitivity Reactions PERIKABIVEN contains soybean oil, which may cause hypersensitivity reactions. Cross reactions have been observed between soybean and peanut. In postmarketing experience, anaphylaxis has been reported following Kabiven administration <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . PERIKABIVEN is contraindicated in patients with known hypersensitivity to egg, soybean, peanut or any of the active or inactive ingredients in PERIKABIVEN <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . If a hypersensitivity reaction occurs, stop infusion of PERIKABIVEN immediately and initiate appropriate treatment and supportive measures.

5.5 Precipitation with Ceftriaxone Precipitation of ceftriaxone-calcium can occur when ceftriaxone is mixed with calcium-containing parenteral nutrition solutions, such as PERIKABIVEN in the same intravenous administration line. Do not administer ceftriaxone simultaneously with PERIKABIVEN via a Y-site. However, in patients other than neonates, ceftriaxone and PERIKABIVEN may be administered sequentially if the infusion lines are thoroughly flushed between infusions with a compatible fluid [ s ee Dosage and Administration ( 2.1 )] . Deaths have occurred in neonates (28 days of age or younger) who received concomitant intravenous calcium-containing solutions with ceftriaxone resulting from calcium-ceftriaxone precipitates in the lungs and kidneys, even when separate infusion lines were used <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Pediatric Use ( 8.4 )]</span>.

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

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

5.8 Refeeding Syndrome Administering PN to severely malnourished patients with parenteral nutrition may result in refeeding syndrome, characterized by the intracellular shift of potassium, phosphorus, and magnesium as patients become anabolic. Thiamine deficiency and fluid retention may also develop. To prevent these complications, closely monitor severely undernourished patients and slowly increase their nutrient intake.

5.9 Diabetes and Hyperglycemia Administration of dextrose at a rate exceeding the patient&apos;s utilization rate may lead to hyperglycemia, hyperosmolar coma, and death. Monitor blood glucose levels and treat hyperglycemia to maintain optimal glucose levels while infusing PERIKABIVEN. Insulin may be administered or adjusted to maintain optimal blood glucose levels during PERIKABIVEN administration.

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

5.11 Vein Damage and Thrombosis The infusion of hypertonic nutrient injections into a peripheral vein may result in vein irritation, vein damage, and/or thrombosis. PERIKABIVEN is indicated for peripheral administration, or may be infused into a central vein; however, peripheral catheters should not be used for solutions with osmolarity of ≥ 900 mOsm/L. The catheter should be removed as soon as possible if thrombophlebitis develops.

5.12 Electrolyte Imbalance and Fluid Overload in Patients with Decreased Renal Function Patients with decreased renal function, including those with pre-renal azotemia, renal obstruction, or intrinsic renal disease, may be at increased risk of electrolyte and fluid volume imbalance when receiving PN, including PERIKABIVEN. In patients with decreased renal function with electrolyte imbalance or fluid overload, the PERIKABIVEN should be used with caution in patients with renal impairment. PERIKABIVEN dosage (e.g., fluid, protein, and electrolyte content) may require adjustment. Monitor renal function parameters. Patients developing signs of decreased renal function should be assessed early by a clinician knowledgeable in renal disease in order to determine the appropriate PERIKABIVEN dosage and other treatment options.

5.13 Aluminum Toxicity PERIKABIVEN contains no more than 25 mcg/L of aluminum. The aluminum contained in PERIKABIVEN 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 Monitoring/Laboratory Tests Monitor fluid status closely in patients with pulmonary edema or heart failure. Throughout treatment, monitor serum triglycerides <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.13 )]</span> , fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, blood count (including platelets), and coagulation parameters. PERIKABIVEN contains Vitamin K that may counteract anticoagulant activity <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span>. 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 6 hours after stopping the infusion.

PRECAUTIONS Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Significant deviations from normal concentrations may require the use of additional electrolyte supplements. Strongly hypertonic nutrient solutions should be administered via an intravenous catheter placed in a central vein, preferably the superior vena cava. Care should be taken to avoid circulatory overload, particularly in patients with cardiac insufficiency. Special care must be taken when giving hypertonic dextrose to a diabetic or pre-diabetic patient. To prevent severe hyperglycemia in such patients, insulin may be required. Administration of glucose at a rate exceeding the patient's utilization rate may lead to hyperglycemia, coma, and death. The effect of infusion of amino acids, without dextrose, upon carbohydrate metabolism of children is not known at this time. It is essential to provide adequate exogenous dextrose calories concurrently with amino acids. Administration of amino acids without carbohydrates may result in the accumulation of ketone bodies in the blood. Correction of this ketonemia may be achieved by the administration of carbohydrate. Essential fatty acid deficiency (EFAD) is becoming increasingly recognized in patients on long term TPN (more than 5 days). The use of fat emulsion to provide 4 — 10% of total caloric intake as linoleic acid may prevent EFAD. Peripheral administration of Aminosyn-PF 7%, Sulfite-Free, (an amino acid injection — pediatric formula) requires appropriate dilution and provision of adequate calories. Care should be taken to assure proper placement of the needle within the lumen of the vein. The venipuncture site should be inspected frequently for signs of infiltration. If venous thrombosis or phlebitis occurs, discontinue infusions or change infusion site and initiate appropriate treatment. Extraordinary electrolyte losses such as may occur during protracted nasogastric suction, vomiting, diarrhea, or gastrointestinal fistula drainage may necessitate additional electrolyte supplementation. Metabolic acidosis can be prevented or readily controlled by adding a portion of the cations in the electrolyte mixture as acetate salts and in the case of hyperchloremic acidosis, by keeping the total chloride content of the infusate to a minimum. Aminosyn-PF 7% contains no chloride. Aminosyn-PF 7% contains no added phosphorus. Patients, especially those with hypophosphatemia, may require the addition of phosphate. To prevent hypocalcemia, calcium supplementation should always accompany phosphate administration. To assure adequate intake, serum levels should be monitored frequently. Aminosyn-PF 7% contains no more than 25 mcg/L of aluminum. To minimize the risk of possible incompatabilities arising from mixing this solution with other additives that may be prescribed, the final infusate should be inspected for cloudiness or precipitation immediately after mixing, prior to administration, and periodically during administration. SPECIAL PRECAUTIONS FOR CENTRAL INFUSIONS ADMINISTRATION BY CENTRAL VENOUS CATHETER SHOULD BE USED ONLY BY THOSE FAMILIAR WITH THIS TECHNIQUE AND ITS COMPLICATIONS. Central vein infusion (with added concentrated carbohydrate solutions) of amino acid solutions requires a knowledge of nutrition as well as clinical expertise in recognition and treatment of complications. Attention must be given to solution preparation, administration and patient monitoring. IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL, BASED ON CURRENT MEDICAL PRACTICES, BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM. SUMMARY HIGHLIGHTS OF COMPLICATIONS (See also Current Medical Literature). 1.

Technical

The placement of a central venous catheter should be regarded as a surgical procedure. One should be fully acquainted with various techniques of catheter insertion. For details of technique and placement sites, consult the medical literature. X-ray is the best means of verifying catheter placement. Complications known to occur from the placement of central venous catheters are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis and air and catheter emboli. 2.

Septic

The constant risk of sepsis is present during administration of total parenteral nutrition. It is imperative that the preparation of the solution and the placement and care of catheters be accomplished under strict aseptic conditions. Solutions should ideally be prepared in the hospital pharmacy under a laminar flow hood using careful aseptic technique to avoid inadvertent touch contamination. Solutions should be used promptly after mixing. Storage should be under refrigeration and limited to a brief period of time, preferably less than 24 hours. Administration time for a single container and set should never exceed 24 hours. 3.

Metabolic

The following metabolic complications have been reported with TPN administration: Metabolic acidosis and alkalosis, hypophosphatemia, hypocalcemia, osteoporosis, hyperglycemia and glycosuria, rebound hypoglycemia, osmotic diuresis and dehydration, elevated liver enzymes, hypo- and hypervitaminosis, electrolyte imbalances and hyperammonemia in children. Frequent evaluations are necessary especially during the first few days of therapy to prevent or minimize these complications. Administration of glucose at a rate exceeding the patient's utilization rate may lead to hyperglycemia, coma and death. CLINICAL EVALUATION AND LABORATORY DETERMINATIONS, AT THE DISCRETION OF THE ATTENDING PHYSICIAN ARE NECESSARY FOR PROPER MONITORING DURING ADMINISTRATION. Do not withdraw venous blood for blood chemistries through the peripheral infusion site, as interference with estimations of nitrogen-containing substances may occur. Blood studies should include glucose, urea nitrogen, serum electrolytes, ammonia, cholesterol, acid-base balance, serum proteins, kidney and liver function tests, osmolarity and hemogram. White blood count and blood cultures are to be determined if indicated. Urinary osmolality and glucose should be determined as necessary.

Pregnancy

Category C Animal reproduction studies have not been conducted with Aminosyn-PF 7%. It is also not known whether Aminosyn-PF 7% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Aminosyn-PF 7% should be given to a pregnant woman only if clearly needed.

INTERACTIONS Coumarin and coumarin derivatives, including warfarin: Anticoagulant activity may be counteracted; monitor laboratory parameters. ( 7.1 )

7.1 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. Do not administer ceftriaxone 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span>. Deaths have occurred in neonates (28 days of age or younger) who received concomitant intravenous calcium-containing solutions with ceftriaxone resulting from calcium-ceftriaxone precipitates in the lungs and kidneys, even when separate infusion lines were used <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Use in Specific Populations ( 8.4 )]</span>.

7.2 Coumarin and Coumarin Derivatives The soybean oil present in KABIVEN has vitamin K 1 . Vitamin K 1 can reverse the anticoagulant activity of coumarin and coumarin derivatives, including warfarin, which work by blocking recycling of vitamin K 1 . Monitor laboratory parameters for anticoagulant activity in patients who are on both KABIVEN and coumarin or coumarin derivatives.

ACTIVE INGREDIENTS: (in each spray) 7.14% of Cysteinum 10X, L-Alanine 10X, L-Arginine 10X, L-Carnitine 10X, L-Glutamine 10X, L-Histidine 10X, L-Isoleucine 10X, L-Leucine 10X, L-Lysine 10X, L-Methionine 10X, L-Ornithine 10X, L-Proline 10X, L-Serine 10X, L-Tryptophan 10X, L-Tyrosine 10X, L-Valine 10X, Apis Mellifica 200C, Biotin 10X, Epidermis Suis 9C, Galium Aparine 5X, Hamamelis Virginiana 3X, Hepar Suis 6X, Human Growth Hormone 60X, Hypophysis Suis 30C, Natrum Muriaticum 200C, Pantothenic Acid 6X, Phosphoricum Acidum 3X, Riboflavinum 6X, Thuja Occidentalis 200C.

INACTIVE INGREDIENTS: Organic alcohol 20% v/v, Purified water.