NDC 63323-712 Kabiven

Dextrose, Soybean Oil, Electrolytes, Lysine, Phenylalanine, Leucine, Valine, Threonine, Methionine, Isoleucine, Tryptophan, Alanine, Arginine, Glycine, Proline, Histidine, Glutamic Acid, Serine, Aspartic Acid And Tyrosine

NDC Product Code 63323-712

NDC CODE: 63323-712

Proprietary Name: Kabiven What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Dextrose, Soybean Oil, Electrolytes, Lysine, Phenylalanine, Leucine, Valine, Threonine, Methionine, Isoleucine, Tryptophan, Alanine, Arginine, Glycine, Proline, Histidine, Glutamic Acid, Serine, Aspartic Acid And Tyrosine What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

NDC Code Structure

NDC 63323-712-10

Package Description: 1026 mL in 1 BAG

NDC 63323-712-15

Package Description: 1540 mL in 1 BAG

NDC 63323-712-20

Package Description: 2053 mL in 1 BAG

NDC 63323-712-25

Package Description: 2566 mL in 1 BAG

NDC Product Information

Kabiven with NDC 63323-712 is a a human prescription drug product labeled by Fresenius Kabi Usa, Llc. The generic name of Kabiven is dextrose, soybean oil, electrolytes, lysine, phenylalanine, leucine, valine, threonine, methionine, isoleucine, tryptophan, alanine, arginine, glycine, proline, histidine, glutamic acid, serine, aspartic acid and tyrosine. The product's dosage form is injection, emulsion and is administered via intravenous form.

Labeler Name: Fresenius Kabi Usa, Llc

Dosage Form: Injection, Emulsion - An emulsion consisting of a sterile, pyrogen-free preparation intended to be administered parenterally.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Kabiven Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • DEXTROSE MONOHYDRATE 9.8 g/100mL
  • SOYBEAN OIL 3.9 g/100mL
  • SODIUM ACETATE 239 mg/100mL
  • POTASSIUM CHLORIDE 174 mg/100mL
  • SODIUM GLYCEROPHOSPHATE ANHYDROUS 147 mg/100mL
  • MAGNESIUM SULFATE HEPTAHYDRATE 96 mg/100mL
  • CALCIUM CHLORIDE 29 mg/100mL
  • LYSINE HYDROCHLORIDE 263 mg/100mL
  • PHENYLALANINE 231 mg/100mL
  • LEUCINE 231 mg/100mL
  • VALINE 213 mg/100mL
  • THREONINE 164 mg/100mL
  • METHIONINE 164 mg/100mL
  • ISOLEUCINE 164 mg/100mL
  • TRYPTOPHAN 55 mg/100mL
  • ALANINE 467 mg/100mL
  • ARGININE 330 mg/100mL
  • GLYCINE 231 mg/100mL
  • PROLINE 199 mg/100mL
  • HISTIDINE 199 mg/100mL
  • GLUTAMIC ACID 164 mg/100mL
  • SERINE 131 mg/100mL
  • ASPARTIC ACID 99 mg/100mL
  • TYROSINE 6.7 mg/100mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • EGG PHOSPHOLIPIDS (UNII: 1Z74184RGV)
  • GLYCERIN (UNII: PDC6A3C0OX)
  • WATER (UNII: 059QF0KO0R)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)
  • ACETIC ACID (UNII: Q40Q9N063P)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Lipid Emulsion - [EPC] (Established Pharmacologic Class)
  • Lipids - [CS]
  • Osmotic Laxative - [EPC] (Established Pharmacologic Class)
  • Increased Large Intestinal Motility - [PE] (Physiologic Effect)
  • Inhibition Large Intestine Fluid/Electrolyte Absorption - [PE] (Physiologic Effect)
  • Osmotic Activity - [MoA] (Mechanism of Action)
  • Potassium Compounds - [CS]
  • Potassium Salt - [EPC] (Established Pharmacologic Class)
  • Osmotic Laxative - [EPC] (Established Pharmacologic Class)
  • Increased Large Intestinal Motility - [PE] (Physiologic Effect)
  • Inhibition Large Intestine Fluid/Electrolyte Absorption - [PE] (Physiologic Effect)
  • Osmotic Activity - [MoA] (Mechanism of Action)
  • Osmotic Laxative - [EPC] (Established Pharmacologic Class)
  • Increased Large Intestinal Motility - [PE] (Physiologic Effect)
  • Inhibition Large Intestine Fluid/Electrolyte Absorption - [PE] (Physiologic Effect)
  • Osmotic Activity - [MoA] (Mechanism of Action)
  • Calculi Dissolution Agent - [EPC] (Established Pharmacologic Class)
  • Magnesium Ion Exchange Activity - [MoA] (Mechanism of Action)
  • Osmotic Laxative - [EPC] (Established Pharmacologic Class)
  • Osmotic Activity - [MoA] (Mechanism of Action)
  • Inhibition Small Intestine Fluid/Electrolyte Absorption - [PE] (Physiologic Effect)
  • Increased Large Intestinal Motility - [PE] (Physiologic Effect)
  • Stimulation Large Intestine Fluid/Electrolyte Secretion - [PE] (Physiologic Effect)
  • Inhibition Large Intestine Fluid/Electrolyte Absorption - [PE] (Physiologic Effect)
  • Blood Coagulation Factor - [EPC] (Established Pharmacologic Class)
  • Increased Coagulation Factor Activity - [PE] (Physiologic Effect)
  • Calcium - [CS]
  • Cations -
  • Divalent - [CS]
  • Amino Acid - [EPC] (Established Pharmacologic Class)
  • Amino Acids - [CS]

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Fresenius Kabi Usa, Llc
Labeler Code: 63323
FDA Application Number: NDA200656 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 08-25-2014 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Kabiven Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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 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. Limitations 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)].

2.1 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.

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 [see 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 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 (2.3)].Use KABIVEN® 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 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.In the absence of additives, once activated, KABIVEN® remains stable for 48 hours at 25°C (77°F).   If not used immediately, the activated bag can be stored for up to 7 days under refrigeration [2° to 8°C (36º to 46°F)]. After removal from refrigeration, the activated bag should be used within 48 hours.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. 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 (2.3)].Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect KABIVEN® to ensure: 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 a yellowish streaking or the accumulation of yellowish droplets in the mixed emulsion.             Discard the admixture if any of the above are observed.

2.4 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 DosageThe 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 Nutrition Provided  by KABIVEN®  recommended dosage Recommended Nutritional Requirements1  Stable Patients  Critically Ill Patients* Fluid mL/kg/day  19 to 38  30 to 40  Minimum needed to deliver adequate macronutrients  Protein** g/kg/dayNitrogen g/kg/day0.6 to 1.3  0.1 to 0.20.8 to 1.0  0.13 to 0.16 1.5 to 2  0.24 to 0.3 Dextrose g/kg/day 1.9 to 3.7  ≤10  ≤5.8 Lipids g/kg/day  0.7 to 1.5  1  ≤1  Total Energy Requirement kcal/kg/day 16 to 32  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 KABIVEN® may be continued for as long as is required by the patient’s condition.Dosing in Renal ImpairmentIn 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.  Patients on dialysis 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 losses2. 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.Infusion Duration and RateThe 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 InstructionsDetermine 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. Determine the preferred duration of infusion (12 to 24 hours).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.Once the infusion rate in mL/kg/hour has been selected, calculate the infusion rate (mL/hour) using the patient’s weight.Compare the patient’s nutrient requirements with the amount supplied by KABIVEN®. Discuss with a pharmacist any additions that may be required.

3 Dosage Forms And Strengths

  • KABIVEN® is a sterile, hypertonic emulsion in a three chamber container.  The individual chambers contain one of the following respectively: amino acids and electrolytes, dextrose, or lipid injectable emulsion. Table 2 describes the individual components of KABIVEN®. Table 2: Contents of KABIVEN® when mixed How Supplied2,566 mL 2,053 mL1,540 mL1,026 mLComposition of KABIVEN®Soybean Oil, USP (g/100 mL) 3.9 Dextrose Anhydrous, USP (g/100 mL) 9.8 Amino Acids, USP (g/100 mL) 3.31 Total Nitrogen (mg/100 mL) 526  Essential amino acids  (mg/100 mL) Lysine, USP (added as the hydrochloride salt)  263 Phenylalanine, USP 231 Leucine, USP 231 Valine, USP 213 Threonine, USP 164 Methionine, USP 164 Isoleucine, USP 164 Tryptophan, USP 55  Nonessential amino acids  (mg/100 mL) Alanine, USP  467 Arginine, USP 330 Glycine, USP 231 Proline, USP 199 Histidine, USP 199 Glutamic Acid 164 Serine, USP 131 Aspartic Acid, USP 99 Tyrosine, USP 6.7  Electrolytes (mg/100 mL) Sodium Acetate Trihydrate, USP   239 Potassium Chloride, USP 174 Sodium Glycerophosphate Anhydrous 147 Magnesium Sulfate Heptahydrate, USP  96 Calcium Chloride Dihydrate, USP 29  Electrolyte Profile1 (mEq/L) Sodium2  31 (31 mmol/L) Potassium 23  (23 mmol/L) Magnesium 7.8 (3.9 mmol/L) Calcium 3.8 (1.9 mmol/L) Phosphorous3  N.A. (9.7 mmol/L) Acetate4 38  (38 mmol/L) Chloride5 45 (45 mmol/L) Sulfate6 7.8 (3.9 mmol/L)  Calorie Content  (kcal/L)  From Dextrose  330 From Lipid 3907 From Amino Acids 130 Total 850 pH8 5.6 Osmolarity (mOsm/L) 1060 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

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 metabolismCardiopulmonary instability (including pulmonary edema, cardiac insufficiency, myocardial infarction, acidosis and hemodynamic instability requiring significant vasopressor support)Hemophagocytic syndrome

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 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 KABIVEN® 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 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 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 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)]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)]

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®Adverse reaction KABIVEN®N=145 (%)Nausea22 (15)Pyrexia13 (9)Hypertension12 (8)Vomiting8 (6)Hemoglobin decreased8 (6)Protein total decreased6 (4)Hypokalemia6 (4)Blood potassium decreased6 (4)Gamma-glutamyltransferase increased6 (4)Hyperglycemia3 (2)Blood alkaline phosphatase increased2 (1)Blood calcium decreased2 (1)Prothrombin time prolonged2 (1)Pruritus2 (1)Tachycardia2 (1)* Terms as reported in clinical studiesLess 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: cholestasisInfections and infestations: infectionNervous system disorders: subependymal hemorrhage

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 work by blocking recycling of vitamin K1. Monitor laboratory parameters for anticoagulant activity in patients who are on both KABIVEN® and coumarin or coumarin derivatives.

8.1 Pregnancy

Risk SummaryThe limited available data on the use of KABIVEN® in pregnant women are not sufficient to inform a drug-associated risk.  However, there are clinical considerations if KABIVEN® is used in pregnant women [see Clinical Considerations].  Animal reproduction studies have not been conducted with KABIVEN®.  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 2 to 4% and 15 to 20%, respectively.  Clinical ConsiderationsDisease-Associated Maternal and/or Embryofetal RiskSevere malnutrition in a pregnant woman is associated with preterm delivery, low birth weight, intrauterine growth restriction, congenital malformations and perinatal mortality. Parenteral nutrition should be considered if a pregnant woman’s nutritional requirements cannot be fulfilled by oral or enteral intake.

8.2 Lactation

Risk SummaryThere are no data available to assess the presence of KABIVEN® 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 mother’s clinical need for KABIVEN®, and any potential adverse effects of KABIVEN® on the breastfed child or from the underlying maternal condition.

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: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.

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 administered 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 (2.4) and Warnings and Precautions (5.11)].

10 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.

11 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:ElectrolytesSodium Acetate Trihydrate, USPCH3COONax3H2OPotassium Chloride, USPKClSodium Glycerophosphate C3H5(OH)2PO4Na2xH2OMagnesium Sulfate Heptahydrate, USP MgSO4x7H2OCalcium Chloride Dihydrate, USPCaCl2x2H2OEssential Amino AcidsLysine (added as the hydrochloride salt)H2N(CH2)4CH(NH2)COOH.HClPhenylalanine Leucine (CH3)2CHCH2CH(NH2)COOHValine(CH3)2CHCH(NH2)COOHThreonineCH3CH(OH)CH(NH2)COOHMethionineCH3S(CH2)2CH(NH2)COOHIsoleucineCH3CH2CH(CH3)CH(NH2)COOHTryptophan  Nonessential Amino AcidsAlanine CH3CH(NH2)COOHArginine H2NC(NH)NH(CH2)3CH(NH2)COOHGlycineH2NCH2COOHProline Histidine Glutamic AcidHOOC(CH2)2CH(NH2)COOHSerineHOCH2CH(NH2)COOHAspartic AcidHOOCCH2CH(NH2)COOHTyrosine 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 C18H32O2 Oleic acid C18H34O2 Palmitic acid C16H32O2 Linolenic acid C18H30O2Stearic acidC18H36O2                                    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.The container is not made with natural rubber latex or polyvinyl chloride (PVC).KABIVEN® contains no more than 25 mcg/L of aluminum.

12.1 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 a 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 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.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term animal studies have not been conducted to evaluate carcinogenic potential of KABIVEN® or its effect on fertility. Genotoxicity studies have not been conducted with KABIVEN® to assess its mutagenic potential.

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

16 How Supplied/Storage And Handling

KABIVEN® is a sterile emulsion available in the following 4 sizes:NDC                            Volume63323-712-25              2,566 mL63323-712-20              2,053 mL63323-712-15              1,540 mL63323-712-10              1,026 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 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 48 hours at 25°C (77°F).  If not used immediately, the activated bag can be stored for up to 7 days under refrigeration [2° to 8°C (36º to 46°F)]. After removal from refrigeration, the activated bag should be used within 48 hours.  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 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.

17 Patient Counseling Information

  • To ensure the safe and effective use of KABIVEN®, this information should be discussed with the patient.Inform patients of the following:KABIVEN® is given by infusion through a central vein catheter only. Allergic reactions to KABIVEN® may occur. There is a risk of infection and sepsis associated with formulations administered intravenously.KABIVEN® 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 KABIVEN® injection at home, inform patients of the following:Patients and/or caregiver must be trained in how to inspect, activate and administer KABIVEN®.Follow the KABIVEN® 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 KABIVEN® 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 KABIVEN® between 20° to 25°C (68° to 77°F).Activate bag just prior to use or refrigerate activated bag at 2° to 8°C (36° to 46°F) for up to 7 days.  After removal from storage at 2° to 8°C (36° to 46°F), the activated bag should be used within 48 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 a 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.

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