Kabiven

• KABIVEN is for intravenous infusion only into a central vein [see Warnings and Precautions (5.11)].
• 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.
• Do not exceed the recommended maximum infusion rate of 2.6 mL/kg/hour [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)].
• Ceftriaxone must not be administered simultaneously with calcium-containing intravenous solutions such as KABIVEN via a Y-site due to precipitation. However, in patients other than neonates, ceftriaxone and KABIVEN may be administered sequentially if the infusion lines are thoroughly flushed between infusions with a compatible fluid [see Contraindications (4), Warnings and Precautions (5.5)].
• 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.

• Inspect the bag prior to activation. Discard the bag in the following situations:
  • ͦEvidence of damage to the bag
  • ͦMore than one chamber is white
  • ͦSolution is yellow
  • ͦAny 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.

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.

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.

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 KABIVEN infusion and initiate a medical evaluation.

KABIVEN 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 [see Adverse Reactions (6.2)].

KABIVEN is contraindicated in patients with known hypersensitivity to egg, soybean, peanut or any of the active or inactive ingredients in KABIVEN [see Contraindications (4)]. If a hypersensitivity reaction occurs, stop infusion of KABIVEN immediately and initiate appropriate treatment and supportive measures.

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, in patients other than neonates, 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)].

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 [see Contraindications (4), Pediatric Use (8.4)].

Parenteral nutrition, such as KABIVEN, 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 KABIVEN.

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.

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'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 KABIVEN. The syndrome is usually reversible when the infusion including the lipid emulsion is stopped.

Administering PN to severely malnourished patients 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.

Administration of dextrose at a rate exceeding the patient'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 KABIVEN. Insulin may be administered or adjusted to maintain optimal blood glucose levels during KABIVEN administration.

The use of KABIVEN is contraindicated in patients with hypertriglyceridemia with serum triglyceride concentrations >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 KABIVEN. In addition, patients with hypertriglyceridemia may have worsening of their hypertriglyceridemia with administration of KABIVEN. Excessive dextrose administration may further increase such risk.

Evaluate patients' 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 KABIVEN 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.

The infusion of hypertonic nutrient injections into a peripheral vein may result in vein irritation, vein damage, and/or thrombosis. KABIVEN is only approved for administration into a central vein, such as the superior vena cava [see Dosage and Administration (2.1)]. Remove the catheter as soon as possible if thrombophlebitis develops.

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 KABIVEN. In patients with decreased renal function with electrolyte imbalance or fluid overload, the KABIVEN 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 KABIVEN dosage.

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.

Monitor fluid status closely in patients with pulmonary edema or heart failure.

Throughout treatment, monitor serum triglycerides [see Warnings and Precautions (5.13)], fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, blood count (including platelets), and coagulation parameters.

KABIVEN contains Vitamin K that may counteract anticoagulant activity [see Drug Interactions (7)].

The lipids contained in KABIVEN may interfere with some laboratory tests (e.g., hemoglobin, triglycerides, lactate dehydrogenase, bilirubin and oxygen saturation) if blood is sampled before the lipids have cleared from the bloodstream. Conduct these tests at least 6 hours after stopping the infusion.

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.

Less common adverse reactions in ≤1% of patients who received KABIVEN were hyperkalemia, hypertriglyceridemia, headache, dizziness, dysgeusia, rash, eczema, blood glucose increased, and increase in blood triglycerides.

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 KABIVEN.

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 KABIVEN and consider discontinuation or dosage reduction if abnormalities occur.

The following additional adverse reactions have been identified during post-approval use of KABIVEN in countries where it is registered. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure.

• Hepatobiliary disorders: cholestasis
• Infections and infestations: infection
• Nervous system disorders: subependymal hemorrhage
• Immune system disorders: hypersensitivity reactions, including anaphylaxis [see Contraindications (4), Warnings and Precautions (5.4)].

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 [see 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 [see Contraindications (4), Use in Specific Populations (8.4)].

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.

The safety and effectiveness of KABIVEN has not been established in pediatric patients of any age.

In the postmarketing setting, clinical decompensation with rapid infusion of intravenous lipid emulsion in neonates and infants, sometimes fatal has been reported [see Warnings and Precautions (5.1)]. Patients, particularly preterm infants, are at risk for aluminum toxicity [see Warnings and Precautions (5.13)].

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. [see Contraindications (4), Warnings and Precautions (5.5)].

KABIVEN is not recommended for use in pediatric patients under the age of two years, including preterm infants, as the fixed content of the formulation does not meet the nutritional requirements of this age group due to the following reasons:

1. 1.Calcium and dextrose needs are not met and lipids, protein and magnesium exceed requirements.
2. 2.The product does not contain the amino acids cysteine and taurine, considered conditionally essential for neonates and infants.

Patients, including pediatric patients, may be at risk for PNALD [see Warnings and Precautions (5.2)].

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.

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.

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.

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 (5.12, 5.13)].

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.

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.

Parenteral Nutrition-Associated Liver Disease and Other Hepatobiliary Disorders

Inform patients and caregivers that use of parenteral nutrition may result in parenteral nutrition-associated liver disease and/or other hepatobiliary disorders [see Warnings and Precautions (5.2)].

Pulmonary Embolism and Respiratory Distress due to Pulmonary Vascular Precipitates

Inform patients and caregivers that pulmonary vascular precipitates causing pulmonary emboli (including some fatalities) and presenting as respiratory distress have been reported in patients receiving parenteral nutrition. If KABIVEN is infused at home, instruct patients or caregivers to visually inspect the prepared solution, the infusion set, and catheter for precipitates, prior to administration as well as periodically during the administration [see Warnings and Precautions (5.3)].

Hypersensitivity Reactions

Inform patients and caregivers that KABIVEN may cause hypersensitivity reactions, including anaphylaxis. If KABIVEN is infused at home, instruct patients or caregivers to stop the infusion of KABIVEN immediately and seek medical attention if they experience signs or symptoms of a hypersensitivity reaction, such as rapid or weak heartbeat, feeling faint, difficulty in breathing or swallowing, vomiting, nausea, headache, sweating, dizziness, hives, rash, itching, flushing, dizziness, fever, or chills [see Warnings and Precautions (5.4)].

Infections

Inform patients and caregivers that patients who receive KABIVEN are at risk of infection. If KABIVEN is infused at home, instruct patients or caregivers to ensure aseptic techniques are used for the preparation and administration of KABIVEN and to monitor for signs and symptoms of infection [see Warnings and Precautions (5.6)].

Fat Overload Syndrome

Inform patients and caregivers that fat overload syndrome has been reported with the use of intravenous lipid emulsions. If KABIVEN is infused at home, instruct patients or caregivers to stop KABIVEN if signs or symptoms of fat overload syndrome occur [see Warnings and Precautions (5.7)].

Refeeding Syndrome

If the patient is severely malnourished, inform patients and caregivers that administering parenteral nutrition including KABIVEN may result in refeeding syndrome [see Warnings and Precautions (5.8)].

Diabetes and Hyperglycemia

Inform patients and caregivers that administration of dextrose at a rate exceeding the patient's utilization rate may lead to hyperglycemia, hyperosmolar coma, and death [see Warnings and Precautions (5.9).

Hypertriglyceridemia

Inform patients and caregivers about the risks of hypertriglyceridemia with KABIVEN use [see Warnings and Precautions (5.10)].

Electrolyte Imbalance and Fluid Overload in Patients with Decreased Renal Function

For patients with decreased renal function, inform them or their caregivers that the patient may be at increased risk of electrolyte and fluid volume imbalance when KABIVEN is being administered [see Warnings and Precautions (5.12)].

Aluminum Toxicity

Inform patients and caregivers that prolonged PN administration in patients with renal impairment, including preterm neonates, may result in aluminum reaching toxic levels associated with central nervous system and bone toxicity [see Warnings and Precautions (5.13)].

Preparation and Administration Instructions

If it is acceptable for a patient or caregiver to administer KABIVEN at home, then the patient or caregiver must be trained on the following: how to inspect and prepare, add compatible additives (when appropriate), administer, and store KABIVEN [see Dosage and Administration (2.1, 2.2, 2.3)]. Inform patients or caregivers not to deviate from the administration instructions given by the healthcare provider.

Manufactured by:

Uppsala, Sweden

Fresenius Kabi, Kabiven and Intralipid are registered trademarks of Fresenius Kabi. U.S. Patents 12213943 and 12390398.

www.freseniuskabinutrition.com/products/kabiven-perikabiven

451206G