Perikabiven

Description for Perikabiven

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 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 (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:

Electrolytes
Sodium Acetate Trihydrate, USP	CH3COONax3H2O
Potassium Chloride, USP	KCl
Sodium Glycerophosphate	C3H5(OH)2PO4Na2xH2O
Magnesium Sulfate Heptahydrate, USP	MgSO4x7H2O
Calcium Chloride Dihydrate, USP	CaCl2x2H2O
Essential Amino Acids
Lysine (added as the hydrochloride salt)	H2N(CH2)4CH(NH2)COOH•HCl
Phenylalanine	CH2CH(NH2)COOH
Leucine	(CH3)2CHCH2CH(NH2)COOH
Valine	(CH3)2CHCH(NH2)COOH
Threonine	CH3CH(OH)CH(NH2)COOH
Methionine	CH3S(CH2)2CH(NH2)COOH
Isoleucine	CH3CH2CH(CH3)CH(NH2)COOH
Tryptophan	CH2CH(NH2)COOH
Nonessential Amino Acids
Alanine	CH3CH(NH2)COOH
Arginine	H2NC(NH)NH(CH2)3CH(NH2)COOH
Glycine	H2NCH2COOH
Proline
Histidine	CH2CH(NH2)COOH
Glutamic Acid	HOOC(CH2)2CH(NH2)COOH
Serine	HOCH2CH(NH2)COOH
Aspartic Acid	HOOCCH2CH(NH2)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:

whereare saturated and unsaturated fatty acid residues. The major component fatty acids are linoleic (48 to 58 %), oleic (17 to 30%), palmitic (9 to13%), 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  C₁₈H₃₀O₂

Stearic acid C₁₈H₃₆O₂

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).

Uses for Perikabiven

PERIKABIVEN^® is indicated as a source of calories, protein, electrolytes and essential fatty acids for adult patients requiring parenteralnutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. PERIKABIVEN^® may be used to prevent essential fattyacid deficiency or treat negative nitrogen balance in adult patients.

Limitations Of Use

PERIKABIVEN^® is not recommended for use in pediatric patients under the age of 2 years, including preterm infants because the fixed contentof the formulation does not meet the nutritional requirements of this age group [see WARNINGS AND PRECAUTIONS and Use In Specific Populations] .

Dosage for Perikabiven

Administration

• PERIKABIVEN^® is for intravenous infusion into a peripheral or central vein [see WARNINGS AND PRECAUTIONS].
• 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 theprimary container before administration of the fluid from the secondary container is completed.
• Ceftriaxone must not be administered simultaneously with calcium-containing intravenous solutions such as PERIKABIVEN^® via a Y-sitedue to precipitation. However, ceftriaxone and PERIKABIVEN^® may be administered sequentially if the infusion lines are thoroughlyflushed between infusions with a compatible fluid [see WARNINGS AND PRECAUTIONS] .
• 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.

Important Preparation Instructions

• 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 Instructions For Use] .
• 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 Instructions For Use]
• For total parenteral nutrition add multivitamins and trace elements via the additive port. Any other additions to the bag should be evaluatedby 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 mixthoroughly after each addition, use aseptic technique and add after the vertical seals have been broken (i.e. bag has been activated) and thethree components are mixed [see Instructions For Use].
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution andcontainer permit. Inspect PERIKABIVEN^® 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 ofyellowish droplets in the mixed emulsion.

    Discard the admixture if any of the above are observed.

• PERIKABIVEN^® should be used immediately after mixing and the introduction of additives. If not used immediately, the storage time andconditions 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.

Instructions For Use

1. INSPECT BAG PRIOR TO ACTIVATION.
   • PERKABIVEN^® is a 3 chambereed bag:
     • One chamber is WHITE.
     • Two chambers are CLEAR
   • Discard bag if:
     • Overpouch is OPENED OR DAMAGED.
     • More than one chamber is WHITE.
     • Solution is YELLOW.
     • Seals are already BROKEN.
2. REMOVE OVERPOUCH

1. Place bag on a clean, flat surface.
2. Tear from OverpouchNOtch, located close to the ports.
3. Tear long sides open to access the inner bag.
4. Discard Overpouch and Oxygen Absorber.

3. ACTIVATE BAG.

1. Place bag on a clean, flat surface with text side up and ports pointing away from you.
2. Roll tightly from top of bag down toward ports.
3. Apply pressure until both Vertical Seals break and entire contents are white. It may take up to 5 seconds of continued pressure to break Vertical Seals.

   NOTE: Both Vertical Seals must be broken from bends to ports. Upper section of Vertical Seals and Horizontal Seal and Horizontal Seal may remain unbroken.

4. After both Vertical Seals are broken, mix contents thoroughly by inveting the bag at least three times to ensure a homogenous mixture.

INSPECT BAG TO CONFIRM ACTIVATION.

• An activated bag has both Vertical Seals broken from bends to ports and entire contents are white.

IDENTIFY CORRECT PORT.

• Additive port is WHITE with arrow pointing towards bag.
• Infusion port is BLUE with arrow pointing away from bag.

6. MAKE ADDITIONS (if prescribed).

WARNING: Ensure additives are compatible.

1. Immediately before injecting additives, break off WHITE Additive Port cap with the arrow pointing toward the bag.
2. Hold base of Additive Port horizontally.
3. Insert needle horizontally through the center of Additive Port's septum and inject additives.
4. Repeat as necessary using aseptic technique.
5. Mix thoroughly after each addition.

NOTE: The membrane of Additive Port is sterile at first use. Use aseptic technique for subsequent additions. The septum can be pierced up to 10 times with the recommended needle size 18 to 23 G11/2 inches (40mm).

7. SPIKE AND HANG BAG.

1. Immediately before insserting the infusion set, break off BLUE infusion Port cap with the arrow pointing away from the bag.
2. Use a non-vented infusion set or close the air-inlet; on a vented set. It is recommended to use 1.2 m in-line filter.
3. Close the roller clamp of the infusion set.
4. Hold the base of infusion Port.
5. Insert spike through infusion Port by rotating your wrist slightly until the spike is inserted.
6. Lift and hold the bag with both hands.
7. Hang the bag by Hole below Handle.

NOTE: The membrane of infusion Port is sterile at first use. Use infusion sets (according to ISO Number 8536-4) with an external spike diameter of 5.5 to 5.7 mm.

FOR SINGLE USE ONLY.

• Discard unused portion.

Dosing Considerations

The dosage of PERIKABIVEN^® should be individualized based on the patient’s clinical condition (ability to adequately metabolize aminoacids, dextrose and lipids), body weight and nutritional/fluid requirements, as well as additional energy given orally/enterally to the patient.

PERIKABIVEN^® is a combination of amino acids, electrolytes, dextrose, and lipids in a fixed volume and concentration. The dosage selectionis based upon fluid requirements which can be used in conjunction with the nutritional requirements to determine final dosage [see Table 1].

PERIKABIVEN^® meets the total nutritional requirements for protein, dextrose and lipids in stable patients, and can be individualized to meetspecific needs with the addition of nutrients. The maximum infusion rate is based upon the dextrose component.

Prior to administration of PERIKABIVEN^® , correct severe fluid, electrolyte and acid-base disorders. Before starting the infusion, obtain serumtriglyceride levels to establish the baseline value.

Recommended Adult Dosage

The recommended dosage of PERIKABIVEN^®

in adults is 27 to 40 mL/kg/day. The recommended daily nutritional requirements for protein,dextrose and lipids compared to the amount of nutrition provided by PERIKABIVEN^® are shown in Table 1.

The maximum daily dosage of PERIKABIVEN^® in adults should not exceed 40 mL/kg/day.

In patients with serum triglyceride concentrations above 400 mg/dL, stop the PERIKABIVEN^® infusion and monitor serum triglyceride levels. Once the triglycerides are <400 mg/dL, restart PERIKABIVEN^® at a lower infusion rate and advance rate in smaller increments towards targetdosage, checking the triglyceride levels prior to each adjustment [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS] .

Table 1: Nutritional Comparison

	Nutrition Provided byPERIKABIVEN® recommended dosage	Recommended Nutritional Requirements1
		StablePatients	Critically Ill Patients*
Fluid mL/kg/day	27 to 40	30 to 40	Minimum needed todeliver adequatemacronutrients
Protein** g/kg/day	0.64 to 0.94	0.8 to1.0	1.5 to 2
Nitrogeng/kg/day	0.1 to 0.15	0.13 to0.16	0.24 to 0.3
Dextrose g/kg/day	1.8 to 2.7	≤10	≤5.8
Lipids g/kg/day	0.95 to 1.4	1	≤1
Total EnergyRequirement kcal/kg/day	18 to 27	20 to 30	25 to 30
* Do not use in patients with conditions that are contraindicated [see CONTRAINDICATIONS ]. ** Protein is provided as amino acids. When infused intravenously amino acids are metabolized and utilized as the building blocks of protein. Treatment with PERIKABIVEN may be continued for as long as is required by the patient’s condition.

Treatment with PERIKABIVEN^® may be continued for as long as is required by the patient’s condition.

Dosing In Renal Impairment

In patients with renal impairment, the dosage of PERIKABIVEN^® should be the recommended adult dosage (see above). Prior toadministration, correct severe fluid or electrolyte imbalances. Closely monitor serum electrolyte levels and adjust the volume ofPERIKABIVEN^® administered as required [see WARNINGS AND PRECAUTIONS].

Renal patients not needing dialysis require 0.6 to 0.8 g of protein/kg/day. Patients on dialysis or continuous renal replacement therapy shouldreceive 1.2 to 1.8 g of protein/kg/day up to a maximum of 2.5 g of protein/kg/day based on nutritional status and estimated protein losses . ThePERIKABIVEN^® dosage can be adjusted based on the treatment for the renal impairment, supplementing protein as indicated.

Additionalprotein may be added to PERIKABIVEN^® bag or infused separately. If required, additional amino acids may be added to the PERIKABIVEN^® bag or infused separately. Compatibility of additions should be evaluated by a pharmacist and questions may be directed to Fresenius KabiUSA, LLC.

Infusion Duration And Rate

The recommended duration of infusion for PERIKABIVEN^® is between 12 and 24 hours, depending on the clinical situation.

The maximum infusion rate of PERIKABIVEN^® is 3.7 mL/kg/hour. This corresponds to 0.09 g/kg/hour of amino acids, 0.25 g/kg/hour ofdextrose (the rate limiting factor) and 0.13 g/kg/hour of lipid.

Dosing Instructions

1. Determine the fluid requirements (27 to 40 mL/kg/day) and the patient’s nutritional requirements (see Table 1) to be delivered, then selectthe corresponding PERIKABIVEN^® bag.
2. Determine the preferred duration of infusion (12 to 24 hours).
3. Ensure that the rate of infusion (PERIKABIVEN^® dosage in mL/kg/day divided by the preferred duration of infusion (hours) does notexceed the maximum infusion rate for the patient (i.e., 3.7 mL/kg/hour). The infusion rate may need to be reduced and duration of infusionincreased in order not to exceed the maximum infusion rate.
4. Once the infusion rate in mL/kg/hour has been selected, calculate the infusion rate (mL/hour) using the patient’s weight.
5. Compare the patient’s nutrient requirements with the amount supplied by PERIKABIVEN^® . Discuss with a pharmacist any additions thatmay be required.

HOW SUPPLIED

Dosage Forms And Strengths

PERIKABIVEN^® is a sterile, hypertonic emulsion in a three chamber container. The individual chambers contain one of the followingrespectively: amino acids and electrolytes, dextrose, or lipid injectable emulsion. Table 2 describes the individual components ofPERIKABIVEN^® .

Table 2: Contents of PERIKABIVEN when mixed

HowSupplied	1,440 mL	1,920 mL	2,400mL
Composition of PERIKABIVEN®
Soybean Oil, USP (g/100 mL)			3.5
Dextrose Anhydrous, USP (g/100 mL)			6.8
Amino Acids, USP (g/100 mL)			2.36
Total Nitrogen (mg/100 mL)			375
Essential amino acids (mg/100 mL)	Lysine, USP (added as the hydrochloride salt)		187
	Phenylalanine, USP		164
	Leucine, USP		164
	Valine, USP		152
	Threonine, USP		116
	Methionine, USP		116
	Isoleucine, USP		116
	Tryptophan, USP		40
Nonessentialamino acids (mg/100 mL)	Alanine, USP		333
	Arginine, USP		235
	Glycine, USP		164
	Proline, USP		141
	Histidine, USP		141
	Glutamic Acid		116
	Serine, USP		94
	Aspartic Acid, USP		71
	Tyrosine, USP		4.8
Electrolytes (mg/100 mL)	Sodium AcetateTrihydrate, USP		170
	Potassium Chloride, USP		124
	SodiumGlycerophosphateAnhydrous		105
	Magnesium SulfateHeptahydrate, USP		68
	Calcium ChlorideDihydrate, USP		20
ElectrolyteProfile1 (mEq/L)	Sodium2		22 (22mmol/L)
	Potassium		17 (17mmol/L)
	Magnesium		5.6 (2.8mmol/L)
	Calcium		2.8 (1.4mmol/L)
	Phosphorous3		N.A. (7.5mmol/L)
	Acetate4		27 (27mmol/L)
	Chloride5		32 (32mmol/L)
	Sulfate6		5.6 (2.8mmol/L)
CalorieContent (kcal/L)	From Dextrose		230
	From Lipid		3507
	From Amino Acids		95
	Total		675
pH8			5.6
Osmolarity (mOsm/L)			750
1. Balanced by ions from amino acids 2. Contributed by sodium glycerophosphate and sodium acetate 3. Contributed by sodium glycerophosphate and phospholipids 4. Derived from sodium acetate and glacial acetic acid (for pH adjustment) 5. Contributed by calcium chloride, lysine hydrochloride, and potassium chloride 6. Derived from magnesium sulfate 7. Total caloric value including lipid, phospholipid and glycerin 8. pH of amino acid with electrolyte solution was adjusted with glacial acetic acid, USP and pH of lipid emulsion was adjusted with sodiumhydroxide, USP

Storage And Handling

PERIKABIVEN^® is a sterile emulsion available in the following 3 sizes:

NDC	Volume
63323-714-24	2,400 mL
63323-714-19	1,920 mL
63323-714-14	1,440 mL

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. If accidentally frozen, discardthe bag. It is recommended that the product be stored at 5°C to 25°C (41°F to 77°F).Do not remove container from overpouch until intended foruse. After breaking the vertical seals, chemical and physical in-use stability of the mixed three chamber bag has been demonstrated for 24 hoursat 25°C (77°F).

The product should be used immediately after the introduction of additives. If not used immediately, the storage time and conditions prior to useshould 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 beinfused within 24 hours. Any mixture remaining must be discarded.

REFERENCES

1. Ayers P. et al. A.S.P.E.N. Parenteral Nutrition Handbook, 2nd ed. 2014 pg. 123.

2. 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

Manufactured by: FRESENIUS KADI, Uppsala, Sweden. Revised: Feb 2022.

Side Effects for Perikabiven

The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information. Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]

• Infections [see WARNINGS AND PRECAUTIONS]
• Fat Overload Syndrome [see WARNINGS AND PRECAUTIONS]
• Refeeding Syndrome [see WARNINGS AND PRECAUTIONS]
• Diabetes/Hyperglycemia [see WARNINGS AND PRECAUTIONS]
• Thrombophlebitis [see WARNINGS AND PRECAUTIONS]
• Hepatobiliary Disorders [see WARNINGS AND PRECAUTIONS]
• Electrolyte Imbalance and Fluid Overload in Renal Impairment [see WARNINGS AND PRECAUTIONS]
• Hypertriglyceridemia [see WARNINGS AND PRECAUTIONS]
• Aluminum Toxicity [see WARNINGS AND PRECAUTIONS]

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot bedirectly 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. Thepooled population exposed to PERIKABIVEN^® was 18 to 87 years old, 48% female, 73% Caucasian. The enrolled patients had variedunderlying 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®

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)
* Terms as reported in clinical studies

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.

Post-Marketing Experience

The following additional adverse reactions have been identified during post-approval use of PERIKABIVEN^® in countries where it isregistered. Because these reactions are reported voluntarily post-approval from a population of uncertain size, it is not always possible toreliably 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: allergic reaction, anaphylaxis
• Infections and infestations: infection
• Vascular disorders: flushed face

Drug Interactions for Perikabiven

Coumarin And Coumarin Derivatives

The soybean oil present in PERIKABIVEN^® has vitamin K₁. Vitamin K₁ can reverse the anticoagulant activity of coumarin and coumarinderivatives, which work by blocking recycling of vitamin K₁. Monitoring for anticoagulant activity is recommended in patients who are on bothPERIKABIVEN^® and coumarin or coumarin derivatives.

Warnings for Perikabiven

Included as part of the "PRECAUTIONS" Section

Precautions for Perikabiven

Death In Preterm Infants

Deaths in preterm infants after infusion of intravenous lipid emulsions have been reported. Autopsy findings included intravascular lipidaccumulation in the lungs.

Preterm and small for gestational age infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levelsfollowing lipid emulsion infusion.

The safe and effective use of PERIKABIVEN^® injection in pediatric patients, including preterm infants, has not been established. PERIKABIVEN^® is not recommended for use in pediatric patients under the age of 2 years including preterm infants.

Hypersensitivity Reactions

Stop infusion immediately and treat patient accordingly if signs or symptoms of a hypersensitivity or allergic reaction develop. Signs orsymptoms may include: tachypnea, dyspnea, hypoxia, bronchospasm, tachycardia, hypotension, cyanosis, vomiting, nausea, headache,sweating, dizziness, altered mentation, flushing, rash, urticaria, erythema, pyrexia and chills.

Infections

Patients who require parenteral nutrition are at high risk of infections due to malnutrition and their underlying disease state. Infection and sepsismay occur as a result of the use of intravenous catheters to administer parenteral nutrition, poor maintenance of catheters, orimmunosuppressive 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 asaseptic 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 andhyperglycemia) and frequent checks of the parenteral access device.

Fat Overload Syndrome

Fat overload syndrome is a rare condition that has been reported with intravenous lipid formulations. A reduced or limited ability to metabolizethe lipid contained in PERIKABIVEN^® accompanied by prolonged plasma clearance may result in a syndrome characterized by a suddendeterioration 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 fatoverload syndrome is unclear. The syndrome is usually reversible when the infusion of the lipid emulsion is stopped. Although it has been mostfrequently observed when the recommended lipid dosage was exceeded, cases have also been described where the lipid formulation wasadministered according to instructions.

Refeeding Syndrome

Refeeding severely undernourished patients with parenteral nutrition may result in the refeeding syndrome, characterized by the intracellularshift 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 thesecomplications.

Diabetes/Hyperglycemia

PERIKABIVEN^® should be used with caution in patients with diabetes mellitus or hyperglycemia. With the administration ofPERIKABIVEN^® , hyperglycemia and hyperosmolar syndrome may result. Administration of dextrose at a rate exceeding the patient'sutilization rate may lead to hyperglycemia, coma and death. Monitor blood glucose levels and treat hyperglycemia to maintain optimum levelswhile infusing PERIKABIVEN^® . Insulin may be administered or adjusted to maintain optimal blood glucose levels during PERIKABIVEN^® administration.

Monitoring/Laboratory Tests

Routine Monitoring

• Frequent clinical evaluation and laboratory determinations are necessary for proper monitoring during administration.
• Monitor fluid status closely in patients with heart failure or pulmonary edema.
• Monitor serum triglycerides, fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, and blood count,including platelet and coagulation parameters, throughout treatment. In situations of severely elevated electrolyte levels stopPERIKABIVEN^® until levels have been corrected.

Essential Fatty Acids

Monitoring patients for signs and symptoms of essential fatty acid deficiency (EFAD) is recommended. Laboratory tests are available todetermine serum fatty acids levels. Reference values should be consulted to help determine adequacy of essential fatty acid status. Increasingessential fatty acid intake (enterally or parenterally) is effective in treating and preventing EFAD.

In PERIKABIVEN^® , the mean composition of linoleic acid (an omega-6 essential fatty acid) is 19 mg/mL (range 17 to 20 mg/mL) and alpha-linolenic acid (an omega-3 essential fatty acid) is 2.3 mg/mL (range 1.8 to 3.8 mg/mL). There are insufficient long-term data to determinewhether PERIKABIVEN^® can supply essential fatty acids in adequate amounts in patients who may have increased requirements.

Thrombophlebitis

PERIKABIVEN^® is indicated for peripheral administration, or may be infused into a central vein. Peripheral catheters should not be used forsolutions with osmolarity of ≥ 900 mOsm/L. The primary complication of peripheral access is venous thrombophlebitis, which manifests aspain, erythema, tenderness or a palpable cord. The catheter should be removed as soon as thrombophlebitis develops.

Precipitation With Ceftriaxone

Precipitation of ceftriaxone-calcium can occur when ceftriaxone is mixed with calcium-containing parenteral nutrition solutions, such asPERIKABIVEN^® in the same intravenous administration line. Ceftriaxone must not be administered simultaneously with PERIKABIVEN^® via a Y-site. However, ceftriaxone and PERIKABIVEN^® may be administered sequentially if the infusion lines are thoroughly flushed betweeninfusions with a compatible fluid [ see DOSAGE AND ADMINISTRATION] .

Hepatobiliary Disorders

Hepatobiliary disorders are known to develop in some patients without preexisting liver disease who receive parenteral nutrition, includingcholecystitis, cholelithiasis, cholestasis, hepatic steatosis, fibrosis and cirrhosis, possibly leading to hepatic failure. The etiology of thesedisorders 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 mayindicate hepatic insufficiency or the presence of an inborn error of amino acid metabolism [see CONTRAINDICATIONS] or hepatic insufficiency.

Monitor liver function parameters and ammonia. Patients developing signs of hepatobiliary disorders should be assessed early by a clinicianknowledgeable in liver diseases in order to identify causative and contributory factors, and possible therapeutic and prophylactic interventions.

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 ofelectrolyte and fluid volume imbalance. PERIKABIVEN^® should be used with caution in patients with renal impairment.PERIKABIVEN^® 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 inrenal disease in order to determine the appropriate PERIKABIVEN^® dosage and other treatment options.

Hypertriglyceridemia

To evaluate the patient’s capacity to eliminate and metabolize the infused lipid emulsion, measure serum triglycerides before the start ofinfusion (baseline value), with each increase in dosage, and regularly throughout treatment.

Reduce dose of PERIKABIVEN^® and monitor serum triglyceride levels in patients with serum triglyceride concentrations above 400 mg/dL toavoid the clinical consequences associated with hypertriglyceridemia. Serum triglyceride levels above 1,000 mg/dL have been associated withan increased risk of pancreatitis.

Impaired lipid metabolism with hypertriglyceridemia may occur in conditions such as inherited lipid disorders, obesity, diabetes mellitus, andmetabolic syndrome. In these cases, increased triglycerides can also be increased by dextrose and/or overfeeding. Monitor overall energy intakeand other sources of lipid and dextrose, as well as drugs that may interfere with lipid and dextrose metabolism.

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 kidneyfunction. Preterm infants are at greater risk because their kidneys are immature, and they require large amounts of calcium and phosphatesolutions that contain aluminum. Patients with impaired kidney function, including preterm infants, who receive parenteral levels of aluminumat greater than 4 to 5 mcg/kg/day, accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading mayoccur at even lower rates of administration of total parenteral nutrition products.

Interference With Laboratory Tests

High levels of lipids in plasma may interfere with some laboratory blood tests such as hemoglobin, triglycerides, bilirubin, LDH, and oxygensaturation, if blood is sampled before lipid has been cleared from the bloodstream. Lipids are normally cleared after a lipid-free interval of 5 to 6hours in most patients.

PERIKABIVEN^® contains Vitamin K₁ which may interfere with anticoagulant activity [see DRUG INTERACTIONS] .

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 oftime, 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 ofPNALD although a causal relationship has not been established. If PERIKABIVEN^® treated patients develop liver test abnormalities considerdiscontinuation or dosage reduction.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

Use In Specific Populations

Pregnancy

Risk Summary

The limited available data on the use of PERIKABIVEN^® in pregnant women are not sufficient to inform a drug-associated risk. However,there are clinical considerations if PERIKABIVEN^® is used in pregnant women [see Clinical Considerations]. Animal reproduction studieshave not been conducted with PERIKABIVEN^® .

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 Considerations

Disease-Associated Maternal and/or Embryofetal Risk

Severe malnutrition in a pregnant woman is associated with preterm delivery, low birth weight, intrauterine growth restriction, congenitalmalformations and perinatal mortality. Parenteral nutrition should be considered if a pregnant woman’s nutritional requirements cannot befulfilled by oral or enteral intake.

Lactation

Risk Summary

There are no data available to assess the presence of PERIKABIVEN^®

and/or its active metabolite(s) in human milk, the effects on the breastfedchild or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’sclinical need for PERIKABIVEN^® , and any potential adverse effects of PERIKABIVEN^® on the breastfed child or from the underlyingmaternal condition.

Pediatric Use

The safety and effectiveness of PERIKABIVEN^® in pediatric patients has not been established. Deaths in preterm infants after infusion ofintravenous lipid emulsion have been reported [see WARNINGS AND PRECAUTIONS] . Patients, particularly preterm infants, are at risk foraluminum toxicity [see WARNINGS AND PRECAUTIONS] .

PERIKABIVEN^® is not recommended for use in pediatric patients under the age of two years, including preterm infants, as the fixed content ofthe 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] .

Newborns – especially those born premature and with low birth weight – are at increased risk of developing hypo – or hyperglycemia andtherefore need close monitoring during treatment with intravenous dextrose solutions to ensure adequate glycemic control in order to avoidpotential 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,necr

Geriatric Use

Clinical studies of PERIKABIVEN^® did not include sufficient numbers of patients aged 65 and over to determine whether they responddifferently from other younger patients. Other reported clinical experience has not identified differences in responses between the elderly andyounger 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.

Hepatic Impairment

In patients with impaired liver function PERIKABIVEN^® should be administered with caution. Frequent clinical evaluation and laboratorytests to monitor liver function such as bilirubin and liver function parameters should be conducted [ see WARNINGS AND PRECAUTIONS] .

Renal Impairment

In patients with impaired renal function, PERIKABIVEN^® should be administered with caution. Frequent clinical evaluation and laboratorytests to monitor renal function such as serum electrolytes (especially phosphate and potassium) and fluid balance should be conducted [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS] .

Overdose Information for Perikabiven

In the event of overdose, fat overload syndrome may result [see WARNINGS AND PRECAUTIONS] . Stop the infusion of PERIKABIVEN^® toallow lipids to clear from serum. The effects are usually reversible after the lipid infusion is stopped. If medically appropriate, furtherintervention may be indicated. The lipid administered and fatty acids produced are not dialyzable.

Contraindications for Perikabiven

The use of PERIKABIVEN^® 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]
• Inborn error of amino acid metabolism
• Cardiopulmonary instability (including pulmonary edema, cardiac insufficiency, myocardial infarction, acidosis and hemodynamicinstability requiring significant vasopressor support)
• Hemophagocytic syndrome

Clinical Pharmacology for Perikabiven

Mechanism Of Action

PERIKABIVEN^® is used as a supplement or as the sole source of nutrition in patients, providing macronutrients (amino acids, dextrose andlipids) 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 tourea 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 importantsubstrate 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 ofgene expression.

Pharmacokinetics

The infused lipid particles provided by PERIKABIVEN^® are expected to be cleared from the blood stream in a manner thought to becomparable to the clearing of chylomicrons. In healthy volunteers, the maximum clearance rate of the triglycerides after fasting overnight hasbeen 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 inpostoperative patients, in sepsis, burns and trauma, while patients with renal impairment and hypertriglyceridemia may show lower utilizationof exogenous lipid emulsions. Due to differences in elimination, patients with these conditions should be closely monitored duringPERIKABIVEN^® administration [see WARNINGS AND PRECAUTIONS] .

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 inPERIKABIVEN^® or reference, inorganic sodium phosphate demonstrated that both compounds resulted in comparable serum inorganicphosphate concentrations after a single intravenous dose. Changes from baseline in the serum levels of sodium, potassium and total calciumwere comparable across the two phosphate sources in this study.

Patient Information for Perikabiven

To ensure the safe and effective use of PERIKABIVEN^® , this information should be discussed with the patient.

Inform Patients Of The Following

• PERIKABIVEN^® is given by infusion through a peripheral or central vein catheter.
• Allergic reactions to PERIKABIVEN^® may occur.
• There is a risk of infection and sepsis associated with formulations administered intravenously.
• PERIKABIVEN^® may cause adverse reactions such as nausea and vomiting, excess fat (lipids) in the blood, high blood sugar, abnormallyincreased 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 druginteractions and side effects.

When Patients Self-Administer PERIKABIVEN^® Injection At Home, Inform Patients Of The Following

• Patients and/or caregiver must be trained in how to inspect, activate and administer PERIKABIVEN^® .
• Follow the PERIKABIVEN^® inspection, activation and administration instructions provided by their home care provider, and PrescribingInformation [see DOSAGE AND ADMINISTRATION].
• Do not deviate from the administration instructions given by the healthcare provider.
• Inspect PERIKABIVEN^® before using for evidence of damage, particulate matter, and/or discoloration.
• 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
• Prior to activation, store PERIKABIVEN^® at 5°C to 25°C (41°F 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 24 hours. Discard any unused portion.
• After activation and prior to administration carefully inspect bag for separation of the lipid emulsion, which can be visibly identified by ayellowish 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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