PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - PERIKABIVEN**®**1920 mL Bag Shipper Label

NDC 63323-714-19

PERIKABIVEN**®**** 4 x 1920 mL**

Amino Acids, Electrolytes, Dextrose, and Lipid Injectable Emulsion, for intravenous use

(2.4%, 0.5%*, 7.5% and 3.5%),

No sulfites added PERIPHERAL INFUSION

Rx only

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CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

PERIKABIVEN 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 PERIKABIVEN 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 ± 1.5g/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 PERIKABIVEN administration [see Warnings and Precautions (5.10, 5.12)].

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 PERIKABIVEN 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.

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DOSAGE FORMS & STRENGTHS SECTION

Highlight: * PERIKABIVEN 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. (3)

• PERIKABIVEN is available in two sizes 1,920 mL and 1,440 mL. (3)

3 DOSAGE FORMS AND STRENGTHS

PERIKABIVEN 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 PERIKABIVEN.

Table 2: Contents of PERIKABIVEN when mixed

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WARNINGS AND PRECAUTIONS SECTION

Highlight: * Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsion in Neonates and Infants: Acute respiratory distress, metabolic acidosis, and death after rapid infusion of intravenous lipid emulsions have been reported. (5.1)

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

5 WARNINGS AND PRECAUTIONS

5.1 Clinical Decompensation with Rapid Infusion of Intravenous Lipid

Emulsion in Neonates and Infants

In the postmarketing setting, serious adverse reactions including acute respiratory distress, metabolic acidosis, and death have been reported in neonates and infants after rapid infusion of intravenous lipid emulsions. Hypertriglyceridemia was commonly reported.

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

5.2 Parenteral Nutrition-Associated Liver Disease and Other Hepatobiliary

Disorders

Risk of Parenteral Nutrition-Associated Liver Disease

Parenteral nutrition-associated liver disease (PNALD), also referred to as intestinal failure-associated liver disease (IFALD), can present as cholestasis or hepatic steatosis, and may progress to steatohepatitis with fibrosis and cirrhosis (possibly leading to chronic hepatic failure). The etiology of PNALD is multifactorial; however, intravenously administered phytosterols (plant sterols) contained in plant-derived lipid emulsions, such as Intralipid (included in PERIKABIVEN), have been associated with development of PNALD.

In a randomized study of neonates and infants expected to be treated with PN for at least 28 days, parenteral nutrition-associated cholestasis (PNAC), a precursor to PNALD, developed more frequently in Intralipid-treated patients than in patients treated with a 4-oil mixed lipid emulsion [see Adverse Reactions (6.1), Use in Specific Populations (8.4)].

Monitor liver tests in patients treated with PERIKABIVEN and consider discontinuation or dosage reduction if abnormalities occur.

Other Hepatobiliary Disorders

Hepatobiliary disorders including cholecystitis and cholelithiasis have developed in some PN-treated patients without preexisting liver disease.

Monitor liver tests when administering PERIKABIVEN. Patients developing signs of hepatobiliary disorders should be assessed early to determine whether these conditions are related to PERIKABIVEN use.

5.3 Pulmonary Embolism and Respiratory Distress due to Pulmonary Vascular

Precipitates

Pulmonary vascular precipitates causing pulmonary emboli (including some fatalities) and respiratory distress have been reported in patients receiving parenteral nutrition.

Excessive addition of calcium and phosphate increases the risk of the formation of calcium phosphate precipitates; however, precipitates have been reported even in the absence of phosphate salt in the solution. Precipitation following passage through an in-line filter and suspected in vivo precipitate formation has also been reported.

Visually inspect the prepared solution, the infusion set, and catheter for precipitates, prior to administration as well as periodically during the administration. If signs of respiratory distress or pulmonary embolism occur, stop the PERIKABIVEN infusion and initiate a medical evaluation.

5.4 Hypersensitivity Reactions

PERIKABIVEN contains soybean oil, which may cause hypersensitivity reactions. Cross reactions have been observed between soybean and peanut. PERIKABIVEN is contraindicated in patients with known hypersensitivity to egg, soybean, peanut or any of the active or inactive ingredients in PERIKABIVEN. If a hypersensitivity reaction occurs, stop infusion of PERIKABIVEN immediately and initiate appropriate treatment and supportive measures.

5.5 Precipitation with Ceftriaxone

Precipitation of ceftriaxone-calcium can occur when ceftriaxone is mixed with calcium-containing parenteral nutrition solutions, such as PERIKABIVEN in the same intravenous administration line. Do not administer ceftriaxone simultaneously with PERIKABIVEN via a Y-site.

However, in patients other than neonates, ceftriaxone and PERIKABIVEN may be administered sequentially if the infusion lines are thoroughly flushed between infusions with a compatible fluid [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)].

5.6 Infections

Parenteral nutrition, such as PERIKABIVEN, can support microbial growth and is an independent risk factor for the development of catheter-related bloodstream infections. To decrease the risk of infectious complications, ensure aseptic techniques are used for catheter placement, catheter maintenance, and preparation and administration of PERIKABIVEN.

Monitor for signs and symptoms of infection including fever and chills, as well as laboratory test results that might indicate infection (including leukocytosis and hyperglycemia). Perform frequent checks of the intravenous catheter insertion site for edema, redness, and discharge.

5.7 Fat Overload Syndrome

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

If signs or symptoms of fat overload syndrome occur, stop PERIKABIVEN. The syndrome is usually reversible when the infusion including the lipid emulsion is stopped.

5.8 Refeeding Syndrome

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

5.9 Diabetes and Hyperglycemia

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

5.10 Hypertriglyceridemia

The use of PERIKABIVEN is contraindicated in patients with hypertriglyceridemia with serum triglyceride concentrations >1,000 mg/dL.

Patients with conditions such as inherited lipid disorders, obesity, diabetes mellitus, or metabolic syndromes have a higher risk of developing hypertriglyceridemia with the use of PERIKABIVEN. In addition, patients with hypertriglyceridemia may have worsening of their hypertriglyceridemia with administration of PERIKABIVEN. Excessive dextrose administration may further increase such risk.

Evaluate patients' capacity to eliminate and metabolize the infused lipid emulsion by measuring serum triglycerides before the start of infusion (baseline value), with each increase in dosage, and regularly throughout treatment. If triglyceride levels are above 400 mg/dL in adults, stop the PERIKABIVEN infusion and monitor serum triglyceride levels to avoid clinical consequences of hypertriglyceridemia such as pancreatitis.

To minimize the risk of new or worsening of hypertriglyceridemia, assess high- risk patients for their overall energy intake including other sources of lipid and dextrose, as well as concomitant drugs that may affect lipid and dextrose metabolism.

5.11 Vein Damage and Thrombosis

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

5.12 Electrolyte Imbalance and Fluid Overload in Patients with Decreased

Renal Function

Patients with decreased renal function, including those with pre-renal azotemia, renal obstruction, or intrinsic renal disease, may be at increased risk of electrolyte and fluid volume imbalance when receiving PN, including PERIKABIVEN. In patients with decreased renal function with electrolyte imbalance or fluid overload, the PERIKABIVEN should be used with caution in patients with renal impairment. PERIKABIVEN dosage (e.g., fluid, protein, and electrolyte content) may require adjustment.

Monitor renal function parameters. Patients developing signs of decreased renal function should be assessed early by a clinician knowledgeable in renal disease in order to determine the appropriate PERIKABIVEN dosage and other treatment options.

5.13 Aluminum Toxicity

PERIKABIVEN contains no more than 25 mcg/L of aluminum.

The aluminum contained in PERIKABIVEN may reach toxic levels with prolonged parenteral administration in patients with impaired kidney function. Preterm infants are at greater risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions that contain aluminum. Patients with impaired kidney function, including preterm infants, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day, accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration of total parenteral nutrition products.

5.14 Monitoring/Laboratory Tests

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

Throughout treatment, monitor serum triglycerides [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.

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

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

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ADVERSE REACTIONS SECTION

Highlight: The most common adverse reactions (≥3%) are hyperglycemia, hypokalemia, pyrexia, and increased blood triglycerides. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or

www.fda.gov/medwatch.

6 ADVERSE REACTIONS

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

• Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsion in Neonates and Infants [see Warnings and Precautions (5.1)].
• Parenteral Nutrition-Associated Liver Disease and Other Hepatobiliary Disorders [see Warnings and Precautions (5.2)].
• Pulmonary Embolism and Respiratory Distress due to Pulmonary Vascular Precipitates [see Warnings and Precautions (5.3)].
• Hypersensitivity Reactions [see Warnings and Precautions (5.4)].
• Precipitation with Ceftriaxone [see Warnings and Precautions (5.5)].
• Infections [see Warnings and Precautions (5.6)].
• Fat Overload Syndrome [see Warnings and Precautions (5.7)].
• Refeeding Syndrome [see Warnings and Precautions (5.8)].
• Diabetes and Hyperglycemia [see Warnings and Precautions (5.9)].
• Hypertriglyceridemia [see Warnings and Precautions (5.10)].
• Vein Damage and Thrombosis [see Warnings and Precautions (5.11)].
• Electrolyte Imbalance and Fluid Overload in Patients with Decreased Renal Function [see Warnings and Precautions (5.12)].
• Aluminum Toxicity [see Warnings and Precautions (5.13)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The clinical data described for PERIKABIVEN reflects exposure in 93 patients exposed for 5 to 7 days in 4 active-controlled trials. The pooled population exposed to PERIKABIVEN was 18 to 87 years old, 48% female, 73% Caucasian. The enrolled patients had varied underlying conditions such as gastrointestinal disorders (55%), vascular disorders (30%), metabolism and nutrition disorders (28%), respiratory, thoracic, and mediastinal disorders (22%), and psychiatric disorders (20%). Most patients received peripheral intravenous infusion doses of ≥80% of their target mean daily exposure.

Adverse reactions occurring in at least 2% of patients who received PERIKABIVEN are shown in Table 3.

Table 3: Adverse Reactions in >2% of Patients Treated with PERIKABIVEN

Less common adverse reactions in ≤1% of patients who received PERIKABIVEN were hyperkalemia, hypomagnesaemia, hypernatremia, tachycardia, hypertension, thrombophlebitis, vomiting, jaundice, rash and increased blood bilirubin.

In a randomized active-controlled, double-blind, parallel-group, multi-center study that included 152 neonates and 9 patients ranging in age from 29 to 153 days who were expected to require PN for at least 28 days, parenteral nutrition-associated cholestasis (PNAC), a precursor to PNALD, developed more frequently in Intralipid-treated patients than in patients treated with a 4-oil mixed lipid emulsion. Intralipid is the lipid emulsion component of PERIKABIVEN.

PNAC (defined as direct bilirubin >2mg/dl with a second confirmed elevation

2mg/dl at least 7 days later) occurred in 11.5% (9/78) of Intralipid-treated patients and 2.4% (2/83) of patients treated with a 4-oil mixed lipid emulsion. Most PNAC events occurred in patients who were treated for longer than 28 days.

The estimated cumulative incidence of PNAC is shown in the Kaplan-Meier cumulative incidence curve in Figure 1.

Figure 1: Cumulative Incidence Curve of Time to Parenteral Nutrition- Associated Cholestasis (PNAC) with Standard Error Bars

Monitor liver tests in patients treated with PERIKABIVEN and consider discontinuation or dosage reduction if abnormalities occur.

6.2 Postmarketing Experience

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

• Gastrointestinal disorders: abdominal distension, abdominal pain
• General disorders and administration site conditions: chest tightness
• Hepatobiliary disorders: cholestasis
• Immune system disorders: allergic reaction, anaphylaxis
• Infections and infestations: infection
• Vascular disorders: flushed face

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NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

PERIKABIVEN is a sterile emulsion available in the following 2 sizes:

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. If accidentally frozen, discard the bag. It is recommended that the product be stored at 5°C to 25°C (41°F to 77°F).

Do not remove container from overpouch until intended for use.

After breaking the vertical seals, chemical and physical in-use stability of the mixed three chamber bag has been demonstrated for 24 hours at 25°C (77°F).

The product should be used immediately after 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.

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