Perikabiven

• It is used to aid diet needs.

• If you have an allergy to amino acids, dextrose, fat emulsion, or any other part of this medicine.
• If you have an allergy to corn, corn products, eggs, peanuts, or soybeans, talk with your doctor.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: High cholesterol, certain amino acid metabolism problems, heart or lung problems, or a certain health problem called hemophagocytic syndrome.

This is not a list of all drugs or health problems that interact with Perikabiven.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take Perikabiven. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• If you have high blood sugar (diabetes), talk with your doctor. This medicine may raise blood sugar.
• Check your blood sugar as you have been told by your doctor.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take this medicine.
• Do not give to a child younger than 2 years of age.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Perikabiven while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Signs of fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or very bad upset stomach or throwing up.
• Signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
• Fast breathing.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Blue skin or nails.
• Headache.
• Sweating a lot.
• Flushing.
• Any unexplained bruising or bleeding.
• This medicine may irritate the vein. It may burn the skin if the drug leaks from the vein when it is given. Tell your nurse if you have any redness, burning, pain, swelling, or leaking of fluid where the drug is going into your body.

• Most of the time, Perikabiven will be given in a hospital or doctor's office. If stored at home, follow how to store as you were told by the doctor.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Administration

• Perikabiven® is for intravenous infusion into a peripheral or 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 Perikabiven® via a Y-site due to precipitation.  However, ceftriaxone and Perikabiven® 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.

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 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)]
• 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 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 of yellowish 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 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.

Instructions for Use

Dosing Considerations

The dosage of Perikabiven® 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.

Perikabiven® 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].   Perikabiven® 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 Perikabiven®, correct severe fluid, electrolyte and acid-base disorders.  Before starting the infusion, obtain serum triglyceride 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 target dosage, checking the triglyceride levels prior to each adjustment [see Contraindications (4) and Warnings and Precautions (5.12)].

                                                      

                                                     Table 1:  Nutritional Comparison

* 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 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 to administration, correct severe fluid or electrolyte imbalances. Closely monitor serum electrolyte levels and adjust the volume of Perikabiven® 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 Perikabiven® dosage can be adjusted based on the treatment for the renal impairment, supplementing protein as indicated. Additional protein 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 Kabi USA, 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 of dextrose (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 select the 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 not exceed 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 infusion increased 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 that may be required.

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 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 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.

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. 

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 Perikabiven® 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.

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.

Diabetes/Hyperglycemia

Perikabiven® should be used with caution in patients with diabetes mellitus or hyperglycemia. With the administration of Perikabiven®, 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 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 stop Perikabiven® 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 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 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 determine whether 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 for solutions with osmolarity of ≥ 900 mOsm/L. The primary complication of peripheral access is venous thrombophlebitis, which manifests as pain, 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 as Perikabiven® 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 between infusions with a compatible fluid [see Dosage and Administration (2.1)].

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.

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. 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 in renal 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 of infusion (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 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.

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.         

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.

Perikabiven® contains Vitamin K1 which may interfere with anticoagulant activity [see Drug Interactions (7.1)].

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 Perikabiven® treated patients develop liver test abnormalities consider discontinuation or dosage reduction. 

Coumarin and Coumarin Derivatives

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

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 studies have 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, 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.

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 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 Perikabiven®, and any potential adverse effects of Perikabiven® on the breastfed child or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of Perikabiven® 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)].

Perikabiven® 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.

Geriatric Use

Clinical studies of Perikabiven® 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.

Hepatic Impairment

In patients with impaired liver function Perikabiven® 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)].

Renal Impairment

In patients with impaired renal function, Perikabiven® 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)].