Intralipid

ADVERSE REACTIONS The adverse reactions observed can be separated into two classes: Those more frequently encountered are due either to a) contamination of the intravenous catheter and result in sepsis, or to b) vein irritation by concurrently infused hypertonic solutions and may result in thrombophlebitis. These adverse reactions are inseparable from the hyperalimentation procedure with or without Intralipid ® . Less frequent reactions more directly related to Intralipid ® are: a) immediate or early adverse reactions, each of which has been reported to occur in clinical trials, in an incidence of less than 1%: dyspnea, cyanosis, allergic reactions, hyperlipemia, hypercoagulability, nausea, vomiting, headache, flush-ing, increase in temperature, sweating, sleepiness, pain in the chest and back, slight pressure over the eyes, dizziness, and irritation at the site of infusion, and, rarely, thrombocytopenia in neonates; b) delayed adverse reactions such as hepatomegaly, jaundice due to central lobular cholestasis, splenomegaly, thrombocytopenia, leukopenia, transient increases in liver function tests, and overloading syndrome (focal seizures, fever, leukocytosis, hepatomegaly. splenomegaly and shock). The deposition of a brown pigmentation in the reticuloendothelial system, the so-called “intravenous fat pigment,” has been reported in patients infused with Intralipid ® . The causes and significance of this phenomenon are unknown.

CONTRAINDICATIONS The administration of Intralipid ® is contraindicated in patients with disturbances of normal fat metabolism such as pathologic hyperlipemia, lipoid nephrosis or acute pancreatitis if accompanied by hyperlipidemia. INTRALIPID ® 20% PHARMACY BULK PACKAGE IS NOT INTENDED FOR DIRECT INTRAVENOUS ADMINISTRATION. DILUTING INTRALIPID ® 20% TO A 10% CONCENTRATION WITH INTRAVENOUS FLUID SUCH AS NORMAL SALINE OR OTHER DILUENTS DOES NOT PRODUCE A DILLITION THAT IS EQUIVALENT IN COMPOSITION TO INTRALIPID ® 10% I.V. FAT EMULSION, AND SUCH A DILUTION SHOULD NOT BE GIVEN BY DIRECT INTRAVENOUS ADMINISTRATION.

DESCRIPTION Intralipid ® 20% (A 20% I.V. Fat Emulsion) Pharmacy Bulk Package is a sterile, non-pyrogenic fat emulsion intended as a source of calories and essential fatty acids for use in a pharmacy admixture program. It 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 so that the final product pH is 8. pH range is 6 to 8.9. Intralipid ® 20% Pharmacy Bulk Package is not intended for direct infusion. It is a sterile dosage form which contains several single doses for use in the preparation of three-in-one or total nutrient admixtures (TNAs) in a pharmacy admixture program. The soybean oil is a refined natural product consisting of a mixture of neutral triglycerides of predominantly unsaturated fatty acids with the following structure: where are saturated and unsaturated fatty acid residues. The major component fatty acids are linoleic (44-62%), oleic (19-30%), palmitic (7-14%), linolenic (4-11%) and stearic (1.4-5.5%) 1 . These fatty acids have the following chemical and structural formulas: Linoleic acid C 18 H 32 O 2 Oleic acid C 18 H 34 O 2 Palmitic acid C 16 H 32 O 2 Linolenic acid C 18 H 30 O 2 Stearic acid C 18 H 36 O 2 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. R 3 is primarily either the choline or ethanolamine ester of phosphoric acid. Phosphatidylcholine Phosphatidylethanolamine Glycerin is chemically designated C 3 H 8 O 3 and is a clear colorless, hygroscopic syrupy liquid. It has the following structural formula: Intralipid ® 20% (A 20% I.V. Fat Emulsion) has an osmolality of approximately 350 mOsmol/kg water (which represents 260 mOsmol/liter of emulsion) and contains emulsified fat particles of approximately 0.5 micron size. The total caloric value, including fat, phospholipid and glycerin, is 2.0 kcal per mL of Intralipid ® 20%. The phospholipids present contribute 47 milligrams or approximately 1.5 mmol of phosphorus per 100 mL of the emulsion. The primary container is manufactured from Excel ® film, a polypropylene based material comprised of three co-extruded layers. The plastic container is made from multilayered film specifically designed for parenteral drugs. It contains no plasticizers and exhibits virtually no leachables. The solution contact layer is a rubberized copolymer of ethylene and propylene. The container is nontoxic and biologically inert. 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 moisture barrier when necessary. structure r1c r2c r3c structure structure structure structure structure structure structure figure stuct

DOSAGE AND ADMINISTRATION Intralipid ® 20% (A 20% I.V. Fat Emulsion) Pharmacy Bulk Package should be administered only as a part of a three-in-one or total nutrient admixture via peripheral vein or by central venous infusion. Directions For Proper Use of Pharmacy Bulk Package. INTRALIPID ® 20% PHARMACY BULK PACKAGE IS NOT INTENDED FOR DIRECT INFUSION. The container closure may be penetrated only once using a suitable sterile transfer device or dispensing set which allows measured dispensing of the contents. The Pharmacy Bulk Package is to be used only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area). Once the closure is penetrated, the contents should be dispensed as soon as possible; the transfer of contents to suitable TPN admixture containers must be completed within 4 hours of closure penetration. The bag should be stored below 25°C (77°F) after the closure has been entered. Date and time of container entry should be noted in the area designated on the container label. Admixtures made using Intralipid ® 20% should be used promptly. See MIXING GUIDELINES AND LIMITATIONS section for admixture storage recommendations. Adult Patients The initial infusion rate of the nutrient admixture in adults should be 0.1 g fat/minute for the first 15 to 30 minutes of infusion. If no untoward reactions occur (see ADVERSE. REACTIONS section), the infusion rate can be increased to 0.2 g fat/minute. For adults, the admixture should not contain more than 500 mL of Intralipid ® 20% on the first day of therapy. If the patient has no untoward reactions, the dose can be increased on the following day. The daily dosage should not exceed 2.5 g of fat/kg of body weight (12.5 mL of Intralipid ® 20% per kg). Intralipid ® should make up no more than 60% of the total caloric input to the patient. Carbohydrate and a source of amino acids should comprise the remaining caloric input. Pediatric Patients The dosage for premature infants starts at 0.5 g fat/kg body weight/24 hours (2.5 mL Intralipid ® 20%) and may be increased in relation to the infant’s ability to eliminate fat. The maximum dosage recommended by the American Academy of Pediatrics is 3 g fat/kg/24 hours 3 The initial rate of infusion in older pediatric patients should be no more than 0.01 g fat/minute for the first 10 to 15 minutes. If no untoward reactions occur, the rate can be changed to permit infusion of 0.1 g of fat/kg/hour. The daily dosage should not exceed 3 g of fat/kg of body weight 3 Intralipid ® should make up no more than 60% of the total caloric input to the patient. Carbohydrate and a source of amino acids should comprise the remaining caloric input. Essential Fatty Acid Deficiency When Intralipid ® is administered to correct essential fatty acid deficiency, eight to ten percent of the caloric input should be supplied by Intralipid ® in order to provide adequate amounts of linoleic and linolenic acids. When EFAD occurs together with stress, the amount of Intralipid ® needed to correct the deficiency may be increased. Administration See MIXING GUIDELINES AND LIMITATIONS section for information regarding mixing this fat emulsion with other parenteral fluids. INTRALIPID ® 20% (A 20% I.V. FAT EMULSION) PHARMACY BULK PACKAGE IS NOT INTENDED FOR DIRECT INFUSION. It must be infused as part of an admixture into a central or peripheral vein. The flow rate of the admixture should be controlled with an infusion pump. Filters of less than 1.2 micron pore size must not be used with admixtures containing Intralipid ® 20%. Conventional administration sets and TPN pooling bags contain polyvinyl chloride (PVC) components that have DEHP (diethyl hexyl phthalate) as a plasticizer. Fat-containing fluids such as Intralipid ® extract DEHP from these PVC components. Therefore it may be advisable to use a non-DEHP administration set for infusing admixtures which contain Intralipid ® . Do not use any bag in which there appears to be an oiling out on the surface of the emulsion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. whenever solution and container permit. MIXING GUIDELINES AND LIMITATIONS Investigations have been conducted which demonstrate the compatibility of Intralipid ® 20% when properly mixed with either Novamine ® (8.5%, 11.4% or 15%) or 8.5% Travasol ® or 10% Travasol ® Amino Acid Injections without Electrolytes for use in TPN therapy. Because of the potential for life threatening events, caution should be taken to ensure that precipitates have not formed in any parenteral nutrition mixture. Perform all manipulations in a suitable work area, such as a laminar flow hood. Failure to follow the Mixing Guidelines and Limitations below, including recommended storage temperature, storage time. order of mixing, etc., may result in an unstable admixture. The following proper mixing sequence must be followed to minimize pH related problems by ensuring that typically acidic Dextrose Injections are not mixed with lipid emulsions alone: Transfer Dextrose Injection to the TPN (Total Parenteral Nutrition) Admixture Container Transfer Amino Acid Injection Transfer Intralipid ® 20% Note: Amino Acid Injection, (Novamine ® 8.5, 11.4 or 15% or 8.5 Travasol ® 8.5 or 15% without electrolytes), Dextrose Injection and Intralipid ® 20% may be simultaneously transferred to the admixture container using an automatic mixer. Admixing should be accompanied by gentle agitation to avoid localized concentration effects. These admixtures should be used promptly with storage under refrigeration (2-8°C) not to exceed 24 hours and must be completely used within 24 hours after removal from refrigeration. It is essential that the admixture be prepared using strict aseptic techniques as this nutrient mixture is a good growth medium for microorganisms. Additives other than those named above may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives (e.g., vitamins and minerals). Additives must not be added directly to Intralipid ® 20% (A 20% I.V. Fat Emulsion) Pharmacy Bulk Package and in no case should Intralipid ® 20% be added to the TPN container first. Bags should be shaken gently after each addition to minimize localized concentration. Supplemental electrolytes, trace metals or multivitamins may be required in accordance with the prescription of the attending physician. The prime destabilizers of emulsions are excessive acidity (low pH) and inappropriate electrolyte content. Careful consideration should be given to addition of divalent cations (Ca ++ and Mg ++ ) which have been shown to cause emulsion instability. Amino acid solutions exert a buffering effect protecting the emulsion. The admixture should be inspected carefully for “breaking or oiling out” of the emulsion. “Breaking or oiling out” is described as the separation of the emulsion and can be visibly identified by a yellowish streaking or the accumulation of yellowish droplets in the admixed emulsion. The admixture should also be examined for particulates. The admixture must be discarded if any of the above is observed.

INDICATIONS AND USAGE Intralipid ® 20% Pharmacy Bulk Package is indicated for use in a pharmacy admixture program for the preparation of three-inone or total nutrition admixtures (TNAs) to provide a source of calories and essential fatty acids for patients requiring parenteral nutrition for extended periods of time (usually for more than 5 days) and a source of essential fatty acids for prevention of EFAD.

WARNINGS Caution should be exercised in administering of Intralipid ® 20% (A 20% I.V. Fat Emulsion) to patients with severe liver damage, pulmonary disease, anemia or blood coagulation disorders, or when there is danger of fat embolism as occurs in post traumatic fractures of the pelvis and of long bones. WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, 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.

OVERDOSAGE In the event of fat overload during therapy, stop the infusion containing Intralipid ® 20% (A 20% I.V. Fat Emulsion) until visual inspection of the plasma, determination of triglyceride concentrations, or measurement of plasma light-scattering activity by nephelometry indicates the lipid has cleared. Re-evaluate the patient and institute appropriate corrective measures. See WARNINGS and PRECAUTIONS.

CLINICAL PHARMACOLOGY Intralipid ® is metabolized and utilized as a source of energy causing an increase in heat production, decrease in respiratory quotient and increase in oxygen consumption. The infused fat particles are cleared from the blood stream in a manner thought to be comparable to the clearing of chylomicrons. Intralipid ® will prevent the biochemical lesions of essential fatty acid deficiency (EFAD), and correct the clinical manifestations of the EFAD syndrome.

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Intralipid I.V. Fat Emulsion EGG PHOSPHOLIPIDS GLYCERIN SODIUM HYDROXIDE SOYBEAN OIL SOYBEAN OIL

NDA020248

Intralipid

I.V. Fat Emulsion

0338-0519

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE LABEL - PRINCIPAL DISPLAY - Intralipid 1000 mL Bag Label NDC 0338-0519-04 Intralipid ® 20% A 20% I.V. Fat Emulsion 1000 mL Excel ® Container Pharmacy Bulk Package Not for Direct Infusion intralipid

(Rev June 2006) Manufactured for Baxter Healthcare Corporation Clintec Nutrition Division Deerfield, IL 60015 USA Manufactured by Fresenius Kabi, Uppsala, Sweden Intralipid ® is a registered trademark of Fresenius Kabi AB. Novamine ® is a registered trademark of Fresenius Kabi AB. Travasol ® is a registered trademark of Baxter Healthcare Corporation.

REFERENCES Padley FB: “Major Vegetable Fats,” The Lipid Handbook Gunstone FD, Harwood JL, Padley FB, eds.), Chapman and Hall Ltd., Cambridge, UK (1986), pp. 88-9. Levene MI, Wigglesworth JS, Desai R: Pulmonary fat accumulation after Intralipid ® infusion in the preterm infant. Lancet 1980; 2(8199):815-8. American Academy of Pediatrics: Use of intravenous fat emulsion in pediatric patients. Pediatrics 1981; 68:5(Nov) 738-43.

HOW SUPPLIED Intralipid ® 20% is supplied as a sterile emulsion in 1000 mL Pharmacy Bulk Package. 1000 mL NDC 0338-0519-04 Intralipid ® 20% is also available in the following fill sizes (see package insert 335 809). 100 mL: 0338-519-48. 250 mL: 0338-519-02 . 500 mL: 0338-519-03

STORAGE Intralipid ® 20% should not be stored above 25°C (77°F). Do not freeze Intralipid ® 20%. If accidentally frozen, discard the bag.

BOXED WARNING Deaths in preterm infants after infusion of intravenous fat emulsion have been reported in the medical literature. 2 Autopsy findings included intravascular fat accumulation in the lungs. Treatment of premature and low birth weight infants with intravenous fat emulsion must be based upon careful benefit-risk assessment. Strict adherence to the recommended total daily dose is mandatory; hourly infusion rate should be as slow as possible in each case and should not in any case exceed 1 g fat/kg in four hours. Premature and small for gestational age infants have poor clearance of intravenous fat emulsion and increased free fatty acid plasma levels following fat emulsion infusion; therefore, serious consideration must be given to administration of less than the maximum recommended doses in these patients in order to decrease the likelihood of intravenous fat overload. The infant’s ability to eliminate the infused fat from the circulation must be carefully monitored (such as serum triglycerides and/or plasma free fatty acid levels). The lipemia must clear between daily infusions.

PRECAUTIONS When Intralipid ® is administered, the patients capacity to eliminate the infused fat from the circulation must be monitored by use of an appropriate laboratory determination of serum triglycerides. Overdosage must be avoided. During long term intravenous nutrition with Intralipid ® , liver function tests should be performed. If these tests indicate that liver function is impaired, the therapy should be withdrawn. Frequent (some advise daily) platelet counts should be done in neonatal patients receiving parenteral nutrition with Intralipid ® . Drug product contains no more than 25 mcg/L of aluminum. Carcinogenesis, Mutagenesis, Impairment of Fertility. Studies with Intralipid ® have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy Category C: Animal reproduction studies have not been conducted with Intralipid ® . It is also not known whether Intralipid ® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Intralipid ® should be given to a pregnant woman only if clearly needed. Nursing Mothers: Caution should be exercised when Intralipid ® is administered to a nursing woman. Pediatric Use: See DOSAGE AND ADMINISTRATION. AVOID OVERDOSAGE ABSOLUTELY.