Alternative IV Lipid Emulsions. Michelle Henry, MPH, RD, CNSC Medical Science Liaison, Fresenius Kabi LLC, USA Oley Conference January 2017

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1 Alternative IV Lipid Emulsions Michelle Henry, MPH, RD, CNSC Medical Science Liaison, Fresenius Kabi LLC, USA Oley Conference January 2017

2 Provide brief background on lipids and their function Discuss the evolution of IVLEs Discuss the IVLEs approved in the US and their component oils Introduce a new alternative lipid emulsion available on the US market Copyright Fresenius Kabi AG 2

3 Biological substances that are soluble in organic solvents but insoluble in water Where are they found? Soybeans/Vegetables Walnuts/Peanuts Fish Avocado/Olives Coconuts Eggs, milk, animal meats Copyright Fresenius Kabi AG 3

4 Dense source of energy Provides essential fatty acids 1,2 Important in structural components of cell membranes 1 Carry lipid soluble vitamins Involved in hormone and enzyme production Important in immune and inflammatory responses 1 1. Hise M, Brown JC. The ASPEN Adult Nutrition Support Core Curriculum. 2 nd Edition, Silver Springs, MD: American Society for Parenteral and Enteral Nutrition. 2. Escott-Stump S, Dorner S, Grodner M. Nutritional Foundations and Clinical Applications: A Nursing Approach. 6 th Edition, St Louis, Missouri. Copyright Fresenius Kabi AG 4

(Intracellular) Hydrophobic non-polar tail Phospholipid bilayer 1. Hise M, Brown JC.

5 Triglycerides 1 The most abundant lipids in the body Glycerol Fatty acids: the fundamental building blocks of lipids Phospholipids 1 (Extracellular) Hydrophilic polar head group The components of the lipid bilayer of cell membranes (Intracellular) Hydrophobic non-polar tail Phospholipid bilayer 1. Hise M, Brown JC. The ASPEN Adult Nutrition Support Core Curriculum. 2 nd Edition, Silver Springs, MD: American Society for Parenteral and Enteral Nutrition. Copyright Fresenius Kabi AG 5

6 H 3 C COOH Stearic acid (18:0) 1 double bond = Monounsaturated Fatty Acids (MUFAs) H 3 C Double bond COOH Oleic acid (18:1ω-9) 2 or more double bonds = Polyunsaturated Fatty Acids (PUFAs) Double bonds H 3 C COOH Alpha-Linolenic acid (18:3ω-3) Copyright Fresenius Kabi AG 6

7 METABOLIC PATHWAYS OF ω-3, ω-6, ω-9 FATTY ACIDS PARENT Essential Fatty Acid PARENT Essential Fatty Acid NON-EFA Omega-9 Fatty Acids delta-6-desaturase delta-6-desaturase Oleic Acid (OA) 18:1 ω9 Octadecatetraenoic Acid 18:4 ω3 elongase Gamma-Linolenic Acid 18:3 ω6 elongase Octadecadienoic Acid 18:2 ω9 Eicosatetraenoic Acid 20:4 ω3 delta-5-desaturase Dihomo-Gamma-Linolenic Acid 20:3 ω6 delta-5-desaturase Eicosadienoic Acid 20:2 ω9 Eicosapentaenoic Acid (EPA) 20:5 ω3 elongase Arachidonic Acid (AA) 20:4 ω6 Eicosatrienoic Acid (Mead Acid) 20:3 ω9 Docosapentaenoic Acid 22:5 ω3 24:5 ω3 elongase Docosatetraenoic Acid 22:4 ω6 24:4 ω6 Tetraene Triene delta-6-desaturase 24:6 ω3 24:5 ω6 Beta-oxidation Docosahexaenoic Acid (DHA) 22:6 ω3 Docosapentaenoic Acid 22:5 ω6 Adapted from Le HD, et al. Prostaglandins Leukot Essent Fatty Acids. 2009;81: With permission from Elsevier. Copyright Fresenius Kabi AG 7

8 FATTY ACID 9 kcal/g Fluidity Receptors Ion Channels Enzymes Eicosanoids Prostaglandins Leukotrienes Thromboxanes Protectins Resolvins Lipoxins Cytokines Immune Cell and Other Cell Types (Various Functions) 1. Hise M, Brown JC. The ASPEN Adult Nutrition Support Core Curriculum. 2 nd Edition, Silver Springs, MD: American Society for Parenteral and Copyright Enteral Fresenius Nutrition. Kabi AG 8

acquired in diet 1 Essential for growth, development, and function 2

essential? Alpha-Linolenic Acid 18:3ω-3 Linoleic Acid 18:2ω-6 1.

Prostaglandins Leukot Essent Fatty Acids. 2009;81:165-170. 3.

9 What is an EFA? An EFA cannot be synthesized by the human body and must therefore be acquired in diet 1 Essential for growth, development, and function 2 Utilized primarily in 3 metabolic pathways 3 : Which fatty acids are essential? Alpha-Linolenic Acid 18:3ω-3 Linoleic Acid 18:2ω-6 1. Wanten G, Calder P. Am J Clin Nutr. 2007;85: Le HD, et al. Prostaglandins Leukot Essent Fatty Acids. 2009;81: Hise M, Brown JC. The ASPEN Adult Nutrition Support Core Curriculum. 2 nd Edition, Silver Springs, MD: American Society for Parenteral and Enteral Nutrition. Copyright Fresenius Kabi AG 9

10 Evolution of IVLEs 10

11 Structured triglyceride Cottonseed Oil First IVLE available, quickly removed for significant side effects 2 100% soy emulsion became the first industrially available IVLE for PN 2 MCT/LCT emulsions made of soy and coconut oil AND IVLE 50:50 soy oil and safflower oil 2 80% olive, 20% soy 2 Fish oil parenteral supplement 2 Structured mixture of MCT and LCT 3 Fish oil-containing formulations 2 IVLE=intravenous lipid emulsions; PN=parenteral nutrition; MCT=medium-chain triglyceride; LCT=long-chain triglyceride 1. Helfrick FW, et al. J Pediatr 1944;25: Vanek WV, et al. Nutr in Clin Pract 2012;27: Osborn HT, et al. Compr Rev Food Sci Food Safety 2002;3: Copyright Fresenius Kabi AG 11

12 US Approvals Intralipid (Soybean Oil) Intralipid (Soybean Oil) No longer available. Soybean Oil + Safflower Oil (Liposyn) Soybean Oil / Medium-Chain TG Structured & Physical Mixture Fish Oil (Omegaven) Smoflipid Soybean Oil + Medium-Chain TG + Olive Oil + Fish Oil 1960s 1970s 1980s 1990s 2000s 2010s Pre-1960 Lipomul (Cottonseed Oil) Soybean Oil + Olive Oil Soybean Oil + Medium-Chain TG Soybean Oil + Medium-Chain TG + Fish Oil Soybean oil + MCT + Olive + Fish oil Removed from market due to significant side effects in 1960s Olive oil + soybean oil MCT=medium-chain triglyceride; TG=triglyceride Approved, but not available for purchase. Copyright Fresenius Kabi AG 12

13 IVLEs Available in the US 1 3

Manufacturer IVLE=intravenous lipid emulsion; MCT=medium chain triglyceride *Distributed Intralipid 1,2 Nutrilipid 3 Clinolipid 2,4 Smoflipid 5 Fresenius Kabi/ Baxter* Oil Source Soybean Oil Soybean

14 Manufacturer IVLE=intravenous lipid emulsion; MCT=medium chain triglyceride *Distributed Intralipid 1,2 Nutrilipid 3 Clinolipid 2,4 Smoflipid 5 Fresenius Kabi/ Baxter* Oil Source Soybean Oil Soybean Oil B. Braun Medical Baxter Fresenius Kabi Fat Composition (%, mean values) 1-5 Olive Oil 80% Soybean Oil 20% Soybean Oil 30% MCT 30% Olive Oil 25% Fish Oil 15% Linoleic α-linolenic Eicosapentaenoic (EPA) Docosahexaenoic (DHA) α-tocopherol (mg/l) 38 n/a Intralipid Prescribing Information, Vanek VW, et al. Nutr Clin Pract. 2012;27: Nutrilipid Prescribing Information 2014, B. Braun Medical, Inc. 4. Clinolipid Prescribing Information, Smoflipid Prescribing Information Copyright Fresenius Kabi AG

15 MCT=medium chain triglyceride * Not approved in the US Intralipid1 Nutrilipid1 Clinolipid1 Smofipid2 Omegaven2* 1. Adapted from: Chang MI, et al. Nutrients 2012;4: (Meisel JA, et al. J Ped Surg. 2011;46: ). 2. Fresenius Kabi, Data on File. Copyright Fresenius Kabi AG 15

16 Only available IVLE source in the U.S. from 1970 to 2016 Soybean oil contains an average of: 50% Linoleic Acid (LA) 7% α-linolenic acid (ALA) 1 Prevents EFAD High ω-6 fatty acid content: precursors to pro-inflammatory eicosanoids 2,3 1. Calder PC. Proc Nutr Soc. 2013;72: Waitzberg DL, et al. JPEN J Parenter Enteral Nutr, 2006;30(4): Calder PC. Intensive Care Med; 2010;36(5)375. Copyright Fresenius Kabi AG 16

17 IVLE with MCT available outside the U.S. since the mid-1980s MCT is found in coconut oil and palm kernel oil 1 Good source of energy 1 (8 kcal/g) Provides rapidly available energy 2,3 Efficient triglyceride clearance from bloodstream 2 Have been added to some IVLEs to decrease ω-6 fatty acid 1 Are always mixed with soybean oil for IVLE 1 1. Wanten GJ, Calder PC. Am J Clin Nutr. 2007;85: Bach AC, Bayaban VK. Am J Clin Nutr. 1982:36: Calder PC. Proc Nutr Soc. 2013;72: Copyright Fresenius Kabi AG 17

18 IVLE with OO available outside the U.S. since 1990s 1 Provides MUFA, primarily oleic acid 1 Less prone to peroxidation than PUFA 2,3 Not converted into active mediators of inflammatory processes 4 Provides small amounts of linoleic and α-linolenic acid for EFA 1. Calder PC. Proc Nutr Soc. 2013;72: Wanten GJ. JPEN J Parenter Enteral Nutr. 2015;39 suppl 1:33S-38S. 3. Hise M, Brown JC. Lipids. The ASPEN Adult Nutrition Support Core Curriculum. 2 nd Edition, Waitzberg DL, et al. JPEN J Parenter Enteral Nutr 2006;30: Copyright Fresenius Kabi AG 18

inflammatory eicosanoids and specialized pro-resolving mediators 4 1. Le HD, et al. Prostaglandins Leukot Essent Fatty Acids 2009; 81:165-170.

19 IVLE with FO available outside the U.S. since mid-1990s Very rich in omega-3 fatty acids Provides conditionally essential fatty acids 1-3 EPA and DHA Provides precursors to less inflammatory eicosanoids and specialized pro-resolving mediators 4 1. Le HD, et al. Prostaglandins Leukot Essent Fatty Acids 2009; 81: Kalish BT, et al. JPEN J Parenter Enteral Nutr 2012;36: Bistrian B. JPEN J Parenter Enteral Nutr 2003;27(3) Kremmyda LS, et al. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2011;155: Copyright Fresenius Kabi AG 19

scale to demonstrate relative inflammatory activity Vanek VW, et

20 Safflower Oil Soybean Oil Medium- Chain Triglyceride Oil Olive Oil Fish Oil Note: This is a relative (not absolute) figurative scale to demonstrate relative inflammatory activity Vanek VW, et al. Nutr Clin Pract. 2012;27: Copyright Fresenius Kabi AG 20

21 21

22 Smoflipid is a new lipid IVLE option for adults in the United States IV lipid emulsion product made with four different types of oils: Soy, MCT, Olive and Fish Provides energy and EFAs Safe, well tolerated, and has demonstrated efficacy Copyright Fresenius Kabi AG 22

Soy Oil (ω-6) Source of essential fatty acids Provides energy 30% MCTs

than other fatty acids2 25% Olive Oil (ω-9) Contains small amount of

Source of conditionally essential fatty acids EPA & DHA4 Precursors to

200 mg/l) is an important antioxidant that protects long-chain

Am J Clin Nutr. 1982;36(5):950-962. Vanek VW, et al. Nutr Clin Pract.

J Parenter Enteral Nutr. 2012; 36:380-8. 5.

23 Soy Oil (ω-6) Source of essential fatty acids Provides energy 30% MCTs Source of rapidly available energy1 Clears faster from the bloodstream than other fatty acids2 25% Olive Oil (ω-9) Contains small amount of linoleic acid and α-linolenic acid Immune neutral3 Fish Oil (ω-3) Source of conditionally essential fatty acids EPA & DHA4 Precursors to less inflammatory eicosanoids5 30% 15% α-tocopherol (approx. 200 mg/l) is an important antioxidant that protects long-chain polyunsaturated fats from peroxidation Deckelbaum RJ, et al. Biochemistry (Mosc) 1990;29(5): ; Bach AC, et al. Am J Clin Nutr. 1982;36(5): Vanek VW, et al. Nutr Clin Pract. 2012;27(2): Kalish BT, Fallon EM, Puder M. J Parenter Enteral Nutr. 2012; 36: Kremmyda et al, Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub; Burrin DG, et al. Adv Nutr. 2014;5(1): Copyright Fresenius Kabi AG 7. Biesalski HK. Gastroenterology. 2009;137(5 Suppl):S92-S

24 Intralipid 1,2 Smoflipid 5 Manufacturer Fresenius Kabi/ Baxter* Fresenius Kabi Oil Source Soybean Oil Soybean Oil 30% MCT 30% Olive Oil 25% Fish Oil 15% IVLE=intravenous lipid emulsion; MCT=medium chain triglyceride *Distributed Fat Composition (%, mean values) 1-5 Linoleic α-linolenic Eicosapentaenoic (EPA) Docosahexaenoic (DHA) Arachadonic (ARA) α-tocopherol (mg/l) Intralipid Prescribing Information, Vanek VW, et al. Nutr Clin Pract. 2012;27: Nutrilipid Prescribing Information 2014, B. Braun Medical, Inc. 4. Clinolipid Prescribing Information, Smoflipid Prescribing Information Copyright Fresenius Kabi AG

25 INDICATIONS AND USAGE Smoflipid is indicated in adults as a source of calories and essential fatty acids for parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated Limitations of Use The omega-6:omega-3 fatty acid ratio and Medium Chain Triglycerides in Smoflipid have not been shown to improve clinical outcomes compared to other intravenous lipid emulsions The usual daily dosage is 1 to 2 grams/kg per day and should not exceed 2.5 grams/ kg per day CONTRAINDICATIONS Known hypersensitivity to fish, egg, soybean, or peanut protein, or to any of the active ingredients or excipients Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides > 1,000 mg/dl Copyright Fresenius Kabi AG 25

26 WARNING: DEATH IN PRETERM INFANTS See full prescribing information for complete boxed warning. Deaths in preterm infants have been reported in literature. Autopsy findings included intravascular fat accumulation in the lungs. Preterm and low-birth-weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion INDICATIONS AND USAGE Smoflipid is indicated in adults as a source of calories and essential fatty acids for parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. Limitations of Use The omega-6: omega-3 fatty acid ratio and Medium Chain Triglycerides in Smoflipid have not been shown to improve clinical outcomes compared to other intravenous lipid emulsions DOSAGE AND ADMINISTRATION For intravenous infusion only into a peripheral or central vein. The usual daily dosage in adults is 1 to 2 grams/kg per day and should not exceed 2.5 grams/kg per day Copyright Fresenius Kabi AG 26

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28 Intralipid 1-3 Nutrilipid 4 Clinolipid 1-3 (ClinOleic outside US) Smoflipid 1-3 Omegaven 1-3 Manufacturer Fresenius Kabi/Baxter* Oil Source Soybean Oil Soybean Oil B Braun Baxter Fresenius Kabi Fresenius Kabi Olive Oil 80% Soybean Oil 20% Soybean Oil 30% MCT 30% Olive Oil 25% Fish Oil 15% Fish Oil 100% *Distributed IVLE=intravenous lipid emulsion; MCT=medium-chain triglyceride COMPASSIONATE US USE ONLY 1. Calder PC, et al. Intensive Care Med 2010;36: Vanek VW, et al. Nutr Clin Pract 2012;27: Vanek VW, et al. Nutr Clin Pract 2014;29: Nutrilipid Prescribing Information 2014, B.Braun Copyright Fresenius Kabi AG 28

INTRAVENOUS LIPID EMULSION (ILE) ASSESSING NEW OPTIONS IN PARENTERAL NUTRITION:

INTRAVENOUS LIPID EMULSION (ILE) IN PARENTERAL NUTRITION: ASSESSING NEW OPTIONS Todd Canada, PharmD, BCNSP, BCCCP, FASHP, FTSHP University of Texas MD Anderson Cancer Center Houston, Texas Disclosures