<<

Alternative IV

Michelle Henry, MPH, RD, CNSC Medical Science Liaison, Fresenius Kabi LLC, USA Oley Conference January 2017 • Provide brief background on and their function

• Discuss the evolution of IVLEs

• Discuss the IVLEs approved in the US and their component oils

• Introduce a new alternative lipid available on the US market

© Copyright Fresenius Kabi AG 2 • Biological substances that are soluble in organic but insoluble in

Where are they found? • /Vegetables • Walnuts/Peanuts • Fish • Avocado/ • Coconuts • Eggs, milk, animal meats

© Copyright Fresenius Kabi AG 3 • Dense source of energy • Provides essential fatty acids1,2

• Important in structural components of cell membranes1 • Carry lipid soluble vitamins

• Involved in hormone and enzyme production

• Important in immune and inflammatory responses1

1. Hise M, Brown JC. The ASPEN Adult Nutrition Support Core Curriculum. 2nd Edition, 2012. 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. 6th Edition, 2012. St Louis, Missouri. © Copyright Fresenius Kabi AG 4 Triglycerides1 • The most abundant lipids in the body • Fatty acids: the fundamental building blocks of lipids (Extracellular) Hydrophilic 1 polar head group Hydrophobic non-polar tail bilayer • The components of the lipid bilayer of cell membranes (Intracellular)

1. Hise M, Brown JC. The ASPEN Adult Nutrition Support Core Curriculum. 2nd Edition, 2012. Silver Springs, MD: American Society for Parenteral and Enteral Nutrition. © Copyright Fresenius Kabi AG 5 H3C (18:0) COOH

1 double bond = Monounsaturated Fatty Acids (MUFAs)

Double bond Oleic acid (18:1ω-9) H3C COOH

2 or more double bonds = Polyunsaturated Fatty Acids (PUFAs)

Double bonds

H3C COOH Alpha-Linolenic acid (18:3ω-3)

© Copyright Fresenius Kabi AG 6 METABOLIC PATHWAYS OF �-3, �-6, �-9 FATTY ACIDS

PARENT Essential PARENT NON-EFA

Omega-9 Fatty Acids

Oleic Acid (OA) 18:1 ω9 delta-6-desaturase delta-6-desaturase

Octadecatetraenoic Acid Gamma-Linolenic Acid Octadecadienoic Acid 18:4 ω3 18:3 ω6 18:2 ω9 elongase elongase

Eicosatetraenoic Acid Dihomo-Gamma-Linolenic Eicosadienoic Acid 20:4 ω3 Acid 20:3 ω6 20:2 ω9 delta-5-desaturase delta-5-desaturase

Eicosapentaenoic Acid (EPA) Arachidonic Acid (AA) Eicosatrienoic Acid 20:5 ω3 20:4 ω6 (Mead Acid) elongase 20:3 ω9

Docosapentaenoic Acid Docosatetraenoic Acid 22:5 ω3 22:4 ω6 elongase Tetraene Triene 24:5 ω3 24:4 ω6 delta-6-desaturase

24:6 ω3 24:5 ω6 Beta-oxidation

Docosahexaenoic Acid (DHA) Docosapentaenoic Acid 22:6 ω3 22:5 ω6

Adapted from Le HD, et al. Prostaglandins Leukot Essent Fatty Acids. 2009;81:165-170. With permission from Elsevier. © Copyright Fresenius Kabi AG 7 FATTY ACID

9 kcal/g

Fluidity Enzymes Receptors Ion Channels • Prostaglandins Cytokines • Leukotrienes • Thromboxanes Immune Cell and • Protectins Other Cell Types • Resolvins (Various Functions) • Lipoxins

1. Hise M, Brown JC. The ASPEN Adult Nutrition Support Core Curriculum. 2nd Edition, 2012. Silver Springs, MD: American Society for Parenteral© andCopyright Enteral Fresenius Nutrition. Kabi AG 8 What is an EFA? • An EFA cannot be synthesized by the human body and must therefore be acquired in diet1 • Essential for growth, development, and function2 • Utilized primarily in 3 metabolic pathways3:

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;85:1171-1184. 2. Le HD, et al. Prostaglandins Leukot Essent Fatty Acids. 2009;81:165-170. 3. Hise M, Brown JC. The ASPEN Adult Nutrition Support Core Curriculum. 2nd Edition, 2012. Silver Springs, MD: American Society for Parenteral and Enteral Nutrition. © Copyright Fresenius Kabi AG 9 Evolution of IVLEs

10 Structured

1960 1961 1984 1996 1998 2000 2005

Cottonseed Oil 100% soy MCT/LCT 80% , parenteral Structured Fish oil-containing First IVLE emulsion became emulsions 20% soy2 supplement 2 mixture formulations 2 available, quickly the first made of of MCT removed for industrially soy and and LCT3 significant side available effects2 IVLE for PN2 AND IVLE 50:50 soy oil and oil2

IVLE=intravenous lipid emulsions; PN=; MCT=medium-chain triglyceride; LCT=long-chain triglyceride

1. Helfrick FW, et al. J Pediatr 1944;25:400–3. 2. Vanek WV, et al. Nutr in Clin Pract 2012;27:150–92. 3. Osborn HT, et al. Compr Rev Sci Food Safety 2002;3:110–20.

© Copyright Fresenius Kabi AG 11 US Approvals

Soybean Oil / Smoflipid® Medium-Chain TG Oil + No longer Structured & Medium-Chain TG available. Physical Mixture + + Fish Oil + Intralipid Intralipid Safflower Oil Fish Oil (Soybean Oil) (Soybean Oil) (Liposyn) (Omegaven)

1960s 1970s 1980s 1990s 2000s 2010s

Soybean Oil + Soybean Oil Medium-Chain Soybean oil + Olive Oil TG + MCT + Pre-1960 + Fish Oil Olive + Fish oil Lipomul Soybean Oil + () Medium-Chain TG

Removed from market due to significant Olive oil + side effects in 1960s soybean oil

Approved, but not MCT=medium-chain triglyceride; TG=triglyceride available for

© Copyright Freseniuspurchase. Kabi AG 12 IVLEs Available in the US

1 3 Intralipid1,2 Nutrilipid3 Clinolipid2,4 Smoflipid5 Fresenius Kabi/ Manufacturer B. Braun Medical Baxter Fresenius Kabi Baxter* Soybean Oil 30% Olive Oil 80% MCT 30% Oil Source Soybean Oil Soybean Oil Soybean Oil 20% Olive Oil 25% Fish Oil 15% Composition (%, mean values)1-5 Linoleic 53 53 17.9 19.5 α-Linolenic 7.5 7.5 2.4 2.5 Eicosapentaenoic (EPA) 0 0 0 2.3 Docosahexaenoic (DHA) 0 0 0 2.3 α-Tocopherol (mg/L) 38 n/a 32 163-225

IVLE=intravenous ; MCT=medium chain triglyceride

*Distributed

1. Intralipid Prescribing Information, 2015. 2. Vanek VW, et al. Nutr Clin Pract. 2012;27:150-192. 3. Nutrilipid Prescribing Information 2014, B. Braun Medical, Inc. 4. Clinolipid Prescribing Information, 2013. 5. Smoflipid Prescribing Information 2016. © Copyright Fresenius Kabi AG Intralipid1 Nutrilipid1 Clinolipid1 Smofipid2 Omegaven2*

MCT=medium chain triglyceride

* Not approved in the US

1. Adapted from: Chang MI, et al. Nutrients 2012;4:1828-1850. (Meisel JA, et al. J Ped Surg. 2011;46:666-673). 2. Fresenius Kabi, Data on File. © Copyright Fresenius Kabi AG 15 • 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 eicosanoids2,3

1. Calder PC. Proc Nutr Soc. 2013;72:263-276. 2. Waitzberg DL, et al. JPEN J Parenter Enteral Nutr, 2006;30(4):351 3. Calder PC. Intensive Care Med; 2010;36(5)375. © Copyright Fresenius Kabi AG 16 • IVLE with MCT available outside the U.S. since the mid-1980s • MCT is found in coconut oil and palm kernel oil1 • Good source of energy1 (8 kcal/g) – Provides rapidly available energy2,3

• Efficient triglyceride clearance from bloodstream2

• Have been added to some IVLEs to decrease ω-6 fatty acid1 – Are always mixed with soybean oil for IVLE1

1. Wanten GJ, Calder PC. Am J Clin Nutr. 2007;85:1171-1184. 2. Bach AC, Bayaban VK. Am J Clin Nutr. 1982:36:950-962. 3. Calder PC. Proc Nutr Soc. 2013;72:263-276. © Copyright Fresenius Kabi AG 17 • IVLE with OO available outside the U.S. since 1990s1 • Provides MUFA, primarily oleic acid1

• Less prone to peroxidation than PUFA2,3

• Not converted into active mediators of inflammatory processes4 • Provides small amounts of linoleic and α-linolenic acid for EFA

1. Calder PC. Proc Nutr Soc. 2013;72:263-276. 2. 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. 2nd Edition, 2012. 4. Waitzberg DL, et al. JPEN J Parenter Enteral Nutr 2006;30:351-367. © Copyright Fresenius Kabi AG 18 • IVLE with FO available outside the U.S. since mid-1990s • Very rich in omega-3 fatty acids

• Provides “conditionally essential” fatty acids1-3 – EPA and DHA

• Provides precursors to less inflammatory eicosanoids and specialized pro-resolving mediators4

1. Le HD, et al. Prostaglandins Leukot Essent Fatty Acids 2009; 81:165-170. 2. Kalish BT, et al. JPEN J Parenter Enteral Nutr 2012;36:380-388. 3. Bistrian B. JPEN J Parenter Enteral Nutr 2003;27(3)168-175. 4. Kremmyda LS, et al. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2011;155:195-218.

© Copyright Fresenius Kabi AG 19 Medium- Safflower Soybean Chain Olive Fish Oil Oil Triglyceride Oil Oil Oil

Note: This is a relative (not absolute) figurative scale to demonstrate relative inflammatory activity Vanek VW, et al. Nutr Clin Pract. 2012;27:150-192. © Copyright Fresenius Kabi AG 20 21 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 • Source of essential fatty acids 30% (ω-6) • Provides energy

• Source of rapidly available energy1 30% MCTs • Clears faster from the bloodstream than other fatty acids2

Olive Oil • Contains small amount of linoleic acid 25% and α-linolenic acid (ω-9) • Immune neutral3

• Source of conditionally essential fatty acids Fish Oil 4 15% EPA & DHA (ω-3) • Precursors to less inflammatory eicosanoids5

α-tocopherol (approx. 200 mg/L) is an important antioxidant that protects long-chain polyunsaturated from peroxidation6.7

1. Deckelbaum RJ, et al. (Mosc) 1990;29(5):1136-1142; 5. Kremmyda et al, Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub; 2011. 2. Bach AC, et al. Am J Clin Nutr. 1982;36(5):950-962. 6. Burrin DG, et al. Adv Nutr. 2014;5(1):82-91. © Copyright Fresenius Kabi AG 23 3. Vanek VW, et al. Nutr Clin Pract. 2012;27(2):150-192. 7. Biesalski HK. Gastroenterology. 2009;137(5 Suppl):S92-S104. 4. Kalish BT, Fallon EM, Puder M. J Parenter Enteral Nutr. 2012; 36:380-8. Intralipid1,2 Smoflipid5 Manufacturer Fresenius Kabi/ Baxter* Fresenius Kabi Soybean Oil 30% MCT 30% Oil Source Soybean Oil Olive Oil 25% Fish Oil 15% Fat Composition (%, mean values)1-5 Linoleic 53 19.5 α-Linolenic 7.5 2.5 Eicosapentaenoic (EPA) 0 2.3 Docosahexaenoic (DHA) 0 2.3 Arachadonic (ARA) 0 0.25 α-Tocopherol (mg/L) 38 163-225 IVLE=intravenous lipid emulsion; MCT=medium chain triglyceride *Distributed

1. Intralipid Prescribing Information, 2015. 2. Vanek VW, et al. Nutr Clin Pract. 2012;27:150-192. 3. Nutrilipid Prescribing Information 2014, B. Braun Medical, Inc. 4. Clinolipid Prescribing Information, 2013. 5. Smoflipid Prescribing Information 2016. © Copyright Fresenius Kabi AG 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 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 , or to any of the active ingredients or excipients • Severe hyperlipidemia or severe disorders of lipid with serum triglycerides > 1,000 mg/dL © Copyright Fresenius Kabi AG 25 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

27 1-3 Intralipid1-3 Nutrilipid4 Clinolipid Smoflipid®1-3 Omegaven1-3 (ClinOleic outside US)

Fresenius Manufacturer B Braun Baxter Fresenius Kabi Fresenius Kabi Kabi/Baxter* Soybean Oil 30% Olive Oil 80% MCT 30% Oil Source Soybean Oil Soybean Oil Fish Oil 100% Soybean Oil 20% Olive Oil 25% Fish Oil 15%

COMPASSIONATE

*Distributed US USE ONLY

IVLE=intravenous lipid emulsion; MCT=medium-chain triglyceride

1. Calder PC, et al. Intensive Care Med 2010;36:735–49 2. Vanek VW, et al. Nutr Clin Pract 2012;27:150-192. 3. Vanek VW, et al. Nutr Clin Pract 2014;29:841. 4. Nutrilipid Prescribing Information 2014, B.Braun

© Copyright Fresenius Kabi AG 28