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Alternative IV Lipid Emulsions

Michelle Henry, MPH, RD, CNSC Medical Science Liaison, Fresenius Kabi LLC, USA

Oley Conference January 2017

© Copyright Fresenius Kabi AG

• 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

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• 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

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.

4


Triglycerides1

• The most abundant lipids in the body

• Fatty acids: the fundamental building blocks of lipids

Phospholipids1

• The components of the lipid bilayer of cell membranes

5 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. G

lyce

rol

Hydrophilic polar head group

Hydrophobic non-polar tail

(Extracellular)

(Intracellular)

Phospholipid bilayer

© Copyright Fresenius Kabi AG 6

H3C COOH

Stearic acid (18:0)

H3C COOH

Double bond

Oleic acid (18:1ω-9)

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

Double bonds

1 double bond = Monounsaturated Fatty Acids (MUFAs)

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


Omega-9 Fatty Acids

Eicosatrienoic Acid (Mead Acid)

20:3 ω9

Oleic Acid (OA) 18:1 ω9

Octadecadienoic Acid 18:2 ω9

Eicosadienoic Acid 20:2 ω9

Arachidonic Acid (AA) 20:4 ω6

Docosapentaenoic Acid 22:5 ω6

Docosatetraenoic Acid 22:4 ω6

24:4 ω6

24:5 ω6

Gamma-Linolenic Acid 18:3 ω6

Dihomo-Gamma-Linolenic Acid 20:3 ω6

Eicosapentaenoic Acid (EPA) 20:5 ω3

Docosahexaenoic Acid (DHA) 22:6 ω3

Docosapentaenoic Acid 22:5 ω3

24:5 ω3

24:6 ω3

Octadecatetraenoic Acid 18:4 ω3

Eicosatetraenoic Acid 20:4 ω3

Arachidonic Acid (AA) 20:4 ω6

Eicosapentaenoic Acid (EPA) 20:5 ω3

Docosahexaenoic Acid (DHA) 22:6 ω3

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METABOLIC PATHWAYS OF 𝛚-3, 𝛚-6, 𝛚-9 FATTY ACIDS -3, 𝛚-6, 𝛚-9 FATTY ACIDS -6, 𝛚-9 FATTY ACIDS -9 FATTY ACIDS

Adapted from Le HD, et al. Prostaglandins Leukot Essent Fatty Acids. 2009;81:165-170. With permission from Elsevier.

PARENT Essential Fatty Acid PARENT Essential Fatty Acid NON-EFA

elongase

elongase

elongase

Beta-oxidation

delta-6-desaturase

delta-5-desaturase

delta-6-desaturase

elongase

delta-6-desaturase

delta-5-desaturase

Tetraene Triene


9 kcal/g

FATTY ACID

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. 2nd Edition, 2012. Silver Springs, MD: American Society for Parenteral and Enteral Nutrition. 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

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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.

Evolution of IVLEs

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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 Food Sci Food Safety 2002;3:110–20.

Fish oil-containing formulations 2

2005

Fish oil parenteral supplement 2

1998

80% olive, 20% soy2

1996

MCT/LCT emulsions

made of soy and

coconut oil AND

IVLE 50:50 soy oil and safflower oil2

1984

100% soy emulsion became

the first industrially available

IVLE for PN2

1961

Structured mixture of MCT and LCT3

Structured triglyceride

2000

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

Cottonseed Oil First IVLE

available, quickly removed for

significant side effects2

1960


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

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US Approvals

Intralipid (Soybean Oil)

Soybean Oil + Safflower Oil

(Liposyn)

Intralipid (Soybean Oil)

Soybean Oil / Medium-Chain TG

Structured & Physical Mixture

Fish Oil (Omegaven)

Smoflipid®

Soybean Oil + Medium-Chain TG

+ Olive Oil + Fish Oil

Soybean Oil + Medium-Chain TG

Soybean Oil + Olive Oil

Soybean Oil + Medium-Chain

TG + Fish Oil

MCT=medium-chain triglyceride; TG=triglyceride

Soybean oil + MCT +

Olive + Fish oil

Olive oil + soybean oil

Lipomul (Cottonseed Oil)

Pre-1960

Removed from market due to significant side effects in 1960s

No longer available.

Approved, but not

available for purchase.

IVLEs Available in the US

13


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.

Intralipid1,2 Nutrilipid3 Clinolipid2,4 Smoflipid5

Manufacturer Fresenius Kabi/ Baxter* B. Braun Medical Baxter Fresenius Kabi

Oil Source Soybean Oil Soybean Oil Olive Oil 80% Soybean Oil 20%

Soybean Oil 30% MCT 30%

Olive Oil 25% Fish Oil 15%

Fat 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


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.

Intralipid1 Nutrilipid1 Clinolipid1 Smofipid2 Omegaven2*

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• 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.


• 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.


• 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.


• 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.


Olive Oil

Soybean Oil

Fish Oil

Medium-Chain

Triglyceride Oil

Safflower 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. 20


• 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

Smoflipid is a new lipid IVLE option for adults in the United States


Olive Oil (ω-9)

Fish Oil (ω-3)

MCTs

Soy Oil (ω-6)

23 1. Deckelbaum RJ, et al. Biochemistry (Mosc) 1990;29(5):1136-1142; 2. Bach AC, et al. Am J Clin Nutr. 1982;36(5):950-962. 3. Vanek VW, et al. Nutr Clin Pract. 2012;27(2):150-192. 4. Kalish BT, Fallon EM, Puder M. J Parenter Enteral Nutr. 2012; 36:380-8.

• Source of essential fatty acids • Provides energy

• Source of rapidly available energy1

• Clears faster from the bloodstream than other fatty acids2

• Contains small amount of linoleic acid and α-linolenic acid

• Immune neutral3

• Source of conditionally essential fatty acids EPA & DHA4

• Precursors to less inflammatory eicosanoids5

30%

30%

25%

15%

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

5. Kremmyda et al, Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub; 2011. 6. Burrin DG, et al. Adv Nutr. 2014;5(1):82-91. 7. Biesalski HK. Gastroenterology. 2009;137(5 Suppl):S92-S104.


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.

Intralipid1,2 Smoflipid5

Manufacturer Fresenius Kabi/ Baxter* Fresenius Kabi

Oil Source Soybean Oil



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


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 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. ----------------------------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

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


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

Intralipid1-3 Nutrilipid4 Clinolipid1-3 (ClinOleic outside US) Smoflipid®1-3 Omegaven1-3

Manufacturer Fresenius Kabi/Baxter* B Braun Baxter Fresenius Kabi Fresenius Kabi

Oil Source Soybean Oil Soybean Oil Olive Oil 80% Soybean Oil 20%



Fish Oil 100%

*Distributed

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

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COMPASSIONATE US USE ONLY

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