Smoflipid 20%: Indications, Dosage, Precautions, Adverse Effects
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SMOFlipid 20% - Product Information

Manufacture: Fresenius Kabi USA, LLC
Country: United States
Condition: Malnourishment, Parenteral Nutrition (Total Parenteral Nutrition)
Class: Nutritional products
Form: Liquid solution, Intravenous (IV)
Ingredients: Soybean oil, refined, Triglycerides, medium-chain, Triglycerides, medium-chain, Fish oil, rich in omega-3 acids, Purified egg phospholipids, All-rac-α-tocopherol, Glycerol, Sodium oleate, Sodium hydroxide

Lipid Injectable Emulsion, Mfr. Std. Soybean oil, medium chain triglycerides, olive oil and fish oil (6%/ 6%/ 5%/ 3% w/v)

Lipid emulsion for intravenous nutrition

Summary Product Information

Route ofhAdministration Dosage Form / Strength Clinically Relevant Nonmedicinal Ingredients
Intravenous Injectable emulsion
20% (6% soybean oil / 6% medium chain triglycerides / 5% olive oil / 3% fish oil)
Purified egg phospholipids All-rac-α-tocopherol
For a complete listing see Dosage Forms, Composition and Packaging section.

Indications and Clinical Use

SMOFlipid 20% (6% soybean oil / 6% medium chain triglycerides / 5% olive oil/ 3% fish oil) is indicated for supply of energy and essential fatty acids and omega-3 fatty acids to adult patients, as part of a parenteral nutrition regimen, when oral or enteral nutrition is impossible, insufficient or contra-indicated.

SMOFlipid can be used in adult populations including geriatrics (See Warnings and Precautions Section).

Contraindications

SMOFlipid is contraindicated in patients with:

  • Hypersensitivity to fish-, egg-, soybean or peanut protein or to any of the active ingredients or excipients.
  • Severe hyperlipidemia.
  • Severe liver insufficiency.
  • Severe blood coagulation disorders.
  • Severe renal insufficiency without access to hemofiltration or dialysis.
  • Acute shock.
  • General contraindications to infusion therapy: acute pulmonary edema, hyperhydration, decompensated cardiac insufficiency.
  • Unstable conditions (e.g. severe post-traumatic conditions, uncompensated diabetes mellitus, acute myocardial infarction, stroke, embolism, metabolic acidosis and severe sepsis and hypotonic dehydration).

Warnings and Precautions

General

Individual capacity to eliminate fat should be monitored according to standard practice, which generally includes checking triglyceride levels. Special caution should be taken in patients with a marked risk for hyperlipidemia (e.g. patients with high lipid dosage and severe sepsis).

Reduction of the dosage or cessation of the lipid emulsion should be considered if serum or plasma triglyceride concentrations during or after infusion exceed 3 mmol/L. An overdose may lead to fat overload syndrome (see section Adverse Reactions).

The addition of other medications or substances to SMOFlipid should generally be avoided unless compatibility is known.

Endocrine and Metabolism

SMOFlipid should be given with caution in conditions of impaired lipid metabolism, which may occur in patients with renal failure, diabetes mellitus, pancreatitis, impaired liver function, hypothyroidism, and sepsis.

Clinical data in patients with diabetes mellitus or renal failure are limited.

Administration of medium-chain fatty acids alone can result in metabolic acidosis. This risk is to a great extent eliminated by the simultaneous infusion of the long chain fatty acids included in SMOFlipid. Concomitant administration of carbohydrates will further eliminate this risk. Hence, simultaneous infusion of carbohydrate or a carbohydrate-containing amino acid solution is recommended.

Hematologic

High levels of lipids in plasma may interfere with some laboratory blood tests, e.g. hemoglobin.

Immune

This intravenous emulsion contains soybean oil, fish oil and egg phospholipids, which may rarely cause allergic reactions. Crossed allergic reaction has been observed between soybean and peanut.

If a hypersensitivity reaction occurs (anaphylactic reaction -such as fever, shivering, rash or dyspnoea) administration of the emulsion should be discontinued immediately and the appropriate treatment and supportive measures should be undertaken until symptoms have resolved (see section Adverce Reactoin).

Special Populations

Pregnant Women

Parenteral nutrition may become necessary during pregnancy. SMOFlipid should only be given to pregnant women after careful consideration. There are no data available on exposure of SMOFlipid in pregnant women.

Nursing Women

Parenteral nutrition may become necessary during lactation. SMOFlipid should only be given to breast-feeding women after careful consideration. There are no data available on exposure of SMOFlipid in breast-feeding women.

Geriatrics

The metabolism of SMOFlipid does not appear to be affected by advanced age.

Monitoring and Laboratory Tests

Standard laboratory tests for monitoring parenteral nutrition should be performed regularly. These include blood glucose levels, liver function tests, triglycerides, acid base metabolism, fluid balance, full blood count and electrolytes.

Adverse Reactions

Adverse Drug Reactions Overview

See Warnings and Precautions

Adverse reactions observed during the administration of lipid emulsions in general, including SMOFlipid, and reported spontaneously from post-marketing experience consisted of:

Table 1 Frequency of Adverse Drug Reactions*
System Organ Class Adverse Drug Reaction Frequency of Occurrence
Immune system disorders Hypersensitivity-reactions (e.g. anaphylactic or anaphylactoid reactions, skin rash, urticaria, flush, headache) Rare (>0.01% – ≤ 0.1%)
Vascular disorders Hypotension, hypertension Rare (>0.01% – ≤ 0.1%)
Respiratory, thoracic and mediastinal disorders Dyspnea Rare (>0.01% – ≤ 0.1%)
Gastrointestinal disorders Lack of appetite, nausea, vomiting Uncommon (≥0.1% – < 1%)
Reproductive system and breast disorders Priapism Very rare (≤ 0.01%)
General disorders and administration site conditions Slight increase in body temperature Common (≥1% – < 10%)
Chills Uncommon (≥0.1% – < 1%)
Heat or cold sensation, paleness, cyanosis, pain in the neck, back, bones, chest and loins Rare (>0.01% – ≤ 0.1%)

* This applies to lipid emulsions in general.

Should these side-effects occur or should the triglyceride level during infusion rise above 3 mmol/L, the infusion of SMOFlipid should be stopped, or if necessary, continued at a reduced dosage.

SMOFlipid should always be a part of a parenteral nutritional treatment including amino acids, glucose and electrolytes. Nausea, vomiting and hyperglycemia are symptoms related to conditions requiring parenteral nutrition regimens and are sometimes believed to be caused by parenteral nutrition.

Monitoring of triglycerides and blood glucose levels are recommended to avoid elevated levels, which may be harmful.

Fat Overload Syndrome

An impaired capacity to eliminate triglycerides may lead to “Fat overload syndrome” which may be caused by overdose. Monitoring for possible signs of metabolic overload is necessary. The cause may be genetic (individual differences in metabolism) or the fat metabolism may be affected by ongoing or previous illnesses. This syndrome may also appear during severe hypertriglyceridemia, and in association with a sudden change in the patient’s clinical condition, such as renal function impairment or infection. The fat overload syndrome is characterized by hyperlipidemia, fever, fat infiltration, hepatomegaly with or without jaundice, splenomegaly, anemia, leukopenia, thrombocytopenia, coagulation disorder, hemolysis and reticulocytosis, abnormal liver function tests and coma.

Should signs of a fat overload syndrome occur, the infusion of SMOFlipid should be interrupted. The symptoms are usually reversible if the infusion of the fat emulsion is discontinued.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The efficacy and safety of SMOFlipid have been studied in 7 clinical trials. Studies have been done in healthy volunteers and adult patients including one long-term study. One large study included 249 adult postoperative patients (ITT population) on total parenteral nutrition for 5 days and in another study in adults, the infusions were given up to two weeks. SMOFlipid is always a component of a regimen providing parenteral nutrition including at least the two other macronutrients (glucose and amino acid solution). Two studies have been performed with SMOFlipid as a part of a fixed regimen delivered in a 3-chamber bag. Altogether 675 subjects from 10 clinical studies have been studied for safety in the trials (338 on SMOFlipid and 337 on comparator products). Twenty-two of the subjects were healthy volunteers in the two Phase I studies with a cross-over design.

The adverse events “Hypoesthesia and/or Paraesthesia” on subjects’ hands and/or forearms were observed in 4 healthy volunteers participating in pharmacokinetics studies (FE-SM-02-DE and FE-SM-01-BE) and coded as possibly related by the investigator. These events were transient, non serious and mild, and resolved spontaneously without added medication or any other action. See Table 2b.

Only one patient in the comparator group was reported to have a drug-related TESAE: one adult male patient had an accidental overdose.

Clinical trials reported pneumonia and respiratory failure as adverse events that were classified as not related to the product. Pneumonia occurred in 3 (1.3%) and 4 (1.7%) patients in the SMOFlipid 20% group and the comparator group while 2 (0.9%) and 3 (1.3%) patients experienced respiratory failure in the SMOFlipid 20% group and the comparator group.

The treatment emergent adverse events classified as “at least possibly related” are presented in Table 2a. All adverse events classified under Gastrointestinal disorders came mainly from postoperative patients after abdominal surgery.

Table 2a Summary of Treatment-Emergent Adverse Drug Reactions in SMOFlipid Studies in Patients
System organ class Adverse event (preferred term) SMOFlipid 20% or Three-chamber bags containing SMOFlipid 20% n= 316* (%) Comparator product n= 315* (%)
Gastrointestinal disorders 23 (7.3) 18 (5.7)
Nausea 13 (4.1) 13 (4.1)
Vomiting 13 (4.1) 6 (1.9)
Flatulence 4 (1.3) 1 (0.3)
Abdominal Pain 1 (0.3) 1 (0.3)
Investigations 10 (3.2) 10 (3.2)
Blood triglycerides increased 6 (1.9) 4 (1.3)
Liver function test abnormal 2 (0.6) 3 (1.0)
Gamma-glutamyltransferase increased 1 (0.3) 3 (1.0)
Blood alkaline phosphatase increased 1 (0.3) 2 (0.6)
Blood pressure increased 1 (0.3) 0
Heart rate increased 1 (0.3) 0
Hepatic enzyme increased 0 1 (0.3)
Glucosuria 1 (0.3) 0
Metabolism and nutrition disorders 8 (2.5) 6 (1.9)
Hyperglycemia 5 (1.6) 3 (1.0)
Hypertriglyceridemia 3 (0.9) 3 (1.0)
Hyperchloremia 1 (0.3) 0
Hypernatremia 1 (0.3) 0
Metabolic acidosis 0 1 (0.3)
Hepatobiliary disorders 6 (1.9) 8 (2.5)
Hyperbilirubinaemia 4 (1.3) 5 (1.6)
Cholestatis 2 (0.6) 2 (0.6)
Cytolytic hepatitis 2 (0.6) 2 (0.6)
Nervous system disorders 3 (0.9) 2 (0.6)
Dysgeusia 2 (0.6) 0
Headache 1 (0.3) 1 (0.3)
Tremor 0 1 (0.3)
General disorders and administration site conditions 2 (0.6) 3 (1.0)
Edema 1 (0.3) 0
Pyrexia 1 (0.3) 0
Infusion site erythema 0 1 (0.3)
Infusion site swelling 0 1 (0.3)
Chest discomfort 0 1 (0.3)
Pain 0 1 (0.3)
Vascular disorders 2 (0.6) 1 (0.3)
Thrombophlebitis 1 (0.3) 1 (0.3)
Hypertension 1 (0.3) 0
Injury, poisoning and procedural complications 0 2 (0.6)
Accidental overdose 0 1 (0.3)
Post gastric surgery syndrome 0 1 (0.3)
Infections and infestations 0 1 (0.3)
Enterobacter sepsis 0 1 (0.3)
Blood and lymphatic system disorders 0 1 (0.3)
Anaemia 0 1 (0.3)
Musculoskeletal and connective tissue disorders 0 1 (0.3)
Muscle spasms 0 1 (0.3)

Note that the numbers in each column can not be added because a subject may have had more than one adverse event.

*Total number of the patients treated

Table 2b Summary of Treatment-Emergent Adverse Drug Reactions in SMOFlipid Studies in Healthy Volunteers
System organ class Adverse event (preferred term) SMOFlipid 20% n= 22* (%) Comparator product n= 22* (%)
Nervous system disorders 5 (22.7) 0
Headache 2 (9.1) 0
Hypoaesthesia 1 (4.5) 0
Paraesthesia (slight sensation of stinging and itchiness in one patient) 3 (13.6) 0
Vascular disorders 1 (4.5) 0
Thrombophlebitis 1 (4.5) 0

Note that the numbers in each column can not be added because a subject may have had more than one adverse event.

*Total number of the patients treated

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Not applicable. There are no other Adverse Drug Reactions reported in the clinical studies than the ones reported in Table 2.

Abnormal Hematologic and Clinical Chemistry Findings

See Table 2.

Post-Marketing Adverse Drug Reactions

There are three cases of Adverse Drug Reactions reported spontaneously since first registration worldwide. One case was assessed as serious. All three patients showed labelled anaphylactic reactions including rash, flushing, chills and erythema.

Drug Interactions

Drug-Drug Interactions

Heparin given in clinical doses causes a transient increase in lipoprotein lipase release into the circulation. This may initially result in increased plasma lipolysis, followed by a transient decrease in triglyceride clearance.

Table 3 Established or Potential Drug-Drug Interactions
Proper name Ref Effect Clinical comment
Heparin T A possible transient decrease in triglyceride clearance These findings are based on basic research and not reported as adverse events in clinical practice.
Coumarin derivatives T May decrease anticoagulant effect Soybean oil has a natural content of vitamin K1. The content is however so low in SMOFlipid that it is not expected to significantly influence the coagulation process in patients treated with coumarin derivatives.

Legend: T = Theoretical

Drug-Food Interactions

No SMOFlipid food interaction studies have been performed.

Drug-Herb Interactions

No SMOFlipid herb interactions studies have been performed.

Drug-Laboratory Interactions

High levels of lipids in plasma may interfere with some laboratory blood tests, e.g. hemoglobin.

Dosage and Administration

Dosing Considerations

The patient’s ability to eliminate the fat infused should determine the dosage and infusion rate.

Recommended Dose and Dosage Adjustment

The standard dose is 1.0 – 2.0 g lipid/kg body weight (b.w.)/day, corresponding to 5 – 10 mL/kg b.w./day.

The maximum infusion rate is 0.15 g lipid/kg b.w./hour, corresponding to 0.75 mL SMOFlipid/kg b.w./hour.

Standard daily dose:
Per kg of body weight For a 70 kg Adult
Usual lipid dose 1.0 – 2.0 g/kg/day 70 to 140 g/day
Infused volume of SMOFlipid 20% 5 to 10 mL/kg/day 350 to 700 mL/day

The recommended duration of infusion for a parenteral nutrition bag is between 12 and 24 hours, depending on the clinical situation. Treatment with parenteral nutrition may be continued for as long as is required by the patient’s condition.

The infusion rate should not exceed 0.15 g lipid/kg b.w./hour.

Administration

Intravenous infusion into a peripheral or central vein.

Overdosage

Overdose leading to Fat Overload Syndrome may occur as a result of too rapid infusion rate, or chronically at recommended rates of infusion in association with a change in the patients clinical conditions e.g. renal function impairment or infection.

Overdosage may lead to side- effects (please see section Adverse Reactions). In these cases the lipid infusion should be stopped or, if necessary, continued at a reduced dosage.

For further information on the management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and Clinical Pharmacology

Mechanism of Action

The fat emulsion has a particle size and biological properties similar to those of endogenous chylomicrons. The constituents of SMOFlipid; soybean oil 6%, medium chain triglycerides 6%, olive oil 5% and fish oil 3%, have except for their energy contents, their own pharmacodynamic properties.

Soybean oil has a high content of essential fatty acids. The omega-6 fatty acid linoleic acid is the most abundant (approx. 55 - 60 %). Alpha-linolenic acid, an omega -3 fatty acid, constitutes about 8%. This part of SMOFlipid provides the necessary amount of essential fatty acids.

Medium-chain fatty acids are rapidly oxidized and provide the body with a form of immediately available energy.

Olive oil mainly provides energy in the form of mono-unsaturated fatty acids, which are much less prone to peroxidation than the corresponding amount of poly-unsaturated fatty acids.

Fish oil is characterized by a high content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). DHA is an important structural component of cell membranes, whereas EPA is a precursor of eicosanoids as prostaglandines, thromboxanes and leukotrienes.

Vitamin E protects unsaturated fatty acids against lipid peroxidation.

Pharmacodynamics

The pharmacodynamic functions of SMOFlipid 20% are the provision of energy, essential fatty acids and omega -3 fatty acids. SMOFlipid 20% comprising of 4 different lipid components, soybean oil, MCT, olive oil, and fish oil is a source of energy with high caloric density, essential fatty acids and omega-3 fatty acids.

The pharmacodynamic properties of SMOFlipid 20% have not been systematically examined in clinical trials because the individual lipid components have been examined in great depth in many years of previous research. The pharmacodynamic effect of SMOFlipid 20% is expected to be a result of the combined effects of the individual components (see section Detailed Pharmacology).

Pharmacokinetics

The individual triglycerides have different clearance rate but SMOFlipid as a mixture is eliminated faster than LCT with lower triglyceride levels during infusion. Olive oil has the slowest clearance rate of the components (somewhat slower than LCT) and MCT the fastest. Fish oil in a mixture with LCT has the same clearance rate as LCT alone.

Once SMOFlipid is administered intravenously it is distributed to all tissues by the vascular circulation.

The components of SMOFlipid are utilized in mainly three metabolic pathways, energy conversion, cell membrane incorporation, and elongation of free-fatty acids. All four lipids are used as energy. Medium chain fatty acids have only one pathway and that is to create energy. The other three components are both used as energy and also incorporated into cell membranes. Furthermore, fish oil has a high content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) . EPA is precursor for mainly anti-inflammatory eicosanoids. The ω3 fatty acid in the soybean oil component (α-linolenic acid; C18:3ω3) is also elongated to EPA and DHA. The ω-6 fatty acid in soybean oil (linoleic acid; C18:2ω6) is converted to γ- linolenic acid and further elongated to arachidonic acid (C20:4ω6), which is precursor for mainly pro-inflammatory eicosanoids.

SMOFlipid is utilized as a nutrient and not excreted. (see section Detailed Pharmacology).

Special Populations and Conditions

Pediatrics

Exploratory studies have been conducted but confirmatory pivotal studies have not been provided.

Geriatrics

The metabolism of SMOFlipid does not appear to be affected by advanced age. The total need of energy supply may be lower than in younger patients.

Gender

There are no differences between the genders regarding the metabolism of SMOFlipid.

Hepatic Insufficiency

Overdosing of energy regardless of origin (glucose or lipids) may cause fat infiltration of the liver and result in further impairment of hepatic insufficiency.

Renal Insufficiency

As SMOFlipid adds to the circulatory volume, it is important to have an adequate renal function. If the renal function is significantly impaired, it is recommended to have access to dialysis or hemofiltration due to the risk of fluid overload.

Storage and Stability

Shelf life of the bag product in the overwrap: 24 months.

For use once the overwrap is removed.

The emulsion is intended for intravenous administration only using correct aseptic technique. Use only undamaged bags.

Gently invert the bag before use. Parenteral emulsions should be inspected visually for precipitate, discoloration, phase separation, and leakage prior to administration. Emulsions showing signs of discoloration, phase separation, and leakage should not be used.

Only administration sets and administration lines made from DEHP-free material should be used.

For single use only. Any unused emulsion should be discarded.

Store up to 25°C. Do not freeze.

Do not use SMOFlipid after the expiry date printed on the container.

Shelf Life After First Opening the Container

From a microbiological point of view the emulsion should be used immediately after removing of the overwrap. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C.

Storage After Mixing

If additions are made to SMOFlipid, admixtures should be used immediately from a microbiological point of view. If admixtures are not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C, unless additions have taken place in controlled and validated aseptic conditions.

Special Handling Instructions

Instructions for Use and Handling

Before Administering the Product in Plastic Bags to Patient, Review These Directions

IV Emulsion

These instructions are only intended as guidelines for product use. Please refer to your own departmental guidelines.



  1. The integrity indicator (Oxalert) A should be inspected before removing the overwrap. If the indicator is black the overwrap is damaged and the product should be discarded.


  2. Place the bag on the clean, flat surface. Remove the overwrap by tearing at the notch and pulling down along the container.
    The Oxalert sachet A and the oxygen absorber B should be discarded.


  3. Place the bag on the clean, flat surface. If additives are to be used break off the tamper-evident arrow flag from the white additive port. If no additives are to be used go to figure 5.


  4. Place the bag on the clean, flat surface. Insert the needle horizontally through the centre of the septum of the additive port and inject the additives (with known compatibility). Use syringes with needles of 18-23 gauge and a length of max. 40 mm.


  5. Use a non-vented infusion set or close the air vent on a vented set. Follow the instructions for use for the infusion set. Use a spike with diameter as specified in ISO 8536-4, 5.6 +/- 0.1 mm.


  6. Place the bag on the clean, flat surface. Break off the tamper-evident arrow flag from the blue infusion port.


  7. Place the bag on the clean, flat surface. Hold the base of the infusion port. Insert the spike through the infusion port, by rotating your wrist slightly until the spike is inserted.


  8. Hang the bag in the hanger cut and start infusion.

Additives

SMOFlipid can be mixed with drugs or vitamins especially formulated for addition to lipid emulsions. SMOFlipid should not be mixed with electrolyte or nutrient solutions, nor should drugs or vitamins be added to the emulsion in the infusion bag unless compatibility of the resulting infusion is evaluated and ensured prior to administration to the patient.

The simultaneous administration of SMOFlipid and amino acid solutions or carbohydrate can be also achieved, using separate infusion sets where the two liquids are allowed to mix in a Y-tube just before the intravenous needle.

When infused alone, SMOFlipid can be administered via central or peripheral vein. When administered as a component of parenteral nutrition (with dextrose and amino acids), the osmolarity of the final infusion will dictate whether the central or peripheral venous route should be used.

The remaining contents of a partly used bag must be discarded and should not be stored for later use. To avoid damaging the spike port, use spike conforming to ISO 8536-4, diameter 5.6 mm ± 0.1 mm.

Dosage Forms, Composition and Packaging

SMOFlipid 20%, lipid injectable emulsion, is a white homogeneous emulsion.

Each 100 mL contains:
Soybean oil, refined 6.0 g
Triglycerides, medium-chain 6.0 g
Olive oil, refined 5.0 g
Fish oil, rich in omega-3 acids 3.0 g
Excipients include:
Glycerol 2.5 g
Purified egg phospholipids 1.2 g
All-rac-α-tocopherol 16 – 23 mg
Sodium hydroxide to adjust pH to pH approx. 8
Sodium oleate 30 mg
Water for injection to 100 mL/td>
Total energy: 840 kJ (200 kcal)
pH: approx. 8
Osmolality 380 mOsm/kg water

Pack sizes:

100 mL in bag: Box of 10 units.

250 mL in bag: Box of 10 units.

500 mL in bag: Box of 12 units.

The packaging consists of an inner bag (primary package) with an oxygen barrier overpouch. An oxygen absorber and an integrity indicator (Oxalert) are placed between the inner bag and the overpouch.

  • The primary plastic container is made from a multilayered film specifically designed for parenteral nutrition drug products. The film is polypropylene based comprising three co-extruded layers. It contains no plasticizers and exhibits virtually no leachables. The container does not contain DEHP (di(2-ethylhexyl)phthalate), PVC or latex. The container is nontoxic and biologically inert.
  • The oxygen barrier overpouch consists of polyethylene terephthalate and polyolefin or polyethylene terephthalate, polyolefin and ethylene-vinyl alcohol copolymer (EVOH).

The overpouch, the oxygen absorber and the integrity indicator should be discarded after opening of the overpouch. The integrity indicator (Oxalert) will react with free oxygen and change colour from clear to black in case of damage in the overpouch.