Smofkabiven: Indications, Dosage, Precautions, Adverse Effects
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Smofkabiven - Product Information

Manufacture: Fresenius Kabi USA, LLC
Country: United States
Condition: Nutrition, Parenteral (Total Parenteral Nutrition)
Class: Nutraceutical products
Form: Liquid solution, Intravenous (IV)
Ingredients: Alanine, Arginine, Calcium chloride dihydrate, Fish oil, Glucose monohydrate, Glycine, Histidine, Isoleucine, Leucine, Lysine acetate, Medium chain triglycerides, Methionine, Olive oil refined, Phenylalanine, Potassium chloride, Proline, Serine, Sodium AC

Amino acids with electrolytes, dextrose and lipid injectable emulsion 5.1 % & 0.7% / 12.7 % / 3.8 %; w/v

Emulsion for Intravenous Nutrition

Summary Product Information

Route of Administration Dosage Form / Strength Clinically Relevant Non-medicinal Ingredients
Intravenous Injectable emulsion.
SmofKabiven [Amino acids with electrolytes, dextrose and lipid injectable emulsion (5.1 % & 0.7 % / 12.7 % / 3.8 %);w/v]
Purified egg phospholipids
All-rac-α-tocopherol

For a complete listing see Dosage Forms, Composition and Packaging section.

Indications and Clinical Use

SmofKabiven [Amino acids with electrolytes, dextrose and lipid injectable emulsion (5.1 % & 0.7 % / 12.7 % / 3.8 %); w/v] is indicated for intravenous infusion into a central vein as parenteral nutrition for adult patients when oral or enteral nutrition is impossible, insufficient or contraindicated.

SmofKabiven are three-component products. Each component is located in a separate chamber. Before use, the seals between the chambers must be broken to mix the components.

Geriatrics

SmofKabiven can be used in adults including geriatrics (see Warning and Precautions section).

Contraindications

SmofKabiven 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
  • Congenital errors of amino acid metabolism
  • Severe renal insufficiency without access to hemofiltration or dialysis
  • Acute shock
  • Uncontrolled hyperglycemia
  • Pathologically elevated serum levels of any of the included electrolytes
  • General contraindications to infusion therapy: acute pulmonary edema, hyperhydration, and decompensated cardiac insufficiency
  • Hemophagocytoic syndrome
  • Unstable conditions (e.g. severe post-traumatic conditions, uncompensated diabetes mellitus, acute myocardial infarction, stroke, embolism, metabolic acidosis, severe sepsis, hypotonic dehydration, and hyperosomolar coma)

Warnings and Precautions

General

The infusion must be stopped immediately if any signs or symptoms of allergic reactions (such as fever, shivering, sweating, headache, skin rashes, or dyspnea) develop.

SmofKabiven [Amino acids with electrolytes, dextrose and lipid injectable emulsion (5.1 % & 0.7 % / 12.7 % / 3.8 %); w/v] should be infused 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.

To avoid risks associated with too rapid delivery, it is recommended to use a continuous and well-controlled infusion, if possible a volumetric pump.

Disturbances of the electrolyte and fluid balance (e.g. abnormally high or low serum levels of the electrolytes) should be corrected before starting the infusion of SmofKabiven.

SmofKabiven should be given with caution to patients prone to retaining electrolytes. Special monitoring is required at the beginning of any intravenous infusion. Should any abnormal sign occur, the infusion must be stopped.

The amount of individual electrolytes to be added is determined by the clinical condition of the patient and by frequent monitoring of serum levels.

Parenteral nutrition should be given with caution in metabolic acidosis, cellular hypoxia and increased serum osmolarity.

Parenteral nutrition infusion may be accompanied by increased urinary excretion of the trace elements, in particular copper and zinc. This should be considered in the dosing of trace elements, especially during long-term parenteral nutrition. Amounts of zinc present in SmofKabiven [Amino acids with electrolytes, dextrose and lipid injectable emulsion (5.1 % & 0.7 % / 12.7 % / 3.8 %);w/v] should be taken into account.

In malnourished patients, initiation of parenteral nutrition can precipitate fluid shifts resulting in pulmonary edema and congestive heart failure as well as a decrease in the serum concentration of potassium, phosphate, magnesium, and water soluble vitamins. These changes can occur within 24 to 48 hours. Therefore, careful and slow initiation of parenteral nutrition is recommended in this patient group, together with close monitoring and appropriate adjustments of fluid, electrolytes, minerals, and vitamins.

SmofKabiven must not be given simultaneously with transfusion blood in the same Y-on-site infusion set due to the risk of pseudoagglutination.

Since an increased risk of infection is associated with the use of any central vein, strict aseptic precautions should be taken to avoid any contamination during catheter insertion and manipulation.

Fat overload syndrome is a rare condition that has been reported with intravenous lipid formulations. A reduced or limited ability to metabolize the lipid contained in SmofKabiven accompanied by prolonged plasma clearance may result in a syndrome characterized by a sudden deterioration in the patient’s condition accompanied by fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, liver fatty infiltration (hepatomegaly), deteriorating liver function, and central nervous system manifestations (e.g. coma).

The cause of the fat overload syndrome is unclear. The syndrome is usually reversible when the infusion of the lipid emulsion is stopped. Although it has been most frequently observed when the recommended lipid dosage was exceeded, cases have also been described where the lipid formulation was administered according to instructions.

Cardiovascular

Fluid status should be closely monitored in patients with pulmonary edema or heart failure.

Endocrine and Metabolism

In patients with hyperglycemia, administration of exogenous insulin might be necessary SmofKabiven should be given with caution in conditions of impaired amino acid metabolism and of impaired lipid metabolism, which may occur in patients with renal failure, diabetes mellitus, pancreatitis, impaired liver function, hypothyroidism, and sepsis.

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. Allergic cross reaction has been observed between soybean and peanut oil.

If a hypersensitivity reaction occurs (signs or symptoms of anaphylactic reaction such as fever, shivering, sweating, headache, skin rash, or dyspnoea) infusion of the emulsion must be stopped immediately and the appropriate treatment and supportive measures should be undertaken until the conditions have been resolved.

Renal

Use with caution in patients with renal insufficiency. Intake of electrolytes such as phosphate and potassium should be carefully controlled to prevent e.g. hyperphosphatemia and hyperkalemia.

Fluid and electrolyte status should be closely monitored in these patients.

Special Populations

Pregnant Women

There are no data available on exposure of SmofKabiven in pregnant women. There are no studies available on reproductive toxicity in animals. Parenteral nutrition may become necessary during pregnancy. Then SmofKabiven should only be given to pregnant women after physicians have carefully considered the potential risks and benefits.

NursingWomen

There are no data available on exposure of SmofKabiven in breast-feeding women. Parenteral nutrition may become necessary during lactation. SmofKabiven should only be given to breast-feeding women after physicians have carefully considered the potential risks and benefits.

Pediatrics

No studies have been performed in the pediatric population.

Geriatrics

Metabolism of SmofKabiven does not appear to be affected by advanced age.

Monitoring and Laboratory Tests

Fluid and electrolyte balance, serum osmolarity, serum triglycerides, acid/base balance, blood glucose (dextrose), liver and kidney function, blood count, including platelets, and coagulation parameters should be monitored throughout treatment. Daily monitoring is recommended during initiation of parenteral nutrition and until the patient and laboratory measurements are stable, followed by regular monitoring as required. Blood cell count and coagulation should be monitored when lipids are given for an extended period.

In patients with renal insufficiency, the phosphate and potassium intake should be carefully controlled to prevent hyperphosphatemia and hyperkalaemia.

Individual capacity to eliminate lipids should be monitored according to standard practice. This is generally done by checking serum triglyceride levels which should not exceed 4 mmol/L during infusion. An overdose may lead to fat overload syndrome, see Adverse Reactions.

The lipid content of SmofKabiven may interfere with certain laboratory measurements (e.g. bilirubin, lactate dehydrogenase, oxygen saturation, hemoglobin) if blood is sampled before lipids have been adequately cleared from the bloodstream. Lipids are cleared after a lipid-free interval of 5 to 6 hours in most patients.

Adverse Reactions

Adverse Drug Reactions Overview

See Warnings and Precautions

Clinical Trial Adverse Drug Reaction

SmofKabiven

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 to identify drug-related adverse events and approximate rates.

The treatment emergent adverse events (TEAEs) classified as “at least possibly related” in the studies 03-3CB7-001 and 03-3CB8-001 with SmofKabiven, are presented in Table 1.

Table 1 - Drug-related TEAEs occurring in studies 03-3CB7-001 and 03-3CB8-001
Drug-related TEAEs by MedDRA preferred term, n (%) of patients SmofKabiven pooled (N=53) Comparator product pooled (N=52)
Number of patients with at least 1 TEAE 17 (32.1) 13 (25.0)
Vomiting 7 (13.2) 2 (3.8)
Nausea 5 (9.4) 7 (13.5)
Flatulence 4 (7.5) 1 (1.9)
Edema 1 (1.9) -
Hyperglycemia 1 (1.9) -
Hypertension 1 (1.9) -
Thrombophlebitis 1 (1.9) 1 (1.9)
Abdominal pain - 1 (1.9)
Anemia - 1 (1.9)

Sorted by frequency in SmofKabiven pooled group.

SmofKabiven and SMOFlipid

Adverse reactions from 7 studies with SmofKabiven and SMOFlipid, the lipid emulsion component of SmofKabiven, that contains 6% soybean oil / 6% medium chain triglycerides / 5% olive oil/ 3% fish oil (w/v) in adults are shown in Table 2.

Table 2 - Summary of Treatment-Emergent Adverse Drug Reactions in SmofKabiven and SMOFlipid Studies
System organ class Adverse event (preferred term) SmofKabiven or 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)
Hyperbilirubinemia 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)
Anemia 0 1 (0.3)
Musculoskeletal and connective tissue disorders 0 1 (0.3)
Muscle spasms 0 1 (0.3)

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

*Total number of patients treated.

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

Not applicable. There were no other ADRs reported from clinical studies than the ones reported in Table 1.

Abnormal Hematological and Clinical Chemistry Findings

No clinically relevant changes indicating impairment of body functions were seen over the course of the study and no notable differences were observed between the treatment groups.

The amino acid component of SmofKabiven was compared in a clinical study to another amino acid solution that is approved in Europe. In the Aminoven 10% study (AS-CS-01-FR), the incidence of adverse drug reactions was comparable between the Aminoven 10% and the Nutrilamine 16 group among 30 ICU patients evaluated for safety.

Table 3 - Adverse Drug Reactions in the Aminoven 10% Study AS-CS-01-FR
Body system Aminoven 10 % group Comparator group
Liver disorders
Alkaline phosphatase elevation
1 (7.5%) 1 (7.5%)
Metabolic disorders
Hyperglycemia + osmotic polyuria
1 (7.5%) -

Post-Marketing Adverse Drug Reactions

Adverse Drug Reactions observed during administration of emulsions for intravenous nutrition in general, including SmofKabiven, and reported spontaneously from post-marketing experience consisted of:

Table 4 - Frequency of Adverse Drug Reactions for lipid emulsions *
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%)
Cardiac disorders Tachycardia 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%)
Metabolism and nutrition disorders Elevated plasma levels of liver enzymes 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, dizziness, headache 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 and therefore to lipid-containing parenteral nutrition.

As with all parenteral infusions extravasation may occur and should be treated according to symptoms.

In case these side effects occur during the infusion of SmofKabiven [Amino acids with electrolytes, dextrose and lipid injectable emulsion (5.1 % & 0.7 % / 12.7 % / 3.8 %); w/v], the infusion should be stopped or, if necessary, continued at a reduced dosage.

Adverse Drug Reactions observed during administration of emulsion for intravenous nutrition in general, including SMOFlipid, and reported spontaneously from post-marketing experience are displayed in Table 4.

Drug Interactions

Drug-Drug Interactions

Some medicinal products, like insulin, may interfere with the body’s lipase system. This kind of interaction seems, however, to be of limited clinical importance.

Intravenous heparin infused in clinical doses and some non-steroidal anti-inflammatory drugs (NSAIDs) cause 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 5 - Potential Drug-Drug Interactions
Proper name Ref Effect Clinical comment
Heparin, NSAIDs T A possible transient decrease in triglyceride clearance These findings are based on basic research and not reported as adverse events in clinical practice.
Insulin T May interfere with the body’s lipase system 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. However, the content is so low in SmofKabiven that it is not expected to impair the therapeutic effects of coumarin derivatives on coagulation.

Legend: NSAID: non-steroidal anti-inflammatory drugs; T = Theoretical

Drug-Food Interactions

No SmofKabiven-food interaction studies have been performed.

Drug-Herb Interactions

No SmofKabiven-herb interactions studies have been performed.

Drug-Laboratory Interactions

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

Dosage and Administration

Dosing Considerations

The patient’s ability to eliminate lipids as well as metabolize nitrogen and glucose, and the nutritional requirements should govern the dosage and infusion rate. The dose should be individualized with regard to the patient’s clinical condition and body weight (bw).

The nitrogen requirements for maintenance of body protein mass depend on the patient’s condition (e.g. nutritional state and degree of catabolic stress or anabolism).

The requirements are 0.6 - 0.9 g amino acids/kg bw/day (0.10 - 0.15 g nitrogen/kg bw/day) in the normal nutritional state or in conditions with mild catabolic stress. In patients with moderate to high metabolic stress with or without malnutrition, the requirements are in the range of 0.9 1.6 g amino acids/kg bw/day (0.15 - 0.25 g nitrogen/kg bw/day). In some very special conditions (e.g. burns or marked anabolism) the nitrogen need may be even higher.

Recommended Dose and Dosage Adjustment

Dosage

The dosage range of 13 – 31 mL SmofKabiven/kg bw/day corresponds to 0.6 - 1.6 g amino acids/kg bw/day (0.10 - 0.25 g nitrogen/kg bw/day) and 14 - 35 kcal/kg bw/day of total energy (12-27 kcal/kg bw/day of non-protein energy). This covers the needs of the majority of patients. In obese patients the dose should be based on the estimated ideal weight.

Infusion Rate

The maximum infusion rate for dextrose (glucose) is 0.25 g/kg bw/h, for amino acid 0.10 g/kg bw/h, and for lipids 0.15 g/kg bw/h.

For SmofKabiven the infusion rate should not exceed 2.0 mL/kg bw/h providing 0.25 g dextrose (glucose), 0.10 g amino acids, and 0.08 g lipids/kg bw/h. The recommended infusion period is 14 - 24 hours.

Maximum Daily Dose

The recommended maximum daily dose of SmofKabiven is 35 mL/kg bw/day providing 1.8 g amino acids/kg bw/day (corresponding to 0.28 g nitrogen/kg bw/day), 4.5 g dextrose (glucose)/kg bw/day, 1.33 g lipids/kg bw/day and a total energy of 39 kcal/kg bw/day (corresponding to 31 kcal/kg bw/day of non-protein energy).

The four different package sizes of SmofKabiven are intended for patients with basal, moderately increased or high nutritional requirements. To provide total parenteral nutrition, trace elements, vitamins, and possibly electrolytes (taking into account the electrolytes already present in SmofKabiven) should be added to SmofKabiven according to the patient’s individual requirements.

Administration

SmofKabiven [Amino acids with electrolytes, dextrose and lipid injectable emulsion (5.1 % & 0.7 % / 12.7 % / 3.8 %); w/v] is intended for infusion into a central vein once the vertical and horizontal seals have been broken and compartments thoroughly mixed. (See Special Handling Instructions)

SmofKabiven may only be mixed with other medicinal products for which compatibility has been documented (see Special Handling Instructions).

Ceftriaxone must not be administered simultaneously with intravenous calcium containing solutions through the same infusion line (e.g. via Y-site) because of the risk of precipitation of ceftriaxone-calcium salt. If the same infusion line is used for sequential administration, the line must be thoroughly flushed with a compatible fluid between infusions.

Overdosage

If symptoms of overdose of lipids or amino acids occur, the infusion should be reduced or discontinued. There is no specific antidote for overdose. Emergency procedures should be general supportive measures, with particular attention to respiratory and cardiovascular systems. Close biochemical monitoring would be essential and specific abnormalities treated appropriately.

If hyperglycemia occurs, it should be treated according to the clinical situation either by appropriate insulin administration and/or adjustment of the infusion rate.

Additionally, overdose might cause fluid overload, electrolyte imbalances, and serum hyperosmolarity.

In rare serious cases, renal replacement therapy may be considered.

For management of a suspected drug overdose, contact your regional Poison Control Centre

Action and Clinical Pharmacology

Mechanism of Action

The primary goal of parenteral nutrition is to provide adequate calories and protein to supply required nutrients and to prevent malnutrition with its associated complications when the patient is unable to receive adequate oral or enteral nutrition. SmofKabiven provides the three macronutrients: glucose (as dextrose), amino acids, and lipids consisting of saturated fatty acids especially MCT (medium-chain triglycerides), monounsaturated and polyunsaturated fatty acids (essential fatty acids), with the electrolytes (sodium, potassium, magnesium, calcium, phosphate, zinc, sulphate, chloride, and acetate).

Amino acids provide the basic substrates for protein synthesis in all tissues and are metabolic precursors and intermediates of numerous other molecules and biochemical pathways. Amino acids provided in excess of requirements are not stored but are used as metabolic fuel. The alpha amino group is removed and the remaining carbon skeleton is transformed into acetyl CoA, acetoacetyl CoA, pyruvate, alpha-ketoglutarate, succinate fumarate, or oxaloacetate.

An adequate supply of amino acids is required for protein synthesis and reduced protein breakdown, especially in metabolic situations with increased endogenous protein degradation, as in many acute or chronic catabolic diseases.

Dextrose (glucose) is the primary source of energy for cells. All body cells have the capacity to metabolize dextrose (glucose) into pyruvate (glycolysis), which may then be oxidized in mitochondria when present, or converted anaerobically to lactate. Channels for entrance of dextrose into body cells may be activated by insulin or, as in red blood cells, be independent from insulin. Dextrose can be stored in the liver as glycogen under the influence of insulin, and converted back as required.

Lipids should be an integral part of a parenteral nutrition regimen. Fatty acids are the most calorically dense form of energy available (9 kilocalories per gram vs approx. 4 kilocalories per gram glucose and amino acids). Fatty acids may be oxidized orincorporated in cell membranes and act as precursors for prostaglandins, leukotrienes, thromboxanes, other bioactive molecules as regulators of gene expression, and as modulators of hormonal functions. Fatty acids also have a role in the propagation of nerve impulses, and in absorption of fat soluble vitamins from the diet.

The two essential fatty acids (EFA) linoleic acid, an omega-6 polyunsaturated fatty acid (PUFA) and α-linolenic acid, an omega-3 polyunsaturated fatty acid, have to be provided intravenously if the gut is dysfunctional. Long-chain omega-3 fatty acids especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil contribute directly to higher levels of eicosanoids without the need of elongation from α-linolenic acid, showing beneficial effects on cell membranes and inflammatory processes.

Stored fat becomes the major fuel source once the carbohydrate store (glycogen) has been depleted. Long-chain fatty acids bypass portal circulation and are presented to the periphery and stored in adipose tissue until needed. Responding to a decrease in insulin levels, long-chain FAs are released and are used by muscle tissue for energy production.

Electrolytes are important to all cells and perform vital functions in the body. Sodium and chloride are the predominant electrolytes in extracellular fluid and are essential in fluid and acid-base balance. Potassium is the most predominant intracellular electrolyte and is important in protein synthesis and nerve transmission. Calcium is required for bone formation, cellular signaling and various enzyme reactions. Phosphate is important in bone maintenance as well as formation of energy compounds. Magnesium regulates many enzymatic reactions. Several enzymes depend on zinc for catalytic activity.

Pharmacodynamics

The lipid emulsion of SmofKabiven is composed of SMOFlipid and has a particle size and biological properties similar to those of endogenous chylomicrons. The different constituents of SMOFlipid, i.e. soybean oil, medium-chain triglycerides, olive oil, and fish oil have their own pharmacodynamic properties. The energy content (9 kcal/g) is the same for all fatty acids.

Soybean oil has a high content of essential fatty acids (linoleic acid and alpha linolenic acid). The omega-6 fatty acid linoleic acid is the most abundant. The ratio of omega-6/omega-3 fatty acid in SMOFlipid 20% is approximately 2.5:1.

Medium-chain fatty acids are rapidly oxidized.

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 prostaglandins, thromboxanes and leukotrienes, thereby modulating inflammation.

Vitamin E protects unsaturated fatty acids against lipid peroxidation.

The amino acids are utilized for tissue protein synthesis and any surplus is channeled to a number of metabolic pathways. Studies have shown a thermogenic effect of amino acid infusion.

Dextrose contributes to maintain or replete the normal nutritional status through provision of energy.

Pharmacokinetics

The ingredients of SmofKabiven (amino acids, with electrolytes, lipids, dextrose) are distributed, metabolized and eliminated in the same manner as if they had been administered individually. The bioavailability of intravenously infused substances such as SmofKabiven is 100%.

The individual triglycerides in SmofKabiven have different clearance rates. Clearance is fastest for medium chain triglycerides (MCT). Fish oil in a mixture with LCT has the same clearance rate as LCT alone.

The principal pharmacokinetic property of the infused amino acids and electrolytes is that the intravenously infused amino acids directly reach the systemic circulation.

Depending on the nutritional state, dextrose can be rapidly metabolized to carbon dioxide and water, stored in the liver and muscles as glycogen, or converted to fat in the adipose tissue.

Special Populations and Conditions

Pharmacokinetic data have not been obtained in special patient populations or conditions.

Pediatrics

Exploratory studies with the lipid compound have been conducted but confirmatory pivotal studies have not been provided. No pediatric studies with SmofKabiven have been performed.

Geriatrics

The metabolism of SmofKabiven does not appear to be affected in elderly.

Gender

There are no differences between the genders regarding the metabolism of SmofKabiven a.

Hepatic Insufficiency

Overdosing of energy regardless of origin (glucose or lipids) may cause steatosis and result in further hepatic impairment.

Renal Insufficiency

As SmofKabiven add to circulatory volume, it is important to have an adequate renal function. In case of renal failure, it is recommended to have access to renal replacement therapy due to the risk of fluid overload.

Storage and Stability

Shelf life of the product in the overwrap: 24 months

Store between 15 °C and 25 °C. Do not freeze.

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

Store bags in overwrap.

For use once the overwrap is removed.

Do not use if package is damaged. Use only if the amino acid and dextrose solutions are clear and colourless or slightly yellow and the lipid emulsion is white, opaque, and homogenous. The contents of the three separate chambers must be mixed before use, and before any additions are made via the additive port.

Once the bag is activated, ensure the vertical seals between chambers are broken at least from the bend in the seals and down to the ports. Then, the bag should be inverted several times to ensure a homogenous mixture which does not show any evidence of phase separation. The upper sections of the vertical seals above the bend and the horizontal seal may remain closed.

Only administration sets and administrations lines made of DEHP-free material should be used. For single use only. Any unused emulsion must be discarded.

Shelf Life After Mixing

Chemical and physical in-use stability of the mixed three chamber bag has been demonstrated for 36 hours at 25 °C. From a microbiological point of view the product should be used immediately. 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 to 8 °C.

Shelf Life After Mixing with Additives

From a microbiological point of view, the product should be used immediately after mixing and additions have been made. If not used immediately, the in-use storage time and conditions prior to use are the responsibility of the user and should normally not be longer than 24 hours at 2 °C to 8 °C. Do not freeze.

Special Handling Instructions

Before administering the product in plastic bag to the patient, review these directions:

The Bag
1. Overwrap Notch
2. Handle
3. Hole (For hanging the bag)
4. Vertical Seals (Must break to activate)
5. Bends in Vertical Seals
6. Horizontal Seal (May remain unopened)
7. Blind Port (NEVER use this port)
8. WHITE Additive Port
9. BLUE Infusion Port
10. Oxygen Absorber (Present between bag and inside overwrap-position may vary)
1. INSPECT BAG PRIOR TO ACTIVATION.
 - One chamber is WHITE.
 - Two chambers are CLEAR.
 a) Discard bag if:
  - More than one chamber is WHITE.
  - Solution is YELLOW.
  - Seals are already BROKEN.


2. REMOVE OVERWRAP.
 a) Place bag on a clean, flat surface.
 b) Tear from Overwrap Notch, located close to the ports.
 c) Tear long sides open to access the inner bag.
 d) Discard Overwrap and Oxygen Absorber.



3. ACTIVATE BAG.
 a) Place bag on a clean, flat surface with text side up and ports pointing away from you 
 b) Roll tightly from top of bag down toward ports.
 c) Apply pressure until both Vertical Seals break and entire contents are white. It may take up to 5 seconds of continued pressure to break Vertical Seals.

NOTE: Both Vertical Seals must be broken from bends to ports. Upper section of Vertical Seals and Horizontal Seal may remain unbroken.

 d) After both Vertical Seals are broken, mix contents thoroughly by inverting the bag at least three times to ensure a homogenous mixture.

4. INSPECT BAG TO CONFIRM ACTIVATION.

 - An activated bag has both Vertical Seals broken from bends to ports and entire contents are white.

5. IDENTIFY CORRECT PORT.
 - Additive port is WHITE with arrow pointing toward bag.
 - Infusion port is BLUE with arrow pointing away from bag.


6. MAKE ADDITIONS (if prescribed).

WARNING: Ensure additives are compatible.
To provide total parenteral nutrition, trace elements, vitamins, and possibly electrolytes (taking into account the electrolytes already present in SmofKabiven) should be added according to the patient’s requirements.

Additives should be thoroughly mixed with components.
 a) Immediately before injecting additives, break off WHITE Additive Port cap with the arrow pointing toward the bag.
 b) Hold base of Additive Port horizontally.
 c) Insert needle horizontally through the center of Additive Port’s septum and inject additives.
 d) Repeat as necessary using aseptic technique.
 e) Mix thoroughly after each addition.

NOTE: The membrane of Additive Port is sterile at first use. Use aseptic technique for subsequent additions. The septum can be pierced up to 10 times with the recommended needle size 18 – 23 G 1½ inches (40mm).



7. SPIKE AND HANG BAG.

 a) Immediately before inserting the infusion set, break off BLUE Infusion Port cap with the arrow pointing away from the bag.
 b) Use a non-vented infusion set or close the air-inlet on a vented set. It is recommended to use a 1.2 µm in-line filter.
 c) Close the roller clamp of the infusion set.
 d) Hold the base of Infusion Port.
 e) Insert spike through Infusion Port byrotating your wrist slightly until the spike is inserted.
 f) Lift and hold the bag with both hands.
 g) Hang the bag by Hole below Handle.

NOTE: The membrane of Infusion Port is sterile at first use. Use infusion sets (according to ISO Number 8536-4) with an external spike diameter of 5.5 – 5.7 mm.

Dosage Forms, Composition and Packaging

SmofKabiven [Amino acids with electrolytes, dextrose and lipid injectable emulsion w/v (5.1 % & 0.7 % / 12.7 % / 3.8 %); w/v] consist of a three chamber bag system. Each bag contains the following partial volumes depending on the four pack sizes.

986 mL 1477 mL 1970 mL 2463 mL Per 100 mL
Amino acid solution with electrolytes (mL) 500 750 1000 1250 50.8
Dextrose 42% (mL) 298 446 595 744 30.2
Lipid emulsion (mL) 188 281 375 469 19.0

This corresponds to the following total compositions:

Table 6 – Contents of mixed product
Contents of Mixed Product
Composition SmofKabiven
Lipids (g/100 mL) 3.8
Dextrose Anhydrous (g/100 mL) 12.7
Amino Acids (g/100 mL) 5.1
Total Nitrogen (g/100 mL) 0.8
Lipids mg/100 mL Soybean oil, refined 1140 mg
Medium chain triglycerides 1140 mg
Olive oil, refined 950 mg
Fish oil, rich in omega-3-acids 570 mg
Total g/100 mg mixed emulsion 3.8 g
Essential amino acids (mg/100 mL) Lysine (as acetate) 340
Phenylalanine 260
Leucine 380
Valine 310
Threonine 220
Methionine 220
Isoleucine 250
Tryptophan 100
Nonessential amino acids (mg/100 mL) Alanine 710
Arginine 610
Glycine 560
Proline 570
Histidine 150
Serine 330
Taurine 50
Tyrosine 20
Electrolytes (mg/100mL) Sodium Acetate Trihydrate 170
Potassium Chloride 230
Sodium Glycerophosphate Anhydrous 210
Magnesium Sulfate Heptahydrate 61
Calcium Chloride Dihydrate 28
Zink Sulfate Heptahydrate 0.66
Electrolyte (mmol/100 mL) Sodium 4.1
Potassium 3.0
Magnesium 0.51
Calcium 0.25
Phosphate1 1.3
Zinc 0.004
Sulfate 0.51
Chloride 3.6
Acetate 10.6
Calorie Content From non-protein (approx.) (kcal/L) 912
From non-protein (approx.) (MJ/L) 3.8
Total (approx.) (kcal/L) 1115
Total (approx.) (MJ/L) 4.7
Table 6 - Contents of Mixed Product (continued)
Contents of Mixed Product
Active Ingredients 986 mL 1477 mL 1970 mL 2463 mL
Essential amino acids (g) Lysine (as acetate) 3.3 5.0 6.6 8.4
Phenylalanine 2.6 3.8 5.1 6.4
Leucine 3.7 5.6 7.4 9.4
Valine 3.1 4.6 6.2 7.6
Threonine 2.2 3.3 4.4 5.4
Methionine 2.2 3.2 4.3 5.4
Isoleucine 2.5 3.8 5.0 6.2
Tryptophan 1.0 1.5 2.0 2.5
Nonessential amino acids (g) Alanine 7.0 10.5 14.0 17.5
Arginine 6.0 9.0 12.0 15.0
Glycine 5.5 8.2 11.0 13.8
Proline 5.6 8.4 11.2 14.0
Histidine 1.5 2.2 3.0 3.7
Serine 3.2 4.9 6.5 8.1
Taurine 0.5 0.75 1.0 1.2
Tyrosine 0.20 0.30 0.40 0.49
Lipid (g) Soybean oil, refined 11.3 16.9 22.5 28.1
Triglycerides, medium chain 11.3 16.9 22.5 28.1
Olive oil, refined 9.4 14.1 18.8 23.4
Fish oil 5.6 8.4 11.3 14.0
Electrolytes (g) Sodium Acetate Trihydrate, 1.7 2.6 3.4 4.2
Potassium Chloride 2.2 3.4 4.5 5.7
Sodium Glycerophosphate (as hydrate) 2.1 3.1 4.2 5.2
Magnesium Sulfate Heptahydrate 0.60 0.90 1.2 1.5
Calcium Chloride Dihydrate 0.28 0.42 0.56 0.69
Zinc Sulfate Heptahydrate 0.0065 0.0097 0.013 0.016
Electrolyte (mmol) Sodium 40 60 80 100
Potassium 30 45 60 74
Magnesium 5.0 7.5 10 12
Calcium 2.5 3.8 5.0 6.2
Phosphate1 12 19 25 31
Zinc 0.04 0.06 0.08 0.1
Sulfate 5.0 7.5 10 13
Chloride 35 52 70 89
Acetate 104 157 209 261
Active Ingredients (g) Amino acids 50 75 100 125
Nitrogen 8 12 16 20
Lipids 38 56 75 94
Dextrose (Glucose) (anhydrous) 125 187 250 313
Calorie Content Total (kcal) 1100 1600 2200 2700
Total (MJ) 4.6 6.7 9.2 11.3
From non-protein (kcal) 900 1300 1800 2200
From non-protein (MJ) 3.8 5.4 7.5 9.2
pH approx. 5.6
Osmolarity (mOsm/L) approx. 1500
Osmolality ( mOsm/kg water) approx. 1800

1 Contribution from both the lipid emulsion and the amino acid solution.

Excipients are:

  • Glycerol
  • Purified egg phospholipids
  • all-rac-α-Tocopherol
  • Sodium hydroxide (pH adjuster)
  • Sodium oleate
  • Acetic acid, glacial (pH adjuster)
  • Hydrochloric acid (pH adjuster)
  • Water for injection

Product Container

The container consists of a multi-chamber inner bag and an overwrap. The inner bag is partitioned into three chambers to keep the components separated until the bag is activated by the user. An oxygen absorber is placed between the inner bag and the overwrap. The inner bag is made of a multilayer polymer film that consists of poly(propylene-co-ethylene), synthetic rubber poly[styrene-block-(butylene-co-ethylene)] (SEBS) and synthetic rubber poly(styrene-block-isoprene) (SIS). The infusion and additive ports are made of polypropylene and synthetic rubber poly[styrene-block-(butylene-co-ethylene)] (SEBS) equipped with synthetic polyisoprene (latex-free) stoppers. The blind port, which is only used during manufacturing, is made of polypropylene equipped with a synthetic polyisoprene (latex-free) stopper.

Pack sizes:

986 mL bag:   1 carton with 4 bags

1477 mL bag: 1 carton with 4 bags

1970 mL bag: 1 carton with 4 bags

2463 mL bag: 1 carton with 3 bags