Smofkabiven Electrolyte Free - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Smofkabiven Electrolyte Free - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: United States
Condition: Nutrition, Parenteral (Total Parenteral Nutrition)
Class: Nutritional products
Form: Liquid solution, Intravenous (IV)
Ingredients: Alanine, Arginine, Glycine, Histidine, Isoleucine, Leucine, Lysine (as acetate), Methionine, Phenylalanine, Proline, Serine, Taurine, Threonine, Tryptophan, Tyrosine, Valine, Glucose (as monohydrate), Soya oil, Medium-chain triglycerides, Olive oil and Fish oil, glycerol, egg lecithin, dl-α-tocopherol, sodium hydroxide, sodium oleate, acetic acid - glacial, hydrochloric acid and water for injections

Pharmaceutical Information

Drug Substance

SmofKabiven Electrolyte Free [Amino acids, dextrose and lipid injectable emulsion (5.1 % / 12.7 % / 3.8 %); w/v]

Chemical Name Molecular Formula and Molecular Mass Structural Formula Physicochemical properties
L-Alanine (S)-2-aminopropionic acid C3H7NO2
89.09

White or almost white crystalline powder or colourless crystals, freely soluble in water, very slightly soluble in alcohol.
L-Arginine (2S)-2-amino-5-guanidinopentanoic acid C6H14N4O2
174.20

White or almost white crystalline powder or colourless crystals, freely soluble in water, very slightly soluble in alcohol.
Glycine Aminoacetic acid C2H5NO2
75.07

White or almost white crystalline powder, freely soluble in water, very slightly soluble in alcohol.
L-Histidine (S)-2-amino-1H-imidazole-4-propionic acid C6H9N3O2
155.15

White or almost white crystalline powder or colourless crystals, soluble in water, very slightly soluble in ethanol (96%).
L-Isoleucine (2S, 3S)-2-amino-3-methylpentanoic acid C6H13NO2
131.17

White or almost white crystalline powder or flakes, sparingly soluble in water, slightly soluble in alcohol. It dissolves in dilute mineral acids and in dilute solutions of alkali hydroxides.
L-Leucine (2S)-2-amino-4-methylpentanoic acid C6H13NO2
131.17

White or almost white crystalline powder or shiny flakes, sparingly soluble in water, practically insoluble in alcohol. It dissolves in dilute mineral acids and in dilute solutions of alkali hydroxides.
L-Lysine Acetate (2S)-2,6-diaminohexanoic acid monoacetate C6H14N2O2·C2H4O2
206.24

White or almost white crystalline powder or colourless crystals, freely soluble in water, very slightly soluble in ethanol (96%).
L-Methionine (2S)-2-amino-4-(methylsulfanyl) butanoic acid C5H11NO2S
149.21

White or almost white crystalline powder or colourless crystals, soluble in water, very slightly soluble in ethanol.
L-Phenylalanine (2S)-2-amino-3-phenylpropanoic acid C9H11NO2
165.19

White or almost white crystalline powder or shiny, white flakes, sparingly soluble in water, very slightly soluble in alcohol. It dissolves in dilute mineral acids and in dilute solutions of alkali hydroxides.
L-Proline (S)-2-pyrrolidinecarboxylic acid C5H9NO2
115.13

White or almost white crystalline powder or colourless crystals, very soluble in water, freely soluble in alcohol.
L-Serine (S)-2-amino-3-hydroxypropionic acid C3H7NO3
105.09

White or almost white crystalline powder or colourless crystals, freely soluble in water, practically insoluble in alcohol.
Taurine 2-aminoethane sulfonic acid C2H7NO3S
125.15

White or almost white crystalline powder or colourless crystals, freely soluble in water
L-Threonine (2S, 3R)-2-amino-3-hydroxybutanoic acid C4H9NO3
119.12

White crystalline powder or colourless crystals, soluble in water, practically insoluble in ethanol.
L-Tryptophan (2S)-2-amino-3-(indol-3-yl) propanoic acid C11H12N2O2
204.23

White or almost white crystalline or amorphous powder, sparingly soluble in water, slightly soluble in alcohol. It dissolves in dilute mineral acids and in dilute solutions of alkali hydroxides.
L-Tyrosine (S)-2-amino-3-(4-hydroxyphenyl) propionic acid C9H11NO3
181.19

White crystalline powder or colourless crystals, very slightly soluble in water, practically insoluble in alcohol. It dissolves in dilute mineral acids and in dilute solutions of alkali hydroxides.
L-Valine (S)-2-amino-3-methylbutanoic acid C5H11NO2
117.15

White or almost white crystalline powder or colourless crystals, soluble in water, very slightly soluble in ethanol.
Dextrose D-glucose monohydrate C6H12O6·H2O
198.2

White crystalline powder with a sweet taste, freely soluble in water, sparingly soluble in alcohol.
Soybean oil Triacylglycerol (triglyceride) with fatty acid chains mainly C16:0, C18:0, C18:1, C18:2, C18:3

R1, R2, R3 represents the chain of the fatty acids linked to the glycerol backbone.
Liquid at room temperature.
Practically insoluble in water, very soluble in acetone and in heptane while slightly soluble in ethanol.
Medium chain triglycerides (MCT) Triacylglycerol (triglyceride) with fatty acid chains mainly C8:0, C10:0
Olive Oil Triacylglycerol (triglyceride) with fatty acid chains mainly C16:0, C18:1, C18:2
Fish Oil Triacylglycerol (triglyceride) fatty acids mainly C20:5, C22:6

Clinical Trials

Study Demographics and Trial Design

One phase 3 open-label, randomised, active-controlled, parallel-group study (03-3CB7-001) was conducted in patients after major intestinal tract surgery requiring parenteral nutrition. The aim was to evaluate safety and tolerance of SmofKabiven compared to another three-chamber bag product, Kabiven (containing a soybean oil emulsion, amino acids and dextrose) available in US and Europe. A total of 53 patients (age range 35-82 years; 17 females) received 15 to 30 mL SmofKabiven or comparator/kg bw/day by central intravenous infusion for five to seven days. Safety parameters were adverse events, blood laboratory, and vital signs.

A phase 3 open-label, randomised, active-controlled, parallel-group study (03-3CB8-001) was performed in patients requiring parenteral nutrition to evaluate safety and tolerance of SmofKabiven Peripheral compared to another peripheral three-chamber bag product available in Europe. A total of 52 patients (age range 20-84 years; 36 females) received up to 40 mL SmofKabiven Peripheral or comparator/kg bw/day into peripheral veins for 5 to 7 days. Safety parameters were adverse events, blood laboratory, vital signs and local tolerance.

Table 1 - Summary of patient demographics for clinical trials on SmofKabiven
Study No. Trial design Dosage (g lipids/kg bw/h) Route of administration Duration (days) Study subjects (n) Age range (years)
03-3CB7-001 Safety open-label, randomized, active-controlled, parallel-group Day 1: 0.6
Days 2-4: 0.9-1.2
Days 5-7: 0.6-1.2
IV 5-7 53 ≥18
03-3CB8-001 Safety open-label, randomized, active-controlled, parallel-group max 1.1 for test product and 1.4 for reference product IV 5-7 52 ≥18
bw: body weight; n: number;

Study Results

The study 03-3CB7-001 provided good evidence that SmofKabiven is well tolerated and safe. Based on the overall number of patients with AEs, safety and tolerability was comparable in both groups. Reported AEs were mild in 14/26 patients in the SmofKabiven group and 17/27 patients in the control group or moderate in 19/26 patients in the SmofKabiven group and 10/27 patients in the control group, respectively. Of these 17 patients in the SmofKabiven group and 11 patients in the control group experienced AEs possibly or probably related to the study drug. Serious AEs (SAEs) occurred in 5 subjects in the SmofKabiven group and in 2 subjects in the control group. No drug related SAE was observed. No clinically significant changes in vital signs were recorded. Eight patients in the SmofKabiven group and 5 in the control group were withdrawn due to an AE.

In study 03-3CB8-001 the majority of patients reported mild or moderate AEs. One of 27 patients in the SmofKabiven Peripheral and 1/25 patients in the comparator group experienced non-related, fatal SAEs. No drug-related SAE was observed in the study. Possible relationship to the study medication was reported for AEs in 1/27 and 2/25 patients after SmofKabiven Peripheral (thrombophlebitis) and comparator treatment (thrombophlebitis and anemia), respectively. One of 27 patients in the SmofKabiven Peripheral group was withdrawn from the study due to an AE (thrombophlebitis). Differences in clinical laboratory measurements between treatment groups and changes between baseline (Study Day 1) and examination after the last study medication were minor in both groups. There were no differences between groups regarding pulse rate, blood pressure, or body temperature. The incidence of local intolerance was higher in the SmofKabiven Peripheral than in the comparator group and was of low to moderate intensity. Evaluation of overall safety and tolerability of both treatments showed a lower number of AEs or pathological clinical laboratory values in the SmofKabiven Peripheral group than in the comparator group.

In addition, studies with individual components contained in SmofKabiven have been carried out as described below:

Lipid Emulsion (SMOFlipid 20%)

Study Demographics and Trial Design

The trial design and patient demographic data for the company sponsored studies investigating SMOFlipid 20% in adult patients are summarised in Table 2 below.

Five clinical studies investigated SMOFlipid 20% versus soybean oil emulsion in 22 healthy adult volunteers and 281 adult patients (total of 303 adults). Of these, 73 patients were treated in a long-term study over 4 week treatment duration. Efficacy was studied in addition to safety in one study. For details of pharmacokinetic studies refer to Detailed Pharmacology.

Table 2 - Summary of patient demographics for clinical trials on SMOFlipid 20%
Study No. Trial design Dosage (g lipids/kg bw/h) Route of administration Duration Study subjects (n) Age (Range)
Healthy volunteers
FE-SM-01-BE Pharmaco-kinetics (5.3.3.1.1) open-label, randomized, active-controlled, crossover 0.15 IV 4 h 10 18-45
FE-SM-02-DE Pharmaco-kinetics (5.3.3.1.2) double-blind, randomized, active-controlled, crossover 0.125 IV 6 h 12 18-45
Adult patients
FE-SM-03-DE Efficacy/Safety (5.3.5.1.1.A) double-blind, randomized, active-controlled, parallel-group 1.5 IV 5 d 249 ≥18
FE-SM-04-CH Safety (SMOFlipid 5.3.5.1.2.A) double-blind, randomized, active-controlled, parallel-group up to max 2 IV 10-14 d 32 ≥18
05-SMOF-006 Safety (SMOFlipid 5.3.5.1.5.A) double-blind, randomized, active-controlled, parallel-group max 1-2 IV 4 weeks 73 18-85

d: day: h: hour

Study Results

In two randomised, two-period crossover studies in healthy volunteers, the elimination of triglycerides appeared to be faster for SMOFlipid 20% compared to a standard soybean oil emulsion.

Three randomised, double-blind clinical phase III studies FE-SM-03-DE, FE-SM-04-CH and 05-SMOF-006 were performed. In FE-SM-04-CH and 05-SMOF-006, safety was investigated and considered comparable in SMOFlipid 20% and the comparator soybean oil emulsions, given in the same dose (20%). Study 05-SMOF-006 performed with 73 patients requiring long-term parenteral nutrition during 4 weeks showed a reduction of the ratio of ω-6/ω-3-fatty acids in red blood cell phospholipids and plasma lipoproteins.

Study FE-SM-03-DE investigated the safety and efficacy of SMOFlipid 20% (compared with a soy bean oil emulsion) in 249 postsurgical patients. SMOFlipid 20% was well-tolerated and safe. Both treatment groups showed similar serum triglyceride concentrations during 5 days study treatment. Due to the different composition of the lipid emulsion, patients receiving SMOFlipid 20% had higher mean concentrations of the ω-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and lower mean concentrations of the ω-6 fatty acid linoleic acid than patients receiving soybean oil emulsion in plasma, platelet phospholipids, and leukocyte phospholipids. The ω-3/ω-6 ratio was significantly increased in the SMOFlipid 20% group compared to the soybean oil emulsion group.

Amino Acids (Aminoven 10%)

Study Demographics and Trial Design

The trial design and patient demographics in this company sponsored study on Aminoven 10% are summarised in Table 5 below. One phase 3 clinical study on Aminoven was performed in 30 critically-ill patients who required parenteral nutrition for 5 to 7 days to evaluate efficacy and safety of Aminoven 10 % compared to an isonitrogenous amino acid solution.

Table 3 - Summary of patient demographics for clinical with Aminoven 10%
Study No. Trial design Dosage (g lipids/kg bw/d) Route of administration Duration (days) Study subjects (n) Age range (years)
AS-CR-01-FR* Efficacy/Safety open, randomized, active-controlled, parallel-group 1.5 IV 5-7 30 ≥18

* Test product: Cosmosteril 10 % is synonymous with Aminoven 10%.

Study Results

Similar results in both treatment groups were shown for the primary efficacy endpoint cumulative nitrogen balance. There were no significant differences with regard to the evolution of nutritional markers such as transthyretine (pre albumin), retinol binding protein, C-reactive protein, and urinary 3-methylhistidine/creatinine ratio between the groups. The number of AEs was comparable between the treatment groups. Administration of Aminoven 10% was not associated with clinically relevant or unexpected AEs, neither by nature nor by incidence. The results of the study showed that both amino acid solutions were well tolerated.

Dextrose 42%

Glucose in varying concentrations is well established as the optimal carbohydrate source for parenteral nutrition.

Detailed Pharmacology

No pharmacology studies have been performed using SmofKabiven. The clinical pharmacology of the individual constituents of SmofKabiven is described below.

The bioavailability of intravenously infused substances is by definition 100%.

Lipid Emulsion (SMOFlipid 20%)

Pharmacokinetics

Two phase 1 pharmacokinetic studies using a randomised two-period crossover design performed in healthy adult men examined the intravascular metabolism of SMOFlipid 20% (study FE-SM-01-BE) and the elimination of triglycerides as well as the pharmacokinetics of other lipid parameters after administration of SMOFlipid 20% (study FE-SM-02-DE). The comparator in both studies was a soybean oil emulsion.

Both studies indicated that SMOFlipid 20% was well metabolized intravascularly and showed advantages over a soybean oil emulsion. Specifically, the less marked increase in triglycerides during infusion of SMOFlipid 20% and the faster elimination after stopping the infusion (i.e. shorter half-life) compared to a soybean oil emulsion are of potential benefit, particularly for patients with a limited triglyceride elimination capacity.

Pharmacodynamics

The pharmacodynamic functions of lipid emulsions are the provision of energy and essential fatty acids linoleic acid and α-linolenic acid. SMOFlipid 20% comprises 4 different lipid components, soybean oil 6%, MCT 6%, olive oil 5%, and fish oil 3% as a source of energy with high caloric density and as source of essential fatty acids from fish oil.

The pharmacodynamic properties of SMOFlipid 20% have not been systematically examined in clinical trials because the individual lipid components have been examined for many years. The pharmacodynamic effect of SMOFlipid 20% is expected to result from the combined effects of the individual components.

Soybean Oil

Soybean oil is the main source of essential fatty acids in SMOFlipid 20%. Both linoleic and α-linolenic acids are long-chain fatty acids (LCFA; >12 carbon atoms) as well as polyunsaturated fatty acids (PUFAs). PUFAs are important constituents of all cell membrane phospholipids and serve as precursors for the synthesis of lipid mediators called eicosanoids (e.g. prostaglandins and leukotrienes). An excess of either ω-6 or ω-3 PUFA in parenteral lipid emulsions may be immunosuppressive. The more balanced the ω-6 to ω-3 ratio, the less immunosuppressive effects of the lipid emulsion were observed in a rat heart allotransplantation model. According to clinical and experimental data, it has been suggested that the most favorable ω-6/ω-3 ratio is in the range of 2:1 to 4:1. The ratio of ω-6/ω-3 fatty acids in SMOFlipid 20% is approximately 2.5:1. ,

Medium-chain Triglycerides (MCT)

MCT are more rapidly cleared from the blood stream than long-chain triglycerides (LCT), and MCFA are more rapidly oxidized compared to LCFA , thus providing the body with a form of immediately available energy. MCFA are not stored in fat tissue and do not accumulate in the liver. Intravenous MCT administration has not been associated with steatosis or hepatic dysfunction. Hepatic metabolism of MCFAs results in stimulation of synthesis of ketone bodies which can be used as an energy source but eventually result in acidosis.

Therefore, it is important not to include an excessive quantity of MCT in a lipid emulsion. An emulsion containing as much as 75% MCT (and 25% LCT) has been tested in critically ill patients without observing any harmful effects. The amount of MCT (30%) in SMOFlipid 20% is considered safe as it is lower than in the physical mixtures of MCT/LCT already commercially available in Europe. Replacing a part of LCT by MCT in SMOFlipid 20% reduces the total amount of PUFAs, and thus reduces the risk of lipid peroxidation and the associated requirements for antioxidants.

Olive Oil

SMOFlipid 20% contains 50 g/L olive oil which includes LCT rich in monounsaturated fatty acid (MUFA). Olive oil is rich in the immunologically inert MUFA oleic acid (C18:1ω9) and mainly provides energy.

MUFAs are less prone to lipid peroxidation than PUFAs due to fewer double bonds in the carbon chains.

Fish Oil

Fish oil is characterized by a high content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both of which belong to the PUFA ω-3 LCFA family. DHA and EPA are important structural and functional components of cell membranes, and EPA is also a precursor of eicosanoids such as prostaglandins, thromboxanes, and leukotrienes, which exhibit a lower inflammatory potential than those derived from ω-6 PUFA arachidonic acid (AA).

Administration of ω-3 fatty acids is followed by an increased ω-3/ω-6 fatty acid ratio in the cell membranes. SMOFlipid contains 15% fish oil. After 5 days post-operative total parenteral nutrition with SMOFlipid ω-3 fatty acids as well as ω-3/ω-6 fatty acid ratio were significantly increased in plasma phospholipids and also in leukocytes and platelets compared to a soybean oil emulsion treatment. As a consequence the EPA/AA ratio was increased resulting in a significantly higher leukotriene B5 (LTB5) release of neutrophils after stimulation versus the control group. Leukotriene B4 (derived from AA) remained similar in both groups leading to a significantly increased LTB5/LTB4 ratio in the SMOFlipid group only.

Amino Acids (Aminoven 10%)

Pharmacokinetics

The amino acids in Aminoven 10% enter the plasma pool of corresponding free amino acids. From the intravascular space, amino acids distribute to the interstitial fluid and into the intracellular space. Plasma and intracellular free amino acid concentrations are endogenously regulated within narrow ranges, depending on age, nutritional status, and pathological condition of the patient.

Balanced amino acid solutions such as Aminoven 10% do not significantly alter the physiological amino acid pool when infused at a constant and slow infusion rate.

Characteristic changes in the physiological plasma amino acid pool occur when the regulative function of essential organs like liver and kidneys are seriously impaired. In such cases special formulated amino acid solutions may be recommended for restoring homeostasis.

Only a small proportion of the infused amino acids is eliminated by the kidneys. For the majority of amino acids plasma half-lives between 10 and 30 minutes have been reported.

Pharmacodynamics

The amino acids contained in Aminoven 10% are all naturally occurring physiological compounds. Amino acid solutions provide the building blocks for protein synthesis and are a source of energy. Furthermore, amino acids serve as precursors of various biochemical pathways and are important signalling molecules mediating multiple cellular communication processes. The individual amino acids show different pharmacodynamic properties.

Dextrose (Glucose 42%)

Pharmacokinetics

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

Pharmacodynamics

Dextrose is the main source of energy for the body and contributes to glucose metabolism.

Microbiology

Not Applicable

Toxicology

Studies performed with SmofKabiven

A local tolerance study in rabbits and an in vitro hemocompatibility study have been performed with SmofKabiven. Both studies showed good local tolerance and no signs of incompatibility.

Further preclinical studies with SmofKabiven have not been performed. However, preclinical data for SMOFlipid as well as amino acid and dextrose solutions of various concentrations and sodium glycerophosphate reveal no specific hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

The following toxicological studies have been performed with SMOFlipid.

Type of study Species SMOFlipid Doses g TG/kg bw/day Observations and conclusions
Single-Dose Toxicity
Rat 9, 18, 36, No significant toxicity associated with SMOFlipid up to a dose level of 18 g TG/kg bw (90 ml/kg bw). At 36 g TG/kg bw. toxic signs were observed due to the excessive administration of fluid volume
Repeat-Dose Toxicity
26-day Rat 12, 15, 18 Two continuous intravenous infusion (24 hours/day) studies with SMOFlipid 20% in rats at doses up to 18 and 9 g TG/kg bw/day and initially scheduled for 42 days and 8 weeks had to be terminated after 26 and 30 days, respectively, due to high mortality in the treated groups. A combination of the physical nature of the test material, the flow rate and 24 hour/day continuous exposure were not compatible with the intended duration of infusion. It was concluded that subchronic or chronic 24-hour a day continuous intravenous infusion of total parenteral nutrition products in the rat model is not feasible. There was no difference between SMOFlipid 20% and Intralipid 20% as the reference product.
30-day Rat 3, 6, 9*
4-week Dog 9* Good tolerance was demonstrated. An adjustment to the intravenous supply of energy was indicated by a dose-related reduction in food intake over time. A dose- and time-related reduction in lymphocytes and thrombocytes was found after high doses, i.e., 9 and 6 g TG/kg bw/day, respectively. Serum cholesterol and phospholipids were increased approx. in proportion to the molar dose of TG and reversed completely within 4 weeks of recovery. Significant morphological changes were fatty changes in hepatocytes (fat in the centriacinar region); lungs (foci of granulomatous pneumonia) and kidney (interstitial nephritis). At the end of the 4-week recovery period all afore described drug substance-related changes had subsided.
13-week Dog 3, 6**
Genotoxicity
In vitro
Bacterial gene mutation S. typhimurium Up to 40 mg/plate No mutagenic effects were observed
Chromosomal aberration Human lymphocytes Up to 5 mg/ml
HPRT-test V79 cells Up to 10 mg/ml
In vivo
Bone marrow cytogenetic test Rat 10 No mutagenic effect was observed
Local Tolerance
Rabbit (iv,ia,pv,sc,im)

Dog
SMOFlipid 20% revealed good local compliance in rabbits after intravenous infusion and following intra-arterial, paravenous and subcutaneous administration. Moderate local changes which had disappeared after 14 days were observed after intramuscular administration.
In the 4-week and 13-week repeat dose toxicity intravenous infusion studies in peripheral veins with SMOFlipid 20%, a similar slight to moderate reaction, mainly characterized by induration and swelling, was seen at the infusion sites in dogs in the test, reference, and control groups at similar incidence and severity. The vascular changes were consistent with the anticipated response to repeated venipuncture
The osmolality of SMOFlipid 20% is approximately 380 mOsm/kg water and similar that of human serum (281-297 mOsm/kg water).

*Reference Soybean oil emulsion

**Reference: 0.9% NaCl solution

No reproductive toxicity studies have been performed with SMOFlipid. However studies have been performed with the individual components of SMOFlipid (LCT, MCT, olive oil, and fish oil) without revealing any toxic potential.

Safety pharmacology studies have not been performed with SMOFlipid. However, SMOFlipid repeat dose toxicity studies did not reveal any adverse effects on any organ system or function.

In toxicological studies performed with SMOFlipid no other effects than those expected after high doses of lipids were observed, based on single dose and repeat dose toxicity. No signs of genotoxic potential were detected in the respective studies. In a local tolerance study in rabbits good local compliance was observed after intravenous infusion and following intra-arterial paravenous and subcutaneous administration. Moderate local changes observed after intramuscular administration disappeared after 14 days.

The following toxicological studies have been performed with Vamine or Novamine as a representative for Aminoven.

Type of study Species Vamine Novamine Doses g N/kg bw/day Observations and conclusions
Safety Pharmacology
Cat 0.86 Study on cardiovascular, respiratory and metabolic functions after intravenous infusion of Vamin 18 EF showed no effects of biological/clinical significance in anesthetized cats.
Single-Dose Toxicity
Mouse 0.95 Vamin 18 EF was given to male mice at a dose of 50 ml/kg bw. for 7.5 hours without any symptoms of toxicity.
Repeat-Dose Toxicity
4-week Rat 3 Vamin 18 EF was infused for 20 h/day. The dose level was adequately high as they are in the order of 13.6 times the maximum recommend daily clinical dose of Vamin 18 Novum. Overall, the animals tolerated the solution very well.
4-week Dog 0.42 In the 4-week study Vamin 14 was intravenously infused into alternate peripheral veins for 4 weeks. In the 13-week study Vamin 18 EF was administered by daily 12 h intravenous infusion into a central vein. In both studies, dogs tolerated the amino acid solutions well and did not show any treatment related clinical chemical or histopathological changes.
13-week Dog 0.94
Genotoxicity
In vitro
Bacterial gene mutation S. typhimurium E. coli Up to 10 mg AA/plate No mutagenic effects were observed for tested amino acid solution.
Mouse lymphoma L5178Y cells Up to 10 mg AA/ml
Reproductive and Developmental Toxicity
Embryo-Fetal Rabbit 0.54 A teratogenicity study in rabbits with Vamin 18 EF given intravenously on day 6-18 of pregnancy for 4 hours/day revealed no significant toxicity in dams or any embryotoxic or teratogenic effects.
Local Tolerance
Rabbit (iv,ia,pv,sc,im)

Dog
Studies on Local Tolerance in the rabbit have been performed with Aminomix Peripheral**. They revealed a good local compliance in rabbits after intravenous infusion and following intra-arterial, paravenous and subcutaneous administration.
In addition, the local tolerance of different Vamin solutions was thoroughly investigated in the respective repeated dose toxicity studies in rats and dogs both as part of the daily clinical observation and by histopathology at the end of the study.
Other Toxicity Studies
Haemolysis (Human blood) In vitro studies investigating hemocompatibility have been performed with Aminomix Peripheral*. Incompatibility or hemolytic reactions were not observed.

* 2 chamber bag containing Glucose (63g per liter) and amino acids (35g per liter)

The following toxicological studies have been performed with Glycerophosphate

Type of study Species Glycerophosphate Doses g /kg bw/day Observations and conclusions
Safety Pharmacology
Cat 0.118 Study on cardiovascular functions after intravenous infusion of DP-Trauma 20% showed no effects of biological/clinical significance in anesthetized cats.
Single-Dose Toxicity
Mouse 0.96 No toxic effects were observed in mice given 60 ml /kg of Na-GP intravenously.
Rat 0.073 Intravenous administration of a single dose of 17 ml/kg of a glycerophosphate containing dipeptide amino acid solution was tolerated well.
1-6 LD 50 was found to be 3800 to 3400 mg/kg, respectively, for alpha and beta glycerophosphate after intravenous administration to rats.
Repeat-Dose Toxicity
4-week Rat 0.409 In a 4-week toxicity study of DP-Trauma 20% a dipeptide/amino acid solution containing sodium glycerophosphate no adverse clinical signs and no clinical or morphological evidence of organ toxicity were observed in rats after daily infusion of 94.6ml/kg over 20 hours.
2-week Dog 1 bid In a 2-week toxicity study of 1000 mg/kg sodium-beta glycerophosphate twice per day was well tolerated and did not cause any signs of toxicity. This corresponds to a dose which was 28.2 times the maximum human dose
4-week Dog 0.066 In a 4-week toxicity study of DP-Trauma 20% a dipeptide/amino acid solution containing sodium glycerophosphate, no adverse clinical signs and no clinical or morphological evidence of organ toxicity were observed in dogs after daily infusion of 15ml/kg over 6 hours.
Genotoxicity
In vitro
Bacterial gene mutation S. typhimurium Up to 5 mg/plate No mutagenic effects were observed.
Mouse lymphoma L5178Y cells Up to 2.16 mg/ml
In vivo
Bone marrow micronucleus Mouse 2,160 mg/kg bw iv bolus No mutagenic effect was observed.
Local Tolerance
Rabbit (iv,ia,pv,sc,im) Studies on Local Tolerance in rabbits have been performed with Aminomix Peripheral*. They revealed good local compliance in rabbits after intravenous infusion and following intra-arterial, paravenous and subcutaneous administration
Dog In addition, the local tolerance of different glycerophosphate containing amino acid solutions was thoroughly investigated in the respective repeated dose toxicity studies in dogs both as part of the daily clinical observation and by histopathology at the end of the study
Other Toxicity Studies
Haemolysis (Human blood) In vitro studies on hemocompatibility have been performed with Aminomix Peripheral*. They did not show any incompatibility reactions or hemolytic properties

*2 chamber bag containing Glucose (63g per liter) and Amino acids (35g per liter)

No teratogenic effects or other embryotoxic injuries could be observed in rabbits with amino acid solutions and are not to be expected from lipid emulsions and sodium glycerophosphate when given at the recommended doses during parenteral nutrition. Nutritional products (amino acid solutions, lipid emulsions, and sodium glycerophosphate) used during parenteral nutrition to maintain normal levels are not expected to be embryotoxic, teratogenic, or to influence reproductive performance or fertility.