This information is intended for use by health professionals

1. Name of the medicinal product

TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, emulsion for infusion

2. Qualitative and quantitative composition

TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, emulsion for infusion is presented in the form of a 3-compartment bag.

Each bag contains a glucose solution with calcium, a lipid emulsion and an amino acid solution with other electrolytes.

Contents per bag

650 mL

1,000 mL

1,500 mL

2,000 mL

27.5% Glucose solution

(corresponding to 27.5 g/100 mL)

173 mL

267 mL

400 mL

533 mL

14.2% Amino acid solution

(corresponding to 14.2 g/100 mL)

347 mL

533 mL

800 mL

1,067 mL

17.5% Lipid emulsion

(corresponding to 17.5 g/100 mL)

130 mL

200 mL

300 mL

400 mL

Composition of the reconstituted emulsion after mixing the contents of the 3 compartments:

Active substances

650 mL

1,000 mL

1,500 mL

2,000 mL

Refined olive oil+ refined soybean oila

22.75 g

35.00 g

52.50 g

70.00 g

Alanine

7.14 g

10.99 g

16.48 g

21.97 g

Arginine

4.84 g

7.44 g

11.16 g

14.88 g

Aspartic acid

1.43 g

2.20 g

3.30 g

4.39 g

Glutamic acid

2.46 g

3.79 g

5.69 g

7.58 g

Glycine

3.42 g

5.26 g

7.90 g

10.53 g

Histidine

2.94 g

4.53 g

6.79 g

9.06 g

Isoleucine

2.46 g

3.79 g

5.69 g

7.58 g

Leucine

3.42 g

5.26 g

7.90 g

10.53 g

Lysine

(equivalent to lysine acetate)

3.88 g

(5.48 g)

5.97 g

(8.43 g)

8.96 g

(12.64 g)

11.95 g

(16.85 g)

Methionine

2.46 g

3.79 g

5.69 g

7.58 g

Phenylalanine

3.42 g

5.26 g

7.90 g

10.53 g

Proline

2.94 g

4.53 g

6.79 g

9.06 g

Serine

1.95 g

3.00 g

4.50 g

5.99 g

Threonine

2.46 g

3.79 g

5.69 g

7.58 g

Tryptophan

0.82 g

1.26 g

1.90 g

2.53 g

Tyrosine

0.13 g

0.20 g

0.30 g

0.39 g

Valine

3.16 g

4.86 g

7.29 g

9.72 g

Sodium acetate, trihydrate

0.97 g

1.5 g

2.24 g

2.99 g

Sodium glycerophosphate, hydrated

2.39 g

3.67 g

5.51 g

7.34 g

Potassium chloride

1.45 g

2.24 g

3.35 g

4.47 g

Magnesium chloride, hexahydrate

0.53 g

0.81 g

1.22 g

1.62 g

Calcium chloride, dihydrate

0.34 g

0.52 g

0.77 g

1.03 g

Glucose

(equivalent to glucose monohydrate)

47.67 g

(52.43 g)

73.33 g

(80.67 g)

110.00 g

(121.00 g)

146.67 g

(161.33 g)

a Mixture of refined olive oil (approximately 80%) and refined soybean oil (approximately 20%) corresponding to a ratio essential fatty acids / total fatty acids of 20%

For the full list of excipients, see section 6.1.

Nutritional intakes of reconstituted emulsion for each of the bag sizes:

650 mL

1,000 mL

1,500 mL

2,000 mL

Lipids

22.8 g

35.0 g

52.5 g

70.0 g

Amino acids

49.4 g

75.9 g

113.9 g

151.9 g

Nitrogen

7.8 g

12.0 g

18.0 g

24.0 g

Glucose

47.7 g

73.3 g

110.0 g

146.7 g

Energy:

Total calories approx.

620 kcal

950 kcal

1,420 kcal

1,900 kcal

Non-protein calories

420 kcal

640 kcal

960 kcal

1,280 kcal

Glucose calories

190 kcal

290 kcal

430 kcal

580 kcal

Lipid caloriesa

230 kcal

350 kcal

520 kcal

700 kcal

Non-protein calories / nitrogen ratio

53 kcal/g

53 kcal/g

53 kcal/g

53 kcal/g

Glucose / lipid calories ratio

45/55

45/55

45/55

45/55

Lipid / total calories

37%

37%

37%

37%

Electrolytes:

Sodium

22.8 mmol

35.0 mmol

52.5 mmol

70.0 mmol

Potassium

19.5 mmol

30.0 mmol

45.0 mmol

60.0 mmol

Magnesium

2.6 mmol

4.0 mmol

6.0 mmol

8.0 mmol

Calcium

2.3 mmol

3.5 mmol

5.3 mmol

7.0 mmol

Phosphateb

9.5 mmol

15.0 mmol

21.9 mmol

29.2 mmol

Acetate

46 mmol

70 mmol

105 mmol

140 mmol

Chloride

30 mmol

45 mmol

68 mmol

90 mmol

pH

6.4

6.4

6.4

6.4

Osmolarity approx..

1,270 mOsm/L

1,270 mOsm/L

1,270 mOsm/L

1,270 mOsm/L

a Includes calories from purified egg phosphatide

b Includes phosphate provided by the lipid emulsion

3. Pharmaceutical form

After reconstitution:

Emulsion for infusion.

Appearance prior to reconstitution:

- The amino acids and glucose solutions are clear, colourless or slightly yellow,

- The lipid emulsion is homogenous with a milky appearance.

4. Clinical particulars
4.1 Therapeutic indications

TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, is indicated for parenteral nutrition for adults and children greater than 2 years of age when oral or enteral nutrition is impossible, insufficient or contraindicated.

4.2 Posology and method of administration

Posology

TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, is not recommended for use in children less than 2 years of age due to inadequate composition and volume (see sections 4.4; 5.1 and 5.2).

The maximum daily dose mentioned below should not be exceeded. Due to the static composition of the multi-chamber bag, the ability to simultaneously meet all nutrient needs of the patient may not be possible. Clinical situations may exist where patients require amounts of nutrients varying from the composition of the static bag. In this situation, the impact of any volume (dose) adjustments must be taken into consideration and the resultant effect this will have on the dosing of all other nutrient components of TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes. In those situations, health care professionals may consider adjusting the volume (dose) of TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes in order to meet these increased requirements.

In adults

The dosage depends on the patient's energy expenditure, clinical status, body weight, and the ability to metabolise the constituents of TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, as well as additional energy or proteins provided orally/enterally; therefore, the bag size should be chosen accordingly.

The average daily requirements are:

- 0.16 to 0.35 g nitrogen /kg body weight (1 to 2 g of amino acids/kg), depending on the patient's nutritional status and degree of catabolic stress. Special populations may require up to 0.4 g nitrogen/kg body weight (2.5 g of amino acids/kg).

- 20 to 40 kcal/kg,

- 20 to 40 mL fluid /kg, or 1 to 1.5 mL per expended kcal.

For TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, the maximal daily dose is defined by amino acids intake, 26 mL/kg corresponding to 2.0 g/kg amino acids, 1.9 g/kg glucose, 0.9 g/kg lipids. For a 70 kg patient, this would be equivalent to 1,820 mL TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes per day, resulting in an intake of 138 g amino acids, 133 g glucose, and 64 g lipids (i.e., 1,171 non-protein kcal and 1,723 total kcal).

In Continuous Renal Replacement Therapy (CRRT): For TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, the maximal daily dose is defined by amino acids intake, 33 mL/kg corresponding to 2.5 g/kg amino acids, 2.4 g/kg glucose, 1.2 g/kg lipids. For a 70 kg patient, this would be equivalent to 2,310 mL TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes per day, resulting in an intake of 175 g amino acids, 169 g glucose, and 81 g lipids (i.e., 1,486 non-protein kcal and 2,187 total kcal).

In patients with morbid obesity: The dosage should be calculated on basis of the ideal body weight (IBW). For TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, the maximal daily dose is defined by amino acids intake, 33 mL/kg IBW corresponding to 2.5 g/kg amino acids, 2.4 g/kg glucose, 1.2 g/kg lipids. For a 70 kg patient, this would be equivalent to 2,310 mL TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes per day, resulting in an intake of 175 g amino acids, 169 g glucose, and 81 g lipids (i.e., 1,486 non-protein kcal and 2,187 total kcal).

Normally, the flow rate must be increased gradually during the first hour and then be adjusted to take into account the dose being administered, the daily volume intake, and the duration of the infusion.

For TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, the maximal infusion rate is 1.3 mL/kg/hour, corresponding to 0.10 g/kg/hour amino acids, 0.10 g/kg/hour glucose, and 0.05 g/kg/hour lipids.

In children, greater than 2 years of age and adolescents

There have been no studies performed in the paediatric population.

The dosage depends on the patient's energy expenditure, clinical status, body weight, and the ability to metabolise constituents of TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, as well as additional energy or proteins given orally/enterally; therefore, the bag size should be chosen accordingly.

In addition, daily fluid, nitrogen, and energy requirements continuously decrease with age. Two groups, ages 2 to 11 years and 12 to 18 years, are considered.

For TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, in the 2 to 11 year age group, amino acid and magnesium concentrations are the limiting factor for daily dose. In this age group, the amino acid concentration is the limiting factor for hourly rate. In the 12 to 18 year age group, amino acid and magnesium concentrations are the limiting factor for daily dose. In this age group, the amino acid concentration is the limiting factor for hourly rate. The resulting intakes are displayed below:

Constituent

2 to 11 years

12 to 18 years

Recommendeda

TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes Max Vol

Recommendeda

TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes Max Vol

Maximum Daily Dose

Fluids (mL/kg/d)

60 – 120

33

50 – 80

26

Amino acids (g/kg/d)

1 – 2 (up to 2.5)

2.5

1 – 2

2

Glucose (g/kg/d)

1.4 – 8.6

2.4

0.7-5.8

1.9

Lipids (g/kg/d)

0.5 – 3

1.2

0.5 – 2 (up to 3)

0.9

Total energy (kcal/kg/d)

30 – 75

31.4

20 – 55

24.7

Maximum Hourly Rate

TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes (mL/kg/h)

2.6

1.6

Amino acids (g/kg/h)

0.20

0.20

0.12

0.12

Glucose (g/kg/h)

0.36

0.19

0.24

0.12

Lipids (g/kg/h)

0.13

0.09

0.13

0.06

aRecommended values from 2018 ESPGHAN/ESPEN/ESPR Guidelines

Normally, the flow rate must be increased gradually during the first hour and then be adjusted to take into account the dose being administered, the daily volume intake, and the duration of the infusion.

In general, it is recommended to start the infusion for small children with low daily dose and gradually increase it up to the maximal dosage (see above).

Maximal infusion rate is 2.6 mL/kg/hour in children 2 to 11 years of age and 1.6 mL/kg/hour in children 12 to 18 years of age.

Method and duration of administration

For single use only.

It is recommended that, after opening the bag, the contents are used immediately and not stored for subsequent infusion.

After reconstitution, the mixture is homogenous with a milky appearance.

For instructions for preparation and handling of the emulsion for infusion, see section 6.6.

Due to its high osmolarity, TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes must only be administered through a central vein.

The recommended duration of infusion for a parenteral nutrition bag is between 12 and 24 hours.

Treatment with parenteral nutrition may be continued for as long as required by the patient's clinical conditions.

4.3 Contraindications

The use of TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes is contraindicated in the following situations:

- In premature neonates, infants, and children less than 2 years of age

- Hypersensitivity to egg, soya-bean, peanut proteins, or corn/corn products (see section 4.4) or to any of the active substances or excipients, listed in section 6.1

- Congenital abnormalities of amino acid metabolism

- Severe hyperlipidaemia or severe disorders of lipid metabolism characterised by hypertriglyceridaemia

- Severe hyperglycaemia

- Pathologically-elevated plasma concentrations of sodium, potassium, magnesium, calcium, and/or phosphorus

4.4 Special warnings and precautions for use

An excessively fast administration of total parenteral nutrition (TPN) solutions may result in severe or fatal consequences.

The infusion must be stopped immediately if any signs or symptoms of an allergic reaction (such as sweating, fever, chills, headache, skin rashes, or dyspnea) develop. This medicinal product contains soybean oil, and egg phosphatide. Soya-bean and egg proteins may cause hypersensitivity reactions. Cross-allergic reactions between soya-bean and peanut proteins have been observed.

TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes contains glucose derived from corn, which may cause hypersensitivity reactions in patients with allergy to corn or corn products (see section 4.3).

Ceftriaxone must not be mixed or administered simultaneously with any calcium-containing IV solutions even via different infusion lines or different infusion sites. Ceftriaxone and calcium-containing solutions may be administered sequentially one after another if infusion lines at different sites are used or if the infusion lines are replaced or thoroughly flushed between infusions with physiological salt-solution to avoid precipitation. In patients requiring continuous infusion with calcium-containing TPN solutions, healthcare professionals may wish to consider the use of alternative antibacterial treatments which do not carry a similar risk of precipitation. If use of ceftriaxone is considered necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone can be administered simultaneously, albeit via different infusion lines at different sites. Alternatively, infusion of TPN solution could be stopped for the period of ceftriaxone infusion, considering the advice to flush infusion lines between solutions (see sections 4.5 and 6.2).

Pulmonary vascular precipitates causing pulmonary vascular embolism and respiratory distress have been reported in patients receiving parenteral nutrition. In some cases, fatal outcomes have occurred. Excessive addition of calcium and phosphate increases the risk of formation of calcium phosphate precipitates (see section 6.2).

Suspected precipitate formation in the blood stream has also been reported.

In addition to inspection of the solution, the infusion set and catheter should also periodically be checked for precipitates.

If signs of respiratory distress occur, the infusion should be stopped and medical evaluation initiated.

Do not add other medicinal products or substances to any components of the bag or to the reconstituted emulsion without first confirming their compatibility and the stability of the resulting preparation (in particular, the stability of the lipid emulsion). Formation of precipitates or destabilisation of the lipid emulsion could result in vascular occlusion (see sections 6.2 and 6.6).

Vascular-access infection and sepsis are complications that may occur in patients receiving parenteral nutrition, particularly in case of poor maintenance of catheters, immunosuppressive effects of illness or drugs. Careful monitoring of signs, symptoms, and laboratory test results for fever/chills, leukocytosis, technical complications with the access device, and hyperglycaemia can help recognise early infections. Patients who require parenteral nutrition are often predisposed to infectious complications due to malnutrition and/or their underlying disease state. The occurrence of septic complications can be decreased with heightened emphasis on aseptic techniques in catheter placement and maintenance, as well as aseptic techniques in the preparation of the nutritional formula.

Specific clinical monitoring is required when an intravenous infusion is started.

Severe water and electrolyte equilibration disorders, severe fluid overload states, and severe metabolic disorders must be corrected before starting the infusion.

Monitor water and electrolyte balance, serum osmolarity, serum triglycerides, acid/base balance, blood glucose, liver and kidney function tests, coagulation tests, and blood count, including platelets, throughout treatment.

Elevated liver enzymes and cholestasis have been reported with similar products. Monitoring of serum ammonia should be considered if hepatic insufficiency is suspected.

Metabolic complications may occur if the nutrient intake is not adapted to the patient's requirements, or the metabolic capacity of any given dietary component is not accurately assessed. Adverse metabolic effects may arise from administration of inadequate or excessive nutrients or from inappropriate composition of an admixture for a particular patient's needs.

Administration of amino acid solutions may precipitate acute folate deficiency; folic acid is, therefore, recommended to be given daily.

Extravasation

Catheter site should be monitored regularly to identify signs of extravasation.

If extravasation occurs the administration should be stopped immediately, keeping the inserted catheter or cannula in place for immediate management of the patient. If possible, aspiration should be performed through the inserted catheter/cannula in order to reduce the amount of fluid present in the tissues before removing the catheter/cannula.

Depending on the extravasated product (including the product(s) being mixed with TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, if applicable) and the stage/extent of any injury, appropriate specific measures should be taken. Options for management may include non-pharmacologic, pharmacologic and/or surgical intervention. In case of large extravasation, plastic surgeon advice should be sought within the first 72 hours.

The extravasation site should be monitored at least every 4 hours during the first 24 hours, then once daily.

The infusion should not be restarted in the same central vein.

Hepatic Insufficiency

Use with caution in patients with hepatic insufficiency because of the risk of developing or worsening neurological disorders associated with hyperammonaemia. Regular clinical and laboratory tests are required, particularly liver function parameters, blood glucose, electrolytes and triglycerides.

Renal Insufficiency

Use with caution in patients with renal insufficiency, particularly if hyperkalaemia is present, because of the risk of developing or worsening metabolic acidosis and hyperazotaemia if extra-renal waste removal is not being performed. Fluid, triglycerides and electrolyte status should be closely monitored in these patients.

Hematologic

Use with caution in patients with coagulation disorders and anaemia. Blood count and coagulation parameters should be closely monitored.

Endocrine and Metabolism

Use with caution in patients with:

- Metabolic acidosis. Administration of carbohydrates is not recommended in the presence of lactic acidosis. Regular clinical and laboratory tests are required.

- Diabetes mellitus. Monitor glucose concentrations, glucosuria, ketonuria and, where applicable adjust insulin dosages.

- Hyperlipidaemia due to the presence of lipids in the emulsion for infusion. Regular clinical and laboratory tests are required.

- Amino acid metabolism disorders.

Hepatobiliary disorders

Hepatobiliary disorders including cholestasis, hepatic steatosis, fibrosis and cirrhosis, possibly leading to hepatic failure, as well as cholecystitis and cholelithiasis are known to develop in some patients on parenteral nutrition. The etiology of these disorders is thought to be multifactorial and may differ between patients. Patients developing abnormal laboratory parameters or other signs of hepatobiliary disorders should be assessed early by a clinician knowledgeable in liver diseases in order to identify possible causative and contributory factors, and possible therapeutic and prophylactic interventions.

Serum triglyceride concentrations and the ability of the body to remove lipids must be checked regularly.

Serum triglyceride concentrations must not exceed 3 mmol/L during the infusion.

If a lipid metabolism abnormality is suspected, it is recommended to measure daily serum triglyceride levels after a period of 5 to 6 hours without administering lipids. In adults, the serum must be clear in less than 6 hours after stopping the infusion containing the lipid emulsion. The next infusion must only be administered when the serum triglyceride concentrations have returned to baseline values.

Fat overload syndrome has been reported with similar products. The reduced or limited ability to metabolise the lipids contained in TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes may result in a "fat overload syndrome" which may be caused by overdose; however, the signs and symptoms of this syndrome may also occur when the product is administered according to instructions (see also section 4.8).

In the event of hyperglycaemia, the infusion rate of TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes must be adjusted and/or insulin administered.

DO NOT ADMINISTER THROUGH A PERIPHERAL VEIN.

When making additions, the final osmolarity of the mixture must be measured before administration. The mixture obtained must be administered through a central or peripheral venous line depending on its final osmolarity. If the final mixture administered is hypertonic, it may cause irritation of the vein when administered into a peripheral vein.

Although there is a natural content of trace elements and vitamins in the product, the levels are insufficient to meet body requirements, and these should be added to prevent deficiencies from developing. See instructions for making additions to this product.

Caution should be exercised in administering TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes to patients with increased osmolarity, adrenal insufficiency, heart failure or pulmonary dysfunction.

In malnourished patients, initiation of parenteral nutrition can precipitate fluid shifts resulting in pulmonary oedema and congestive heart failure, as well as a decrease in the serum concentration of potassium, phosphorus, magnesium, or water-soluble vitamins. These changes can occur within 24 to 48 hours; therefore, careful and slow initiation of parenteral nutrition is recommended together with close monitoring and appropriate adjustments of fluid, electrolytes, trace elements, and vitamins.

Do not connect bags in series in order to avoid the possibility of air embolism due to residual gas contained in the primary bag.

To avoid risks associated with excessively rapid infusion rates, it is recommended to use a continuous and controlled infusion.

TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes must be administered with caution to patients with a tendency towards electrolyte retention.

Intravenous infusion of amino acids is accompanied by increased urinary excretion of trace elements, in particular copper and zinc. This should be taken into account in the dosing of trace elements, especially during long-term intravenous nutrition.

Interference with laboratory tests

The lipids contained in this emulsion may interfere with the results of certain laboratory tests (see section 4.5).

Special precautions in paediatrics

When administered to children greater than 2 years of age, it is essential to use a bag that has a volume corresponding to the daily dosage.

TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes is not suitable for use in children less than 2 years of age because:

- The glucose intake is too low, leading to a low glucose / lipid ratio

- The absence of cysteine makes the amino acid profile inadequate

- Calcium is too low

Vitamin and trace elements supplementation is always required. Paediatric formulations must be used.

Geriatric population

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes must not be administered simultaneously with blood through the same infusion tubing because of the possibility of pseudoagglutination.

The lipids contained in this emulsion may interfere with the results of certain laboratory tests (for example, bilirubin, lactate dehydrogenase, oxygen saturation, blood haemoglobin) if the blood sample is taken before the lipids are eliminated (these are generally eliminated after a period of 5 to 6 hours without receiving lipids).

Precipitation of ceftriaxone-calcium can occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous administration line. Ceftriaxone must not be mixed or administered simultaneously with calcium-containing intravenous solutions, including TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, through the same infusion line (e.g., via Y-site). However, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid (see sections 4.4 and 6.2).

TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes contains vitamin K, naturally present in lipid emulsions. The amount of vitamin K in recommended doses of TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes are not expected to influence effects of coumarin derivatives.

Due to the potassium content of TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, special care should be taken in patients treated with potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene), angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or the immunosuppressants tacrolimus or cyclosporine in view of the risk of hyperkalaemia.

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.

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

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no clinical data from the use of TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes in pregnant women. No animal reproductive studies have been performed with TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes (see section 5.3). Taking into account the use and indications of TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, the product may be considered during pregnancy, if necessary. TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes should only be given to pregnant women after careful consideration.

Breast-feeding

There is insufficient information on the excretion of TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes components/metabolites in human milk. Parenteral nutrition may become necessary during breast-feeding. TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes should only be given to breast-feeding women after careful consideration.

Fertility

No adequate data are available.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

Potential undesirable effects may occur as a result of inappropriate use (for example: overdose, excessively fast infusion rate) (see sections 4.4 and 4.9).

At the beginning of the infusion, any of the following abnormal signs (sweating, fever, shivering, headache, skin rashes, dyspnoea) should be cause for immediate discontinuation of the infusion:

The following adverse drug reactions (ADRs) were reported with TRIOMEL 9 g/l nitrogen 1070 kcal/l in a randomised, double-blind, active-controlled, efficacy and safety study. Twenty-eight patients with various medical conditions (i.e., postsurgical fasting, severe malnutrition, enteral intake insufficient or forbidden) were included and treated; patients in the TRIOMEL group received drug product up to 40 mL/kg/d over 5 days.

The pooled data from clinical trials and the postmarketing experience indicate the following adverse drug reactions (ADRs) related to TRIOMEL.

System Organ Class

MedDRA Preferred Term

Frequencya

Cardiac Disorders

Tachycardia

Common

Metabolism and Nutrition Disorders

Decreased appetite

Common

Hypertriglyceridaemia

Common

Gastrointestinal Disorders

Abdominal pain

Common

Diarrhoea

Common

Nausea

Common

Vascular Disorders

Hypertension

Common

General disorders and administration site conditions

Extravasation which may result at infusion site level in: pain, irritation, swelling/oedema, erythema/warmth, skin necrosis, blisters/vesicles, inflammation, induration, skin tightness

Not knownb

Pyrexia

Not knownb

Chills

Not knownb

aFrequency is defined as very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); or not known (cannot be estimated from the available data)

bADRs reported during post-marketing experience with TRIOMEL

The following class-like-adverse drug reactions (ADRs) have been described in other sources in relation to similar parenteral nutrition products; the frequency of these events is not known.

- Blood and Lymphatic System Disorders: Thrombocytopenia

- Hepatobiliary Disorders: Cholestasis, Hepatomegaly, Jaundice

- Immune System Disorders: Hypersensitivity

- Injury, poisoning and procedural complications: Parenteral nutrition associated liver disease (see section 4.4)

- Investigations: Blood alkaline phosphatase increased, Transaminases increased, Blood bilirubin increased, Elevated liver enzymes

- Renal and Urinary Disorders: Azotemia

- Vascular disorders: Pulmonary vascular precipitates (pulmonary vascular embolism and respiratory distress) (see section 4.4).

Fat overload syndrome (very rare)

Fat overload syndrome has been reported with similar products. This may be caused by inappropriate administration (e.g. overdose and/or infusion rate higher than recommended, see section 4.9); however, the signs and symptoms of this syndrome may also occur at the start of an infusion when the product is administered according to instructions. The reduced or limited ability to metabolise the lipids contained in TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes accompanied by prolonged plasma clearance may result in a “fat overload syndrome”. This syndrome is associated with a sudden deterioration in the patient's clinical condition and is characterised by findings such as fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidaemia, liver fatty infiltration (hepatomegaly), deteriorating liver function, and central nervous system manifestations (e.g. coma). The syndrome is usually reversible when infusion of the lipid emulsion is stopped.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

In the event of inappropriate administration (overdose and/or infusion rate higher than recommended), nausea, vomiting, chills, headache, hot flush, hyperhidrosis and electrolyte disturbances and signs of hypervolemia or acidosis may occur and result in severe or fatal consequences. In such situations, the infusion must be stopped immediately. If medically appropriate, further intervention may be indicated.

Hyperglycaemia, glucosuria, and a hyperosmolar syndrome may develop if glucose infusion rate exceeds clearance.

The reduced or limited ability to metabolise lipids may result in a "fat overload syndrome", the results of which are usually reversible after the infusion of the lipid emulsion is stopped (see also section 4.8).

In some serious cases, haemodialysis, haemofiltration or haemodiafiltration may be necessary.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Solutions for parenteral nutrition/combinations

ATC code: B05BA10.

TRIOMEL's content in nitrogen (L series amino acids) and energy (glucose and triglycerides) enables maintaining an adequate nitrogen/energy balance.

This formulation also contains electrolytes.

The lipid emulsion included in TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes is an association of refined olive oil and refined soybean oil (ratio 80/20), with the following approximate distribution of fatty acids:

- 15% saturated fatty acids (SFA)

- 65% monounsaturated fatty acids (MUFA)

- 20% polyunsaturated essential fatty acids (PUFA)

The phospholipid/triglyceride ratio is 0.06.

Olive oil contains significant amounts of alpha-tocopherol which, combined with a moderate PUFA intake, contribute to improved vitamin E status and the reduction of lipid peroxidation.

The amino acid solution contains 17 L-series amino acids (including 8 essential amino acids), which are required for protein synthesis.

Amino acids also represent an energy source. Their oxidation results in excretion of nitrogen in the form of urea.

The amino acid profile is as follows:

- Essential amino acids/total amino acids: 44.8%

- Essential amino acids (g)/total nitrogen (g): 2.8%

- Branched-chain amino acids/total amino acids: 18.3%

The carbohydrate source is glucose.

5.2 Pharmacokinetic properties

The ingredients of TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes (amino acids, electrolytes, glucose and lipids) are distributed, metabolised and removed in the same way as if they had been administered individually.

5.3 Preclinical safety data

No preclinical studies with TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes have been performed.

Preclinical toxicity studies performed using the lipid emulsion contained in TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes have identified the changes, which are conventionally found with a high intake of a lipid emulsion: fatty liver, thrombocytopenia and elevated cholesterol.

Preclinical studies performed using the solutions of amino acids and glucose contained in TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes of different qualitative compositions and concentrations have not, however, revealed any specific toxicity.

6. Pharmaceutical particulars
6.1 List of excipients

Lipid emulsion compartment:

• Purified egg phosphatide

• Glycerol

• Sodium oleate

• Sodium hydroxide (for pH adjustment)

• Water for injections.

Compartment of amino-acid solution with electrolytes:

• Glacial acetic acid (for pH adjustment)

• Water for injections.

Compartment of glucose solution with calcium:

• Hydrochloric acid (for pH adjustment)

• Water for injections.

6.2 Incompatibilities

Do not add other medicinal products or substances to any components of the bag or to the reconstituted emulsion without first confirming their compatibility and the stability of the resulting preparation (in particular, the stability of the lipid emulsion).

Incompatibilities may be produced, for example, by excessive acidity (low pH) or inappropriate content of divalent cations (Ca2+ and Mg2+), which may destabilise the lipid emulsion.

As with any parenteral nutrition admixture, calcium and phosphate ratios must be considered. Excess addition of calcium and phosphate, especially in the form of mineral salts, may result in the formation of calcium phosphate precipitates.

TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes contains calcium ions which pose additional risk of coagulation precipitated in citrate anticoagulated/preserved blood or components.

Ceftriaxone must not be mixed or administered simultaneously with intravenous calcium-containing solutions, including TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, through the same infusion line (e.g., via Y-connector) because of the risk of precipitation of ceftriaxone-calcium salt (see sections 4.4 and 4.5).

Due to the risk of precipitation, TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes should not be administered through the same infusion line or admixed together with ampicillin or fosphenytoin.

Check compatibility with solutions administered simultaneously through the same administration set, catheter, or cannula.

Do not administer before, simultaneously with, or after blood through the same equipment because of the risk of pseudoagglutination.

6.3 Shelf life

2 years if the overwrap is not damaged.

After reconstitution

Chemical and physical in-use stability has been demonstrated for 7 days at 2°C- 8°C followed by 48 hours at temperature not exceeding 30°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 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

After addition of supplements (electrolytes, trace elements and vitamins; see section 6.6)

For specific admixtures, chemical and physical in-use stability has been demonstrated for 7 days at 2°C - 8°C followed by 48 hours at temperature not exceeding 30°C.

From a microbiological point of view, any admixture should be used immediately. If not used immediately, in-use storage times and conditions, after mixing and prior to use, are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C, unless addition of supplements has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Do not freeze.

Store in the overpouch.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature and contents of container

The 3-compartment bag is a multilayer plastic bag. The inner (contact) layer of the bag material is made of a blend of polyolefinic copolymers and is compatible with amino acid solutions, glucose solutions, and lipid emulsions. Other layers are made of polyethylene vinyl acetate (EVA), and of copolyester.

The glucose compartment is fitted with an injection site to be used for addition of supplements.

The amino acid compartment is fitted with an administration site for insertion of the spike of the infusion set.

The bag is packaged in an oxygen barrier overpouch with an oxygen absorber sachet.

Pack sizes:

650 mL bag: 1 carton with 10 bags

1,000 mL bag: 1 carton with 6 bags

1,500 mL bag: 1 carton with 4 bags

2,000 mL bag: 1 carton with 4 bags

1 bag of 650 mL, 1,000 mL, 1,500 mL, 2,000 mL

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

To open

Remove the protective overpouch.

Discard the oxygen absorber sachet.

Confirm the integrity of the bag and of the non-permanent seals. Use only if the bag is not damaged; if the non-permanent seals are intact (i.e., no mixture of the contents of the 3 compartments); if the amino acid solution and the glucose solution are clear, colourless, or slightly yellow, and practically free of visible particles; and if the lipid emulsion is a homogeneous liquid with a milky appearance.

Mixing the solutions and the emulsion

Ensure that the product is at room temperature when breaking the nonpermanent seals.

Manually roll the bag onto itself, starting at the top of the bag (hanger end). The nonpermanent seals will disappear from the side near the inlets. Continue to roll the bag until the seals are open along approximately half of their length.

Mix by inverting the bag at least 3 times.

After reconstitution, the mixture is a homogeneous emulsion with a milky appearance.

Additions

The capacity of the bag is sufficient to enable additions such as vitamins, electrolytes, and trace elements.

Any additions (including vitamins) may be made into the reconstituted mixture (after the non-permanent seals have been opened and after the contents of the 3 compartments have been mixed).

Vitamins may also be added into the glucose compartment before the mixture is reconstituted (before opening the non-permanent seals and before mixing the 3 compartments).

Additions must be performed by qualified personnel under aseptic conditions.

TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes, formulation may be supplemented with electrolytes, inorganic/organic phosphate and with commercially available preparations of multi-vitamin products (such as Cernevit) and multi-trace element products (such as Nutryelt). The maximal total levels for additions listed in the table below were demonstrated by stability data and should not be considered dosage recommendations. The electrolyte supplementation should be dictated by the patient's clinical needs and should not exceed nutritional guidelines. The electrolytes already present in the bag should be taken into account when reaching the maximal total level.

Compatibility may vary between products from different sources and health care professionals are advised to carry out appropriate checks when mixing TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes with other parenteral solutions.

Possible supplementations for 1000 mL TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes (for paediatrics)

Included level

Maximal further addition

Maximal total level

Sodium

35 mmol

115 mmol

150 mmol

Potassium

30 mmol

120 mmol

150 mmol

Magnesium

4.0 mmol

1.6 mmol

5.6 mmol

Calcium

3.5 mmol

1.5 mmol

5.0 mmol

Inorganic Phosphate

0 mmol

0/10 mmol b

0/10 mmol b

Organic Phosphate

15 mmol a

10/0 mmol b

25/15 mmol a,b

Other supplementations (trace elements, vitamins, selenium and zinc) c

Trace elements – Junyelt d

1 vial per bag (10mL concentrate solution)

Vitamins e

1 vial (lyophilizate)

Selenium

60 µg per bag

Zinc

3 mg per bag

a Phosphate provided by the lipid emulsion

b Values depending of the kind of phosphate added (i.e. 0 mmol inorganic phosphate + 10 mmol organic phosphate or 10 mmol inorganic phosphate + 0 mmol organic phosphate)

c For all bag formats, the trace elements, vitamins, selenium and zinc supplementation could be the same as for 1L bag

d Junyelt (Composition per vial: Zinc 15.30 µmol; Copper 3.15 µmol; Manganese 0.091 µmol; Iodine 0.079 µmol; Selenium 0.253 µmol)

e Combination of 1 vial multi-vitamin product (Composition per vial: Vit. B1 (Thiamine) 2.5 mg, Vit. B2 (Riboflavin) 3.6 mg, Vit. B6 (Pyridoxine) 4.0 mg, Vit. B5 (Pantothenic acid) 15 mg, Vit. C (Ascorbic acid) 100 mg, Vit. B8 (Biotin) 0.06 mg, Vit. B9 (Folic acid) 0.4 mg, Vit. B12 (Cyanocobalamin) 0.005 mg, Vit. PP (Nicotinamide) 40 mg) and 1 vial multi-vitamin product (Composition per vial: Vit.A (as Retinol palmitate) 2300 IU, Vit.D (as ergocaciferol) 400 IU, Vit.E (Alpha-tocopherol) 6.4 mg, Vit. K (phytomenadione) 200 µg)

Possible supplementations for 1000 mL TRIOMEL 12 g/l nitrogen 950 kcal/l with electrolytes (for adults)

Included level

Maximal further addition

Maximal total level

Sodium

35 mmol

115 mmol

150 mmol

Potassium

30 mmol

120 mmol

150 mmol

Magnesium

4.0 mmol

1.6 mmol

5.6 mmol

Calcium

3.5 mmol

1.5 mmol

5.0 mmol

Inorganic Phosphate

0 mmol

0/10 mmol b

0/10 mmol b

Organic Phosphate

15 mmol a

10/0 mmol b

25/15 mmol a,b

Other supplementations (trace elements, vitamins, selenium and zinc) c

Trace elements – Nutryelt d

2 vials per bag (10mL concentrate solution)

Vitamins – Cernevit e

1 vial (5 mL lyophilizate)

Selenium

500 µg per bag

Zinc

20 mg per bag

a Phosphate provided by the lipid emulsion

b Values depending of the kind of phosphate added (i.e. 0 mmol inorganic phosphate + 10 mmol organic phosphate or 10 mmol inorganic phosphate + 0 mmol organic phosphate)

c For all bag formats, the trace elements, selenium and zinc supplementation could be the same as for 1L bag; vitamin supplementation is per L of emulsion

d Nutryelt (Composition per vial: Zinc 153 µmol; Copper 4.7 µmol; Manganese 1.0 µmol; Fluorine 50 µmol; Iodine 1.0 µmol; Selenium 0.9 µmol; Molybdenum 0.21 µmol; Chromium 0.19 µmol; Iron 18 µmol)

e Cernevit (Composition per vial: Vit. A (as Retinol palmitate) 3500 IU, Vit. D3 (Cholecalciferol) 220 IU, Vit. E (Alpha-tocopherol) 11.2 IU, Vit. C (Ascorbic acid) 125 mg, Vit. B1 (Thiamine) 3.51 mg, Vit. B2 (Riboflavin) 4.14 mg, Vit. B6 (Pyridoxine) 4.53 mg, Vit. B12 (Cyanocobalamin) 6 µg, Vit. B9 (Folic acid) 414 µg, Vit. B5 (Pantothenic acid) 17.25 mg, Vit. B8 (Biotin) 69 µg, Vit. PP (Nicotinamide) 46mg)

When making additions, the final osmolarity of the mixture must be measured before administration via a peripheral vein.

To perform an addition:

- Aseptic conditions must be observed.

- Prepare the injection site of the bag.

- Puncture the injection site and inject the additives using an injection needle or a reconstitution device.

- Mix content of the bag and the additives.

Preparation of the infusion

Aseptic conditions must be observed.

Suspend the bag.

Remove the plastic protector from the administration outlet.

Firmly insert the spike of the infusion set into the administration outlet.

Administration

For single use only.

Only administer the product after the nonpermanent seals between the 3 compartments have been broken and the contents of the 3 compartments have been mixed.

Ensure that the final emulsion for infusion does not show any evidence of phase separation.

After opening the bag, the contents must be used immediately. The opened bag must never be stored for a subsequent infusion. Do not reconnect any partially used-bag.

Do not connect bags in series in order to avoid the possibility of air embolism due to gas contained in the primary bag.

Any unused product or waste material and all necessary devices must be discarded.

7. Marketing authorisation holder

Baxter Healthcare Limited

Caxton Way

Thetford

Norfolk

IP24 3SE

United Kingdom

8. Marketing authorisation number(s)

PL 00116/0662

9. Date of first authorisation/renewal of the authorisation

22/03/2019

10. Date of revision of the text

22/03/2019