Triomel

TRIOMEL 9 g/l nitrogen 1070 kcal/l, emulsion for infusion

TRIOMEL is presented in the form of a 3-compartment bag.

Each bag contains a glucose solution, a lipid emulsion and an amino acid solution.

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

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:

a: Includes calories from purified egg phosphatide

b: Includes phosphate provided by the lipid emulsion

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.

TRIOMEL 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.

Posology

TRIOMEL 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 any volume (dose) adjustments must take into consideration the resultant effect this will have on the dosing of all other nutrient components of TRIOMEL. For example, paediatric patients may require greater than 0.2 mmol/kg/day of phosphate. In those situations, health care professionals may consider adjusting the volume (dose) of TRIOMEL 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, 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,

- 20 to 40 kcal/kg,

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

For TRIOMEL, the maximal daily dose defined by amino acids intake, 35 mL/kg corresponding to 2.0 g/kg amino acids, 3.9 g/kg glucose, and 1.4 g/kg lipids. For a 70 kg patient, this would be equivalent to 2,450 mL TRIOMEL per day, resulting in an intake of 140 g amino acids, 270 g glucose, and 98 g lipids (i.e., 2,058 non-protein kcal and 2,622 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, the maximal infusion rate is 1.8 mL/kg/hour, corresponding to 0.10 g/kg/hour amino acids, 0.19 g/kg/hour glucose, and 0.07 g/kg/hour lipids.

In children greater than 2 years of age

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, 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 in the 2 to 11 year age group, the limiting factors are amino acid concentration for daily dose and lipid concentration for hourly rate. In the 12 to 18 year age group, the limiting factors are amino acid concentration for both daily dose and hourly rate. The resulting intakes are displayed below:

a: Recommended values from 2005 ESPGHAN/ESPEN 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).

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 can 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.

The use of TRIOMEL is contraindicated in the following situations:

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

- Hypersensitivity to egg, soybean, or peanut proteins, 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 characterized by hypertriglyceridemia,

- Severe hyperglycemia,

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. Soybean and egg proteins may cause hypersensitivity reactions. Cross-allergic reactions between soybean and peanut proteins have been observed.

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).

Precipitates of various natures have been reported even in the absence of phosphate salt in the solution.

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 destabilization of the lipid emulsion could result in vascular occlusion (see sections 6.2 and 6.6).

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

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

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 hyperglycemia can help recognize 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.

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, 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 hyperazotemia 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.

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 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 hyperglycemia, the infusion rate of TRIOMEL 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 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.

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 is not suitable for the 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;

- Phosphates are too low and other electrolytes are not included,

- The bag volumes are not appropriate.

In children greater than 2 years of age, additional glucose should be infused to reach the above-mentioned recommended daily dose. Phosphates and calcium should be supplemented to reach the recommended amounts in children (approximately 0.2 mmol/kg/d).

Maximal infusion rate is 3.3 mL/kg/hour in children 2 to 11 years of age and 2.1 mL/kg/hour in children 12 to 18 years of age.

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

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

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.

No interaction studies have been performed.

TRIOMEL 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).

TRIOMEL contains vitamin K, naturally present in lipid emulsions. The amount of vitamin K in recommended doses of TRIOMEL are not expected to influence effects of coumarin derivatives.

There are no clinical data from the use of TRIOMEL in pregnant or lactating women. Taking into account the use and indications of TRIOMEL, the product may be considered during pregnancy and breastfeeding, if necessary.

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

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 randomized, 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.

a: Frequency 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).

b: ADRs 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

- 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 metabolize the lipids contained in TRIOMEL 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 characterized by findings such as fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, 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.

In the event of inappropriate administration (overdose and/or infusion rate higher than recommended), signs of hypervolaemia and acidosis may occur.

An excessively fast infusion or administration of an inappropriately large volume of the product may cause nausea, vomiting, chills and electrolyte disturbances. In such situations the infusion must be stopped immediately.

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.

Pharmacotherapeutic group: Solutions for parenteral nutrition/combinations

ATC code: B05 BA10.

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

This formulation without electrolytes allows individual electrolyte intake to be adapted to meet specific requirements.

The lipid emulsion included in TRIOMEL 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.

The ingredients of TRIOMEL (amino acids, glucose and lipids) are distributed, metabolised and removed in the same way as if they had been administered individually.

No preclinical studies with TRIOMEL have been performed.

Preclinical toxicity studies performed using the lipid emulsion contained in TRIOMEL have identified the changes, which are conventionally found with a high intake of a lipid emulsion: fatty liver, thrombocytopaenia and elevated cholesterol.

Preclinical studies performed using the solutions of amino acids and glucose contained in TRIOMEL of different qualitative compositions and concentrations have not, however, revealed any specific toxicity.

Lipid emulsion compartment:

Purified egg phosphatide, Glycerol, Sodium oleate, Sodium hydroxide (for pH adjustment), Water for injections.

Amino acid solution compartment:

Glacial acetic acid (for pH adjustment), Water for injections.

Glucose solution compartment:

Hydrochloric acid (for pH adjustment), Water for injections.

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 destabilize 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.

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.

2 years if the overwrap is not damaged.

After reconstitution

It is recommended that the product be used immediately after the non-permanent seals between the 3 compartments have been opened. However, the stability of the reconstituted emulsion has been demonstrated for 7 days (between 2°C and 8°C) followed by 48 hours at temperature not exceeding 25°C.

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

For specific admixtures, in-use stability has been demonstrated for 7 days (between 2°C and 8°C) followed by 48 hours at temperature not exceeding 25°C.

From a microbiological point of view, any admixture should be used immediately. If not used immediately, 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 to 8°C, unless addition of supplements has taken place in controlled and validated aseptic conditions.

Do not freeze.

Store in the overpouch.

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

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:

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 1,000 mL, 1,500 mL and 2,000 mL

Not all pack sizes may be marketed.

To open

Remove the protective overpouch.

Discard the oxygen absorber sachet.

Confirm the integrity of the bag and of the nonpermanent seals. Use only if the bag is not damaged; if the nonpermanent 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 nonpermanent 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 nonpermanent seals and before mixing the 3 compartments).

When making additions to formulations containing electrolytes, the amount of electrolytes already present in the bag should be taken into account.

Additions must be performed by qualified personnel under aseptic conditions.

TRIOMEL may be supplemented with electrolytes according to the tables below:

a: Value corresponding to the addition of inorganic phosphate.

b: Including phosphate provided by the lipid emulsion.

Trace elements and vitamins:

Stability has been demonstrated with commercially-available preparations of vitamins and trace elements (containing up to 1 mg of iron).

Compatibility for other additives is available upon request.

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.

Baxter Healthcare Limited

Caxton Way

Thetford

Norfolk

IP24 3SE

United Kingdom

PL 00116/0646

Date of first authorisation: 22^nd January 2010

Date of last renewal: 21^st July 2013

28^th August 2017