Numeta g19e

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Numeta G19E (Numeta G19E)

Composition:

Active substances: L-alanine; L-arginine; L-aspartic acid; L-cysteine; L-glutamic acid; glycine; L-histidine; L-isoleucine; L-leucine; L-lysine monohydrate (equivalent to lysine); L-methionine; L-ornithine hydrochloride (equivalent to ornithine); L-phenylalanine; L-proline; L-serine; taurine; L-threonine; L-tryptophan; L-tyrosine; L-valine; sodium chloride; potassium acetate; calcium chloride dihydrate; magnesium acetate tetrahydrate; sodium glycerophosphate hydrate; glucose monohydrate (equivalent to anhydrous glucose); refined olive oil and refined soybean oil;

1 bag with a volume of 1000 ml contains:

• Proportional content of olive oil (approximately 80% by weight) and soybean oil (approximately 20% by weight).

After mixing, 1 packet contains:

* The proportional content of olive oil (approximately 80% by weight) and soybean oil (approximately 20% by weight) is calculated to achieve a content of 20% essential fatty acids (linoleic acid plus α-linolenic acid) of the total amount of fatty acids.

After reconstitution, the mixture contains:

* Phosphate for 3-in-1 mixture includes phosphorus from the lipid emulsion (egg phospholipids)

Excipients: amino acid solution: L-malic acid, water for injections;

glucose solution: concentrated hydrochloric acid, water for injections;

lipid emulsion: egg phospholipids for injections, glycerol, sodium oleate, sodium hydroxide, water for injections.

Pharmaceutical form. Infusion emulsion.

Main physicochemical properties: amino acid solution – clear, colorless or slightly yellow, practically free of particles; glucose solution – clear, colorless or slightly yellow, practically free of particles; lipid emulsion – homogeneous milky-colored liquid.

Pharmacotherapeutic group.

Solutions for parenteral nutrition. Combinations.

ATC code B05B A10.

Pharmacological properties.

Pharmacodynamics.

The nitrogen content (20 L-amino acids, including 8 essential amino acids) in Numeta G19E, as well as energy sources (glucose and triglycerides), allows maintaining an adequate nitrogen/energy balance. Nitrogen and energy are necessary for normal functioning of all body cells and are essential for protein synthesis, growth, wound healing, immune system function, muscle function, and many other cellular-level processes.

Numeta G19E also contains electrolytes.

The amino acid profile is as follows:

• essential amino acids/total amino acid content – 47.5%;
• branched-chain amino acids/total amino acid content – 24.0%.

The lipid emulsion contained in Numeta G19E is a mixture of refined olive oil and refined soybean oil (in an approximate ratio of 80/20) with the following fatty acid distribution:

• 15% saturated fatty acids (SFA);
• 65% monounsaturated fatty acids (MUFA);
• 20% polyunsaturated fatty acids (PUFA).

The phospholipid/triglyceride ratio is 0.06. A moderate content of essential fatty acids (EFA) improves the status of their higher derivatives while simultaneously correcting EFA deficiency.

Olive oil contains significant amounts of alpha-tocopherol, which, in combination with moderate intake of PUFAs, helps normalize vitamin E levels and is important for limiting lipid peroxidation.

Glucose is the source of carbohydrates. Glucose is the primary source of energy in the body.

Pharmacokinetics.

The ingredients of the infusion emulsion (amino acids, electrolytes, glucose, lipids) are distributed, metabolized, and eliminated via the same pathways as each individual ingredient separately. The preparation is administered intravenously; therefore, its bioavailability is 100%, and its components are distributed into all body cells and metabolized.

Clinical characteristics.

Indications.

For parenteral nutrition in children aged 2 years and adolescents aged 16–18 years when oral or enteral nutrition is impossible, inadequate, or contraindicated.

Contraindications.

Contraindications for the use of Numeta G19E as an activated dual-chamber bag (without lipid emulsion) for intravenous infusion:

• Hypersensitivity to egg or soy proteins, peanut, or to any of the active substances, excipients, or components of the bag material;
• Inborn errors of amino acid metabolism;
• Pathologically elevated plasma concentrations of sodium, potassium, magnesium, calcium, and/or phosphorus;
• Severe hyperglycemia.

Addition of lipids (administration of Numeta G19E as an activated triple-chamber bag with emulsion for intravenous infusion) is contraindicated in the following clinical situations:

• Severe hyperlipidemia or severe disorders of lipid metabolism characterized by hypertriglyceridemia.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interaction studies with Numeta G19E have not been conducted.

Numeta G19E must not be administered simultaneously with blood transfusion through the same infusion system due to the risk of pseudoagglutination.

In patients of any age (including adults), ceftriaxone must not be mixed or administered simultaneously with any intravenous calcium-containing solutions, including Numeta G19E, even via different infusion systems or at different infusion sites, due to the risk of precipitation of ceftriaxone-calcium salt (see section "Special precautions for use").

However, in patients older than 28 days, ceftriaxone and calcium-containing solutions may be administered sequentially if different infusion systems or different infusion sites are used, or if the infusion system is replaced or thoroughly flushed with saline solution between infusions to prevent precipitation.

Olive and soybean oils contain natural vitamin K1, which is an antagonist of coumarin (or coumarin derivatives, including warfarin) anticoagulant activity.

Since Numeta G19E contains potassium, special attention should be paid to patients who are concurrently receiving potassium-sparing diuretics (such as amiloride, spironolactone, triamterene) or ACE inhibitors, angiotensin II receptor antagonists, or the immunosuppressants tacrolimus and cyclosporine due to the risk of hyperkalemia.

Lipids contained in this emulsion may affect the results of certain laboratory tests (such as bilirubin, lactate dehydrogenase, oxygen saturation, blood hemoglobin) if blood samples are taken before lipid clearance. Lipids are generally cleared within 5–6 hours, unless additional administration is ongoing.

Special precautions for use.

Infusion should be stopped immediately if any signs or symptoms of an allergic reaction occur (such as fever, sweating, shivering, headache, skin rash, or shortness of breath).

Numeta G19E contains glucose derived from corn starch. Therefore, this product should be used with caution in patients with a known allergy to corn or corn products.

Ceftriaxone must not be mixed or administered simultaneously with any calcium-containing intravenous solutions, including Numeta G19E, in patients of any age (including adults), even via different infusion systems or at different infusion sites, due to the risk of precipitation of calcium ceftriaxone salt.

However, in patients older than 28 days, ceftriaxone and calcium-containing solutions may be administered sequentially one after another, provided that different infusion systems or different infusion sites are used, or if the infusion system has been replaced or thoroughly flushed with saline solution between infusions to prevent precipitation.

Pulmonary embolism and respiratory distress due to precipitates in pulmonary vessels have been reported in patients receiving parenteral nutrition. In some cases, fatal outcomes have occurred. Excessive addition of calcium and phosphates increases the risk of calcium phosphate precipitate formation (see section "Incompatibilities"). There have also been reports of suspected precipitate formation within the vascular system.

In addition to checking the solution, the infusion set and catheter should be periodically inspected for precipitate formation.

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

No substance should be added to the infusion bag without prior verification of ingredient compatibility, as precipitate formation or lipid emulsion destabilization may lead to vascular occlusion (see sections "Incompatibilities" and "Dosage and administration").

Infection and sepsis may occur as a result of using intravenous catheters for parenteral drug administration or due to poor catheter care. Immunosuppressive effects of disease or medications may predispose to infection and sepsis. Close monitoring for symptoms and laboratory signs—such as fever/chills, leukocytosis, technical complications related to the medical device access system, and hyperglycemia—can help detect infection at an early stage. Patients requiring parenteral nutrition are often predisposed to infectious complications due to malnutrition and/or their underlying disease. Strict adherence to aseptic techniques is essential during catheter insertion, catheter care, and preparation of parenteral nutrition formulations.

Fat overload syndrome has been reported during administration of other parenteral nutrition products. Reduced or limited capacity to metabolize the fats contained in Numeta G19E may lead to fat overload syndrome.

Refeeding severely malnourished patients may lead to refeeding syndrome, characterized by intracellular depletion of potassium, phosphate, and magnesium due to anabolic processes in the patient. Thiamine deficiency and fluid retention may also develop. Parenteral nutrition should therefore be initiated cautiously and slowly, with careful monitoring of fluid, electrolyte, trace element, and vitamin levels.

Numeta G19E must be administered only via central veins, except when appropriate dilution has been performed (see section "Dosage and administration"). When adding other substances to the product, the final osmolarity of the mixture must be calculated before administration via a peripheral vein to avoid venous irritation or tissue damage in case of extravasation. Peripheral administration of Numeta G19E has led to extravasation and, consequently, soft tissue damage and skin necrosis.

Bags must not be connected in series (sequentially), to avoid potential air embolism from residual gas in the first bag.

If necessary, fats, vitamins, additional electrolytes, and trace elements should be supplemented.

Precautionary measures

Do not add other medicinal products or substances to any of the three chambers of the bag or to the reconstituted solution/emulsion without prior confirmation of compatibility and final product stability (particularly lipid emulsion stability) (see sections "Incompatibilities" and "Dosage and administration").

Protect Numeta G19E from light exposure from the moment of mixing until administration.

Water and electrolyte balance should be monitored regularly throughout the treatment period, including serum osmolarity, serum triglyceride concentration, acid-base balance, blood glucose levels, liver and kidney function, blood cell counts (including platelets), and coagulation parameters.

Administration of Numeta G19E in unstable clinical conditions (e.g., after severe trauma, in decompensated diabetes mellitus, during the acute phase of circulatory shock, acute myocardial infarction, severe metabolic acidosis, severe sepsis, or hyperosmolar coma) should be carefully monitored and adjusted according to the patient's clinical needs.

Cardiovascular system

Use with caution in patients with pulmonary edema or heart failure. Water balance should be closely monitored.

Kidneys

Use with caution in patients with renal insufficiency. Water and electrolyte balance should be closely monitored in such patients.

Severe disturbances in water-electrolyte balance, severe fluid overload, and severe metabolic disorders should be corrected before initiating infusion.

Liver/Gastrointestinal system

Use with caution in patients with severe hepatic insufficiency, including cholestasis, or elevated liver enzymes. Liver function parameters should be closely monitored.

Endocrine system and metabolism

Metabolic complications may occur if nutrient intake is not adapted to the patient’s needs or if metabolic capacity for any dietary component is inaccurately assessed. Undesirable metabolic effects may result from administration of inappropriate or excessive nutrients or from inadequate formulation of the mixture relative to the individual patient’s requirements.

Serum triglyceride levels and the body’s ability to metabolize fats should be monitored regularly. Monitoring of serum triglyceride levels is recommended when clinically necessary, especially if impaired fat metabolism is suspected.

In case of hyperglycemia, the infusion rate of Numeta G19E should be adjusted and/or insulin administered (see section "Overdose").

Blood

Use with caution in patients with severe coagulation disorders. Blood cell counts and coagulation parameters should be closely monitored.

Use during pregnancy or breastfeeding

There are no data on the use of Numeta G19E in pregnant women or women who are breastfeeding. The physician must carefully evaluate the potential risks and benefits for each individual patient before prescribing Numeta G19E.

Ability to affect reaction speed when driving or operating machinery

Not applicable.

Method of Administration and Dosage

Dosage

The dosage depends on energy requirements, body weight, age, clinical condition of the patient, and the patient's ability to metabolize the components of Numeta G19E, as well as the amount of additional energy or protein entering the body via oral/enteral routes. The overall composition of electrolytes and macronutrients depends on the number of activated chambers (see section "Composition").

The maximum daily dose should not be exceeded. Due to the fixed composition of the multi-chamber bag, it may be impossible to simultaneously meet all of the patient's nutritional requirements. There may be clinical situations in which patients require nutrients in amounts different from those contained in the multi-chamber bag.

The maximum recommended infusion rate per hour and the maximum daily volume depend on the components of the medicinal product. The first of these achievable limits determines the maximum daily dose. Table 1 provides the maximum recommended infusion rates per hour and the maximum daily volume.

Table 1

a Restrictive parameter according to the guidelines of the European Society for Clinical Nutrition and Metabolism – European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPEN-ESPGHAN).

Method of administration

The solution (in bags and administration sets) should be protected from light exposure from the moment of mixing until administration.

Due to its high osmolarity, undiluted Numeta G19E must be administered only through a central vein. However, adequate dilution of Numeta G19E with water for injections reduces osmolarity and allows administration via infusion into a peripheral vein. The formula below shows how dilution affects the osmolarity of the bag contents.

Final osmolarity = (bag volume × initial osmolarity) / (volume of added water + bag volume).

Examples of osmolarities of the admixtures from activated 3-chamber bags after addition of water for injections are shown in Table 2.

Table 2

The infusion rate should be gradually increased during the first hour. At the end of the infusion, the infusion rate should be gradually reduced over the last hour. The infusion rate should be adjusted according to the dose administered, daily volume, and duration of infusion.

The contents of a single bag should not be used for longer than 24 hours. Cyclic infusions should be scheduled according to the patient's metabolic tolerance.

Parenteral nutrition therapy may be continued as long as the patient's clinical condition requires it.

This preparation contains electrolytes, and other electrolyte preparations may be added depending on the patient's clinical needs.

Vitamins and trace elements may be added according to the patient's clinical needs.

Instructions for Use of Bags

For single use only.

Do not use damaged bags.

Check the integrity of the bag and the non-permanent partitions. Use only undamaged bags with intact non-permanent partitions (i.e., no mixing of the contents of the three chambers), provided that the solutions in the amino acid and glucose chambers are clear, colorless or slightly yellow, practically free of particles, and the lipid emulsion appears as a homogeneous milky liquid (see Figure 1).

Figure 1

Before opening the outer wrapper, check the color of the oxygen indicator. Compare it with the reference color printed next to the "OK" mark and shown in the printed area of the indicator label. Do not use the preparation if the color of the oxygen indicator does not match the reference color printed next to the "OK" mark.

Opening: Remove the protective outer wrapper (see Figure 2). Discard the outer wrapper and the sachet containing the oxygen absorber/indicator.

Figure 2

Mixing: Ensure the preparation is at room temperature before breaking the non-permanent partitions. Place the bag on a clean, flat surface.

Activation of 3 Chambers (breaking two non-permanent partitions)

Begin twisting the bag from the side of holder D (see Figure 3).

Figure 3

Apply pressure until the inter-chamber partitions open (see Figure 4).

Figure 4

Then change direction and twist the bag toward holder D; continue until the partition is fully opened.

Continue in the same direction to complete opening the second inter-chamber partition (see Figure 5).

Figure 5

Turn the bag over at least three times to thoroughly mix the contents (see Figure 6). The mixed solution should appear as a milk-like emulsion.

Figure 6

Remove the protective cap from the administration port (see Figure 7) and connect the intravenous administration set.

Figure 7

Activation of 2 Chambers (breaking the non-permanent partition between the amino acid and glucose chambers)

To break only the partition between the amino acid and glucose chambers, begin twisting from the corner of holder D of the partition (see Figure 8) separating the amino acid and glucose chambers, and press to open the partition between these two chambers.

Figure 8

Orient the bag so that the compartment containing the lipid emulsion is closest to the operator, and twist the bag while protecting the lipid emulsion compartment from rupture with the palms of the hands (see Figure 9).

Figure 9

Apply pressure with one hand, twisting the bag toward the tubes (see Figure 10).

Figure 10

Then begin twisting the bag toward holder D, pressing with the other hand, and continue until the partition between the amino acid and glucose compartments is fully opened (see Figure 11).

Figure 11

Turn the bag over at least three times to thoroughly mix the contents (see Figure 12). The mixed solution should appear as a clear, colorless or slightly yellow liquid.

Figure 12

Remove the protective cap from the administration port (see Figure 13) and connect the intravenous administration set.

Figure 13

Additives.

Additives, including trace elements and vitamins, should be protected from light from the moment of mixing until administration. Exposure to ambient light may lead to the formation of peroxides and other degradation products, which can be prevented by light protection. Any additives may be introduced into the reconstituted mixture (after opening the non-permanent partitions and mixing the contents of two or three chambers). Vitamins may also be added to the glucose chamber before reconstitution (before opening the non-permanent partitions and mixing the solutions and emulsion).

To perform addition

Aseptic techniques must be followed.

Prepare the injection site on the bag.

Puncture the bag and inject the additive substances using an injection needle or reconstitution device.

Mix the contents of the bag and the added substances.

Preparation for Infusion

Aseptic techniques must be followed.

Hang the bag.

Remove the protective cap from the administration port.

Firmly insert the infusion set needle into the administration port.

Performing the Infusion

Administer the preparation only after opening the non-permanent partitions between two or three chambers and mixing the contents of two or three chambers.

Ensure the absence of signs of phase separation in the ready-to-use, activated 3-chamber emulsion for infusion, or the absence of particles in the prepared 2-chamber infusion solution.

After opening, the bag contents must be used immediately. Storage for subsequent infusion is prohibited.

Under no circumstances should a partially used bag be connected.

Do not connect bags in series to prevent air embolism due to possible residual gas in the first bag.

Any unused medicinal products or waste, as well as all necessary disposable materials, must be disposed of and cannot be reused.

Children.

The preparation is used in children aged 2 years and adolescents aged 16–18 years for parenteral nutrition.

Overdose.

In cases of improper use (overdose and/or exceeding the recommended infusion rate), symptoms such as nausea, vomiting, tremor, electrolyte imbalance, and signs of hypervolemia or acidosis with fatal outcome may occur. In such situations, infusion must be stopped immediately. Additional interventions may be indicated based on medical necessity.

If the glucose infusion rate exceeds its clearance, hyperglycemia, glucosuria, and hyperosmolar syndrome may develop.

Reduced or limited ability to metabolize lipids may lead to the development of fat overload syndrome, the consequences of which usually resolve after discontinuation of lipid administration (see section "Adverse Reactions").

There is no specific antidote for overdose. Emergency procedures generally consist of supportive measures, with particular attention to the respiratory and cardiovascular systems. In some severe cases, hemodialysis, hemofiltration, or hemodiafiltration may be required.

Careful monitoring of blood biochemistry is extremely important; any detected deviations from normal require appropriate treatment.

Side effects.

Side effects observed in clinical trials and during the post-marketing period.

The safety of Numeta G19E was evaluated in one Phase III clinical trial. The study included one hundred fifty-nine (159) children who received Numeta G19E.

Table 3 lists the side effects observed in this study and during the post-marketing period.

Table 3

1 Blood samples were taken during infusion (not in the fasting state).

2 Frequency was determined according to the following criteria: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

3 These adverse reactions were reported only with peripheral administration of Numeta G13E and G16E formulations when insufficiently diluted (see section "Special precautions for use").

Other reactions.

Below are described adverse reactions observed after administration of other parenteral nutrition mixtures.

• Fat overload syndrome: may develop due to improper use of the product (e.g. overdose and/or exceeding the recommended infusion rate; see section "Overdose"); however, signs of this syndrome may also appear even when the drug is administered according to instructions. Impaired or limited ability to metabolize lipids contained in Numeta G19E is associated with prolonged plasma clearance and may lead to the development of fat overload syndrome. This syndrome is associated with sudden deterioration in the patient's clinical condition and is characterized by pathological changes such as hyperlipidemia, elevated body temperature, fatty infiltration of the liver (hepatomegaly), worsening liver function, anemia, leukopenia, thrombocytopenia, coagulation disorders, and manifestations from the central nervous system (e.g. coma). The syndrome usually resolves after discontinuation of the lipid emulsion.
• Pulmonary vascular precipitates (pulmonary embolism and respiratory distress) (see section "Special precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions that occur after marketing authorization is of great importance. This procedure allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life.

24 months.

Shelf life after reconstitution

It is recommended to use the product immediately after opening the non-permanent partitions between two or three chambers. However, stability data on reconstituted mixtures indicate that the product remains stable for 7 days at a temperature of 2 to 8 °C, followed by storage for 48 hours at 30 °C.

Shelf life after supplementation (with electrolytes, trace elements, vitamins, water)

Stability of individual mixtures of Numeta G19E has been demonstrated during use for 7 days at a temperature of 2 to 8 °C, followed by storage for 48 hours at 30 °C.

From a microbiological standpoint, the product should be used immediately. If not used immediately, the responsibility for duration and storage conditions during use lies with the user; storage duration should generally not exceed 24 hours at 2 to 8 °C, except when reconstitution/dilution/supplementation is performed under controlled and validated aseptic conditions.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze. Keep out of reach of children.

Incompatibilities.

This medicinal product should not be mixed with other medicinal products unless compatibility studies are available (see section "Method of administration and dosage").

As with other parenteral nutrition mixtures, the calcium-phosphate ratio must be considered. Excessive addition of calcium and phosphate, especially in the form of mineral salts, may lead to precipitation of calcium phosphate.

Ceftriaxone must not be mixed or co-administered with any calcium-containing intravenous solutions, including Numeta G19E, in patients of any age, even via different infusion systems or at different infusion sites, due to the risk of precipitation of calcium ceftriaxone salt.

Due to the risk of precipitate formation, Numeta G19E should not be administered through the same infusion system together with ampicillin, fosphenytoin, or furosemide.

Numeta G19E must not be administered simultaneously with blood through the same infusion system (see section "Interaction with other medicinal products and other forms of interaction").

Numeta G19E contains calcium ions, which may pose an additional risk of coagulation of precipitated blood or its components to which citrate has been added as an anticoagulant/preservative.

Packaging.

1000 mL (5% glucose solution – 383 mL; 5.9% amino acid solution with electrolytes – 392 mL; 12.5% lipid emulsion – 225 mL) in a three-chamber plastic bag. The three-chamber plastic bag is packaged in a protective film wrapper containing an oxygen absorber and an oxygen indicator. 6 bags per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Baxter S.A. / Baxter SA

Manufacturer's address and location of manufacturing site.

Boulevard Rene Branquart 80, Lessines, 7860, Belgium / Boulevard Rene Branquart 80, Lessines, 7860, Belgium