Numeta G13E Emulsion for infusion

NUMETA G13E is indicated for parenteral nutrition in preterm newborn infants when oral or enteral nutrition is not possible, insufficient or contraindicated.

Posology
The dosage depends on energy expenditure, the patient's weight, age, clinical status, and on the ability to metabolise the constituents of NUMETA G13E, as well as on additional energy or proteins given orally/enterally. Total electrolyte and macronutrient composition is dependent on the number of activated chambers (See section 2). The maximum daily dose 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.

The maximal recommended hourly rate of infusion and volume per day depend on the constituent. The first of these limits to be reached sets the maximum daily dose. The guidelines for maximal recommended hourly rate of infusion and volume per day are:

• Activated 2CB (240 ml)
• Activated 3CB (300 ml)

Maximal rate of infusion in ml/kg/h
5,1
6,4

Corresponding to:
Amino acid in g/kg/h
0,20 a
0,20 a

Glucose in g/kg/h
0,85
0,85

Lipids in g/kg/h
0
0,16

Maximal amount in ml/kg/day
102,3
127,9

Corresponding to:
Amino acid in g/kg/d
4,0 a
4,0 a

Glucose in g/kg/d
17,1
17,1

Lipids in g/kg/d
0
3,2

a Limiting parameter according to ESPEN-ESPGHAN guidelines

NUMETA G13E may not be appropriate for some preterm infants, as the clinical condition of the patient may require administration of individualised formulations to meet the specific needs of the patient as assessed by the clinician.

Method of administration:
For instructions for preparation, and handling of the solution/emulsion for infusion, see section 6.6.

The solution (in bags and administration sets) should be protected from light exposure from point of admixture through administration (see section 4.4 and 6.6). Due to its high osmolarity, undiluted NUMETA G13E can only be administered through a central vein; however, sufficient dilution of NUMETA G13E with water for injection lowers the osmolarity and allows peripheral infusion. The formula below indicates how the dilution impacts osmolarity of the bags:

Final osmolarity = Volume of bag * Initial osmolarity / (Water added + Volume of bag)

The table below shows examples of osmolarity for activated 2CB and activated 3CB admixtures after addition of water for injection:

• Amino Acids and Glucose (Activated 2CB)
• Amino Acids, Glucose, and Lipids (Activated 3CB)

Initial volume in the bag (ml)
240
300

Initial osmolarity (mOsm/l approximately)
1400
1150

Volume of water added (ml)
240
300

Final volume after addition (ml)
480
600

Osmolarity after addition (mOsm/l approximately)
700
575

The flow rate should be increased gradually during the first hour. Upon discontinuation of NUMETA G13E, the flow rate should be decreased gradually during the last hour. The administration flow rate must be adjusted taking into account the dose being administered, the daily volume intake, and the duration of the infusion, see section 4.9.

In preterm newborn infants, continuous parenteral administration over 24 hours is usually recommended; however, the same bag should not be activated, hung and infused longer than 24 hours. Cyclic infusions should be managed according to the patient's metabolic tolerance. Treatment with parenteral nutrition may be continued for as long as is required by the patient's clinical conditions.

NUMETA G13E contains electrolytes and may be further supplemented using commercial electrolyte preparations according to the doctor's judgment and the clinical needs of the patient, see section 6.6. Vitamins and trace elements can be added according to the doctoru2019s judgment and the clinical needs of the patient, see section 6.6.

The general contraindications for administering NUMETA G13E as an activated 2 chamber bag for intravenous infusion are as follows:

• Hypersensitivity to egg, soy or peanut proteins, or to any of the active substances, excipients listed in section 6.1, or components of the container.
• Congenital abnormality of the amino acid metabolism.
• Pathologically elevated plasma concentrations of sodium, potassium, magnesium, calcium and/or phosphorus.
• Concomitant treatment with ceftriaxone, even if separate infusion lines are used. See sections 4.4, 4.5 and 6.2.
• Severe hyperglycaemia

The addition of lipids (administering NUMETA G13E as an activated 3 chamber bag for intravenous emulsion) is contraindicated in the following additional clinical situations:

• Severe hyperlipidaemia, or severe disorders of lipid metabolism characterised by hypertriglyceridemia

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

NUMETA G13E contains glucose produced from cornstarch. Therefore, NUMETA G13E should be used with caution in patients with known allergy to corn or corn products.

Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys in premature newborns have been described. In preterm newborn infants, concomitant treatment with ceftriaxone is contraindicated (see section 4.3).

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 the formation of calcium phosphate precipitates (see section 6.2). Suspected precipitate formation in the blood stream have 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.

No additions to the bag should be made without first checking the compatibility, as formation of precipitates or destabilisation of the lipid emulsion could result in vascular occlusion, see sections 6.2 and 6.6.

Infection and sepsis may occur as a result of the use of intravenous catheters to administer parenteral formulations, or poor maintenance of catheters. Immunosuppressive effects of illness, or medicines, may promote infection and sepsis. Careful symptomatic and laboratory monitoring 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 technique in catheter placement, maintenance, as well as aseptic technique in nutritional formula preparation.

Fat overload syndrome has been reported with other parenteral nutrition products. A reduced or limited ability to metabolise the lipids contained in NUMETA G13E, or an overdose, may result in a u201cfat overload syndromeu201d (see section 4.8 and 4.9).

Refeeding severely undernourished patients may result in the refeeding syndrome that is characterised by the shift of potassium, phosphorus, and magnesium intracellularly as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop. Careful and slow initiation of parenteral nutrition is recommended, with close monitoring of fluids, electrolytes, trace elements and vitamins.

NUMETA G13E must only be administered through a central vein, except if appropriate dilution is performed (see section 4.2). When making additions to the formulation, the final osmolarity of the mixture must be calculated before administration via peripheral vein to avoid vein irritation or tissue damage in the case of extravasation of the solution. Peripheral administration of NUMETA G13E has resulted in extravasation leading to soft tissue injury and skin necrosis.

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

Lipids, vitamins, additional electrolytes and trace elements should be administered as required.

PRECAUTIONS
Do not add other medicinal products or substances to one of the three chambers of the bag or to the reconstituted solution/emulsion without first confirming their compatibility and the stability of the resulting preparation (in particular, stability of the lipid emulsion) (see sections 6.2 and 6.6).

Light exposure of solutions for intravenous total parenteral nutrition after admixture may have adverse effects on clinical outcome in neonates, due to generation of peroxides and other degradation products. NUMETA G13E should be protected from light from the point of admixture through administration (see section 6.6).

Routinely monitor water and electrolyte balance, including magnesium, serum osmolarity, serum triglycerides, acid/base balance, blood glucose, liver and kidney function, blood count including platelets, and coagulation parameters throughout treatment. In case of unstable conditions (for example, following severe post-traumatic conditions, uncompensated diabetes mellitus, acute phase of circulatory shock, acute myocardial infarction, severe metabolic acidosis, severe sepsis and hyperosmolar coma) delivery of NUMETA G13E should be monitored and adjusted to meet the clinical needs of the patient.

There are limited data on the administration of NUMETA G13E in preterm infants less than 28 weeks gestational age.

Cardiovascular
Use with caution in patients with pulmonary oedema or heart failure. Fluid status should be closely monitored.

Renal
Use with caution in patients with renal insufficiency. Fluid and electrolyte status, including magnesium, should be closely monitored in these patients.

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

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

Endocrine and Metabolism
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. Serum triglyceride concentrations and the ability of the body to metabolise lipids must be checked regularly. If a lipid metabolism abnormality is suspected, monitoring of serum triglycerides is recommended as clinically necessary.

In the event of hyperglycemia, the infusion rate of NUMETA G13E must be adjusted and/or insulin administered, see section 4.9.

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

Special precaution relating to excipients
Contains glucose which may have an effect on the glycaemic control of patients with diabetes mellitus.

No pharmacodynamic interaction studies have been performed with NUMETA G13E. NUMETA G13E must not be administered simultaneously with blood through the same infusion tubing because of the risk of pseudoagglutination. As for other calcium-containing infusion solutions concomitant treatment with ceftriaxone and NUMETA G13E is contraindicated in preterm newborn infants (see sections 4.3, 4.4 and 6.2).

Olive and soybean oil have a natural content of vitamin K1 that may counteract the anticoagulant activity of coumarin (or coumarin derivatives including warfarin). Due to the potassium content of NUMETA G13E special care should be taken in patients simultaneously treated with potassium sparing diuretics (e.g., amiloride, spironolactone, triamterene) or with ACE inhibitors, angiotensin II receptor antagonists, or the immunosuppressants tacrolimus and cyclosporine in view of the risk of hyperkalaemia.

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. Lipids are generally eliminated after a period of 5 to 6 hours when no additional lipids are administered. Please also refer to section 6.2.

Pregnancy
Not applicable since the product is intended for preterm newborn infants.

Breastfeeding
Not applicable since the product is intended for preterm newborn infants.

Fertility
The product contains glucose, a paediatrics amino acids solution, electrolytes, and a lipid emulsion; effects on fertility are unlikely.

Not relevant.

Adverse Reactions from Clinical Trials and Post - marketing experience
The safety and administration of NUMETA G13E was assessed in a single phase III study. One hundred and fifty-nine (159) paediatric patients were included in the study and received NUMETA products (113 preterm infants received NUMETA G13E, 28 full-term infants to toddlers up to 2 year of age (full-term infants and toddlers) received NUMETA G16E) and 18 children and adolescents (children/adolescents) up to 16 years of age received NUMETA G19E).

The pooled data from clinical trials and the post-marketing experience indicate the following undesirable effects related to NUMETA:

Clinical Trial and Post - marketing experience Adverse Reactions

System Organ Class (SOC) Preferred MedDRA Term Frequency b

Metabolism and nutrition disorders
Hypophosphataemia a Common
Hyperglycaemia a Common
Hypercalcaemia a Common
Hypertriglyceridaemia a Common
Hyperlipidaemia a Uncommon
Hyponatraemia a Common

Hepatobiliary disorders
Cholestasis Uncommon

Skin and subcutaneous tissue disorders
Skin Necrosis c Not known
Soft Tissue Injury c Not known

General disorders and administration site condition
Extravasation c Not known

a Blood samples drawn during the infusion (without fasting conditions).
b Frequency is based upon the following categories: Very Common (u22651/10); Common (u22651/100 - <1/10), Uncommon (u22651/1000 - <1/100), Rare (u22651/10000 - <1/1000), Very Rare (<1/10000), Not known (cannot be estimated based on available data).

c These undesirable effects have been reported only for NUMETA G13E and G16E when peripherally administered with insufficient dilution (see Section 4.4)

Other (Class) Reactions
The following adverse reactions have been reported with other parenteral nutrition admixtures:

• Fat overload syndrome: 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 when NUMETA G13E is administered according to instructions. The reduced or limited ability to metabolise the lipids contained in NUMETA G13E accompanied by prolonged plasma clearance may result in a u201cfat overload syndromeu201d. This syndrome is associated with a sudden deterioration in the patient's clinical condition and is characterised by findings such as hyperlipidaemia, fever, liver fatty infiltration (hepatomegaly), deteriorating liver function, anaemia, leukopenia, thrombocytopenia, coagulation disorders, acute respiratory distress, metabolic acidosis, and central nervous system manifestations (e.g. coma). The syndrome is usually reversible when the infusion of the lipid emulsion is stopped.
• Pulmonary vascular precipitates (pulmonary vascular emboli and pulmonary distress) (see section 4.4).

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

Hyperglycaemia, glucosuria, and hyperosmolar syndrome may develop if the glucose infusion rate exceeds clearance. An overdose or reduced or limited ability to metabolise lipids may result in fat overload syndrome, the results of which are usually reversible after infusion of the lipid emulsion is stopped, see section 4.8.

In neonates and infants, the fat overload syndrome has been associated with metabolic acidosis and respiratory distress. There is no specific antidote for overdose. Emergency procedures should be general supportive measures, with particular attention to respiratory and cardiovascular systems. In some serious cases, haemodialysis, haemofiltration, or haemodiafiltration may be necessary. Severe cases of fat overload syndrome treated with exchange transfusions have been reported in the literature.