4.1. Therapeutic indications

Supply of energy, essential fatty acids including omega-3 and omega-6 fatty acids, amino acids, and fluids for parenteral nutrition of patients in states of moderate to severe catabolism when oral or enteral nutrition is impossible, insufficient or contraindicated.

Omeflex special without electrolytes is indicated in adults, adolescents and children older than two years.

4.2. Posology and method of administration

Posology

The dosage should be adapted to the patients' individual requirements.

It is recommended that Omeflex special without electrolytes be administered continuously. A stepwise increase of the infusion rate over the first 30 minutes up to the desired infusion rate avoids possible complications.

Adults

The maximum daily dose amounts to 35 ml/kg body weight, corresponding to

2.0 g amino acids

/kg body weight per day

5.04 g glucose

/kg body weight per day

1.4 g lipid

/kg body weight per day.

The maximum rate of infusion is 1.7 ml/kg body weight per hour, corresponding to

0.1 g amino acids

/kg body weight per hour

0.24 g glucose

/kg body weight per hour

0.07 g lipid

/kg body weight per hour.

For a patient weighing 70 kg this corresponds to a maximum infusion rate of 119 ml per hour. The amount of substrate administered is then 6.8 g of amino acids per hour, 17.1 g of glucose per hour and 4.8 g of lipids per hour.

Paediatric population

Newborn infants, infants and toddlers less than two years of age

Omeflex special without electrolytes is contraindicated in newborn infants, infants and toddlers < 2 years of age in whom the amino acid cysteine may be considered conditionally essential (see section 4.3).

Children from 2 – 18 years of age.

No clinical studies were performed in the paediatric population.

Omeflex special without electrolytes can provide only a basic nutrient and energy supply to the paediatric patients. Depending on the individual need Carnitine supplementation may be considered in paediatric patients expected to receive PN for more than 4 weeks.

The exact dosage depends on the patient's energy expenditure and the ability to metabolize the active ingredients of Omeflex special without electrolytes and therefore, should be individually adapted according to age, body weight, clinical condition and underlying disease.

Since Omeflex special without electrolytes does not contain electrolytes these nutrients have to be administered separately as appropriate.

Due to the individual needs of paediatric patients, Omeflex special without electrolytes may not cover sufficiently the total energy, nutrient, electrolyte and fluid requirements. In such cases additional amino acids, carbohydrates and/or lipids, minerals and/or fluids must be provided in addition, as appropriate.

For calculation of dosage account must be taken of the hydration status of the paediatric patient.

The bag size should be chosen accordingly.

In addition, the daily fluid, glucose and energy requirements decrease with age. Thus, two age groups, from 2 to 12 years and 12 to 18 years, are considered.

Maximum daily dose

According to the paediatric guidelines the dose depends not only on the age but also on the medical condition (acute, stable and recovery phase) of the paediatric patient.

For Omeflex special without electrolytes in the paediatric age group 2 to 12 years the glucose concentration is the limiting nutrient in the acute phase, and the amino acid concentration in the stable and recovery phase.

For the age group 12 to 18 years the maximum daily dose is limited by the glucose concentration in all medical conditions.

The resulting maximum daily doses are given in the table below.

2 to ≤ 12 years

12 to 18 years

Recommended

Omeflex special without electrolytes

Recommended

Omeflex special without electrolytes

Acute phase

Stable Phase

Recovery phase

Acute phase

Stable Phase

Recovery phase

Maximum daily dose [ml/kg/d]

25

35.5

9.5

20

30

corresponding to

corresponding to

Fluids [ml/kg/d]

60 - 100

25

35.5

50 - 70

9.5

20

30

Amino acids [g/kg/d]

1.0 - 2.0 (2.5)

1.4

1.99

1.0 - 2.0

0.53

1.12

1.68

Glucose [g/kg/d]

Acute phase

1.4 – 3.6

3.6

-

0.7 – 1.4

1.37

-

-

Stable phase

2.2 – 5.8

-

5.11

1.4 – 2.9

-

2.88

-

Recovery phase

4.3 – 8.6

-

2.9 – 4.3

-

-

4.3

Lipids [g/kg/d]1)

≤ 3

1.0

1.42

≤ 3

0.38

0.8

1.2

Energy [kcal/kg/d]

Acute phase

30 - 45

29.5

-

20 - 30

11.2

-

-

Stable phase

40 - 60

-

41.9

25 - 40

-

23.6

-

Recovery phase

55 - 75

-

30 - 55

-

-

35.4

Acute phase = resuscitation phase when the patient requires vital organ support (sedation, mechanical ventilation, vasopressors, fluid resuscitation); Stable phase = patient is stable on, or can be weaned, from this vital support; Recovery phase = patient who is mobilizing.

1) In order to prevent essential fatty acid (EFA) deficiency a lipid emulsion dosage providing a minimum linoleic acid (LA) intake of

0.1 g/kg/day can be given, which also provides an adequate intake of linolenic acid (ALA) with all 20% lipid emulsions currently registered for pediatric use (Lapillonne et al. 2018).

For children, it might be necessary to start the nutritional therapy with half of the target dosage.

The dosage should be increased stepwise according to the individual metabolic capacity up the maximum dosage.

Maximum infusion rate

According to the paediatric guidelines the maximum hourly infusion rate depends not only on age but also on the medical condition (acute, stable and recovery phase) of the paediatric patient.

For Omeflex special without electrolytes the glucose infusion rate is the limiting factor for both paediatric age groups in all medical conditions.

The resulting maximum hourly infusions rates are given in the table below.

2 to ≤ 12 years

12 to 18 years

Recommended

Omeflex special without electrolytes

Recommended

Omeflex special without electrolytes

Acute phase

Stable Phase

Recovery phase

Acute phase

Stable Phase

Recovery phase

Maximum infusion rate [ml/kg/h]

0.63

1.25

1.67

0.42

0.83

1.25

corresponding to

corresponding to

Amino acids [g/kg/h]

≤ 0.1

0.035

0.07

0.094

≤ 0.1

0.024

0.046

0.07

Glucose [g/kg/h]

Acute phase

0.09

0.09

-

-

0.03 – 0.06

0.06

-

-

Stable phase

0.09 - 0.18

-

0.18

-

0.06 – 0.12

-

0.12

-

Recovery phase

0.18 - 0.24

-

-

0.24

0.12 – 0.18

-

-

0.18

Lipids [g/kg/h]

≤ 0.15

0.025

0.05

0.067

≤ 0.15

0.017

0.033

0.05

Patients with renal/hepatic impairment

The doses should be adjusted individually in patients with hepatic or renal insufficiency (see also section 4.4).

Patients with intradialytic parenteral nutrition (IDPN)

Intradialytic parenteral nutrition is intended for non-acutely ill malnourished dialysis patients where nutritional counselling or treatment with oral nutritional supplements was ineffective. The selection of the appropriate Omeflex special without electrolytes volume to be used for IDPN should be guided by the gap between spontaneous intakes and the recommended intakes. Additionally, metabolic tolerance needs to be taken into consideration. For Omeflex special without electrolytes in patients on IDPN, the maximum hourly infusion rate is 2.3 ml/kg/hour, corresponding to 0.13 g/kg/hour amino acids, 0.33 g/kg/hour glucose, and 0.092 g/kg/hour lipids administered for 4 hours. Taking into consideration the known amino acid (retention rate 73%) and glucose losses (25g/ 4-hour dialysis session) during dialysis the patient will finally receive 0.095 g/kg/hour amino acids, 0,24 g/kg/hour glucose and 0.092 g/kg/hour lipids in a 4-hour dialysis session. For a 70 kg patient this corresponds to 27 g of amino acids, 67 g of glucose, 26 g of lipids and 644 ml of fluid.

Duration of treatment

The duration of treatment for the indications stated is not limited. During the administration of Omeflex special without electrolytes it is necessary to provide an appropriate amount of electrolytes, trace elements and vitamins.

Duration of infusion of one single bag

The recommended duration of infusion for a parenteral nutrition bag is maximum 24 h.

Method of administration

Intravenous use. For central venous infusion only.

During intradialytic parenteral nutrition (IDPN) the bag should be administered through the venous drip chamber of the extracorporeal circulation lines.

4.3. Contraindications

● hypersensitivity to the active substances, to egg, fish, peanut or soya protein or to any of the excipients listed in section 6.1.

● inborn errors of amino acid metabolism

● severe hyperlipidaemia characterized by hypertriglyceridaemia (≥ 1000 mg/dl or 11.4 mmol/l)

● severe coagulopathy

● hyperglycaemia not responding to insulin doses of up to 6 units insulin/hour

● acidosis

● intrahepatic cholestasis

● severe hepatic insufficiency

● severe renal insufficiency in absence of renal replacement therapy

● aggravating haemorrhagic diatheses

● acute thrombo-embolic events, lipid embolism.

On account of its composition, Omeflex special without electrolytes must not be used in newborn infants, infants and toddlers under 2 years of age.

General contraindications to parenteral nutrition include:

● unstable circulatory status with vital threat (states of collapse and shock)

● acute phases of cardiac infarction and stroke

● unstable metabolic condition (e.g. severe postaggression syndrome, coma of unknown origin)

● inadequate cellular oxygen supply

● disturbances of the electrolyte and fluid balance

● acute pulmonary oedema

● decompensated cardiac insufficiency.

4.4. Special warnings and precautions for use

Caution should be exercised in cases of increased serum osmolarity.

Disturbances of the fluid, electrolyte or acid-base balance must be corrected before the start of infusion.

Too rapid infusion can lead to fluid overload with pathological serum electrolyte concentrations, hyperhydration and pulmonary oedema.

Any sign or symptom of anaphylactic reaction (such as fever, shivering, rash or dyspnoea) should lead to immediate interruption of the infusion.

Controls of the serum electrolytes, the water balance, the acid-base balance and of blood cell counts, coagulation status, hepatic and renal function are necessary.

Omeflex special without electrolytes is almost electrolyte free and therefore, used especially in patients with limited and/or specific electrolyte requirements. Sodium, potassium, calcium, magnesium and phosphate should be replaced according to clinical status related specific requirements. Close monitoring of electrolyte levels are required.

Refeeding or repletion of malnourished or depleted patients may cause hypokalaemia, hypophosphataemia and hypomagnesaemia. Close monitoring of serum electrolytes is mandatory. Adequate supplementation of electrolytes according to deviations from normal values is necessary.

The serum triglyceride concentration should be monitored when infusing Omeflex special without electrolytes.

Depending on the patient's metabolic condition, occasional hypertriglyceridaemia may occur. If the plasma triglyceride concentration exceeds 4.6 mmol/l (400 mg/dl) during administration of lipids, it is recommended to reduce the infusion rate. The infusion must be interrupted if the plasma triglyceride concentration exceeds 11.4 mmol/l (1000 mg/dl), as these levels have been associated with acute pancreatitis.

Patients with impaired lipid metabolism

Omeflex special without electrolytes should be administered cautiously to patients with disturbances of lipid metabolism with increased serum triglycerides, e.g. renal insufficiency, diabetes mellitus, pancreatitis, impaired hepatic function, hypothyroidism (with hypertriglyceridaemia), sepsis, and metabolic syndrome. If Omeflex special without electrolytes is given to patients with these conditions, more frequent monitoring of serum triglycerides is necessary to assure triglyceride elimination and stable triglyceride levels below 11.4 mmol/l (1000 mg/dl).

In combined hyperlipidaemias and in metabolic syndrome, triglyceride levels react to glucose, lipids and overnutrition. Adjust dose accordingly. Assess and monitor other lipid and glucose sources, and drugs interfering with their metabolism.

The presence of hypertriglyceridaemia 12 hours after lipid administration also indicates a disturbance of lipid metabolism.

Like all solutions containing carbohydrates, the administration of Omeflex special without electrolytes can lead to hyperglycaemia. The blood glucose level should be monitored. If there is hyperglycaemia, the rate of infusion should be reduced or insulin should be administered. If the patient is receiving other intravenous glucose solutions concurrently, the amount of additionally administered glucose has to be taken into account.

An interruption of administration of the emulsion may be indicated if the blood glucose concentration rises to above 14 mmol/l (250 mg/dl) during administration.

Trace elements and vitamins should be supplemented according to nutritional and clinical requirements.

Omeflex special without electrolytes should not be given simultaneously with blood in the same infusion set due to the risk of pseudoagglutination (see also section 4.5).

Omeflex special without electrolytes is a preparation of complex composition. It is, therefore, strongly advisable not to add other solutions (as long as compatibility is not proven – see section 6.2).

As with all intravenous solutions, especially for parenteral nutrition, strict aseptic precautions are necessary for the infusion of Omeflex special without electrolytes.

Paediatric population

There is as yet no clinical experience of the use of Omeflex special without electrolytes in children and adolescents.

Elderly patients

Basically the same dosage as for adults applies, but caution should be exercised in patients suffering from further diseases like cardiac insufficiency or renal insufficiency that may frequently be associated with advanced age.

Patients with diabetes mellitus, impaired cardiac or renal function

Like all large-volume infusion solutions, Omeflex special without electrolytes should be administered with caution to patients with impaired cardiac or renal function.

There is only limited experience of its use in patients with diabetes mellitus or renal failure.

In patients with renal insufficiency close monitoring of phosphate levels is required to prevent hyperphosphataemia. In contrast, in patients treated with continuous renal replacement therapy regular monitoring and adequate replacement of phosphate is necessary to prevent hypophosphataemia.

Special warnings/precautions regarding excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per multichamber bag, i.e. it is essentially 'sodium- free'.

Interference with laboratory tests

The fat content may interfere with certain laboratory measurements (e.g. bilirubin, lactate dehydrogenase, oxygen saturation) if blood is sampled before fat has been adequately cleared from the blood stream.

4.5. Interaction with other medicinal products and other forms of interaction

Some drugs, like insulin, may interfere with the body's lipase system. This kind of interaction seems, however, to be of only 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.

Soya-bean oil has a natural content of vitamin K1. This may interfere with the therapeutic effect of coumarin derivatives which should be closely monitored in patients treated with such drugs.

Omeflex special without electrolytes should not be given simultaneously with blood in the same infusion set due to the risk of pseudoagglutination (see also section 4.4).

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of Omeflex special without electrolytes in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

Parenteral nutrition may become necessary during pregnancy. Omeflex special without electrolytes should only be given to pregnant women after careful consideration.

Breast-feeding

Components/metabolites of Omeflex special without electrolytes are excreted in human milk, but at therapeutic doses no effects on the breastfed newborns/infants are anticipated. Nevertheless, breast-feeding is not recommended for mothers on parenteral nutrition.

Fertility

No data from the use of Omeflex special without electrolytes available.

4.7. Effects on ability to drive and use machines

Omeflex special without electrolytes has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Under conditions of correct use, in terms of dosing monitoring, observation of safety restrictions and instructions, undesirable effects may still occur. The following listing includes a number of systemic reactions that may be associated with the use of Omeflex special without electrolytes.

Undesirable effects are listed according to their frequencies as follows:

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)

Not known

(frequency cannot be estimated from the available data)

Blood and lymphatic system disorders

Rare:

Hypercoagulation

Not known:

Leucopenia, thrombocytopenia

Immune system disorders

Rare:

Allergic reactions (e.g. anaphylactic reactions, dermal eruptions, laryngeal, oral and facial oedema)

Metabolism and nutrition disorders

Uncommon:

Loss of appetite

Very rare:

Hyperlipidaemia, hyperglycaemia, metabolic acidosis

The frequency of these undesirable effects is dose-dependent and may be higher under the condition of absolute or relative lipid overdose.

Nervous system disorders

Rare:

Headache, drowsiness

Vascular disorders

Rare:

Hypertension or hypotension, flush

Respiratory, thoracic and mediastinal disorders

Rare:

Dyspnoea, cyanosis

Gastrointestinal disorders

Uncommon:

Nausea, vomiting

Hepatobiliary disorders

Not known:

Cholestasis

Skin and subcutaneous tissue disorders

Rare:

Erythema, sweating

Musculoskeletal and connective tissue disorders

Rare:

Pain in the back, bones, chest and lumbar region

General disorders and administration site conditions

Rare:

Elevated body temperature, feeling cold, chills

Very rare:

Fat overload syndrome (details see below)

Should adverse reactions occur, the infusion must be stopped.

Should the triglyceride level rise to above 11.4 mmol/l (1000 mg/dl) during infusion, the infusion must be stopped. With levels above 4.6 mmol/l (400 mg/dl), the infusion may be continued at a reduced dosage (see section 4.4).

If the infusion is restarted, the patient should be carefully monitored, especially at the beginning, and serum triglycerides should be determined at short intervals.

Information on particular undesirable effects

Nausea, vomiting and lack of appetite are symptoms often related to conditions for which parenteral nutrition is indicated, and may be associated with parenteral nutrition at the same time.

Fat overload syndrome

Impaired capacity to eliminate triglycerides can lead to “fat overload syndrome” which may be caused by overdose. Possible signs of metabolic overload must be observed. The cause may be genetic (individually different metabolism) or the fat metabolism may be affected by ongoing or previous illnesses. This syndrome may also appear during severe hypertriglyceridaemia, even at the recommended infusion rate, and in association with a sudden change in the patient's clinical condition such as renal function impairment or infection. The fat overload syndrome is characterised by hyperlipidaemia, fever, fat infiltration, hepatomegaly with or without icterus, splenomegaly, anaemia, leucopenia, thrombocytopenia, coagulation disorder, haemolysis and reticulocytosis, abnormal liver function tests and coma. The symptoms are usually reversible if the infusion of the fat emulsion is discontinued.

Should signs of a fat overload syndrome occur, the infusion of Omeflex special without electrolytes should be discontinued immediately.

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

4.9. Overdose

Symptoms of fluid overdose

Hyperhydration, electrolyte imbalance and pulmonary oedema

Symptoms of amino acid overdose

Renal amino acid losses with consecutive amino acid imbalances, sickness, vomiting and shivering

Symptoms of glucose overdose

Hyperglycaemia, glucosuria, dehydration, hyperosmolality, hyperglycaemic-hyperosmolar coma

Symptoms of lipid overdose

See section 4.8.

Treatment

Immediate cessation of infusion is indicated for overdose. Further therapeutic measures depend on the particular symptoms and their severity. When infusion is recommenced after the symptoms have declined, it is recommended that the infusion rate be raised gradually with monitoring at frequent intervals.