SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

NuTRIflex® Lipid peri Emulsion for Infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Nutriflex Lipid peri Emulsion for Infusion contains:

from the larger upper, left chamber (500, 750 and 1000 mL)	in 1250 ml Size 1	in 1875 ml Size 2	in 2500 ml Size 3	Quantity per 1000 ml
Glucose monohydrate	88.0 g	132.0 g	176.0 g	70.4 g
equivalent to anhydrous glucose	80.0 g	120.0 g	160.0 g	64.0 g
Sodium dihydrogen phosphate dihydrate	1.170 g	1.755 g	2.340 g	0.936 g
Zinc acetate dihydrate	6.625 mg	9.938 mg	13.250 mg	5.30 mg

from the smaller upper, right chamber (250, 375 and 500 ml)	in 1250 ml Size 1	in 1875 ml Size 2	in 2500 ml Size 3	Quantity per 1000 ml
Soya bean oil, refined	25.0 g	37.5 g	50.0 g	20.0 g
Medium chain triglycerides	25.0 g	37.5 g	50.0 g	20.0 g

from the lower chamber (500, 750 and 1000 mL)	in 1250 ml Size 1	in 1875 ml Size 2	in 2500 ml Size 3	Quantity per 1000 ml
Isoleucine	2.34 g	3.51 g	4.68 g	1.87 g
Leucine	3.13 g	4.70 g	6.26 g	2.50 g
Lysine hydrochloride equivalent to Lysine	2.84 g 2.26 g	4.26 g 3.39 g	5.68 g 4.52 g	2.27 g 1.81 g
Methionine	1.96 g	2.94 g	3.92 g	1.57 g
Phenylalanine	3.51 g	5.27 g	7.02 g	2.81 g
Threonine	1.82 g	2.73 g	3.64 g	1.46 g
Tryptophan	0.57 g	0.86 g	1.14 g	0.46 g
Valine	2.60 g	3.90 g	5.20 g	2.08 g
Arginine	2.70 g	4.05 g	5.40 g	2.16 g
Histidine hydrochloride monohydrate equivalent to Histidine	1.69 g 1.25 g	2.54 g 1.88 g	3.38 g 2.50 g	1.35 g 1.00 g
Alanine	4.85 g	7.28 g	9.70 g	3.88 g
Aspartic acid	1.50 g	2.25 g	3.00 g	1.20 g
Glutamic acid	3.50 g	5.25 g	7.00 g	2.80 g
Glycine	1.65 g	2.48 g	3.30 g	1.32 g
Proline	3.40 g	5.10 g	6.80 g	2.72 g
Serine	3.00 g	4.50 g	6.00 g	2.40 g
Sodium hydroxide	0.800 g	1.200 g	1.600 g	0.640 g
Sodium chloride	1.081 g	1.622 g	2.162 g	0.865 g
Sodium acetate trihydrate	0.544 g	0.816 g	1.088 g	0.435 g
Potassium acetate	2.943 g	4.415 g	5.886 g	2.354 g
Magnesium acetate tetrahydrate	0.644 g	0.966 g	1.288 g	0.515 g
Calcium chloride dihydrate	0.441 g	0.662 g	0.882 g	0.353 g

Electrolyte contents for Nutriflex Lipid peri after mixing the chamber bags:

Electrolytes [mmol]	in 1250 ml Size 1	in 1875 ml Size 2	in 2500 ml Size3	Quantity per 1000 ml
Sodium	50	75	100	40
Potassium	30	45	60	24
Magnesium	3.0	4.5	6.0	2.4
Calcium	3.0	4.5	6.0	2.4
Zinc	0.03	0.045	0.06	0.024
Chloride	48	72	96	38.4
Acetate	40	60	80	32
Phosphate	7.5	11.25	15	6

		in 1250 ml	in 1875 ml	in 2500 ml	Quantity per
		Size 1	Size 2	Size 3	1000 ml
Amino acid content	[g]	40	60	80	32
Nitrogen content	[g]	5.7	8.6	11.4	4.6
Carbohydrate content	[g]	80	120	160	64
Lipid content	[g]	50	75	100	40

For the full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Emulsion for infusion.

The lower chamber and the larger upper chamber (amino acids and glucose solutions): clear, colourless up to faintly, straw-coloured solutions.

The smaller top chamber (lipid emulsion): oil-in-water emulsion, milky white Physico-chemical characteristics of Nutriflex Lipid peri after mixing the chamber contents:

	in 1250 ml Size 1	in 1875 ml Size 2	in 2500 ml Size 3	Quantity per 1000 ml
Energy in the form of lipid [kJ (kcal)]	1990 (475)	2985 (715)	3980 (950)	1590 (380)
Energy in the form of carbohydrate [kJ (kcal)]	1340 (320)	2010 (480)	2680 (640)	1075 (255)
Energy in the form of amino acids [kJ (kcal)]	670 (160)	1005 (240)	1340 (320)	535 (130)
Non-protein energy [kJ (kcal)]	3330 (795)	4995 (1195)	6660 (1590)	2665 (635)
Total energy [kJ (kcal)]	4000 (955)	6000 (1435)	8000 (1910)	3200 (765)

Osmolality [mOsm/kg]	950	950	950	950
Theoretical osmolarity [mOsm/l]	840	840	840	840
pH	5.0 - 6.0	5.0 - 6.0	5.0 - 6.0	5.0 - 6.0

CLINICAL PARTICULARS

4.1    Therapeutic indications

Supply of energy, essential fatty acids, amino acids, electrolytes and fluids in the setting of parenteral nutrition of patients in states of mild to moderately severe catabolism when oral or enteral nutrition is impossible, insufficient or contraindicated.

4.2.    Posology and method of administration

Posology

The dosage is adapted to the patients’ individual requirements.

It is recommended that Nutriflex Lipid peri be administered continuously. A stepwise increase of the infusion rate over the first 30 minutes up to the desired infusion rate avoids possible complications.

Adolescents from 14 years of age and adults

The maximum daily dose amounts to 40 ml/kg body weight, corresponding to:

1.28 g amino acids /kg body weight per day 2.56 g glucose /kg body weight per day 1.6 g lipid /kg body weight per day.

The maximum rate of infusion is 2.5 ml/kg body weight per hour, corresponding to:

0.08 g amino acids /kg body weight per hour 0.16 g glucose /kg body weight per hour 0.1 g lipid /kg body weight per hour.

For a patient weighing 70 kg this corresponds to a maximum infusion rate of 175 ml per hour. The amount of substrate administered is then 5.6 g of amino acids per hour, 11.2 g of glucose per hour and 7 g of lipids per hour.

Paediatric population

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

Nutriflex Lipid peri is contraindicated in newborn infants, infants and toddlers < 2 years of age (see section 4.3).

Children from 2 to 13 years of age

The given dosage recommendations are guiding data based on average requirements. The dosage should be individually adapted according to age, developmental stage and illness. For calculation of dosage account must be taken of the hydration status of the paediatric patient.

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.

Daily dose for 2 - 4 years of age: 45 ml/kg body weight, corresponding to:

1.44 g amino acids /kg body weight per day 2.88 g glucose /kg body weight per day 1.8 g lipid /kg body weight per day.

Daily dose for 5 - 13 years of age: 30 ml/kg body weight, corresponding to:

0.96 g amino acids /kg body weight per day 1.92 g glucose /kg body weight per day

1.2 g lipid /kg body weight per day.

The maximum rate of infusion is 2.5 ml/kg body weight per hour, corresponding to:

0.08 g amino acids /kg body weight per hour 0.16 g glucose /kg body weight per hour 0.1 g lipid /kg body weight per hour.

Due to the individual needs of paediatric patients, Nutriflex Lipid peri may not cover sufficiently the total energy and fluid requirements. In such cases carbohydrates and/or lipids and/or fluids must be provided in addition, as appropriate.

Patients with renal/hepatic impairment

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

Duration of treatment

The duration of treatment for the indications stated should not exceed 7 days.

Method of administration

Intravenous use. Infusion into a peripheral or central vein.

4.3 Contraindications

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

•    congenital disorders of amino acid metabolism

•    severe hyperlipidaemia

•    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, Nutriflex Lipid peri 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.

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

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

The serum triglyceride concentration should be monitored when infusing Nutriflex Lipid peri.

Depending on the patient’s metabolic condition, occasional hypertriglyceridaemia may occur. If the plasma triglyceride concentration rises to above 3 mmol/l during administration of lipids, it is recommended that the infusion rate be reduced. Should the plasma triglyceride concentration remain above 3 mmol/l, the administration should be stopped until the level normalises.

Like all solutions containing carbohydrates, the administration of NuTRIflex® Lipid peri 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.

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

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

Nutriflex Lipid peri should not be given simultaneously with blood in the same infusion set due to the risk of pseudoagglutination.

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, Nutriflex Lipid peri 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.

Patients with impaired lipid metabolism

Nutriflex Lipid peri should be administered cautiously to patients with disturbances of lipid metabolism, e.g. renal insufficiency, diabetes mellitus, pancreatitis, impaired hepatic function, hypothyroidism (with hypertriglyceridaemia) and sepsis. If Nutriflex Lipid peri is given to patients with these conditions, monitoring of serum triglycerides is necessary. The presence of hypertriglyceridaemia 12 hours after lipid administration also indicates a disturbance of lipid metabolism.

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

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

Substitution of electrolytes, vitamins and trace elements may be necessary as required.

As Nutriflex Lipid peri contains zinc and magnesium, care should be taken when it is co-administered with solutions containing these elements.

As with all intravenoussolutions strict aseptic precautions are necessary for the infusion of NuTRIflex® Lipid peri.

Nutriflex Lipid peri 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).

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 Interactions 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.

Potassium-containing solutions like Nutriflex Lipid peri should be used with caution in patients receiving drugs that increase serum potassium concentration, such as potassium-sparing diuretics (triamterene, amiloride, spironolactone), ACE inhibitors (e.g. captopril, enalapril), angiotensin-II-receptor antagonists (e.g. losartan, valsartan), cyclosporin and tacrolimus.

Corticosteroids and ACTH are associated with sodium and fluid retention.

4.6    Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of Nutriflex Lipid peri in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Parenteral nutrition may become necessary during pregnancy. Nutriflex Lipid peri should only be given to pregnant women after careful consideration.

Breast-feeding

Components/metabolites of Nutriflex Lipid peri 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 available

4.7    Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

The following listing includes a number of systemic reactions that may be associated with the use of Nutriflex Lipid peri. Under conditions of correct use, in terms of dosing monitoring, observation of safety restrictions and instructions, most of them are rare (> 1/10,000 to < 1/1,000).

(> 1/10)

(> 1/100 to < 1/10)

(> 1/1,000 to < 1/100)

(> 1/10,000 to < 1/1,000)

(< 1/10,000)

(frequency cannot be estimated from the available data)

Blood and lymphatic system disorders

Rare:    Hypercoagulation

Immune system disorders

Rare:    Allergic reactions (e.g. anaphylactic reactions, dermal

eruptions, laryngeal, oral and facial oedema)

Metabolism and nutrition disorders

Very rare:    Hyperlipidaemia, hyperglycaemia, metabolic acidosis,    ketoacidosis

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:    Drowsiness

Vascular disorders

Rare:    Hypertension or hypotension, flush

Respiratory, thoracic and mediastinal disorders

Rare:    Dyspnoea, cyanosis

Gastrointestinal disorders

Uncommon:    Nausea, vomiting, loss of appetite

Skin and subcutaneous tissue disorders

Rare:    Erythema

General disorders and administration site conditions

Common:    After a few days, vein irritation, phlebitis or thrombophlebitis may

occur.

Rare:    Headache, elevated body temperature, sweating, feeling cold, chills,

pain in the back, bones, chest and lumbar region

Very rare:    Fat overload syndrome (details see below)

If signs of vein wall irritation, phlebitis or thrombophlebitis occur, change of the infusion site should be considered.

Should adverse reactions occur or should the triglyceride level rise to above 3 mmol/l during infusion, the infusion should be stopped or, if necessary, continued at a reduced dosage.

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, lack of appetite and hyperglycaemia are symptoms often related to conditions indicating parenteral nutrition or may be associated with parenteral nutrition.

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, leukopenia, 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 Nutriflex Lipid peri 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 and electrolyte 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.

5.    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Solutions for parenteral nutrition, combinations ATC code: B 05BA10

Mechanism of action

The purpose of parenteral nutrition is to supply all necessary nutrients for the growth and regeneration of tissue as well as energy necessary to maintain all body functions.

Here the amino acids are of particular importance since some of them are essential components for protein synthesis. The simultaneous administration of energy sources (carbohydrates/lipids) is necessary to avoid false energetic utilisation of amino acids while still providing for the further energy-consuming processes.

Glucose is ubiquitously metabolised within the organism. Some tissues and organs, such as CNS, bone marrow, erythrocytes, tubular epithelium, cover their energy requirement exclusively from glucose. In addition glucose acts as a structural building block for various cell substances.

On account of their high energy density, lipids are an efficient form of energy supply. Long-chain triglycerides provide the organism with essential fatty acids for the synthesis of cell components. For these purposes the lipid emulsion contains medium-chain and long-chain triglycerides (deriving from soya-bean oil).

Medium-chain triglycerides are more rapidly hydrolysed, eliminated from the circulation and completely oxidised than long-chain triglycerides. They are a favoured energy substrate, particularly when there is disturbance of the degradation and/or utilisation of long-chain triglycerides, e.g. when there is a lipoprotein lipase deficiency and/or a deficiency in lipoprotein lipase cofactors.

Unsaturated fatty acids derived from the long-chain triglyceride fraction serve primarily for prophylaxis and treatment of essential fatty acid deficiency.

5.2    Pharmacokinetic properties

PRA/S/KS/9801/785088380343140963_spc-doc.doc

Absorption

Nutriflex Lipid peri is infused intravenously. Hence, all substrates are available for metabolism immediately.

Distribution

The dose, rate of infusion, metabolic situation and individual factors of the patient (level of fasting) are of decisive importance for the maximum triglyceride concentrations reached. When used according to the instructions with due regard to the dosage guidelines the triglyceride concentrations do not, in general, exceed 3 mmol/l.

When the dosage guidelines are followed, medium-chain fatty acids and long-chain fatty acids are practically completely bound to plasma albumin. Therefore, when the dosage guidelines are followed, medium and long-chain fatty acids do not pass the blood-brain barrier and, hence, do not pass into the cerebrospinal fluid.

Amino acids are incorporated in a variety of proteins in different organs of the body. In addition each amino acid is maintained as free amino acid in the blood and inside cells.

As glucose is water-soluble, it is distributed with the blood over the whole body. At first, the glucose solution is distributed in the intravascular space and then it is taken up into the intracellular space.

No data are available concerning transport of the components through the placental barrier.

Biotransformation

Amino acids, that do not enter protein synthesis, are metabolised as follows. The amino group is separated from the carbon skeleton by transamination. The carbon chain is either oxidised directly to CO₂ or utilised as substrate for gluconeogenesis in the liver. The amino group is also metabolised in the liver to urea.

Glucose is metabolised to CO₂ and H₂O via the known metabolic routes. Some glucose is utilised for lipid synthesis.

After infusion triglycerides are hydrolysed to glycerol and fatty acids. Both are incorporated in physiological pathways for energy production, synthesis of biological active molecules, gluconeogenesis and resynthesis of lipids.

Elimination

Only minor amounts of amino acids are excreted unchanged in urine.

Excess glucose is excreted in urine only if the renal threshold of glucose is reached.

Both the triglycerides of soya-bean oil and medium-chain triglycerides are completely metabolised to CO₂ and H₂O. Small amounts of lipids are lost only during sloughing of cells from skin and other epithelial membranes. Renal excretion does virtually not occur.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.

Toxic effects of mixtures of nutrients given as substitution therapy at the recommended dosage are not to be expected.

Reproductive toxicity

Phytoestrogens such as B-sitosterol can be found in various vegetable oils, especially in soya-bean oil. Impairment of fertility was determined in rats and rabbits after subcutaneous and intravaginal administration of B-sitosterol. According to the current state of knowledge the observed effects in animals do not seem to have relevance for clinical use

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Citric acid monohydrate, egg lecithin, glycerol, sodium oleate, water for injections.

6.2    Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3    Shelf life

Unopened 2 years

After removing the protective overwrap and after mixing of contents of the bag Chemical and physical in-use stability after mixing the contents has been demonstrated for 7 days at 28 °C plus 48 hours at 25 °C.

After first opening (spiking of the infusion port)

The emulsion is to be used immediately after opening of the container.

6.4    Special precautions for storage

Do not store above 25 °C.

Do not freeze.

Keep the bag in the outer carton in order to protect from light.

6.5.    Nature and Contents of Container

NuTRIflex® Lipid peri is available in flexible plastic bags of 1250 ml, 1875 ml or 2500 ml.

The containers are divided into three compartments, separated by internal peel seals.

The design of the bag permits the mixing of amino acids, glucose, lipids, and electrolytes in the lower chamber. On breaking the seals, aseptic mixing of the solutions and the emulsion occurs.

6.6 Special precautions for disposal and other handling

Preparation of the mixed emulsion:

Remove inner bag from its protective overwrap and proceed as follows:

•    put the bag on a solid, flat surface

•    mix glucose with amino acids by pressing the upper left chamber against the peel seam, then add the fat emulsion by pressing the upper right chamber against the peel seam

•    mix the contents of the bag thoroughly.

Preparation for infusion:

•    fold the bag and hang it on the infusion stand by the centre hanging loop

•    remove the protective cap from the infusion port and carry out infusion using the standard technique

The mixture is a milky white homogenous oil-in-water emulsion.

Only use bags that are undamaged and in which the amino acid and glucose solutions are clear and colourless up to straw-coloured solutions. Do not use bags where there is a discolouration or discernible phase separation (oil drops) in the chamber containing lipid emulsion.

Nutriflex Lipid peri is supplied in single dose containers. Container and unused residues must be discarded after use.

Do not reconnect partially used containers.

The emulsion should always be brought to room temperature prior to infusion.

If accidentally frozen discard the bag.

If filters are used they must be lipid-permeable.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

B Braun Melsungen AG Carl-Braun-Str. 1 D-34212 Melsungen Germany

8. MARKETING AUTHORISATION NUMBER(S)

PL 03551/0028

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

25/02/2009

10 DATE OF REVISION OF THE TEXT

20/05/2016

PRA/S/KS/9801/785088380343140963_spc-doc.doc