iMeds.se

Nutriflex Omega Special

Document: Nutriflex Omega special emulsion for infusion ENG SmPC change

Summary of Product Characteristics

1. Name of the medicinal product

Nutriflex Omega special emulsion for infusion

2. Qualitative and quantitative composition

The ready-for-use emulsion for intravenous infusion contains after mixing the chamber contents:

from the upper, left-hand chamber
(glucose solution)

in 1000 ml

in 625 ml

in 1250 ml

in 1875 ml

in 2500 ml

Glucose monohydrate

158.4 g

99.00 g

198.0 g

297.0 g

396.0 g

equivalent to anhydrous glucose

144.0 g

90.00 g

180.0 g

270.0 g

360.0 g

Sodium dihydrogen phosphate dihydrate

2.496 g

1.560 g

3.120 g

4.680 g

6.240 g

Zinc acetate dihydrate

7.024 mg

4.390 mg

8.780 mg

13.17 mg

17.56 mg

from the upper, right-hand chamber
(fat emulsion)

in 1000 ml

in 625 ml

in 1250 ml

in 1875 ml

in 2500 ml

Medium-chain triglycerides

20.00 g

12.50 g

25.00 g

37.50 g

50.00 g

Soya-bean oil, refined

16.00 g

10.00 g

20.00 g

30.00 g

40.00 g

Omega-3-acid triglycerides

4.000 g

2.500 g

5.000 g

7.500 g

10.00 g

from the lower chamber (amino acid solution)

in 1000 ml

in 625 ml

in 1250 ml

in 1875 ml

in 2500 ml

Isoleucine

3.284 g

2.053 g

4.105 g

6.158 g

8.210 g

Leucine

4.384 g

2.740 g

5.480 g

8.220 g

10.96 g

Lysine hydrochloride

3.980 g

2.488 g

4.975 g

7.463 g

9.950 g

equivalent to lysine

3.186 g

1.991 g

3.982 g

5.973 g

7.962 g

Methionine

2.736 g

1.710 g

3.420 g

5.130 g

6.840 g

Phenylalanine

4.916 g

3.073 g

6.145 g

9.218 g

12.29 g

Threonine

2.540 g

1.588 g

3.175 g

4.763 g

6.350 g

Tryptophan

0.800 g

0.500 g

1.000 g

1.500 g

2.000 g

Valine

3.604 g

2.253 g

4.505 g

6.758 g

9.010 g

Arginine

3.780 g

2.363 g

4.725 g

7.088 g

9.450 g

Histidine hydrochloride monohydrate

2.368 g

1.480 g

2.960 g

4.440 g

5.920 g

equivalent to histidine

1.753 g

1.095 g

2.191 g

3.286 g

4.381 g

Alanine

6.792 g

4.245 g

8.490 g

12.73 g

16.98 g

Aspartic acid

2.100 g

1.313 g

2.625 g

3.938 g

5.250 g

Glutamic acid

4.908 g

3.068 g

6.135 g

9.203 g

12.27 g

Glycine

2.312 g

1.445 g

2.890 g

4.335 g

5.780 g

Proline

4.760 g

2.975 g

5.950 g

8.925 g

11.90 g

Serine

4.200 g

2.625 g

5.250 g

7.875 g

10.50 g

Sodium hydroxide

1.171 g

0.732 g

1.464 g

2.196 g

2.928 g

Sodium chloride

0.378 g

0.237 g

0.473 g

0.710 g

0.946 g

Sodium acetate trihydrate

0.250 g

0.157 g

0.313 g

0.470 g

0.626 g

Potassium acetate

3.689 g

2.306 g

4.611 g

6.917 g

9.222 g

Magnesium acetate tetrahydrate

0.910 g

0.569 g

1.137 g

1.706 g

2.274 g

Calcium chloride dihydrate

0.623 g

0.390 g

0.779 g

1.169 g

1.558 g


in 1000 ml

in 625 ml

in 1250 ml

in 1875 ml

in 2500 ml

Amino acid content [g]

56.0

35.1

70.1

105.1

140.1

Nitrogen content [g]

8

5

10

15

20

Carbohydrate content [g]

144

90

180

270

360

Lipid content [g]

40

25

50

75

100

Electrolytes [mmol]

in 1000 ml

in 625 ml

in 1250 ml

in 1875 ml

in 2500 ml

Sodium

53.6

33.5

67

100.5

134

Potassium

37.6

23.5

47

70.5

94

Magnesium

4.2

2.65

5.3

7.95

10.6

Calcium

4.2

2.65

5.3

7.95

10.6

Zinc

0.03

0.02

0.04

0.06

0.08

Chloride

48

30

60

90

120

Acetate

48

30

60

90

120

Phosphate

16

10

20

30

40

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Emulsion for infusion

Amino acids and glucose solutions: clear, colourless up to straw-coloured solutions

Lipid emulsion: oil-in-water emulsion, milky white

in 1000 ml

in 625

ml

in 1250 ml

in 1875 ml

in 2500 ml

Energy in the form of lipids
[kJ (kcal)]

1590 (380)

995 (240)

1990 (475)

2985 (715)

3980 (950)

Energy in the form of carbohydrates [kJ (kcal)]

2415 (575)

1510 (360)

3015 (720)

4520 (1080)

6030 (1440)

Energy in the form of amino acids [kJ (kcal)]

940 (225)

590 (140)

1170 (280)

1755 (420)

2340 (560)

Non-protein energy [kJ (kcal)]

4005 (955)

2505 (600)

5005 (1195)

7510 (1795)

10010 (2390)

Total energy [kJ (kcal)]

4945 (1180)

3095 (740)

6175 (1475)

9265 (2215)

12350 (2950)

Osmolality [mOsm/kg]

2115

Theoretical osmolarity [mOsm/l]

1545

pH

5.0 - 6.0

4. Clinical particulars

4.1 Therapeutic indications

Supply of energy and essential fatty acids including omega-3 and omega 6-fatty acids, amino acids, electrolytes and fluids in the setting of parenteral nutrition of patients in states of moderate to 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 Omega special 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 per kg body weight, corresponding to

2.0 g amino acids per kg body weight per day

5.04 g glucose per kg body weight per day

1.4 g lipid per kg body weight per day.

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

0.1 g amino acids per kg body weight per hour

0.24 g glucose per kg body weight per hour

0.07 g lipid per 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

Nutriflex Omega specialis contraindicated in newborn infants, infants and toddlers < 2 years of age (see section 4.3). Safety and efficacy in children > 2 years and adolescents have not been established.

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 is not limited. During long-term administration of Nutriflex Omega special it is necessary to provide for appropriate supply of trace elements and vitamins.

Method of administration

Intravenous use. For central venous infusion only.

4.3 Contraindications

On account of its composition Nutriflex Omega special must not be used in newborn infants, infants and toddlers under 2 years of age.

General contraindications to parenteral nutrition include:


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.

The serum triglyceride concentration should be monitored when infusing Nutriflex Omega special.

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 Omega special 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 Omega special should not be given simultaneously with blood in the same infusion set due to the risk of pseudoagglutination.

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 Omega special contains zinc and magnesium, care should be taken when it is co-administered with solutions containing these elements.

As with all intravenous solutions strict aseptic precautions are necessary for the infusion of Nutriflex Omega special.

Nutriflex Omega special 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).

Paediatric population

There is as yet no clinical experience of the use of Nutriflex Omega special 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, Nutriflex Omega special 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 Omega special 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 Omega special 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.


Special warnings/precautions regarding excipients


Vitamin E (-tocopherol) can interfere with the effect of vitamin K in clotting factor synthesis. This should be considered in patients with blood coagulation disorders or suspected vitamin K deficiencyand in patients treated with coumarin anticoagulants.

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.

Potassium-containing solutions like Nutriflex Omega special 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 ofNutriflex Omega special in pregnant women. Animal studies undertaken with a lipid emulsion containing twice the amount of omega-3 acid triglycerides and a correspondingly smaller amount of long-chain triglycerides as compared to Nutriflex Omega special 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 Omega specialshould only be given to pregnant women after careful consideration.

Breast-feeding

Components/metabolites of Nutriflex Omega specialare 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 beassociated with the use of Nutriflex Omega special. 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).


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

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: Headache, 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, 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 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 Omega special 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 national reporting system listed in Appendix V.


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 and fish oil).

The long-chain triglyceride fraction contains omega-6 and omega-3 triglycerides for supply of polyunsaturated fatty acids. They are primarily intended for the prevention and treatment of essential fatty acid deficiency, but also as a source of energy. Nutriflex Omega special contains essential omega-6 fatty acids, mainly in the form of linoleic acid, and omega-3 fatty acids in the form of alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid. The ratio of omega-6/omega-3 fatty acids in Nutriflex Omega special is approximately 3:1.

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.


5.2 Pharmacokinetic properties

Absorption

Nutriflex Omega special 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.

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.


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-chain and long-chain fatty acids do not pass the blood-brain barrier and, hence, do not pass into the cerebrospinal fluid.

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 CO2or utilised as substrate for gluconeogenesis in the liver. The amino group is also metabolised in the liver to urea.

Glucose is metabolised to CO2and 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.

In detail, long-chain omega-3- polyunsaturated fatty acids replace arachidonic acid as an eicosanoid substrate in cell membranes and decrease the generation of inflammatory eicosanoids and cytokines in the body. This may be of benefit in patients at risk of developing a hyperinflammatory state and sepsis.

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 CO2and 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

Preclinical studies, including safety pharmacology, reproductive and developmental toxicity studies, with a lipid emulsion containing twice the amount of omega-3 acid triglycerides and a correspondingly smaller amount of long chain triglycerides revealed no effects other than those expected following administration of high doses of lipids.

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

Phytoestrogens such as ß-sitosterol can be found in various vegetable oils, especially in soya-bean oil. Impairment of fertility was observedin rats and rabbits after subcutaneous and intravaginal administration of ß-sitosterol. After administration of pure ß-sitosterol a decrease of the testicular weight and a reduction of the sperm concentration in male rats and a lowered pregnancy rate in female rabbits were recorded. However, 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 (for pH adjustment)

Egg lecithin

Glycerol

Sodium oleate

all-rac--tocopherol

Sodium hydroxide (for pH adjustment)

Water for injections

6.2 Incompatibilities

Nutriflex Omega special may only be mixed with other medicinal products for which compatibility has been documented.

Compatibility data for different additives (e.g. electrolytes, trace elements, vitamins) and the corresponding shelf life of such admixtures can be provided on demand by the manufacturer.

6.3 Shelf life

Unopened

2 years

After removing the protective overwrap and after mixing of the contents of the bag

Chemical and physical in-use stability after mixing the contents has been demonstrated for 7 days at 2-8 °C. After removing this bag from the refrigerator it is stable for 48 hours at 25 °C.


After admixture of compatible additives

From a microbiological point of view, the product should be used immediately after admixture of additives. If not used immediately after admixture of additives, in-use storage times and conditions prior to use are the responsibility of the user.

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. If accidentally frozen, discard the bag.

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

6.5 Nature and contents of container

Nutriflex Omega special is supplied in flexible multichamber bags of polyamide/polypropylene containing:


The multichamber bag is packed in a protective overwrap. An oxygen absorber is placed between the bag and the overwrap; the sachet of inert material contains powdered iron.


The two upper chambers can be connected with the lower chamber by opening the intermediate seam (peel seam).

The design of the bag permits mixing of the amino acids, glucose, lipids and electrolytes in a single chamber. Opening the peel seam results in sterile mixing to form an emulsion.

The different container sizes are presented in cartons containing five bags.
Pack sizes: 5 x 625 ml, 5 x 1250 ml, 5 x 1875 ml and 5 x 2500 ml.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

Preparation of the mixed emulsion:

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


Preparation for infusion:



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 Omega special 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 filters are used they must be lipid-permeable.

7. MARKETING AUTHORISATION HOLDER

B. Braun Melsungen AG
Carl-Braun-Straße 1
34212 Melsungen

Germany

Postal address:
B. Braun Melsungen AG

34209 Melsungen

Germany

Phone: +49-5661-71-0

Fax: +49-5661-71-4567

8. MARKETING AUTHORISATION NUMBER

<[To be completednationally]>

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION


<[To be completednationally]>

10. Date of revision of the Text

29 July 2015