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Document: Tetraspan 60 mg per ml solution for infusion ENG SmPC change

• Tetraspan 60 mg per ml solution for infusion SmPC
• Tetraspan 60 mg per ml solution for infusion ENG SmPC

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Summary of Product Characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

Tetraspan 60 mg/ml solution for infusion.

1 000ml of solution contain:

Hydroxyethylstarch (HES) 60.0 g

(Molar substitution: 0.42)

(Average molecular weight: 130,000 Da)

Sodium chloride 6.25 g

Potassium chloride 0.30 g

Calcium chloride dihydrate 0.37 g

Magnesium chloride hexahydrate 0.20 g

Sodium acetate trihydrate 3.27 g

L-Malic acid 0.67 g

Electrolyte concentrations:

Sodium 140 mmol/l

Potassium 4.0 mmol/l

Calcium 2.5 mmol/l

Magnesium 1.0 mmol/l

Chloride 118 mmol/l

Acetate 24 mmol/l

L-Malate 5.0 mmol/l

For thefull list of excipients, see section 6.1.

Solution for infusion.

Clear, colourless, aqueous solution.

pH: 5.66.4

Theoretical osmolarity: 296 mOsmol/l

Acidity (titration to pH 7.4): <2.0 mmol/l

Treatment of hypovolaemia due to acute blood loss when crystalloids alone are not considered sufficient. (see sections 4.2, 4.3 and 4.4).

Posology

Use of Hydroxyethyl starch should be restricted to the initial phase of volume resuscitation with a maximum time interval of 24 h.

The daily volumeand the infusion rate depend on the amountof blood lostand how much fluid is required to restore haemodynamic parameters.

The first10-20 ml should be infused slowly and under careful monitoring of the patient so that any anaphylactic/ anaphylactoid reaction can be detected as earlyas possible.

The volumelimitations given by the degree of haemodilution should be observed, see sections 4.4 and 4.8.

Adults

Maximum daily volume:

The maximum daily doseis 30ml/kgbody weight (BW) (equivalent to 1.8g Hydroxyethylstarchper kg BW).This is equivalent to 2 100 ml Tetraspan 60 mg/ml for a patient weighing 70 kg.

Maximum infusion rate:

The maximum infusion rate depends on the clinical situation. Patients in acute shock canbe givenup to 20 ml per kg BW per hour (equivalent to 0.33 ml per kg BW per min or 1.2 g Hydroxyethylstarch per kg BWper hour).

In life-threatening situations, 500 ml canbe administered rapidly as apressure infusion. See also section 4.2‘Method of administration’.

The lowest possible effective dose should be applied. Treatment should be guided by continuous haemodynamic monitoring so that the infusion is stopped as soon as appropriate haemodynamic goals have been achieved. The maximum recommended daily dose must not be exceeded.

Elderly patients

See section 4.4.

Paediatric population:

Data are limited in children therefore it is recommended not to use Hydroxyethyl starch products in this population.

Method of administration

Intravenoususe.

In the case of a rapid infusion under pressure, usingplastic container with air space inside, the container and infusion set should be emptied of air before theinfusionis started.This is to avoid the risk of air embolism that might otherwise beassociated with the infusion.

• hypersensitivity to the active substances or to any of the other excipients listed in section 6.1

• sepsis

• burns

• renal impairment or renal replacement therapy

• intracranial or cerebral haemorrhage

• critically ill patients (typically admitted to the intensive care unit)

• hyperhydration

• pulmonary oedema

• dehydration

• hyperkalaemia

• severe hypernatraemia or severe hyperchloraemia

• severely impaired hepatic function

• congestive heart failure

• severe coagulopathy

• organ transplant patients

Because of the risk of allergic (anaphylactic/ anaphylactoid) reactions, the patient should be monitored closely and the infusion instituted at a low rate. (See section 4.8).

The indication for volume replacement with Hydroxyethyl starch has to be considered carefully, and haemodynamic monitoring is required for volume and dose control. (See also section 4.2.)

Volume overload due to overdose or too rapid infusion must always be avoided. The dosage mustbe adjustedcarefully, particularlyin patients with pulmonary and cardiocirculatory problems.Serum electrolytes, fluid balance and renal function should be monitoredclosely. Electrolytes and fluids should be substituted according to individual requirements.

Hydroxyethyl starch products are contraindicated in patients with renal impairment or renal replacement therapy (see section 4.3). The use of Hydroxyethyl starch must be discontinued at the first sign of renal injury. An increased need for renal replacement therapy has been reported up to 90 days after Hydroxyethyl starch administration. Monitoring of renal function in patients is recommended for at least 90 days.

Particular caution should be exercised when treating patients with impaired hepatic function or in patients with blood coagulation disorders.

Severe haemodilution resulting from high doses of Hydroxyethyl starch solutions must also be avoided in the treatment of hypovolaemic patients.

In the case of repeated administration, blood coagulation parameters, should be monitored carefully. Discontinue the use of Hydroxyethyl starch at the first sign of coagulopathy.

In patients undergoing open heart surgery in association with cardiopulmonary bypass the use of Hydroxyethyl starch products is not recommended due to the risk of excess bleeding.

Sufficientfluid intake must be ensured.

Elderly patients

Elderly patients, who are more likely to suffer from cardiac insufficiency and renal impairment, should be closely monitored during treatment, and the dosage should be carefully adjusted, in order to avoid cardiocirculatory and renal complications resulting from hypervolaemia.

Surgery and trauma:

There is a lack of robust long term safety data in patients undergoing surgical procedures and in patients with trauma. The expected benefit of treatment should be carefully weighed against uncertainty with regard to this long term safety. Other available treatment options should be considered.

Paediatric population:

Data are limited in children therefore it is recommended not to use Hydroxyethyl starch products in this population. (see section 4.2)

Influence on laboratory tests

Transiently raised alpha-amylase levels can occur after administration of solutions with Hydroxyethyl starch. This should not be interpreted as a sign of pancreatic injury(see section 4.8).

Aminoglycosides

The adverse effects of aminoglycosides on kidneys may be increased in combination with Hydroxyethyl starch infusions.

Medicinal products causing potassium or sodium retention

Consideration should be given to the concomitant administration of medicinal products that can cause potassium or sodium retention.

Digitalis glycosides

Raised calcium levels can increase the risk of toxic effects of digitalis glycosides.

Pregnancy

There are no or limited amount of data from the use ofHydroxyethyl starchin pregnant women. Animal reproduction toxicitystudies with similar products have revealed vaginal bleeding, embryotoxicity and teratogenicity after repeated treatment in test animals (see section 5.3).

Harmful effects on the foetus can occur with Hydroxyethyl starch-related anaphylactic/anaphylactoid reactions in treated pregnant women.

Tetraspan 60 mg/ml should be used during pregnancy only if the potential benefits outweigh the possible risksto the foetus.This should be borne in mind in particular if treatment with Tetraspan 60 mg/ml is being considered during the first trimester.

Special care must be taken to avoid overdose resulting in hypervolaemia with consecutive pathological haemodilution and foetal hypoxia (see section 5.3).

Breast-feeding

Itis not known whether Hydroxyethylstarchpasses intobreast milk, caution should be exercised on administration to breast-feeding women. The temporary cessation of breast-feeding may be considered.

Fertility

No data available.

This medicinal product has no influence on the ability to drive and use machines.

General

The most common sideeffects observed are directly related to the therapeutic effect of starch solutions and the volume given, i.e. dilution of the blood as a result of the fillingof the intravascular space without administeringblood componentsat the same time.Coagulation factor dilution canalso occur. Serious anaphylactic/anaphylactoid reactions have been reported and may require immediate action (please refer also to the section ‘Anaphylactic/Anaphylactoid reactions’ below).

	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)	Frequency not know (cannot be estimated from the available data)
Blood and lymphatic system disorders	Decreased haematocrit, reduced concentration of plasma proteins	Dilution of coagulation factors, prolongation of bleeding time and aPTT, reduced level of FVIII/vWF complex (1) (see section 4.4)
Hepatobiliary disorders					Hepatic injury
Immune system disorders				Anaphylactic/Anaphylactoid reactions of various degrees (see " Anaphylactic/Anaphy­lactoid reactions" below)
Renal and urinary disorders					Renal injury
General disorders and administration site conditions			Itching which responds poorly to any therapy (2)
Investigations	Increased serum -amylase levels (3)

Anaphylactic/Anaphylactoidreactions

After administration of Hydroxyethyl starch , anaphylactic/anaphylactoidreactions of various degrees canoccurwhich are not dose-dependent.Therefore, all patients receiving starch infusion should be monitored closely for anaphylactic/anaphylactoidreactions. In the eventof an anaphylactic/anaphylactoidreaction, the infusion should be discontinued immediately and the usualacute treatment initiated.

It is not possible to predict by tests which patients may be expected to suffer an anaphylactic/anaphylactoid reaction nor is it possible to predict the course and severity of such a reaction.Prophylaxis with corticosteroids has not been shown to have a preventive effect.

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

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Symptoms

Overdose with Tetraspan would lead to unintended hypervolaemiaand circulatory overload with a significant fall in haematocrit and plasma proteins. This may be associated with consecutive impairment of heart and lung function (pulmonary oedema).

Treatment

In this case, the infusion must be discontinued immediately and administration of diuretics considered.If an overdose occurs, the patient should be treated symptomatically and electrolytes should be monitored.

Pharmacotherapeutic group: Blood substitute and plasma proteins,

ATC code: B05A-A07

Mechanism of action,pharmacodynamic effects

Tetraspan is a colloidal plasma volume substitute containing Hydroxyethyl starchin a balanced electrolyte solution. The averagemolecular weight is 130,000 Daltons and its molar substitution is 0.42.

Tetraspan 60 mg/mlis iso-oncotic, i.e. the increase in the intravascular plasma volume is equivalent to the infused volume.

With isovolaemic administration, the volume expanding effect persistsfor at least 4-9 hours. The duration of the volume effect is primarily based on molar substitution and to a lesser extent on the averagemolecular weight. Intravascular hydrolysis of Hydroxyethyl starchpolymers results in a continuous release of smaller molecules which alsoare oncotically active before they are excreted via the kidneys.

Tetraspan 60 mg/mlmay lower the haematocrit and the plasma viscosity.

Tetraspan also has a favourable effect on the microcirculation by altering the flow characteristics of the blood.

The cation pattern in the crystalloid component of Tetraspan 60 mg/ml is adapted to physiological plasma electrolyte concentrations. The anion pattern is a combination of chloride, acetate and malate, the purpose of which is to minimise the risk of hyperchloraemia and acidosis. Additionsof acetate and malate instead of lactate anions are intended to reduce the risks of lactic acidosis.

General

The characteristics of the electrolytes contained in Tetraspan are the same as in normal physiology.

Absorption

As Tetraspan is administered intravenously, the bioavailability is 100%.

Distribution

Hydroxyethyl starch is a mixture of several differentmolecules with a different molecular weight and degree of substitution. Like all colloids, Hydroxyethyl starch, too, is temporarily stored particularly in the cells of the mononuclear phagocyte system (MPS), however, without producing any irreversible toxic effects on liver, lungs, spleen and lymph nodes. Minor quantities of the stored active substance in the skin are still histologically detectable several months after administration. Such storage phenomena are assumed to be the cause for the itching that has been observed after long-term administration of high doses of Hydroxyethyl starch.

Hydroxyethyl starchdoes not pass the blood-brain barrier. No relevant Hydroxyethyl starchconcentrations were detected in the umbilical cord excluding the possibility of a maternal-foetal transfer of Hydroxyethyl starch .

Biotransformation/Elimination

Elimination is dependent on the degree of substitutionand to a lesser extent on molecular weight.Molecules which in terms of size are belowthe so-called renal threshold are excretedby glomerular filtration. Larger molecules are first degraded by alpha-amylase before theyare excretedrenally. The rate at which the molecules are degradeddecreases with increasingdegree of substitutionof the molecules.

After a single infusion of 1 000 ml Tetraspan 60 mg/ml, plasma clearance is 19 ml/min and AUC 58 mg×h×ml^–1. The terminal serum half-life is about 4-5hours.

Pharmacokinetics in paediatric patients

No pharmacokinetic data from treatment of children are available.

No toxicological animal studies have been conducted with Tetraspan 60 mg/ml.

Published animal toxicological studies with repeated hypervolaemic treatment with similar Hydroxyethyl starch products have revealed bleeding and extensive histiocytosis (accumulation of foam-like histiocytes/macrophages) in several organs with an increase in weight of the liver, kidneys and spleen. Infiltration of fat and vacuolation of organs as well as elevations of plasma AST and ALT have been reported. It has been suggested that some of the effects described were caused by haemodilution, increased circulatory load and uptake and accumulation of starch in phagocytic cells.

Similar Hydroxyethyl starchproducts have been reported to be non-genotoxic in standard tests.

Reproductive toxicity studies of Hydroxyethyl starchproducts showed vaginal bleeding and signs of embryo-/foetotoxicity and teratogenicity associated with repeated administration to test animals. These effects may be due to haemodilution and result in foetal hypoxia and hypervolaemia. Bleeding canalso be in part adirect consequence of the effects that Hydroxyethyl starch hason the blood coagulation.

Sodium hydroxide (for pH adjustment)

Waterfor injections

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

Unopened

Polyethylene plastic bottle (Ecoflac plus): 3 years

Plastic bag (Ecobag): 2 years

After first opening

The product should be administered immediately after connecting the container to the administration set.

Do not freeze.

Tetraspan 60 mg/ml is available in the following types of packaging and contents:

10 x 500ml

20 x 250 ml

20 x 500 ml

Not all pack sizes may be marketed.

No special requirements for disposal.

Administration should commence immediately after connecting the container to the administration set.

For single use only.

Use as soon asthe primary packaging is opened. Any unused contents should be discarded.

Use only if the solution is clear, colourlessand the packaging is undamaged.

Do not re-connect partially used containers.

B. Braun Melsungen AG

Carl-Braun-Strasse1

34212 Melsungen

Germany

Postal address:

34209 Melsungen, Germany

Telephone: +49 5661 71 0

Telefax: +49 5661 71 4567

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28 February 2014