Hemate P - instructions for use, dose, side effects, contraindications

Active substanceCoagulation factor VIII + Willebrand factorCoagulation factor VIII + Willebrand factor

Similar drugsTo uncover

lyophilizate in / in

Dosage form: & nbsplyophilizate for the preparation of a solution for intravenous administration

Composition:

1 bottle with lyophilizate contains:

Active substances:
Coagulation factor VIII	250 ME	500 ME	1000 ME
Willebrand factor	600 ME	1200 ME	2400 ME
Excipients:
Human albumin	40-60 mg	80-120 mg	160-240 mg
Glycine	75-125 mg	150-250 mg	300-500 mg
Sodium chloride	10-20 mg	20-40 mg	40-80 mg
Sodium citrate dihydrate	17.5-35 mg *	35-70 mg *	70-140 mg *

* Corresponds to the content of sodium citrate anhydrous.

1 bottle of solvent contains:
Water for injections	5 ml	10ml	15 ml

Description:

White or almost white lyophilizate.

Reconstituted solution: from a colorless to light yellow color, a clear or slightly opalescent liquid.

Solvent: colorless transparent liquid.

Pharmacotherapeutic group:hemostatic agent

ATX: & nbsp

B.02.B.D.06 Factors of blood coagulation von Willebrand and VIII in combination

Pharmacodynamics:

Willebrand factor

Hemate® P exhibits the same properties as the endogenous von Willebrand factor.

In addition to the function of protecting the coagulation factor VIII, von Willebrand factor It causes adhesion of platelets at the site of vascular injury and plays an important role in platelet aggregation.

The appointment of von Willebrand factor allows to correct hemostasis disorders in patients suffering from a deficiency of von Willebrand factor at two levels:

- von Willebrand factor promotes the adhesion of platelets at the site of vascular damage (since it binds both to the subendothelial layer of the vessels and to the platelet membrane), providing primary hemostasis, as evidenced by a decrease in bleeding time. This effect occurs immediately. It is known that it depends on the presence of a large number of Willebrand factor multimers with a high molecular weight;

- von Willebrand factor contributes to a delayed correction of the associated deficiency of factor VIII. After intravenous administration von Willebrand factor binds to endogenous factor VIII (which is produced in patients in sufficient quantity), and, stabilizing this factor, prevents its rapid degradation. Therefore, with the introduction of a pure vWF (low factor VIII), a slightly delayed normalization of the level of factor VIII (FVIII: C) after the first infusion is observed, and with the introduction of vWF drugs containing factor VIII,normalization of the level of factor VIII is noted immediately after the first infusion.

Coagulation factor VIII

Hemate® P exhibits the same properties as the endogenous coagulation factor VIII.

Complex factor VIII / von Willebrand factor consists of two molecules (factor coagulation of blood VIII and von Willebrand factor), performing various physiological functions.

After administration to patients with hemophilia, factor VIII is associated with a factor Willebrand in the vascular bed.

Activated factor VIII acts as a co-factor for activated factor IX, accelerating the conversion of factor X to activated factor X.

The activated factor X promotes the conversion of prothrombin into thrombin. Thrombin, in turn, converts fibrinogen into fibrin and promotes the formation of a thrombus. Hemophilia A is a hereditary, sex-linked disorder in the blood clotting system due to a decrease in the level of factor VIII.

The disease manifests itself in the form of profuse bleeding and hemorrhages in the joints, muscles and internal organs spontaneously or as a result of accidental trauma or surgical intervention. Replacement Therapy of Coagulation Factor VIII Deficiency in Plasmaallows temporarily normalizing the content of the factor, and also reduce the tendency to bleeding.

Pharmacokinetics:

Willebrand factor

The pharmacokinetic properties of Hemate® P were evaluated in 28 patients with von Willebrand disease [type 1 n= 10; type 2A n= 10; type 2M n= 1, type 3 n= 7] outside of bleeding. The half-life of the vWF: RCo factor (half-life model) is 9.9 hours (on average, from 2.8 to 51.1 hours). The initial half-life is 1.47 hours (on average, from 0.28 to 13.86 hours). Increased ristocetin-cofactor activity of VWF: RCo in vivo is 1.9 (IU / dL) / (IU / kg) [on average, 0.6 to 4.5 (IU / dl) / (IU / kg)]. The average area under the concentration-time curve is 1664 IU / dl x h (average, from 142 to 3846 IU / dl x h), the average retention time (IED) was 13.7 hours (on average, from 3.0 to 44.6 hours); the average clearance is 4.81 ml / kg / h (on average, from 2.08 to 53.0 ml / kg / h).

The maximum level of von Willebrand factor in plasma was usually achieved approximately 50 minutes after administration. The maximum level of coagulation factor VIII was observed 1-1.5 hours after administration.

Coagulation factor VIII

After intravenous administration, a rapid increase in the activity of the coagulation factor VIII in the plasma is first observed, followed by a rapid decrease in activity followed by a slow decrease in activity.Studies in patients with hemophilia A showed that the half-life was 12.6 hours (on average, from 5.0 to 27.7 hours). The increase in the activity of the clotting factor VIII in vivo was 1.73 IU / dL per IU / kg (average, 0.5 to 4.13). In one study, the average retention time was 19.0 hours (on average, from 14.8 to 40.0 hours), the average area under the concentration-time curve was 36.1 (% x h) / (IU / kg ) (average, from 14.8 to 724) (% h) (IU / kg), the average clearance is 2.8 ml / kg / h (average, from 1.4 to 6.7 ml / kg / h ).

Indications:

- Treatment and prevention of bleeding or blood loss during surgery patients with von Willebrand disease, if monotherapy with desmopressin is ineffective or contraindicated;

- Treatment and prevention of bleeding in patients with hemophilia A (congenital deficiency of the coagulation factor VIII);

- can be used to treat and prevent bleeding in patients with acquired coagulation factor VIII deficiency and in patients with antibodies to the coagulation factor VIII.

Contraindications:Hypersensitivity to the coagulation factor VIII, von Willebrand factor or any other component of the drug.

Pregnancy and lactation:

Due to the fact that hemophilia A is rare in women, there is no experience of using the drug during pregnancy and lactation.

With Willebrand's disease, the situation is different, since it is inherited autosomally. Women are sick even more often than men because of the additional risk associated with loss of blood during menstruation, pregnancy, childbirth and the development of gynecological diseases.

On the basis of postmarketing research, the use of von Willebrand factor substitutes for the treatment and prevention of bleeding can be recommended.

Clinical evidence for vWF substitution therapy during pregnancy and lactation are absent.

Thus, during pregnancy and lactation, the drug should be used only if there are indisputable indications.

Dosing and Administration:

A hobby should be performed by a doctor who has experience in treating hemophilia.

Von Willebrand's Disease

Typically, 1 IU / kg vWF: RCo) increases the level of circulating von Willebrand factor in the blood of the patient by 0.02 IU / ml (2%).

Willebrand factor> 0.6 IU / ml (60%) and factor VIII: C> 0.4 IU / ml (40%) should be sought.

Usually to ensure hemostasis recommended administration 40-80 IU / kg vWF and 20-40 IU / kg of factor VIII per kg body weight.

It may require an initial dose of 80 IU vWF / kg, especially in patients with von Willebrand disease type 3, where maintenance of adequate levels of von Willebrand factor administration may require higher dosages than other types of von Willebrand disease.

Prevention of bleeding during surgery and serious injuries

To prevent excessive blood loss during and after operations, the drug should be administered 1 or 2 hours before the operation begins.

Every 12-24 hours, the administration of appropriate doses should be repeated.

Dose and duration of therapy depends on the clinical condition of the patient, type and severity of bleeding, and the content of von Willebrand factor and coagulation factor VIII.

When using von Willebrand factor preparations containing coagulation factor VIII, the attending physician should consider the possibility of an excessive increase in the level of factor VIII with prolonged treatment. After 24-48 hours of therapy in order to avoid an uncontrolled increase in the content of factor VIII should assess the need to reduce or increase the dose interval between dosing.

Dosage regimen in children is calculated taking into account the body weight, that is, it is based on the same principles as in adults. The frequency of drug administration should always depend on the clinical effectiveness in each individual case.

Hemophilia A

Doses and duration of substitution therapy depend on the extent, severity of the deficiency of the coagulation factor VIII, the localization and severity of bleeding, and the clinical condition of the patient.

The number of units of introduced factor VIII is measured in international units (ME), which corresponds to the current standard of the World Health Organization (WHO) for preparations containing coagulation factor VIII. The activity of factor VIII in plasma is expressed as a percentage (relative to normal human plasma) or in ME (relative to the International Standard for Factor VIII Content in Plasma).

One ME of factor VIII activity is equivalent to the amount of factor VIII in one milliliter of normal human plasma.

Calculation of the required dose of factor VIII is based on an empirically established pattern according to which 1 IU per kilogram of body weight increases the activity of factor VIII at approximately 2% of normal activity (2 IU / dl).

The required dose is calculated using the following formula:

Required number of units = body weight [kg] x required increase in factor VIII [% or IU / dL] x 0.5.

The dose and frequency of the administration should always be calculated taking into account the clinical effectiveness in each individual case.

In the event of the following bleeding, the activity of factor VIII for the relevant period should not be lower than the indicated level of plasma activity (in% of normal level or in IU / dL).

Table of calculation of doses of the drug for bleeding and in surgical practice:

Severity of bleeding /

Type of surgical procedure

The required level of factor VIII (% or IU / dl)

Frequency of doses (hours) /

Duration of therapy (days)

Bleeding:

Early hemarthrosis,muscle or mouth bleeding

20-40

Repeated infusion of the drug,

every 12-24 hours. At least 1 day, until the bleeding stops (according to pain) or healing occurs.

More massive bleeding, muscle bleeding or bruising

30-60

Repeated infusions of the drug every 12-24 hours for 3-4 days, or more, until the pain syndrome or severe disability disappears.

Life-threatening bleeding

60-100

Repeated infusions every 8-24hours to eliminate the threat to life.

Surgery:

Small, including tooth extraction

30-60

Every 24 hours, at least 1 day, until healing takes place.

Large

80-100

(before and after surgery)

Repeated infusions every 8-24 hours to adequate wound healing, then therapy for at least 7 days to maintain factor VIII activity at 30-60% (IU / dl).

During the course of treatment, it is recommended to determine the level of factor VIII in order to calculate the administered dose and the frequency of infusions. With extensive surgical intervention, monitoring of substitution therapy with coagulation analysis (factor VIII activity) is mandatory. There is a significant 4 individual variability in the response to treatment with factor VIII, in vivo different recovery and half-life values are achieved.

With the long-term prophylaxis of bleeding in patients with severe hemophilia A, factor VIII is normally administered at a dose of 20-40 IU / kg with an interval of 2-3 days.

In some cases, especially in young patients, more short intervals and higher doses.

The possibility of forming antibodies (inhibitors) to factor VIII should be taken into account. It is necessary to monitor the production of factor VIII inhibitors in patients.If the expected level of factor VIII activity is not achieved with the preparation or if bleeding is stopped when the calculated dose is administered, an analysis should be carried out for the presence of factor VIII inhibitors. In patients with a high content of inhibitors, factor VIII therapy may not be effective, and alternative therapies should be considered in such cases. The management of such patients should be carried out by physicians experienced in the treatment of hemophilia patients (see also the "Special instructions" section).

Dosage regimen for children is calculated taking into account the body weight, that is, it is based on the same principles as in adults. The frequency of drug administration should always depend on the clinical effectiveness in each individual case.

Instructions for preparing a solution

General Instructions

1. The solution of the reconstituted lyophilizate ranges from clear to slightly opalescent. After filtration and before introduction it is recommended to inspect reconstituted preparation for the presence of particles and discoloration. Even instructions for dissolving are performed exactly, sometimes small solutions remain in solution flakes or particles.Device for, additions solvent with built-in the filter completely delays these particles. Filtering does not affect calculation dose. Do not use a cloudy solution or solution containing sediment (small particle) after filtration.

2. Preparation of the reconstituted solution of the preparation and the kit are carried out under aseptic conditions.

3. The unused preparation or solution of the preparation, as well as its packaging, should be disposed of in accordance with local requirements.

Preparation of the reconstituted solution

Heat the solvent to room temperature. Make sure that the caps from the bottles with the solvent and the preparation are removed, the plugs are treated with an antiseptic solution and dried before opening the device for the addition of a solvent with a built-in filter *.

1. Remove the cover from the packaging of the device for adding a solvent with a - built-in filter. Not Remove the device for adding the solvent with the built-in filter from the blister pack!

2. Place the solvent bottle on a flat, clean surface without opening it. Take the device to add solvent with a built-in filter together with a blister packing and, tightly while holding the bottle, pierce the stopper of the vial with a sharp tip of the blue part of the device, pressing vertically down.

3. Gently holding the edge of the blister pack, remove the blister pack vertically upwards from the solvent addition device. Make sure that you have removed only the blister pack, not the device itself.

4. Place a vial of the drug on a flat surface and flip a solvent vial over it with a solvent addition device attached to it. Then pierce the stopper of the vial with the core of the transparent part of the device for adding the solvent, pressing vertically downwards. The solvent will automatically move into the vial with the drug.

5. With one hand, grasp the device for adding the solvent from the side of the vial with the drug, the other from the side of the vial with the solvent and gently unfold the device in two parts, avoiding strong foaming when dissolving the lyophilizate. The solvent bottle with the blue part of the device for adding the solvent should be discarded.

6.Carefully twist the bottle with the drug and make sure that the drug is completely dissolved. Do not shake the bottle.

7. Draw air into an empty sterile syringe and, while holding the vial in the upright position, attach the syringe to the Luer tip on the solvent addition device with the built-in filter. Enter the air into the vial with the drug.

Fence and disposal of the drug:

8. By pressing the plunger of the syringe, flip the bottle together with the syringe. Slowly pulling the plunger of the syringe, put into it a reconstituted solution.

9. After the reconstituted solution is put into the syringe, grasp the syringe barrel (holding the syringe down with the piston) and detach the device for adding the solvent with the built-in filter from the syringe.

* The device for adding a solvent with a built-in filter ("Mix-2Vial ™ 20/20") is intended for single use; Do not use the device in the event of damage to the package, or after the expiry date indicated on the paper part of the blister package as follows: "EXP, year-month"

For the introduction of Hemate® P it is recommended to use disposable plastic syringes, since the solution can remain on the glass walls of the all-glass syringes.The drug should be heated to room temperature or body temperature before administration.

The drug is administered slowly intravenously at a rate that does not cause discomfort to the patient, after making sure that the blood does not enter the syringe with the drug. The reconstituted solution of the drug, drawn into the syringe, should be used immediately.

In the case where administration of large amounts of the preparation is indicated, a drip administration can be used. To do this, the reconstituted solution of the drug is added to the required volume of the infusion solution.

The rate of administration of the drug should not exceed 4 ml per minute.

If a patient experiences a reaction that may be caused by the administration of Hemate® P, it is necessary to reduce the rate of administration of the drug or to stop the administration depending on the clinical state of the patient.

The reconstituted solution remains chemically and physically stable for 48 hours at a temperature of no higher than +25 ° C. However, from the point of view of aseptic, since Hemate® P does not contain preservatives, the reconstituted drug solution should be administered immediately after dilution.Storage of the reconstituted solution should not exceed 8 hours at room temperature.

Side effects:

The adverse events presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence. Frequency of occurrence is determined in the following way: Often (≥1/10), often (≥1 / 100 and <1/10), infrequently (≥ 1/1 000 and <1/100), rarely (≥ 1/10 000 and <1/1 000), rarely (< 1/10 000), is unknown. Frequency categories were formed on the basis of post-registration observation.

Classification in accordance with the defeat of organs and organ systems (MedDRA)

Undesirable

phenomenon

Frequency

occurrence

Violations of the blood and lymphatic system

Hypervolaemia

Hemolysis

Formation of inhibitors to the von Willebrand factor Formation of inhibitors to factor VIII

Unknown

Rarely

General disorders and disorders at the site of administration

Fever

Burning and tingling at the injection site

Rarely

Immune system disorders

Dhypersensitivity (allergic reactions)

Rarely

Violations from

sides of blood vessels

Thrombosis

Cases of thromboembolism

Rarely

Violations from the blood and lymphatic system: if it is necessary to use large doses of the drug or its frequent use, or in the presence of inhibitors, or if additional treatment is necessary before and after surgery, all signs of hypervolemia should be monitored in all patients. In addition, patients with blood groups A, B and AB should be tested for intravascular hemolysis and / or hematocrit.

General disorders and disorders at the site of administration: In very rare cases, fever, burning and tingling at the injection site were noted.

Immune system disorders: increased sensitivity or allergic reactions (including angioedema, chills, redness of face and neck, generalized urticaria, headache, rash, arterial hypotension, drowsiness, nausea, anxiety, tachycardia, a feeling of tightness in the chest, tingling, vomiting, wheezing) were very rare and in some cases could lead to severe anaphylactic reactions (including shock).

Von Willebrand's Disease

Violations from the blood and lymphatic system: in patients with Willebrand's disease, especially 3 types, neutralizing antibodies (inhibitors) to the von Willebrand factor can very rarely form. The appearance of antibodies leads to clinical inefficiency of drug treatment.

These antibodies are precipitating, and their appearance may be accompanied by anaphylactic reactions. Therefore, in patients with anaphylactic reactions, the presence of inhibitors should be determined.

In all such cases, specialized care is recommended in the hematology unit or center.

Vascular disorders: In very rare cases there is a risk of developing thrombosis / cases of thromboembolism (including thromboembolism of pulmonary arteries).

Patients receiving von Willebrand factor preparations have a risk of increased activity factor VIII (FVIII:C) in plasma, which increases the likelihood of development thrombosis (see also section "Special instructions").

Haemophilia A

Violations from the blood and lymphatic system: in patients with hemophilia A, neutralizing antibodies (inhibitors) to the coagulation factor VIII can very rarely be produced. Appearance antibodies leads to clinical inefficiency of drug treatment.In these cases, treatment is recommended in a specialized hematology unit or center.

The experience of using "Hemate® P" in previously untreated patients, obtained during clinical trials, is very limited, therefore, statistically reliable quantitative data on clinically proven cases of specific inhibitors

Overdose:

Symptoms of an overdose of the human factor of blood coagulation VIII were not observed. At the same time, the risk of thrombosis during use of too high doses, especially von Willebrand factor preparations containing high concentrations of factor VIII.

Interaction:

There are no known drug interactions of the coagulation factor VIII with other drugs.

Pharmaceutical incompatibility

Do not mix the preparation with other medicinal products and solvents, except for the solvent included in the preparation

Special instructions:

As with any drug containing a plasma protein and administered intravenously, it is possible to develop hypersensitivity reactions (allergic reactions).Patients should be informed of early symptoms of hypersensitivity reactions, such as rashes, generalized urticaria, a feeling of restraint in chest, wheezing, arterial hypotension and anaphylaxis. When these symptoms appear, patients are advised to immediately stop using the drug and consult a doctor. It is necessary to follow standard methods of treatment of shock in case of development of shock state.

Hemate® P contains up to 70 mg of sodium per 1000 ME, which should be considered with the recommended diet for sodium control.

Viral safety

Standard measures to prevent transmission of infection due to the use of medicines made from human blood or plasma consist of the selection of donors, screening of individual donor samples and plasma pools for the presence of markers, as well as included in the production process inactivation procedures and / or virus removal. Despite this, when using products derived from human blood or plasma, the emergence of infectious diseases due to transmission of infectious agents can not be completely ruled out.This provision applies to unknown viruses and pathogens.

The measures taken are effective for enveloped viruses, such as the human immunodeficiency virus, hepatitis B and C viruses, and the non-enveloped hepatitis A virus.

The measures taken may be less effective for non-enveloped viruses, such as parvovirus B19. Infection caused by parvovirus B 19 may have serious consequences for pregnant women (infection of the fetus) and those with immunodeficiency or enhanced erythropoiesis (eg, hemolytic anemia).

Patients who regularly or repeatedly take drugs obtained from human plasma are recommended to vaccinate against hepatitis A and B.

Each time the introduction of Hemate® II is to be fixed name and serial number the drug used to maintain communication between the patient and the drug series.

Von Willebrand's Disease

There is a risk of thrombosis, including thromboembolism of the pulmonary arteries, especially in patients with known clinical and laboratory risk factors (eg, in the absence prevention of thrombosis during the perioperative period, in the absence of early mobilization, obesity, overdose, oncological diseases).

Therefore, for patients at risk should be monitored for early symptoms of thrombosis. Prevention of venous thromboembolism should be carried out in accordance with current recommendations.

When using Hemate® P for von Willebrand disease, the attending physician should know, that prolonged treatment may lead to an excessive increase in activity level coagulation factor VIII (FVIII:C). Patients receiving vWF drugs containing factor VIII should be monitored for factor VIII activity (FVIII:C) in plasma to avoid prolonged the drug used to maintain communication between the patient and the drug series.

Von Willebrand's Disease

There is a risk of thrombosis, including thromboembolism of pulmonary arteries, especially in patients with known clinical and laboratory risk factors (for example, in the absence prevention of thrombosis during the perioperative period, in the absence of early mobilization, obesity, overdose, oncological diseases).

Therefore, for patients at risk should be monitored for early symptoms of thrombosis.Prevention of venous thromboembolism should be carried out in accordance with current recommendations.

When using Hemate® P for von Willebrand disease, the attending physician should be aware that prolonged treatment may lead to an excessive increase in activity level coagulation factor VIII (FVIII.C). Patients receiving vWF drugs containing factor VIII should be monitored for factor VIII activity (FVIII:C) in plasma to avoid a prolonged increase in the level of activity of factor VIII (FVIII:C), which is associated with an increased risk of thrombotic complications. It should also be appropriate prevention thrombosis.

In patients with von Willebrand disease, especially 3 types, neutralizing antibodies (inhibitors) to the von Willebrand factor can be produced. If the expected level of ristocetin-cofactor activity of von Willebrand factor is not reached (VWF:RCo) in plasma or with an adequate dose can not stop bleeding, it is necessary to carry out an analysis for the presence of inhibitors of von Willebrand factor. If the patient has a high level of Willebrand factor inhibitors, the therapy may not be effective, and in this case other methods of treatment should be considered.

Haemophilia A

The development of neutralizing antibodies (inhibitors) to factor VIII is a known complication in the treatment of patients with hemophilia A. Factor VIII inhibitors are usually immunoglobulins of class G (IgG), which are measured in Bethesda units (BE) in milliliter of plasma. The risk of producing inhibitors is related to the degree of exposure to anti-hemophilic factor VIII; this risk is greatest during the first 20 days of use. In rare cases, inhibitors can begin to be produced more than 100 days after the beginning of the use of coagulation factor VIII.

Patients receiving coagulation factor VIII person, should be under careful medical and laboratory control to detect the production of antibodies to factor VIII. Treatment of Hemate® P patients with high levels of antibodies to factor VIII may not be effective, in which case consideration should be given to the selection of other treatments (see also "Side effects").

Effect on the ability to drive transp. cf. and fur:

Effects on the ability to drive a vehicle or moving machinery have not been noted.

Form release / dosage:

Lyophilizate for the preparation of a solution for intravenous administration, 250 ME + 600 ME, 500 ME + 1200 ME or 1000 ME + 2400 ME.

Packaging:

For 250 ME of the clotting factor VIII and 600 ME of von Willebrand factor into vials of clear colorless glass (type I, HeF) or 500 ME / 1000 ME of the clotting factor VIII and 1200 IU / 2400 ME of von Willebrand factor into vials of clear colorless glass ( And type, Hebrew F.), sealed with a plug of bromine of butyl rubber and coated with aluminum caps with a plastic disc complete with a solvent (water for injection) of 5 ml (for 250 ME + 600 ME), 10 ml (for 500 ME + 1200 ME) and 15 ml (for 1000 ME + 2400 ME) in the bottles transparent colorless glass (I type, Eur.F.), sealed with a stopper of chlorobutyl rubber and coated with aluminum caps with plastic disc.

Device for adding a solvent with a built-in 15 μm filter ("Mix-2Vial™ 20/20 ") is packed in a blister polyethylene terephthalate / paper laminated with polyethylene.

1 bottle with lyophilizate, 1 vial with solvent and 1 device for adding a solvent with a built-in filter with instructions for use in a cardboard pack.

Additionally, there is a kit for intravenous administration of the drug. Kit for intravenous administration of the drug (disposable syringe,needle-butterfly, 2 disinfecting wipes in individual sealed packages and a non-sterile adhesive plaster) are placed in a separate pack.

One cardboard tutu with the preparation and one cardboard pack with the kit for The intravenous infusion is folded together and fastened with a plastic band.

Storage conditions:

At a temperature of no higher than 25 ° C in a dark place.

Do not freeze.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date stated on the package.

Terms of leave from pharmacies:On prescription

Registration number:PL-000596

Date of registration:21.09.2011

The owner of the registration certificate:CESEL Behring GmbHCESEL Behring GmbH Germany

Manufacturer: & nbsp

CSL BEHRING, GmbH Germany

Representation: & nbspGlaxoSmithKline Trading, ZAOGlaxoSmithKline Trading, ZAO

Information update date: & nbsp16.09.2015

Illustrated instructions

Instructions

Hemate® P (Hfemate® P)