Haemate P 500 and 1000 Powder and solvent for solution for injection or infusion

Haemate P 500 IU

Haemate P 500 is presented as a powder and solvent for solution for injection or infusion containing nominally 1200 International Units (IU) human plasma-derived von Willebrand Factor-ristocetin co-factor activity (VWF:RCo) and 500 IU human coagulation factor VIII activity (FVIII:C)per vial.

von Willebrand Factor

Haemate P 500 contains approximately 120 IU/ml (1200 IU/10ml) human plasma-derived VWF:RCo when reconstituted with 10 ml water for injections.

Factor VIII

Haemate P 500 contains approximately 50 IU/ml (500 IU/10ml) human plasma-derived coagulation Factor VIII:C when reconstituted with 10 ml water for injections.

Haemate P 1000 IU

Haemate P 1000 is presented as a powder and solvent for solution for injection or infusion containing nominally 2400 International Units (IU) human plasma-derived von Willebrand Factor-ristocetin co-factor activity (VWF:RCo) and 1000 IU human coagulation factor VIII activity (FVIII:C) per vial.

von Willebrand Factor

Haemate P 1000 contains approximately 160 IU/ml (2400 IU/15ml) human plasma-derived VWF:RCo when reconstituted with 15 ml water for injections.

Factor VIII

Haemate P 1000 contains approximately 66.6 IU/ml (1000 IU/15ml) human plasma-derived coagulation Factor VIII:C when reconstituted with 15 ml water for injections.

The specific activity of Haemate P is approximately 3-17 IU VWF:RCo/mg protein.

The factor VIII (FVIII) potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The specific activity of Haemate P is approximately 2-6 IU FVIII:C/mg protein.

For a full list of excipients, see 6.1

Powder and solvent for solution for injection or infusion

von Willebrand Disease (VWD):

Prophylaxis and treatment of haemorrhage or surgical bleeding, when desmopressin (DDAVP) treatment alone is ineffective or contra-indicated

Haemophilia A (congenital factor VIII deficiency):

Prophylaxis and treatment of bleeding

This product may be used in the management of acquired factor VIII deficiency and for the treatment of patients with antibodies against factor VIII (see section 4.4).

Treatment of VWD and Haemophilia A should be supervised by a physician experienced in the treatment of haemostatic disorders.

Posology

von Willebrand Disease:

Generally, 1 IU/kg VWF:RCo raises the circulating level of VWF:RCo by 0.02 IU/ml (2%).

Levels of VWF:RCo greater than 0.6 IU/ml (60%) and of FVIII:C greater than 0.4 IU/ml (40%) should be achieved.

Usually, 40-80 IU/kg bodyweight VWF:RCo and 20-40 IU/kg bodyweight FVIII:C are recommended to achieve haemostasis.

An initial dose of 80 IU/kg VWF:RCo may be required, especially in patients with type 3 von Willebrand disease where maintenance of adequate levels may require higher doses than in other types of von Willebrand disease.

Prevention of haemorrhage in case of surgery or severe trauma

For prevention of excessive bleeding during or after surgery, the injection should be started 1 to 2 hours before the surgical procedure.

An appropriate dose should be re-administered every 12 - 24 hours. The dose and duration of treatment will depend on the clinical status of the patient, the type and severity of bleeding and both the VWF:RCo and FVIII:C levels.

When using a factor VIII-containing von Willebrand factor product, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII:C. After 24 - 48 hours of treatment, in order to avoid an uncontrolled rise in FVIII:C, reduced doses and/or prolongation of the dose interval should be considered.

Dosing in children is based on bodyweight and is therefore generally based on the same guidelines as for adults. The frequency of administration should always be tailored to clinical effectiveness in the individual case.

Haemophilia A:

The dosage and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and on the patient's clinical condition.

The number of units of factor VIII administered is expressed in International Units, which are related to the current World Health Organisation (WHO) standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an International Standard for factor VIII in plasma).

One IU of factor VIII activity is equivalent to that quantity of factor VIII in one ml of normal human plasma.

The calculation of the required dosage of FVIII:C is based on the empirical finding that 1 IU factor VIII:C per kg bodyweight raises the plasma factor VIII activity by about 2% of normal activity (2 IU/dl). The required dosage is determined using the following formula:

Required units = body weight (kg) x desired factor VIII:C rise (% or IU/dl) x 0.5.

The amount to be administered and the frequency of administration should always be tailored to clinical effectiveness in the individual case.

In the case of the following haemorrhagic events, the factor VIII activity should not fall below the indicated plasma activity level (in % of normal or IU/dl) within the corresponding period.

The following table can be used to guide dosing in bleeding episodes and surgery:

During the course of treatment, appropriate determination of FVIII:C levels is advised, to guide the dose to be administered and the frequency of repeated infusions. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma FVIII:C activity) is indispensable. Individual patients may vary in their response to factor VIII, achieving different levels of in vivo recovery and demonstrating different half-lives.

For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 - 40 IU factor VIII:C per kg bodyweight at intervals of 2 to 3 days. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.

Patients should be monitored for the development of factor VIII inhibitors. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor VIII inhibitor is present. . In patients with high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of patients with haemophilia. See section 4.4.

There are no data from clinical studies regarding the dosage of Haemate P in children with haemophilia A.

Method of administration

If necessary, the preparation should be warmed to room or body temperature, then reconstituted as described in section 6.6. Then the product should be administered slowly via the intravenous route at a rate comfortable for the patient. If it is not administered immediately, storage should not exceed 8 hours at room temperature. Once the product has been transferred into a syringe, it should be used immediately.

Where a large volume is required, infusion is an alternative option. The reconstituted preparation should be transferred to an approved infusion system.

The injection or infusion rate should not exceed 4 ml per minute. The patient should be observed for any immediate reaction. Should any reaction occur which might be related to administration of Haemate P, the rate of infusion should be decreased or administration stopped, as appropriate. See section 4.4.

Hypersensitivity to any of the constituents of Haemate P.

As with any intravenous infusion of a plasma-derived protein, allergic type hypersensitivity reactions are possible. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If these symptoms occur, the patient should be advised to discontinue use of the product immediately and contact their physician.

In case of shock, the current medical standards for shock treatment should be implemented.

Haemate P contains up to 70 mg sodium per 1000 IU. This should be taken into consideration for patients on a sodium-controlled diet.

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV and for the non-enveloped virus HAV. The measures taken may be of limited value against other non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia).

Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma-derived products.

It is strongly recommended that every time that Haemate P is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

von Willebrand Disease:

There is a risk of occurrence of thrombotic events, particularly in patients with known clinical or laboratory risk factors. Therefore, patients at risk must be monitored for early signs of thrombosis. Prophylaxis against venous thromboembolism should be instituted, according to the current recommendations.

When using a factor VIII-containing VWF product, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII:C. In patients receiving FVIII-containing VWF products, plasma levels of FVIII:C should be monitored to avoid sustained excessive FVIII:C plasma levels which may increase the risk of thrombotic events, and anti-thrombotic measures should be considered.

Patients with von Willebrand disease, especially type 3 patients, may develop neutralising antibodies (inhibitors) to VWF. If the expected VWF:RCo activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an appropriate assay should be performed to determine if a VWF inhibitor is present. In patients with high levels of inhibitor, VWF therapy may not be effective and other therapeutic options should be considered.

Haemophilia A:

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units per ml of plasma using the modified assay. The risk of developing inhibitors is correlated to the exposure to anti-haemophilic factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days. Patients treated with human coagulation factor VIII should be carefully monitored for the development of inhibitory antibodies by appropriate clinical observations and laboratory tests. In patients with high levels of inhibitor, therapy may not be effective and other therapeutic options should be considered. See section 4.8.

No interactions of human coagulation factor VIII or von Willebrand factor products with other medicinal products are known.

Animal reproduction studies have not been conducted with Haemate P.

Based on the rare occurrence of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and breast-feeding is not available.

The situation is different in von Willebrand disease because of its autosomal heredity. Women are affected more than men because of additional bleeding risks such as menstruation, pregnancy, labour, childbirth and gynaecological complications. Based on post-marketing experience, substitution of VWF in the prevention and treatment of acute bleeding is not contra-indicated. There are no clinical studies available on substitution therapy in pregnant or lactating women.

Therefore, Haemate P should be administered to pregnant and lactating women only if clearly indicated and the benefit outweighs the risk.

No effects on ability to drive and use machines have been observed.

The following adverse reactions are based on experience from clinical trials and on post-marketing experience. The following standard categories of frequency are used:

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed very rarely, and may in some cases progress to severe anaphylaxis (including shock).

When very large or frequently repeated doses are needed, e.g. when inhibitors are present or when pre- and post-surgical care is involved, all patients should be monitored for signs of hypervolaemia. In addition, those patients with blood groups A, B and AB should be monitored for signs of intravascular haemolysis and/or decreasing haematocrit values.

On rare occasions, fever has been observed.

Inhibitor development

Patients with haemophilia A may develop neutralising antibodies (inhibitors) to factor VIII. If such inhibitors occur, the condition will manifest itself as an inadequate clinical response.

In all such cases, it is recommended that a specialised haemophilia centre be contacted.

The experience from clinical trials with Haemate P in previously untreated patients (PUPs) is very limited. Therefore, no valid figures on incidence of clinically relevant specific inhibitors can be provided.

Patients with von Willebrand disease, especially type 3 patients, may very rarely develop neutralising antibodies (inhibitors) to VWF. If such inhibitors occur, the condition will manifest itself as an inadequate clinical response. Such antibodies are precipitating and may occur concomitantly with anaphylactic reactions. Therefore, patients experiencing anaphylactic reaction should be evaluated for the presence of an inhibitor.

In all such cases, it is recommended that a specialised haemophilia centre be contacted.

Vascular disorders

In von Willebrand disease there is a risk of thrombotic events, particularly in patients with known risk factors.

In patients receiving VWF products, sustained excessive FVIII:C plasma levels may increase the risk of thrombotic events, see section 4.4.

For safety with respect to transmissible agents, see section 4.4.

No symptoms of overdose with human von Willebrand factor and/or coagulation factor VIII have been reported. Thromboembolic events may occur in case of major overdose.

Pharmacotherapeutic Group: Antihaemorrhagics: blood coagulation factors, von Willebrand factor and coagulation factor VIII in combination.

ATC code: B02BD06.

von Willebrand Factor:

Haemate P behaves in the same way as endogenous von Willebrand factor.

In addition to its role as a factor VIII protecting protein, von Willebrand factor mediates platelet adhesion to sites of vascular injury and plays the main role in platelet aggregation.

Administration of von Willebrand factor allows correction of the haemostatic abnormalities exhibited by patients who suffer from VWF deficiency (VWD) at two levels:

- VWF re-establishes platelet adhesion to the vascular sub-endothelium at the site of vascular damage (as it binds to both the vascular sub-endothelium and to the platelet membrane), providing primary haemostasis as shown by the shortening of the bleeding time. This effect occurs immediately and is known to depend to a large extent on the level of polymerisation of the protein, i.e. content of high molecular weight VWF-multimers.

- VWF produces delayed correction of the associated factor VIII deficiency. Administered intravenously, VWF binds to endogenous factor VIII (which is produced normally by the patient), and by stabilising this factor, avoids its rapid degradation.

Because of this, administration of pure VWF (VWF product with a low FVIII level) restores the FVIII:C level to normal as a secondary effect after the first infusion with a slight delay.

Administration of a FVIII:C-containing VWF preparation restores the FVIII:C level to normal immediately after the first infusion.

Factor VIII:

Haemate P behaves in the same way as endogenous factor VIII.

The factor VIII/von Willebrand factor complex consists of two molecules (FVIII and VWF) with different physiological functions. When infused into a haemophiliac patient, factor VIII binds to VWF in the patient's circulation.

- Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed.

Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendency.

von Willebrand Factor:

The pharmacokinetics of Haemate P has been evaluated in 28 VWD patients (type 1, n=10; type 2A, n=10; type 2M, n=1; type3, n=7) in the non-bleeding state.

The median terminal half-life of VWF:RCo (two compartment model) was 9.9 hours (range: 2.8 to 51.1). The median initial half-life was 1.47 hours (range: 0.28 to 13.86). The median in vivo recovery for VWF:RCo activity was 1.9 IU/dl per IU/kg (range: 0.6 to 4.5). The median area under the curve (AUC) was 1664 IU/dl x hours (range: 142 to 3846), the median residence time (MRT) was 13.7 hours (range: 3.0 to 44.6) and the median clearance was 4.81 ml/kg/h (range: 2.08 to 53.0).

Peak plasma levels of VWF usually occur at around 50 minutes after injection.

Factor VIII:

After intravenous injection, there is a rapid increase in plasma factor VIII (FVIII:C) activity, followed by a rapid decrease in activity and a subsequent slower rate of decrease in activity. Studies in patients with Haemophilia A have demonstrated a median half-life of 12.6 hours (range: 5.0 to 27.7). An overall median FVIII in vivo recovery of 1.73 IU/dl per IU/kg (range: 0.5 to 4.13) was obtained. In one study, the median residence time (MRT) was found to be 19.0 hours (range: 14.8 to 40.0), the median area under the curve (AUC) was 36.1 % x hours/IU/kg (range: 14.8 to 72.4) and the median clearance was 2.8 ml/kg/h (range: 1.4 to 6.7).

Peak plasma FVIII levels occur between 1 and 1.5 hours after injection.

Haemate P contains the active ingredients, factor VIII and von Willebrand factor, both of which are derived from human plasma and act like the endogenous constituents of plasma.

Single dose toxicity testing revealed no adverse findings in different species even at dose levels several times higher than the recommended human dose. Repeated dose toxicity testing is impracticable due to the development of antibodies to heterologous protein. To date Haemate P has not been reported to be associated with embryo-foetal toxicity, oncogenic or mutagenic potential.

Human albumin

Glycine

Sodium chloride

Sodium citrate

Sodium hydroxide or hydrochloric acid (in small amounts for pH adjustment)

Supplied diluent: Water for injections 10 ml (Haemate P 500), 15ml (Haemate P 1000)

This medicinal product must not be mixed with other medicinal products, diluents and solvents, except those mentioned in section 6.1.

Only the provided injection/infusion sets should be used because treatment failure can occur as a consequence of human factor VIII adsorption to the internal surfaces of some infusion equipment.

3 years.

Following reconstitution, physico-chemical stability has been demonstrated for 48 hours at room temperature (max +25°C). From a microbiological point of view and since Haemate P contains no preservatives, the reconstituted product should be used immediately. If it is not administered immediately, storage should not exceed 8 hours at room temperature.

Once the product has been transferred into a syringe, it should be used immediately.

Do not store above 25 °C. Do not freeze.

Keep the vials in the outer carton, in order to protect from light.

6.5.1 Immediate containers:

Substance vial:

Injection vial of colourless, moulded glass type II (Ph. Eur.), sealed with rubber infusion stopper (latex-free), plastic disc and aluminium cap.

1 vial (hermetically sealed under vacuum) with dried substance

Solvent (diluent) vial (Water for Injections):

1 injection vial of tubular glass with inner surface treatment, colourless glass type I (Ph. Eur.), sealed with rubber infusion stopper (latex-free), plastic disc and aluminium cap.

1 vial with 10 or 15 ml water for injections

6.5.2 Administration set: (in separate box)

1 filter transfer device 20/20

1 disposable 10 or 15 ml syringe

1 venipuncture set

2 alcohol swabs

1 plaster

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

General instructions

• The solution should be clear or slightly opalescent. After filtering/withdrawal (see below), the reconstituted product should be inspected visually for particulate matter prior to administration. Even if the directions for use for the reconstitution procedure are precisely followed, it is not uncommon for a few flakes or particles to remain.

Note: the filter included in the Mix2Vial transfer device will remove any particles.

Filtration does not influence dosage calculations. Do not use visibly cloudy solutions or solutions containing flakes or particles after filtration.

• Reconstitution and withdrawal must be carried out under aseptic conditions.

Reconstitution:

Bring the solvent to room or body temperature. Remove the product and diluent vial flip caps, wipe both stoppers with an alcohol swab and allow to dry before opening the Mix2Vial package.

Withdrawal and application

Administer the solution slowly via the intravenous route, taking care that no blood enters the syringe. See section 4.2.

CSL Behring GmbH

Emil-von-Behring-Strasse 76

35041 Marburg

Germany

Haemate P 500: PL 15036/0009

Haemate P 1000: PL 15036/0010

12 April 2005

15 July 2010