HAEMATE P 500 IU FVIII 1200 IU VWF

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

19/11/2014

םש

רישכת

תילגנאב

רפסמו

:םושירה

HAEMATE-P 250 I.U. (

113 53 22360 00

), HAEMATE-P 500 I.U. (

113 51 22459 00

) HAEMATE-P 1000 I.U (

113 52

22460 00

)

םש

לעב

םושירה

Genmedix

דבלב תורמחהה טורפל דעוימ הז ספוט

תושקובמה תורמחהה ןולעב קרפ יחכונ טסקט שדח טסקט

4.2 Posology

and

method

of

administration

Prophylaxis

[…]

Prophylaxis

[…]

Previously untreated patients

The safety and efficacy of Haemate in previously untreated patients

have not yet been established.

4.4 Special

Warnings

and

Precautions

for use

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 (BU) 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 inhibitors 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 also section

“4.8 Undesirable effects".

Haemophilia A

Inhibitors

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 (BU) per ml of

plasma using the modified assay. The risk of developing

inhibitors is correlated to the exposure to factor VIII, this risk

being highest within the first 20 exposure days. Rarely,

inhibitors may develop after the first 100 exposure days.

Cases of recurrent inhibitor (low titre) have been observed after

switching from one factor VIII product to another in previously treated

patients with more than 100 exposure days who have a previous

history of inhibitor development. Therefore, it is recommended to

monitor all patients carefully for inhibitor occurrence following any

product switch.

In general, all patients treated with human coagulation factor

VIII should be carefully monitored for the development of

inhibitors by appropriate clinical observations and laboratory

tests. If the expected factor VIII activity plasma levels are not

attained, or if bleeding is not controlled with an appropriate

dose, testing for FVIII inhibitor presence should be performed.

In patients with high levels of inhibitor, factor VIII therapy may

not be effective and other therapeutic options should be

considered. The management of such patients should be directed

by physicians with experience in the care of haemophilia A

patients and those with factor VIII inhibitors.See also section

4.8.

4.6

Fe

rti

lit

y,

pr

eg

na

nc

y

an

d

lac

tat

io

n

Therefore, VWF and FVIII should be used during pregnancy and

lactation only if clearly indicated

Therefore, VWF and FVIII should be used during pregnancy

and lactation only if clearly indicated and the benefit outweighs

the risk.

4.8

Undes

irable

effects

Summary of the safety profile

During treatment with Haemate in adults and adolescents the following

adverse reactions may occur:

Hypersensitivity or allergic reactions, thromboembolic events and

pyrexia. Furthermore patients may develop inhibitors to FVIII and

VWF.

[…]

Paediatric Population

Frequency, type and severity of adverse reactions in children are

expected to be the same as in adults.

4.9

overdos

e

No symptoms of overdose with VWF and FVIII have been

reported. However, the risk of thrombosis cannot be

excluded in case of an extremely high overdose, especially

of FVIII-containing VWF products with a high FVIII

content.

No symptoms of overdose with VWF and FVIII have been

reported. However, the risk of thrombosis cannot be excluded in

case of an extremely high overdose dose, especially of FVIII-

containing VWF products with a high FVIII content.

Thromboembolic events may occur in case of major overdose.

1.

NAME OF THE MEDICINAL PRODUCT

Haemate

®

P 250 IU FVIII / 600 IU VWF

Powder and solvent for solution for injection or infusion

Haemate

®

P 500 IU FVIII / 1200 IU VWF

Powder and solvent for solution for injection or infusion

Haemate

®

P 1000 IU

FVIII / 2400 IU VWF

Powder and solvent for solution for injection or infusion

2.

QUALITATIVE

AND QUANTITATIVE COMPOSITION

One vial Haemate P 250 IU FVIII / 600 IU VWF contains nominally:

250 IU human coagulation factor VIII (FVIII).

600 IU human von Willebrand factor (VWF).

After reconstitution with 5 ml water for injections the solution contains 50 IU/ml of FVIII and 120

IU/ml of VWF.

One vial Haemate P 500 IU FVIII / 1200 IU VWF contains nominally:

500 IU human coagulation factor VIII (FVIII).

1200 IU human von Willebrand factor (VWF).

After reconstitution with 10 ml water for injections the solution contains 50 IU/ml of FVIII and 120

IU/ml of VWF.

One vial Haemate P 1000 IU FVIII / 2400 IU VWF

contains nominally:

1000 IU human coagulation factor VIII (FVIII).

2400 IU human von Willebrand factor (VWF).

After reconstitution with 15 ml water for injections the solution contains 66.6 IU/ml of FVIII and

160 IU/ml of VWF.

The FVIII potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The

specific FVIII activity of Haemate P is approximately 2 - 6 IU of FVIII/mg protein

The VWF potency (IU) is measured according to ristocetin cofactor activity (VWF:RCo) compared

to the International Standard for von Willebrand factor concentrate (WHO)The specific VWF

activity of Haemate P is approximately 5 - 17 IU of VWF:RCo/mg protein.

Haemate P is produced from the plasma of human donors.

Excipient with known effect:

Sodium:

Haemate P 250 IU FVIII / 600 IU VWF and Haemate P 500 IU FVIII / 1200 IU VWF –

approximately 113 mmol/l (2.6 mg/ml)

Haemate P 1000 IU FVIII / 2400 IU VWF – approximately 150 mmol/l (3.5 mg/ml)

For the full list of excipients, see section 6.1

3.

PHARMACEUTICAL FORM

Powder and solvent for solution for injection or infusion.

White powder and clear, colourless solvent for solution for injection/infusion.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Congenital and acquired deficiency of blood clotting factor VIII:

severe or moderate haemophilia,

prophylaxis during operation.

Von Willebrand's disease.

Haemophilia A (congenital factor VIII deficiency)

Prophylaxis and treatment of bleeding in patients with haemophilia A.

This product may be used in the management of acquired factor VIII deficiency and for treatment of

patients with antibodies against factor VIII.

Von Willebrand Disease (VWD)

Prophylaxis and treatment of haemorrhage or surgical bleeding, when desmopressin (DDAVP)

treatment alone is ineffective or contra-indicated.

4.2

Posology and method of administration

Treatment of VWD and Haemophilia A should be supervised by a physician experienced in the

treatment of haemostatic disorders.

Posology

von Willebrand's disease:

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

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

Usually 40 - 80 IU/kg of von Willebrand factor (VWF:RCo) and 20 - 40 IU FVIII:C/kg of body

weight (BW) are recommended to achieve haemostasis.

An initial dose of 80 IU/kg von Willebrand factor may be required, especially in patients with type 3

von Willebrand disease where maintenance of adequate levels may require greater 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 start 1 to 2 hours

before the surgical procedure.

An appropriate dose should be re-administered every 12 - 24 hours. The dose and duration of the

treatment depend on the clinical status of the patient, the type and severity of bleeding, and both

VWF:RCo and FVIII:C levels.

When using a FVIII-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.

Paediatric population

Dosing in children is based on body weight and is therefore generally based on the same guidelines as

for adults. The frequency of administration should always be oriented to the 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 (IU), which are

related to the current WHO standard for factor VIII products. Factor VIII activity in plasma is

expressed either as a percentage (relative to normal human plasma) or in IU (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.

On demand treatment

The calculation of the required dosage of factor VIII is based on the empirical finding that 1 IU factor

VIII per kg body weight raises the plasma factor VIII activity by about 2 %

(2 IU/dl) of normal activity. The required dosage is determined using the following formula:

Required units = body weight [kg] x desired factor VIII rise [% or IU/dl] x 0.5.

The amount to be administered and the frequency of administration should always be oriented to the

clinical effectiveness in the individual case.

In the case of the following haemorrhagic events, the factor VIII activity should not fall below the

given 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:

Degree of haemorrhage/ Type

of surgical procedure

Factor VIII level

required (% or IU/dl)

Frequency of doses (hours) /

Duration of therapy (days)

Haemorrhage

Early haemarthrosis, muscle

bleeding or oral bleeding

20 - 40

Repeat every 12 - 24 hours.

At least 1 day, until the

bleeding episode as indicated

by pain is resolved or healing

is achieved.

More extensive haemarthrosis,

muscle bleeding or haematoma

30 - 60

Repeat infusion every

12 - 24 hours for 3 - 4 days or

more until pain and acute

disability are resolved.

Life-threatening haemorrhages

60 - 100

Repeat infusion every

8 - 24 hours until threat is

resolved.

Surgery

Minor

including tooth extraction

30 - 60

Every 24 hours, at least 1 day,

until healing is achieved.

Major

80 - 100

(pre- and

postoperative)

Repeat infusion every

8 - 24 hours until adequate

wound healing, then therapy

for at least another 7 days to

maintain a factor VIII activity

of 30% - 60% (IU/dl).

Prophylaxis

For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses

are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. In some cases,

especially in younger patients, shorter dosage intervals or higher doses may be necessary.

During the course of treatment, appropriate determination of factor VIII 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, a precise monitoring of the substitution therapy by means of coagulation

analysis (plasma factor VIII 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.

Patients should be monitored for the development of factor VIII inhibitors. See also section 4.4.

Previously untreated patients

The safety and efficacy of Haemate P in previously untreated patients have not yet been established.

Paediatric population

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

Method of administration

For intravenous use.

Reconstitute the product as described in section 6.6. The reconstituted preparation should be warmed

to room or body temperature before administration. Inject slowly intravenously at a rate comfortable

for the patient. Once the product is transferred into the syringe it should be used immediately.

In case larger amounts of the factor have to be administered, this can also be done by infusion. For

this purpose transfer the reconstituted product into an approved infusion system.

The injection or infusion rate should not exceed 4 ml per minute. Observe the patient for any

immediate reaction. If any reaction takes place that might be related to the administration of

Haemate P, the rate of infusion should be decreased or the application should be stopped, as required

by the clinical condition of the patient (see also section 4.4).

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4

Special warnings and precautions for use

Hypersensitivity

Allergic type hypersensitivity reactions are possible. If symptoms of hypersensitivity occur, patients

should be advised to discontinue use of the medicinal product immediately and contact their

physician. Patients should be informed of the early signs of hypersensitivity reactions including

hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. In case

of shock, the current medical standards for shock treatment should be observed.

Haemate P contains up to 70 mg sodium per 1000 IU FVIII / 2400 IU VWF. To be taken into

consideration by patients on a controlled sodium diet.

Von Willebrand Disease

There is a risk of occurrence of thrombotic events including pulmonary embolism, particularly in

patients with known clinical or laboratory risk factors (e.g. in the perioperative period without

conduct of thromboprophylaxis, no early mobilization, obesity, overdose, cancer). 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 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 antithrombotic measures should be considered.

Patients with VWD, 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, therapy may not be effective and

other therapeutic options should be considered.

Haemophilia A

Inhibitors

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 (BU)

per ml of plasma using the modified assay. The risk of developing inhibitors is correlated to the

exposure to factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors

may develop after the first 100 exposure days.

Cases of recurrent inhibitor (low titre) have been observed after switching from one factor VIII

product to another in previously treated patients with more than 100 exposure days who have a

previous history of inhibitor development. Therefore, it is recommended to monitor all patients

carefully for inhibitor occurrence following any product switch.

In general, all patients treated with human coagulation factor VIII should be carefully monitored for

the development of inhibitors by appropriate clinical observations and laboratory tests. If the

expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an

appropriate dose, testing for FVIII inhibitor presence should be performed. In patients with high

levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should be

considered. The management of such patients should be directed by physicians with experience in

the care of haemophilia A patients and those with factor VIII inhibitors.See also section 4.8 .

Virus safety

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 human

immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) and for the

non-enveloped hepatitis A virus (HAV).

The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19.

Parvovirus B19 infection may be serious for pregnant women (fetal 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 FVIII/VWF 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.

4.5

Interaction with other medicinal products and other forms of interaction

No interaction of VWF and FVIII with other medicinal products have been studied.

4.6

Fertility, pregnancy and lactation

Animal reproduction studies have not been conducted with Haemate P.

von Willebrand disease

The situation is different in von Willebrand disease because of its autosomal heredity. Women are

even more affected than men, because of additional bleeding risks like menstruation, pregnancy,

labour, child birth and gynecological complications. Based on post-marketing experience

substitution of VWF in the treatment and prevention of acute bleedings can be recommended. There

are no clinical studies available on substitution therapy with VWF in pregnant or lactating women.

Haemophilia A

Based on the rare occurrence of haemophilia A in women, experience regarding the use of factor

VIII during pregnancy and breastfeeding is not available.

Therefore, VWF and FVIII should be used during pregnancy and lactation only if clearly indicated

and the benefit outweighs the risk.

4.7

Effects on ability to drive and use machines

Haemate P has no influence on the ability to drive and use machines.

4.8

Undesirable effects

The following adverse reactions are based on postmarketing experience

Summary of the safety profile

During treatment with Haemate P in adults and adolescents the following adverse reactions may

occur:

Hypersensitivity or allergic reactions, thromboembolic events and pyrexia. Furthermore patients

may develop inhibitors to FVIII and VWF.

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification.

Frequencies have been evaluated according to the following convention:

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 (cannot be estimated from the available data).

MedDRA SOC

Adverse Reaction

Frequency

Blood and Lymphatic System

Disorders

Hypervolemia

Haemolysis

VWF inhibition

FVIII inhibition

Unknown

Unknown

Very rare

Very rare

General Disorders and

Administration Site Conditions

Fever

Very rare

Immune System Disorders

Hypersensitivity (allergic

reactions)

Very rare

Vascular Disorders

Thrombosis

Thromboembolic events

Very rare

Very rare

Description of selected adverse reactions

Blood and lymphatic system disorders

When very large or frequently repeated doses are needed, or when inhibitors are present or when

pre- and post- surgical care is involved, all patients should be monitored for signs of hypervolemia.

In addition, those patients with blood groups A, B and AB should be monitored for signs of

intravascular haemolysis and/or decreasing haematocrit values.

General disorders and administration site conditions

On very rare occasions, fever has been observed.

Immune system disorders

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).

Von Willebrand Disease

Blood and lymphatic system disorders

Patients with VWD, 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 to 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

Very rarely, there is a risk of thrombotic/thromboembolic events (including pulmonary embolism).

In patients receiving VWF products sustained excessive FVIII:C plasma levels may increase the risk

of thrombotic events (see also section 4.4).

Haemophilia A

Blood and lymphatic system disorders

Patients with haemophilia A may very rarely develop neutralising antibodies (inhibitors) to factor

VIII. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In

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

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

Paediatric Population

Frequency, type and severity of adverse reactions in children are expected to be the same as in

adults.

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. Any suspected

adverse events should be reported to the Ministry of Health according to the National Regulation by

using an online form

https://sideeffects.health.gov.il/

and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com

4.9

Overdose

No symptoms of overdose with VWF and FVIII have been reported. However, the risk of

thrombosis cannot be excluded in case of an extremely high dose, especially of FVIII-containing

VWF products with a high FVIII content.

Thromboembolic events may occur in case of major overdose.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

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 VWF.

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 VWF 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 both to 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 to the high content of high

molecular weight VWF-multimers.

VWF produces delayed correction of the associated FVIII deficiency. Administered

intravenously, VWF binds to endogenous FVIII (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 FVIII.

The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von

Willebrand factor) with different physiological functions.

When infused into a haemophiliac patient, factor VIII binds to von Willebrand factor 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 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 level of factor VIII is increased, thereby enabling a

temporary correction of the factor deficiency and correction of the bleeding tendency.

5.2

Pharmacokinetic properties

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, type 3 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 hours). The median initial

half-life was 1.47 hours (range: 0.28 to 13.86 hours). The median in vivo recovery for VWF:RCo

activity was 1.9 (IU/dL)/(IU/kg) [range: 0.6 to 4.5 (IU/dL)/(IU/kg)]. The median AUC was 1664

IU/dL*h ( (range 142 to 3846 IU/dL*h), the median MRT was 13.7 hours (range 3.0 to 44.6 hours)

and the median clearance was 4.81 ml/kg/h (range 2.08 to 53.0 ml/kg/h).

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

Factor VIII

After intravenous injection, there is a rapid increase of plasma Factor VIII activity (FVIII:C) 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 hours). An

overall median FVIII in vivo recovery of 1.73 IU/dL per IU/kg (range 0.5 – 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 hours),

the median area under the curve (AUC) was 36.1 % * hours / IU/kg (range 14.8 to 72.4), the median

clearance was 2.8 mL/kg/h (range 1.4 to 6.7).

Peak FVIII level occur between 1 and 1.5 h after injection.

Paediatric population

No pharmacokinetic data are available in patients younger than 12 years.

5.3

Preclinical safety data

Haemate P contains factor VIII and von Willebrand factor as active ingredients which are derived

from human plasma and act like endogenous constituents of plasma. Single dose applications of

Haemate P to various animal species did not reveal toxic effects. Preclinical studies with repeated

dose applications (chronic toxicity, cancerogenicity and mutagenicity) cannot be reasonably

performed in conventional animal models due to the development of antibodies following the

application of heterologous human proteins.

To date, Haemate P has not been reported to be associated with embryo-foetal toxicity, oncogenic or

mutagenic potential.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Human serum albumin

Glycine

Sodium chloride

Sodium citrate

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

Supplied solvent: Water for injections 5/10/15 ml

6.2

Incompatibilities

This medicinal product must not be mixed with other medicinal products, diluents and solvents

except those mentioned in section 6.1.

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials. From a microbiological point

of view and as Haemate P contains no preservative, the reconstituted product should be used

immediately. If it is not administered immediately, storage shall not exceed 8 hours below 25°C.

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

6.4

Special precautions for storage

Do not store Haemate P above 25 °C.

Do not freeze. Keep container in the outer carton.

6.5

Nature and contents of container

Immediate containers

Substance vials:

250 IU FVIII /600 IU VWF: Injection vials of colourless, tubular glass type I (Ph. Eur.), sealed with

rubber infusion stopper (latex-free), plastic disc and aluminium cap.

500 IU FVIII /1200 IU VWF and 1000 IU FVIII /2400 IU VWF: Injection vials of colourless,

moulded glass type II (Ph. Eur.) sealed with rubber infusion stopper (latex-free), plastic disc and

aluminium cap.

Solvent vials (for water for injections):

Injection vials of tubular glass with inner surface treatment, glass Type I (Ph. Eur.), colourless,

sealed with rubber infusion stopper (latex-free), plastic disc and aluminium cap.

Presentations

Pack with 250 IU FVIII /600 IU VWF containing:

1 vial with powder

1 vial with 5 ml water for injections

1 filter transfer device 20/20

Pack with 500 IU FVIII / 1200 IU VWF containing:

1 vial with powder

1 vial with 10 ml water for injections

1 filter transfer device 20/20

Pack with 1000 IU FVIII / 2400 IU VWF containing:

1 vial with powder

1 vial with 15 ml water for injections

1 filter transfer device 20/20

6.6

Special precautions for disposal and other handling

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 and discoloration 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. The filter included in the

Mix2Vial device removes those particles completely. Filtration does not influence dosage

calculations. Do not use visibly cloudy solutions or solutions still containing flakes or particles

after filtration.

Reconstitution and withdrawal must be carried out under aseptic conditions.

Reconstitution:

Bring the solvent to room temperature. Ensure product and solvent vial flip caps are removed and

the stoppers are treated with an antiseptic solution and allowed to dry prior to opening the Mix2Vial

package.

1. Open the Mix2Vial package by peeling off the

lid. Do

not

remove the Mix2Vial from the blister

package!

2. Place the

solvent vial

on an even, clean surface

and hold the vial tight. Take the Mix2Vial

together with the blister package and push the

spike of the

blue

adapter end

straight down

through the solvent vial stopper.

3. Carefully remove the blister package from the

Mix2Vial set by holding at the rim, and pulling

vertically

upwards. Make sure that you only pull

away the blister package and not the Mix2Vial

set.

4. Place the

product vial

on an even and firm

surface. Invert the solvent vial with the Mix2Vial

set attached and push the spike of the

transparent

adapter end

straight down

through the product

vial stopper. The solvent will automatically flow

into the product vial.

5. With one hand grasp the product-side of the

Mix2Vial set and with the other hand grasp the

solvent-side and unscrew the set carefully into

two pieces to avoid excessive build up of foam

when dissolving the product. Discard the solvent

vial with the blue Mix2Vial adapter attached.

6. Gently swirl the product vial with the

transparent adapter attached until the substance is

fully dissolved. Do not shake.

7. Draw air into an empty, sterile syringe. While

the product vial is upright, connect the syringe to

the Mix2Vial´s Luer Lock fitting. Inject air into

the product vial.

Withdrawal and application

8. While keeping the syringe plunger pressed, turn

the system upside down and draw the solution into

the syringe by pulling the plunger back slowly.

9. Now that the solution has been transferred into

the syringe, firmly hold on to the barrel of the

syringe (keeping the syringe plunger facing down)

and disconnect the transparent Mix2Vial adapter

from the syringe.

For injection of Haemate P the use of plastic disposable syringes is recommended as the ground

glass surfaces of all-glass syringes tend to stick with solutions of this type.

Administer solution slowly intravenously (see section 4.2), taking care to ensure that no blood enters

the syringe filled with product.

Any unused product or waste material should be disposed of in accordance with national

requirements.

7.

MANUFACTURER

CSL Behring GmbH

Emil-von-Behring-Str. 76

35041 Marburg

Germany

REGISTRATION NUMBER(S)

HAEMATE-P 250 I.U. FVIII/ 600 IU VWF

113 53 22360

HAEMATE-P 500 I.U. FVIII/ 1200 IU VWF

113 51 22459

HAEMATE-P 1000 I.U. FVIII/ 2400 IU VWF

113 52 22460

9.

REGISTRATION HOLDER

Genmedix, 12 Beit Harishonim St., Emek-Heffer Industrial Park, 3877701.

This leaflet format has been determined by the Ministry of Health and the content has been checked and

approved in April 2015