Public Assessment Report - DIMDI · acute bleeding or the risk of bleeding and cover standard situations of the affected patients: A mainly prophylactic treatment has to be provided

Willfact 1000 IU DE/H/1935/001/MR EPAR 1/24 Paul-Ehrlich-Institut, Germany

Public Assessment Report

Willfact 1000 IU

Human von Willebrand Factor

DE/H/1935/001/MR

Applicant: LFB BIOMEDICAMENTS

This module reflects the scientific discussion for the approval of Willfact 1000 IU. The procedure has been finalised at 2010-12-14. For information on changes after this date please refer to the module ‘Update’.


TABLE OF CONTENTS I.1 General comments on the submitted dossier 4

I.2 General comments on compliance with GMP, GLP, GCP and agreed ethical principles 4

II. Recommendation 4

III. Scientific Overview 4

IV. Overall conclusion and benefit/risk assessment 8

V. Product Information 9


INFORMATION OF THE INITIAL PROCEDURE 1. Name of the product

Willfact 1000 IU 2. Type of application

Full application according article 8.3 (i) Directive 2001/83/EC

3. Active substance Human von Willebrand Factor

4. Form

Powder and solvent for solution for injection

5. Strength 1000 IU/vial (100 IU/ml)

6. Marketing Authorisation Holder

LFB BIOMEDICAMENTS 3, avenue des Tropiques BP305 – LES ULIS 91958 Courtabœuf Cedex France

7. Reference Member State

Paul-Ehrlich-Institut Germany

8. Concerned Member States AT, CZ, DK, EE, ES, HU, LT, LV, NO, PL, PT, SE, SI, SK, UK

9. Procedure-number DE/H/1935/001/MR

10. Timetable Submission of application: 2010-09-01 Start of procedure: 2010-09-15 Termination of procedure: 2010-12-14


I.1 General comments on the submitted dossier

Willfact 1000 IU is a stand alone application according Art. 8(3) of Directive 2001/83 EC.

I.2 General comments on compliance with GMP, GLP, GCP and agreed ethical principles

The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for the manufacture and assembly of Willfact 1000 IU. The Applicant stated the toxicological investigations on single-dose toxicity, genotoxicity, local tolerance and one of the immunogenicity studies (i.e. intradermal application in rabbits and intravenous administration in vVW pig model) were performed following GLP recommendations. There is no statement on GLP compliance concerning the pharmacodynamic and pharmacokinetic studies. All clinical studies were performed in compliance with GCP.

II. RECOMMENDATION

Based on the review of data on quality, safety and efficacy, the RMS considers that the application for Willfact 1000 IU, in the indication “Prevention and treatment of haemorrhages or surgical bleeding in von Willebrand disease when desmopressin (DDAVP) treatment alone is ineffective or contraindicated”, can be approved. A national marketing authorisation was granted on 15 May 2009. The current approved trade name in Germany is WILLFACT 1000 I.E. The proposed name for the Mutual Recognition Procedure is Willfact 1000 IU.

III. SCIENTIFIC OVERVIEW

Quality

Willfact 1000 IU is a human plasma-derived von Willebrand factor which is marketed as a freeze-dried powder containing 1000 IU/vial which is reconstituted with 10 ml of the solvent sterile Water for Injections to prepare the solution for injection. After reconstitution, one vial contains 1000 IU of human von Willebrand factor solution at a concentration of 100 IU/ml to be administered intravenously. The specific activity, before the addition of human albumin, is ≥ 50 IU VWF:RC of/mg protein. The content of human FVIII is ≤ 10 IU/100 IU VWF:RCo. In addition, the finished product contains human albumin, arginine hydrochloride, glycine, sodium citrate and calcium chloride dihydrate. The final product comprises two vials (one for the powder and one for the solvent), a transfer system with a filtering air vent used to dissolve the freeze-dried powder with sWFI and a filter needle used to draw up the reconstituted solution into a syringe for injection. Willfact is purified from solvent/detergent-treated cryoprecipitate through a combination of anion-exchange and affinity chromatography. The VWF preparation is then diluted and filtered through 35 nm filters (nanofiltration). After concentration and formulation, the product is freeze-dried and further heated at +80° C for 72 h. The manufacturing process of Willfact includes three virus inactivation and elimination steps against enveloped and non-enveloped viruses. Willfact is stable for 36 months at a temperature of 25°C when protected from light. Stability after reconstitution was shown for 24 hours at room temperature.


The overall viral safety strategy includes selection of qualified donors and testing of plasma donations. Plasma is collected in Germany and single donations are screened by an adequate testing program for viral infections (HIV-1 and HIV-2 antibodies, HBsAg and HCV antibodies). Further manufacturing pools are tested by NAT for HIV-1 RNA, HBV DNA, HAV RNA, HCV RNA and B19V DNA. Donors with an increased risk for sporadic or variant Creutzfelt-Jakob-Disease are excluded. The donor selection and plasma donation testing strategy for viral markers is considered adequate. Von Willebrand Factor is purified by precipitation and chromatographic steps. Significant reduction of TSE agents at three process steps (alumin-adsorption, DEAE-Toyopearl chromatography and nanofiltration) has been demonstrated. In addition, three steps for virus inactivation/removal have been introduced into the manufacturing process. (1) S/D treatment is performed with 1% Polysorbate 80 and 0.3% TnBP for 7 hours at a temperature of 25±1°C. Effective inactivation of enveloped viruses has been shown. (2) The intermediate product is subjected to a nanofiltration with a pore size of 35nm which has been demonstrated to remove efficiently the large enveloped viruses, such as HIV-1 and PRV, but also smaller viruses such as BVDV as a model of HCV and SV-40, a model for HBV, due to their similar sizes. (3) The final dry heat treatment at 80-87°C for 72-75h was introduced into production in order to inactivate small non-enveloped viruses which may not be removed by the nanofiltration step. A lower limit (0.5%) has been set for the residual moisture in the lyophilised Willfact. Adequate inactivation of BVDV, HAV and PPV, a model for B19V, has been shown. The combination of three production steps with complementary mechanisms for virus inactivation or virus removal (S/D treatment, nanofiltration, dry heat treatment) results in a high overall reduction capacity for both enveloped and non-enveloped viruses. All quality data provided demonstrate that the manufacturing process is reproducible within the set specifications. The proposed specification tests and limits are in accordance with the final product specification and further control parameters tested. The results are appropriate to ensure that the routinely manufactured batches are considered to be of acceptable quality and meeting state of the art requirements. Non clinical

Willfact (vWF SD-35-DH) is a plasma protein powder containing 1000 IU of human plasma-derived von Willebrand factor designed for intravenous use after being reconstituted with 10 ml of sterilized water for injection (i.e. VWF concentration 100 IU/ml). Composition (quantity per vial):

vWF 1000 IU (active ingredient) trisodium citrate 0.1 mmol (buffering agent) calcium chloride 0.01 mmol (stabiliser) glycine 0.67 mmol (stabiliser) arginine hydrochloride 1.90 mmol (stabiliser) human albumin 100 mg (stabiliser) Furthermore, there are traces of heparin (max 0.05 IU/ml), aluminium (<10 µg/l) and co-purified proteins, like e.g. fibrinogen, fibronectin, factor II, V, VII, IX, X, and XII. The non-clinical testing program for Willfact comprises investigation of pharmacodynamic and pharmacokinetic aspects in homozygous VWD pigs, single dose toxicity in mice, in vitro mutagenicity (AMES test), local tolerance in rabbits and immunogenic potential in pigs and rabbits.


The pharmaco-toxicological studies of the test substance Willfact (vWF SD-35-DH) were performed in comparison to its predecessor, i.e. the currently marketed Facteur-Willebrand-LFB (code names VWF-LFB or vWF SD), as the reference substance in order to investigate whether the additional steps, i.e. nanofiltration and dry heating, might affect the pharmacodynamic efficacy and/or the non clinical safety profile of the active ingredient. In summary, the type and number of preclinical studies performed are considered appropriate and sufficient to conclude that there is no evidence for concern for the pharmacological-toxicological profile and to support marketing authorisation of vWF SD-35-DH within this MR procedure. Clinical

The heterogeneous clinical disorder summarised under the clinical entity of von Willebrand disease historically initiated different therapeutic approaches aiming at specific needs of affected patients. LFB developed a plasma-derived medicinal product containing clinically active von Willebrand factor but almost devoid of factor VIII. In contrast to products containing both, von Willebrand factor (vWF) and a certain amount of coagulation factor VIII (FVIII), the applicant claims the opportunity of a highly specific individual substitutive therapy with this product. Because FVIII deficiency in most patients with vWD is secondary to the vWF defect, the administration of exogenous vWF corrects low FVIII-levels by stabilisation of the endogenously synthesised FVIII. Therapeutic approaches deal with different situations of acute bleeding or the risk of bleeding and cover standard situations of the affected patients: A mainly prophylactic treatment has to be provided as well as acute intervention (e.g. trauma) or planned medical situations as surgery or invasive procedures. Current standard therapy in severely affected patients who are unresponsive to Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) includes correction of the deficient vWF together with FVIII with substitutes containing both, vWF and FVIII. Acute bleeding situations require initially a corrected FVIII-level as well as a substitution of vWF to achieve acute clinical effect. Further treatment require less FVIII due to stabilising effects of vWF. As mentioned above, vWD is a heterogenous clinical entity with several phenotypes and expressions. Therapeutic suggestions and clinical guidelines necessarily focus on the most homogenous subgroup (type 3 vWD). Results of clinical experience from this artificially “standardised” patient group consequently need adaptation to the individual clinical needs. Currently available vWF-containing products are characterised by different content of vWF (and FVIII), different ratios of vWF:FVIII, different quality (e.g. virus inactivation steps) and other specific features. Current therapeutic approaches in vWD include a “dual approach” representing use of a combined FVIII/vWF concentrate in any clinical situation including major surgery as well as an “optimised specific approach” representing vWF and if needed co-administration of FVIII for the first injection and use of vWF alone for subsequent injections. The clinical data package for Willfact comprises the following studies:


Clinical programme – vWF SD-35-DH studies

Type of study

PK (BA/ BE)

PK (BA/ BE)

PK Efficacy Study

Efficacy Study

Efficacy Study

Efficacy Study

Safety Study

European

study French study

French study

French study

Europeanstudy

Prophylaxis study

Children study

Post-approval

study

Study Identifier

32-73-804 32-73-803

part 1

32-73-803part 1,

amendment no. 5

32-73-803 part 2

32-73-805 42-73-406 42-73-305 42-99-302

Location of Study Report

Module 5.3.1.2

Module 5.3.1.2

Module 5.3.3.4

Module 5.3.5.2

(final report and

amendment n°1)

Module 5.3.5.2

(final report and

amendment n°1)

Module 5.3.5.4

Module 5.3.5.4

(protocol)

Module 5.3.6

(protocol)

Objectives of the Study

to compare vWF SD-35-

DH vs. FVIII/VWF

to compare vWF SD

vs. vWF SD-

35-DH

Assess effect of FVIII on vWF SD-

35-DH

Prevention and

treatment of bleedings and safety

Prevention and


Long-term prophylaxis of bleedings and safety

Prevention and


Safety of vWF SD-35-DH in current practice

Study Design

and Type of Control

single-dose, cross over

randomized mulitcentre European

trial

single-dose, cross over, non-randomize

d multicentre

French trial

uncontrolled single-

dose French multicentre

trial

uncontrolled French

multicentre trial

uncontrolled European multicentre

trial

uncontrolled

multicentre trial

uncontrolled

multicentre trial

uncontrolled

multicentre trial

Test Product(s); Dosage Regimen, Type of

Adminis-tration

vWF SD-35-DH

60 U/kg IV or

HAEMATE® 60 U/kg IV or INNOBRAND® 60 U/kg IV

vWF SD-35-DH

100 IU/kg or

vWF SD 100 IU/kg

IV

vWF SD-35-DH

100 IU/kg IV

and FVIII40 IU/kg IV

vWF SD-35-DH one or

multiple doses of 50

IU/kg

vWF SD-35-DH one or

multiple doses of 60 IU/kg every

12, 24 hours or

every other day

vWF SD-35-DH

single doses of 40-60 IU/kg IV two-three

times weekly

vWF SD-35-DH 60-100

IU/kg IV and FVIII

20-40 IU/kg IV if

needed

vWF SD-35-DH at

the discretion

of the investigator

Number of Subjects

20 8 8 33 20 15 planned3 enrolled

15 planned (at least 8)

150 planned156 enrolled*

Healthy Subjects

or diagnosis

of patients

Various types of VWD

patients

Type 3 VWD

patients

Type 3 VWD

patients


patients


patients


patients


patients


patients

Duration of

Treatment Single-dose

Single-dose

Single-dose

Depending on the event to be prevent

or treated


or treated

One year


or treated


or treated Duration of follow-

up 1 month ≥6 months ≥6 months ≥12 months ≥18 months 3 years

BA Bioavailability, BE Bioequivalence * at 1st August 2008

The applicant has in general demonstrated efficacy and safety of Willfact in an adequate patient population and study design. Provided data cover efficacy in surgical procedures, bleeding episodes and prophylaxis. As assumed from the results of the PK-studies, clinical experience supports the hypothesis of clinically effective endogenous FVIII release by vWF administration, alone in a majority of scheduled and unscheduled events. With respect to the paediatric population, data will be supplemented by the ongoing clinical trial. In general, the clinical data package meets the requirements of GUIDELINE ON THE


CLINICAL INVESTIGATION OF HUMAN PLASMA DERIVED VON WILLEBRAND FACTOR PRODUCTS (CPMP/BPWG/220/02).

IV. OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT

Willfact is approved in the following indication: “In the prevention and treatment of haemorrhages or surgical bleeding in von Willebrand disease when desmopressin (DDAVP) treatment alone is ineffective or contraindicated.” Willfact should not be used in the treatment of haemophilia A. The manufacturing process of Willfact fulfils the current scientific and regulatory criteria. The overall viral safety strategy is considered to be in compliance with the current requirements on virus safety. The results from non-clinical studies do not raise any concern for human use of Willfact.

The indication “prevention and treatment of haemorrhages in von Willebrand disease” has been supported by clinical trials which have been performed according to regulatory and scientific requirements.

In conclusion, on the basis of submitted quality, non-clinical and clinical data it is considered that Willfact demonstrates adequate evidence of efficacy and safety for the approved indication as well as a favourable risk/benefit profile.


V. PRODUCT INFORMATION

SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT

Willfact 1000 IU Powder and solvent for solution for injection. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Willfact is presented as powder and solvent for solution for injection containing nominally 1000 IU human von Willebrand factor per vial. Every 1 ml of reconstituted solution contains Willfact 100 IU human von Willebrand factor when reconstituted with 10 ml of water for injection. The product contains approximately 100 IU/ml human von Willebrand factor when reconstituted with 10 ml of water for injections. Before the addition of albumin, the specific activity of Willfact 1000 IU is ≥ 50 IU VWF:RCo/mg protein. The von Willebrand factor potency (IU) is measured according to ristocetin cofactor activity (VWF:RCo) compared to the International Standard for von Willebrand factor concentrate. The quantity of human factor VIII in Willfact is ≤ 10 IU/100 IU VWF:RCo. The FVIII potency (IU) is determined using the European Pharmacopoeia chromogenic assay. For a full list of excipients, see section 6.1. One vial (1000 IU) of Willfact contains 0.3 mmol (6.9 mg) sodium. 3. PHARMACEUTICAL FORM

Powder and solvent for solution for injection. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications

Willfact is indicated in the prevention and treatment of haemorrhages or surgical bleeding in von Willebrand disease when desmopressin (DDAVP) treatment alone is ineffective or contraindicated. Willfact should not be used in the treatment of haemophilia A. 4.2 Posology and method of administration

Treatment of von Willebrand disease should be supervised by a physician experienced in the treatment of haemostatic disorders.


Posology

Generally, 1 IU/kg of von Willebrand factor 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. Haemostasis cannot be ensured until FVIII coagulant activity (FVIII:C) has reached 0.4 IU/ml (40 %). A single injection of von Willebrand factor will only lead to a maximum increase in FVIII:C after at least 6-12 hours. The single administration of von Willebrand factor cannot immediately correct the FVIII:C level. If the patient’s baseline plasma FVIII:C level is below this critical level, in all situations where a rapid correction of haemostasis should be achieved, such as the treatment of haemorrhage, severe trauma or emergency surgery, it is necessary to administer a factor VIII product with the first injection of von Willebrand factor, in order to achieve a haemostatic plasma level of FVIII:C. However, if an immediate rise in FVIII:C is not necessary, for example in a planned operation, or if the baseline FVIII:C level is sufficient to ensure haemostasis, the physician may decide to omit the co-administration of FVIII at the first injection. Start of treatment:

The first dose of Willfact is 40 to 80 IU/kg for the treatment of haemorrhage or trauma, in conjunction with the required amount of factor VIII product, calculated according to the patient's baseline plasma level of FVIII:C, in order to achieve an appropriate plasma level of FVIII:C, immediately before the intervention or as soon as possible after the onset of the bleeding episode or severe trauma. In case of surgery, it should be given 1 hour before the procedure. An initial dose of 80 IU/kg of Willfact 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 VWD. For elective surgery, treatment with Willfact should start 12-24 hours before surgery and should be repeated 1 hour before the procedure. In this case, co-administration of factor VIII product is not required since endogenous FVIII:C has usually reached the critical level of 0.4 IU/ml (40 %) before surgery. However, this should be confirmed in each patient. Subsequent injections:

If required, treatment should be continued with an appropriate dose of Willfact, with 40 - 80 IU/kg per day in 1 or 2 injections daily over one to several days. 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. Long-term prophylaxis

Willfact can be administered as long-term prophylaxis in a dose which is determined individually for each patient. Willfact doses between 40 and 60 IU/kg, administered two to three times per week, reduce the number of haemorrhagic episodes. There is no data from a clinical study to characterise the response to use of Willfact in children less than 6 years of age.


The use of Willfact in children under 12 years of age is only documented in individual cases; the use of Willfact in patients previously untreated with von Willebrand factor is not documented in the clinical studies. Method of administration

Dissolve the preparation as described under 6.6. The product should be administered via the intravenous route at a maximum rate of 4 ml/minute. 4.3 Contraindications

Hypersensitivity to the active substance or any of the ingredients. 4.4 Special warnings and precautions for use

In actively bleeding patients it is recommended to co-administer a FVIII product with the von Willebrand factor product with a low FVIII content as a first line treatment. As with any intravenous administration of a plasma-derived protein, allergy type hypersensitivity reactions are possible. Patients must be closely monitored and carefully observed for any symptoms throughout the injection period. Patients should be informed of the early signs of hypersensitivity reactions such as hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If these symptoms occur, administration should be discontinued immediately. In case of shock, standard medical treatment for shock should be implemented. 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. The measures taken may be of limited value against non-enveloped viruses such as HAV and parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoesis (e.g. haemolytic anaemia). Appropriate vaccination (hepatitis A and hepatitis B) should be considered for patients regularly receiving human plasma-derived von Willebrand factor. Note that the name and batch number of the drug must be documented for every administration of Willfact to help establish a link between the patient and the batch number. 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 thromboembolisms should be instituted according to the current recommendations.


When using a FVIII-containing VWF preparation, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII:C. In patients receiving factor VIII-containing von Willebrand factor 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. 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 the bleeding cannot be controlled with an appropriate dose, an assay should be performed to determine if a VWF inhibitor is present. In patients with high levels of inhibitor, von Willebrand factor therapy may not be effective and other therapeutic options should be considered. One vial (1000 IU) of Willfact contains 0.3 mmol (6.9 mg) sodium. For more than 3300 IU injected (more than 1 mmol sodium), to be taken into consideration by patients on a controlled sodium diet. 4.5 Interaction with other medicinal products and other forms of interaction

No interactions of human von Willebrand factor products with other medicinal products are known. 4.6 Fertility, pregnancy and lactation

Animal studies are insufficient to assess its safety with respect to fertility, reproduction, pregnancy, embryonic/fœtal development or peri- and postnatal development. The safety of Willfact during pregnancy and lactation has not been investigated in controlled clinical studies. Willfact should be administered to pregnant and lactating von Willebrand factor deficient women only if clearly indicated. 4.7 Effects on ability to drive and use machines

No effects on the ability to drive or use machines have been observed. 4.8 Undesirable effects

Although Willfact is considered safe, allergic or anaphylactic reactions may occur. The undesirable effects listed below were assessed on the basis of the following frequency specifications: Very common (1/10) Common (1/100 to <1/10) Uncommon (1/1,000 to <1/100) Rare (1/10,000 to <1/1,000) Very rare (<1/10,000), not known (frequency cannot be estimated from the available data) Immune system disorders Uncommon: Hypersensitivity or allergic reactions. These may in some cases progress to severe anaphylaxis (including shock).


Psychiatric disorders Uncommon: Restlessness Nervous system disorders Uncommon: Headache, tingling, lethargy Cardiac disorders Uncommon: Tachycardia Vascular disorders Uncommon: Hypotension, flushing Respiratory thoracic and mediastinal disorders Uncommon: Wheezing Gastrointestinal disorders Uncommon: Nausea, vomiting Skin and subcutaneous tissue disorders Uncommon: Angioedema, generalised urticaria, hives General disorders and administration site conditions Uncommon: Burning and stinging at the infusion site, chills, tightness of the chest Rare: Fever Investigations Very rare: Neutralising antibodies (inhibitors) to VWF Patients with von Willebrand disease, especially type 3 patients, may very rarely develop neutralising antibodies (inhibitors) to VWF. Patients treated with VWF should be carefully monitored for the development of inhibitors using appropriate clinical observations and laboratory tests. If such inhibitors occur, the condition will manifest itself as an inadequate clinical response. Such antibodies are precipitating and occur in close association with anaphylactic reactions. In all such cases, it is recommended that a specialised haemophilia centre be contacted. Therefore, patients experiencing anaphylactic reaction should be evaluated for the presence of an inhibitor. After correction of the factor Willebrand deficiency, due to the risk of a thrombotic episode in certain risk situations, monitoring for early signs of thrombosis or disseminated intravascular coagulation and prevention of thromboembolic complications should be undertaken according to current practices. In patients receiving FVIII-containing VWF products sustained excessive FVIII:C plasma levels may increase the risk of thrombotic events. 4.9 Overdose

No case of overdose with Willfact has been reported. Thromboembolic events may occur in case of major overdose.


5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-haemorrhagics: Human von Willebrand factor ATC code: B02BD Willfact behaves in the same way as endogenous von Willebrand factor. Administration of von Willebrand factor allows correction of the haemostatic abnormalities exhibited by patients who suffer from von Willebrand factor deficiency at two levels: VWF re-establishes platelet adhesion to the vascular subendothelium at the site of

vascular damage (as it binds both to the vascular subendothelium and to the platelet membrane) providing primary haemostasis as shown by the shortening of the bleeding time. This effect is known to depend to a large extent on the level of multimerisation of the active substance.

Von Willebrand factor produces delayed correction of the associated factor VIII

deficiency. Administered intravenously, von Willebrand factor 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 von Willebrand factor (vWF product with a low FVIII level) restores the FVIII:C level to normal as a secondary effect after the first infusion. Administration of a FVIII:C containing VWF preparation restores the FVIII:C level to normal immediately after the first infusion.

5.2 Pharmacokinetic properties

A pharmacokinetic study with Willfact was carried out on 8 patients with type 3 von Willebrand disease. It demonstrated that for VWF:RCo: The mean AUC0-∞ is 3444 IU.h/dl after single dose of 100 IU/kg Willfact, The plasma peak is reached between 30 minutes and 1 hour after injection, The mean recovery is 2.1 [IU/dl]/[IU/kg] of the injected preparation, The half-life is between 8 and 14 hours, with a mean value of 12 hours, The mean clearance is 3.0 ml/h/kg. Normalisation of FVIII level is progressive, varies and usually requires between 6 and 12 hours. This effect is sustained for 2 to 3 days. The increase in FVIII level is progressive and returns to normal after 6 to 12 hours. The FVIII level increases by a mean of 6 % (IU/dl) per hour. Thus, even in patients with an initial FVIII:C level less than 5 % (IU/dl), the FVIII:C level increases to around 40 % (IU/dl) 6 hours after the injection, and this level is maintained over 24 hours. 5.3 Preclinical safety data

Based on data obtained from several preclinical studies using animal models, there is no evidence for other toxic effect of Willfact than those related to the immunogenicity of human proteins in laboratory animals. Repeated dose toxicity testing is impracticable due to the development of antibodies to heterologous protein in animal models. The preclinical safety data do not suggest that Willfact has any mutagenic potential.


6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder: human albumin, arginine hydrochloride, glycine, sodium citrate and calcium chloride dihydrate. Solvent: water for injections. 6.2 Incompatibilities

Willfact must not be mixed with other medicinal products except for plasma-derived coagulation FVIII produced by LFB-BIOMEDICAMENTS, with which a compatibility study was carried out. This FVIII coagulation factor is however not marketed in all European countries. Only licensed polypropylene injection sets should be used, because treatment failure can occur as a consequence of human von Willebrand factor adsorption to the internal surface of some injection equipment. 6.3 Shelf life

3 years. Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. 6.4 Special precautions for storage

Do not store above 25°C. Store in the original package in order to protect from light. Do not freeze. 6.5 Nature and contents of container

1 pack contains: powder in a vial (Type I glass) + 10 ml solvent in an injection vial (Type I glass) with a transfer system incorporating a sterilising air vent and a filter-needle.


6.6 Special precautions for disposal and other handling

Reconstitution: The currently applicable guidelines for aseptic procedures must be followed. The transfer system is only used to reconstitute the drug, as described below. It is not intended in administering the drug to the patient. Bring the two vials (powder and solvent) to ambient temperature. Remove the protective cap from the solvent vial (water for injections) and from the

powder vial. Disinfect the surface of each stopper. Remove the translucent protective sheath from the transfer system and insert the exposed

needle through the centre of the stopper of the solvent vial with a rotating movement. Remove the second protective sheath from the other end of the transfer system. Keeping both vials horizontally (vented spike pointing upwards), quickly insert the needle

into the centre of the stopper of the powder vial. Ensure that the needle always remains in the solvent to preserve the vacuum.

Immediately place the system in a vertical position; the solvent vial is above the powder vial, to allow the solvent to transfer into the powder.

Allow the solvent to flow over all of the powder during the transfer. Ensure that all of the solvent is transferred.

Remove the empty vial (solvent) with the transfer system. Gently swirl the vial for a few minutes with a rotating movement to avoid the formation of

foam until the powder has completely dissolved. The powder generally dissolves instantaneously and should have dissolved in less than 10 minutes. The solution is clear or slightly opalescent. Cloudy solutions or solutions with deposits must not be used. Administration: Draw the product into a sterile syringe using the enclosed filter needle. Remove the needle from the syringe and replace it with an intravenous or epicranial

needle. Remove the air from the syringe and insert into a vein after disinfecting the surface. Inject intravenously as a single dose as immediately after reconstitution, at a maximum

rate of 4 ml/minute. Any unused product or waste material should be disposed of in accordance with local requirements.


7. MARKETING AUTHORISATION HOLDER

LFB-BIOMEDICAMENTS 3, avenue des Tropiques BP 305 - LES ULIS 91958 Courtabœuf Cedex FRANCE 8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally] 10. DATE OF REVISION OF THE TEXT

{MM/YYYY}


Package leaflet: Information of the user

WILLFACT 1000 IU Powder and solvent for solution for injection

Human von Willebrand factor Read all of this leaflet carefully before you start using this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or pharmacist. This medicine has been prescribed for you. Do not pass it on to others. It may harm them,

even if their symptoms are the same as yours. If any of the side effects gets serious, or if you notice any side effects not listed in this

leaflet, please tell your doctor or pharmacist. In this leaflet: 1. What Willfact is and what it is used for 2. Before you use Willfact 3. How to use Willfact 4. Possible side effects 5. How to store Willfact 6. Further information 1. WHAT WILLFACT IS AND WHAT IT IS USED FOR

Willfact is a medicine used to stop bleeding that contains human von Willebrand factor (VWF) as active ingredient. Willfact is indicated in the prevention and treatment of surgical or other bleeding in patients with von Willebrand disease when desmopressin (DDAVP) treatment alone is ineffective or contra-indicated. 2. BEFORE YOU USE WILLFACT Contraindications Do not use Willfact if you are hypersensitive (allergic) to human von Willebrand factor or to one of the

ingredients of Willfact. if you suffer from haemophilia A.


Take special care with Willfact: Your treatment with Willfact should always be supervised by a physician experienced in the treatment of haemostatic disorders. If you experience heavy bleeding and a blood examination shows that your Factor VIII blood value is reduced, you will receive the VWF preparation in addition to a Factor VIII preparation within the first twelve hours. Allergic reactions As with every protein medicine for intravenous use derived from human blood or plasma, hypersensitivity reactions in the form of an allergy may occur. During your injection, you will be observed specifically to determine whether you experience any early signs of hypersensitivity, e.g. stinging, hives (generalised urticaria), tightness of the chest, wheezing , drop in blood pressure (hypotension) and allergic severe reactions (anaphylaxis). If these symptoms occur, the injection will be interrupted immediately. Risk of thrombosis Blood vessels may also become blocked by blood clots (thrombosis). This risk exists particularly if your previous medical history or laboratory results indicate that you present certain risk factors. In this case you will be monitored very carefully for the early signs of thrombosis, and a preventative treatment (prophylaxis) against vein blockages by blood clots should be introduced. When using a Factor VIII-containing VWF product, your physician should be aware that the treatment may cause an excessive rise in FVIII:C. If you receive such FVIII-containing VWF product, your physician should monitor your FVIII:C plasma level regularly. This ensures that your FVIII:C plasma level is not sustained excessive, which may increase the risk of thrombotic events. Limited effectiveness It is possible that, in patients with von Willebrand disease, especially type 3 patients, proteins may be formed that neutralise the effect of VWF. These proteins are called antibodies or inhibitors. If the laboratory results give corresponding indications, or if the bleeding does not stop despite a sufficient dose of Willfact, your physician will check whether VWF inhibitors are being formed in your body. If these inhibitors are present in high concentration, treatment with VWF may not be effective, and other treatment options should be considered. The new treatment will be provided by a physician who has experience in the treatment of haemostatic disorders. Safety of the raw material in Willfact (plasma) The use of medicines derived from human blood or plasma is by definition associated with the risk of infections. Various standard measures are taken to counter this, including the targeted 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, the possibility of transmitting of infective agents cannot be totally excluded when medicinal products prepared from human blood or plasma are administered. 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) or hepatitis C virus (HCV). The measures taken may be of limited value against non-enveloped viruses such as hepatitis A virus and parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or certain forms of anaemia.


Vaccinations If you are treated regularly with human plasma-derived von Willebrand factor, appropriate vaccinations (hepatitis A and hepatitis B) are recommended. Recording of batch number Every time Willfact is administered, the physician or one of his/her employees will record the name and batch number of the product in order to be able if necessary to trace precisely which batch(s) you have received. The batch number indicates the production run in which the batch of product in question was produced. Using other medicines Please tell your doctor or pharmacist if you are taking/using or have recently taken/used any other medicines, including medicines obtained without a prescription. Using Willfact with food and drink There are no known interactions of VWF preparations with foods or drinks. Therefore you do not have to avoid any specific foods or drinks. Pregnancy and breast-feeding Willfact should be used during pregnancy and breastfeeding only if it is clearly indicated. The safety of Willfact during pregnancy and breastfeeding has not been evaluated in controlled clinical studies. Animal studies are not sufficient to establish its safety with respect to fertility, pregnancy and development of the child during pregnancy and after birth. Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines No effects on ability to drive or use machines have been observed. Important information about some of the ingredients of Willfact Willfact contains 6.9 mg of sodium per vial. You should take it into consideration if you are on a salt-free or low-salt diet. 3. HOW TO USE WILLFACT

Treatment should only be initiated under the supervision of a physician experienced in the treatment of haemostatic disorders. Dosage The dose you take depends on your health condition and body weight. The first dose of Willfact is 40 to 80 IU/kg for the treatment of haemorrhage or trauma, in conjunction with the required amount of factor VIII product, calculated according to your baseline plasma level of FVIII:C, in order to achieve an appropriate plasma level of FVIII:C, immediately before the intervention or as soon as possible after the onset of the bleeding episode or severe trauma.


If required, you will receive further doses of Willfact of 40 to 80 IU/kg per day in one or two injections daily over one to several days. Willfact can also be administered as long-term prophylaxis; the dose level is also determined individually in this case. Willfact doses between 40 and 60 IU/kg administered two to three times per week reduce the number of haemorrhagic episodes. Please talk to your doctor if you feel that the effect of Willfact is too strong or too weak. If you use more Willfact than you should: No symptoms of overdose with Willfact have been reported. However, the risk of thrombosis cannot be excluded in case of major overdose. If you have any further questions on the use of this product, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS

Like all medicines, Willfact can cause side effects, although not everybody gets them. The assessment of side-effects is based on the following frequency specifications: Very common: Affects more than 1 user in 10. Common: Affects 1 to 10 users in 100. Uncommon: Affects 1 to 10 users in 1,000. Rare: Affects 1 to 10 users in 10,000. Very rare: Affects less than 1 user 10,000. Not known: Frequency cannot be estimated from the available data. Although the safety of Willfact is considered good, allergic or anaphylactic reactions could occur. The following side-effects occurred “uncommonly”: Accelerated heartbeat (tachycardia) Tightness of the chest Headache Restlessness Tingling Wheezing Nausea Vomiting Quincke’s oedema (angiooedema) Nettle rash (generalised urticaria) Hives Drop in blood pressure (hypotension) Burning and stinging at the infusion site Chills Flushing/heat


Hypersensitivity - or allergic reactions In some cases, the aforementioned signs may progress to severe allergic reaction (anaphylaxis) including shock.

Listlessness (lethargy) The following side-effects were observed “rarely”: Fever The following side-effects occurred “very rarely”: Antibodies (inhibitors) against VWF: very rarely, proteins may be formed in patients with von Willebrand disease, especially type 3 patients, which neutralise the effect of VWF. These proteins are called antibodies or inhibitors. However, this has never been observed during Willfact treatment. Patients treated with VWF should be carefully monitored by their doctors for the development of inhibitors by appropriate clinical observations and laboratory tests. If such inhibitors occur, the condition will manifest itself as an inadequate clinical response. The antibodies form antibody-antigen complexes and occur concomitantly to anaphylactic reactions. After correction of the factor Willebrand deficiency, you must be monitored for early signs of thrombosis or disseminated intravascular coagulation and receive treatment to prevent thrombosis in situations involving an increased risk of thrombosis (after operations, during confinement to bed, in cases of deficiency in a coagulation inhibitor or fibrinolytic enzyme). If you receive FVIII-containing VWF preparations, the risk of thrombosis may also be increased due to persistently elevated FVIII:C plasma levels. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE WILLFACT

Store in the original package in order to protect from light. Do not store above 25°C. Do not freeze.

The product should be used immediately after reconstitution. However, its stability has been demonstrated for 24 hours at 25°C.

Keep product out of the reach and sight of children. Do not use the product after the expiry date stated on the vial label and carton. Do not use Willfact if you notice that the solution is cloudy or that it contains any deposit. Any unused product or waste material should be disposed of in accordance with local regulations.


6. FURTHER INFORMATION

What Willfact contains The active substance is: human von Willebrand factor (1000 IU/vial), expressed in International Units (IU) of Ristocetin Cofactor activity (VWF:RCo). After reconstitution with 10 ml of water for injections, one vial contains 100 IU human von Willebrand factor per 1 ml. Before the addition of albumin, the specific activity is greater than or equal to 50 IU of VWF:RCo/mg of total protein. The other ingredients are: Powder: human albumin, arginine hydrochloride, glycine, sodium citrate and calcium chloride dihydrate. Solvent: water for injections. What Willfact looks like and contents of the pack

Willfact is presented as powder and solvent for solution for injection (1000 IU/10 ml). One pack of Willfact contains one vial with 1000 IU human von Willebrand factor and one vial with 10 ml water for injections for reconstitution with a transfer system incorporating a sterilising air vent and a filter needle. Marketing Authorisation Holder and Manufacturer

LFB-BIOMEDICAMENTS 3, avenue des Tropiques, BP 305 - LES ULIS, 91958 Courtabœuf Cedex FRANCE This medicinal product is authorised in the Member States of the EEA under the following names:

Austria Willfact 100 I.E./ml Pulver und Lösungsmittel zur Herstellung einer Injektionslösung

Czech Republic Willfact Denmark Willfact Estonia Willfact Germany WILLFACT 1000 I.E. Hungary Willfact Latvia Willfact Lithuania Willfact 100 TV/ ml, milteliai ir tirpiklis injekciniam tirpalui Norway Willfact Poland Willfact Portugal Willfact Slovenia Willefact 1000 i.e Prašek in vehikel za raztopino za injiciranje Slovak Republic Willfact Spain Willfact Sweden Willfact United Kingdom Willfact This leaflet was last approved in {MM/YYYY}.


The following information is intended for medical or healthcare professionals only: Reconstitution: The currently applicable guidelines for aseptic procedures must be followed. The transfer system is only used to reconstitute the drug, as described below. It is not intended in administering the drug to the patient. Bring the two vials (powder and solvent) to ambient temperature if necessary. Remove the protective cap from the solvent vial (water for injections) and from the

powder vial. Disinfect the surface of each stopper. Remove the translucent protective sheath from the transfer system and insert the exposed

needle through the centre of the stopper of the solvent vial with a rotating movement. Remove the second protective sheath from the other end of the transfer system. Keeping both vials horizontally (vented spike pointing upwards), quickly insert the needle

into the centre of the stopper on the powder vial. Ensure that the needle always remains in the solvent to preserve the vacuum.

Immediately place the system in a vertical position, the solvent vial is above the powder vial, to allow the solvent to transfer into the powder.

Allow the solvent to flow over all of the powder during transfer. Ensure that all of the solvent is transferred.

The vacuum is automatically broken at the end of the transfer process (sterile air). Remove the empty vial (solvent) with the transfer system. Gently swirl the vial for a few minutes with a rotating movement to avoid the formation of

foam until the powder has completely dissolved. The powder generally dissolves immediately and should have dissolved in less than 10 minutes. The solution is clear or slightly opalescent. Cloudy solutions or solutions with deposit must not be used. Administration: Draw the product into a sterile syringe using the enclosed filter needle. Remove the needle from the syringe and replace it with an intravenous or epicranial

needle. Remove the air from the syringe and insert into a vein after disinfecting the surface. Inject intravenously as a single dose as immediately after reconstitution, at a maximum

rate of 4 ml/minute.

Documents

Public Assessment Report - DIMDI · acute bleeding or the risk of bleeding and cover standard situations of the affected patients: A mainly prophylactic treatment has to be provided