Veyvondi - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

VEYVONDI 650 IU powder and solvent for solution for injection.

VEYVONDI 1300 IU powder and solvent for solution for injection.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

VEYVONDI 650 IU powder and solvent for solution for injection

Each vial of powder contains nominally 650 International Units (IU) vonicog alfa.

After reconstitution with the 5 mL solvent provided, VEYVONDI contains approximately 130 IU/mL vonicog alfa.

VEYVONDI 1300 IU powder and solvent for solution for injection

Each vial of powder contains nominally 1300 International Units (IU) vonicog alfa.

After reconstitution with the 10 mL solvent provided, VEYVONDI contains approximately 130 IU/mL vonicog alfa

The specific activity of VEYVONDI is approximately 110 IU VWF:RCo/mg protein.

The potency of VWF (IU) is measured using the European Pharmacopeia ristocetin cofactor activity assay (VWF: RCo). The ristocetin cofactor activity of recombinant human von Willebrand factor was determined against the International Standard for von Willebrand factor concentrate (WHO).

Vonicog alfa is a purified recombinant human von Willebrand factor (rVWF). It is manufactured by recombinant DNA (rDNA) technology in the Chinese Hamster Ovary (CHO) cell line without the addition of any exogenous human-or animal-derived protein in the cell culture process, purification or final formulation.

The product contains only trace amounts of human recombinant coagulation factor VIII (< 0.01 IU FVIII / IU VWF: RCo) as determined using the European Pharmacopoeia chromogenic assay for factor VIII (FVIII).

Excipient(s) with known effect

Each 650 IU powder vial contains 5.2 mg sodium.

Each 1300 IU powder vial contains 10.4 mg sodium.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

The powder is a white to off-white lyophilized powder

The solvent is a clear and colourless solution.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

VEYVONDI is indicated in adults (age 18 and older) with von Willebrand Disease (VWD), when desmopressin (DDAVP) treatment alone is ineffective or not indicated for the – Treatment of haemorrhage and surgical bleeding – Prevention of surgical bleeding.

VEYVONDI should not be used in the treatment of Haemophilia A.

4.2 Posology and method of administration

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

Posology

Dosage and frequency of administration must be individualized according to clinical judgement and based on the patient's weight, type and severity of the bleeding episodes/surgical intervention and based on monitoring of appropriate clinical and laboratory measures. Dose based on bodyweight may require adjustment in underweight or overweight patients.

Generally, 1 IU/kg (VWF:RCo/VEYVON­DI/vonicog alfa) raises the plasma VWF:RCo by 0.02 IU/mL (2%).

Haemostasis cannot be ensured until Factor VIII coagulant activity (FVIII:C) is at least 0.4 IU/mL (> 40% of normal activity). Depending on the patient’s baseline FVIII:C levels, a single infusion of rVWF will, in a majority of patients, lead to an increase above 40% in endogenous FVIII:C activity within 6 hours and will result in sustaining this level up to 72 hours post infusion. The dose and duration of the treatment depend on the clinical status of the patient, the type and severity of the bleeding, and both VWF:RCo and FVIII:C levels. If the patient’s baseline plasma FVIII:C level is < 40% or is unknown and in all situations where a rapid correction of haemostasis should be achieved, such as treatment of an acute haemorrhage, severe trauma or emergency surgery, it is necessary to administer a recombinant factor VIII product with the first infusion of VEYVONDI, in order to achieve a haemostatic plasma level of FVIII:C.

However, if an immediate rise in FVIII:C is not necessary, or if the baseline FVIII:C level is sufficient to ensure haemostasis, the physician may decide to omit the co-administration of rFVIII at the first infusion with VEYVONDI.

In case of major bleeding events or major surgeries requiring repeated, frequent infusions, monitoring of FVIII:C levels is recommended, to decide if rFVIII is required for subsequent infusions to avoid excessive rise of FVIII:C.

Treatment of bleeding episodes (On demand treatment)

Start of treatment

The first dose of VEYVONDI should be 40 to 80 IU/kg body weight. Replacement levels of VWF:RCo > 0.6 IU/mL (60%) and FVIII:C > 0.4 IU/mL (40%) should be achieved. Dosing guidelines for treatment of minor and major haemorrhages are provided in Table 1.

VEYVONDI should be administered with recombinant factor VIII if the FVIII:C levels are < 40%, or are unknown, to control bleeding. The rFVIII dose should be calculated according to the difference between the patient’s baseline plasma FVIII:C level, and the desired peak FVIII:C level to achieve an appropriate plasma FVIII:C level based on the approximate mean recovery of 0.02 (IU/mL)/(IU/kg). The complete dose of VEYVONDI should be administered followed by rFVIII within 10 minutes.

Calculating dose:

VEYVONDI dose [IU] = dose [IU/kg] x weight [kg]

Subsequent infusions:

A subsequent dose of 40 IU to 60 IU/kg of VEYVONDI should be infused every 8 to 24 hours as per the dosing ranges in Table 1, or as long as clinically appropriate. In major bleeding episodes, maintain trough levels of VWF:RCo greater than 50% for as long as deemed necessary.

Based on experience from clinical studies, once VWF has been replaced, endogenous FVIII levels will remain normal or near normal as long as VEYVONDI is continued to be administered.

Table 1

Dosing recommendations for the treatment of minor and major haemorrhages

aIf rFVIII is administered, see rFVIII package insert for reconstitution and administration instructions.

bA bleed could be considered major if red blood cell transfusion is either required or potentially indicated or if bleeding occurs in a critical anatomical site (e.g., intracranial or gastrointestinal haemorrhage).

Prevention of bleeding/haemo­rrhage and treatment in case of elective surgery

Prior to Surgery:

In patients with inadequate levels of FVIII, a dose of 40–60 IU/kg VEYVONDI should be administered 12–24 hours prior to initiating elective surgery (pre-operative dose), to ensure preoperative endogenous FVIII levels of at least 0.4 IU/mL for minor and at least 0.8 IU/mL for major surgery.

For prevention of excessive bleeding in case of elective surgery, within 3 hours prior to initiation of any surgical procedure, the FVIII:C levels should be assessed. If the FVIII:C levels are at the recommended target level of:

• – at least 0.4 IU/mL for minor and oral surgery and

• – at least 0.8 IU/mL for major surgery,

a dose of VEYVONDI alone should be administered within 1 hour prior to the procedure.

If the FVIII:C levels are not at the recommended target levels, rFVIII should be administered in addition to vonicog alfa to raise VWF:RCo and FVIII:C, within 1 hour prior to the procedure. Please refer to Table 2 for FVIII:C recommended target levels. The dose depends on VWF and FVIII levels of the patient, the type and severity of the expected bleeding.

Table 2

Recommended Target Peak Plasma Levels of VWF:RCo and FVIII:C to be Achieved Prior to Surgery for the Prevention of Excessive Bleeding During and After Surgery

aAdditional rFVIII may be required to attain the recommended FVIII:C target peak plasma levels. Dosing guidance should be done based on the IR.

b A = Target peak plasma VWF:RCo – baseline plasma VWF:RCo

cIR = Incremental Recovery as measured in the subject. If the IR is not available, assume an IR of 0.02 IU/mL per IU/kg.

During and After Surgery :

After the initiation of the surgical procedure, the VWF:RCo and FVIII:C plasma levels should be monitored and the intra- and post-operative substitution regimen should be individualised according to the PK results, intensity and duration of the haemostatic challenge, and the institution’s stan­dard of care. In general, the frequency of VEYVONDI dosing for post-operative substitution should range from twice a day to every 48 hours. Please refer to Table 3 for treatment recommendations for subsequent maintenance doses.

Table 3

Recommended Target Trough Plasma Levels of VWF:RCo and FVIII:C and Minimum Duration of Treatment for Subsequent Maintenance Doses

_____________­________ for the Prevention of Excessive Bleeding After Surgery ________________

Paediatric population

The safety and efficacy of VEYVONDI in children aged 0 to 18 years have not yet been established. No data are available.

Method of administration

VEYVONDI is for intravenous use. The reconstituted product should be inspected visually prior to administration.

The rate of administration should be slow enough to ensure the comfort of the patient, up to a maximum of 4 mL/min. The patient should be observed for any immediate reaction. If any reaction, such as tachycardia, occurs that might be related to the administration of the product, the rate of infusion should be reduced or stopped as required by the clinical condition of the patient. When coadministration of rVWF and rFVIII is considered necessary, they can be pre-mixed in a single syringe to achieve the appropriate dose. The contents of each vial of rVWF and rFVIII can be drawn into a single syringe by using a separate unused reconstitution device (see section 6.2 for incompatibilities). For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

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

Known allergic reaction to mouse or hamster proteins.

4.4 Special warnings and precautions for use

In actively bleeding patients it is recommended to co-administer a FVIII product with VEYVONDI as a first line treatment and depending on the FVIII activity levels (see section 4.2).

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Hypersensitivity reactions

Hypersensitivity reactions (including anaphylaxis) have occurred. Patients and/or their caregivers should be informed of the early signs of hypersensitivity reactions, which may include but are not limited to tachycardia, tightness of the chest, wheezing and/or acute respiratory distress, hypotension, generalised urticaria, pruritus, rhinoconjuncti­vitis, angioedema, lethargy, nausea, vomiting, paresthesia, restlessness, and may progress to anaphylactic shock. In case of shock, standard medical treatment for shock should be implemented.

Patients should be closely monitored and carefully observed for any symptoms throughout the infusion period. If signs and symptoms of severe allergic reactions occur, immediately discontinue administration of VEYVONDI and provide appropriate supportive care.

Adequate medical treatment and provisions should be available for immediate use for a potential anaphylactic reaction, especially for patients with a history of allergic reactions.

VEYVONDI contains trace amounts of mouse immunoglobulin G (MuIgG) and Hamster proteins (less than or equal to 2 ng/IU VEYVONDI). Patients treated with this product may develop hypersensitivity reactions to these non-human mammalian proteins. VEYVONDI contains trace amounts of recombinant coagulation factor VIII.

Thrombosis and Embolism

There is a risk of occurrence of thrombotic events, particularly in patients with known clinical or laboratory risk factors for thrombosis including low ADAMTS13 levels. Therefore, patients at risk have to be monitored for early signs of thrombosis, and prophylaxis measures against thromboembolism should be instituted according to current recommendations and standard of care.

In patients requiring frequent doses of VEYVONDI in combination with recombinant factor VIII, plasma levels for FVIII:C activity should be monitored to avoid sustained excessive FVIII:C plasma levels, which may increase the risk of thrombotic events.

Any FVIII that would be administered along with VEYVONDI should be a pure FVIII product. A combination with a FVIII product containing VWF would pose an additional risk of thrombotic events.

Neutralizing antibodies (Inhibitors)

Patients with VWD, especially Type 3, may develop neutralising antibodies (inhibitors) to von Willebrand factor. If the expected plasma levels of (VWF:RCo) are not attained, or if bleeding is not controlled with an appropriate dose, an appropriate assay should be performed to determine if a von

Willebrand factor inhibitor is present. In patients with high levels of anti-VWF antibodies, von Willebrand factor therapy may not be effective and other therapeutic options should be considered.

Treatment of VWD patients who have high-titer binding antibodies (due to previous treatment with pdVWF) may require a higher dose to overcome the binding antibody effect and such patients could be managed clinically by administration of higher doses of vonicog alfa based on the PK data for each individual patient.

Excipient related considerations

This medicinal product contains 5.2 mg sodium in each 650 IU vial or 10.4 mg sodium in each

1300 IU vial. This is equivalent to 2.2% of the WHO recommended maximum daily intake of 2 g sodium for an adult, assuming a body weight of 70 kg and a dose of 80 IU/kg body weight. This is 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 reproduction studies have not been conducted with VEYVONDI.

Pregnancy

Experience in the treatment of pregnant or breast-feeding women is not available. VEYVONDI should be administered to pregnant woment only if clearly indicated, taking into consideration that delivery confers an increased risk of haemorrhagic events in these patients.

Breast-feeding

It is unknown whether VEYVONDI is excreted in human milk.Therefore, VEYVONDI should be administered to lactating von Willebrand factor deficient women only if clearly indicated. Healthcare professionals should balance the potential risks and only prescribe VEYVONDI if needed

Fertility

The effects of VEYVONDI on fertility have not been established.

4.7 Effects on ability to drive and use machines

VEYVONDI has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

During treatment with VEYVONDI the following adverse reactions may occur:

Hypersensitivity or allergic reactions, thromboembolic events, inhibitor formation against VWF.

Tabulated list of adverse reactions

The table 4 lists the adverse reactions reported in clinical trials, post-authorisation safety studies or post-marketing reporting.

Frequency categories are defined 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). Within each frequency grouping, undesirable effects are presented in the order of decreasing seriousness.

Table 4

Summary of Adverse Reactions reported in Clinical Trials, Post-authorisation safety studies or post-marketing with VEYVONDI in von Willebrand Disease

a Frequency by Subject: Total number of subjects experiencing the AE (related and unrelated) divided by total number of subjects (N) and multiplied by 100. Not known: cannot be estimated from the available data (observed during post-marketing surveillance).

Description of selected adverse reactions

In clinical trials, one case of clinically asymptomatic deep vein thrombosis (DVT) was reported for a subject in the surgery study who had total hip replacement.

In addition, one post-marketing case of DVT has been reported spontaneously for an elderly patient.

Hypersensitivity

There is a possibility of developing hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, rhinoconjuncti­vitis, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) which may in some cases progress to anaphylaxis (including shock).

Patients with von Willebrand disease, especially Type 3, may very rarely develop neutralising antibodies (inhibitors) to von Willebrand factor. If such inhibitors occur, the condition may manifest itself as an inadequate clinical response. Such antibodies may occur in close association with hypersensitivity or anaphylactic reactions. Therefore, patients experiencing hypersensitivity or anaphylactic reactions should be tested and evaluated for the presence of an inhibitor.

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

Thrombogenicity

There is a risk of occurrence of thrombotic events, particularly in patients with known clinical or laboratory risk factors including low ADAMTS13 levels. Therefore, patients at risk have to be monitored for early signs of thrombosis, and prophylaxis measures against thromboembolism should be instituted according to current recommendations and standard of care.

Immunogenicity

The immunogenicity of VEYVONDI was assessed in clinical trials by monitoring the development of neutralizing antibodies against VWF and FVIII, as well as binding antibodies against VWF, Furin, Chinese Hamster Ovary (CHO) protein and mouse IgG. No treatment-emergent development of neutralizing antibodies against human VWF or neutralizing antibodies against human rFVIII was observed. One of the 80 subjects who received VEYVONDI peri-operatively in clinical studies developed treatment-emergent binding antibodies against VWF following a surgery for whom no adverse events or lack of haemostatic efficacy has been reported. Binding antibodies against impurities such as rFurin, CHO-protein or mouse IgG were not observed after treatment with VEYVONDI.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

No symptoms of overdose with von Willebrand factor have been reported. Thromboembolic events may occur in case of major overdose.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antihaemorrhagics: blood coagulation factor von Willebrand factor. ATC code: B02BD10

Mechanism of action

VEYVONDI is a recombinant human von Willebrand factor (rVWF). VEYVONDI behaves in the same way as endogenous von Willebrand factor.

Administration of VEYVONDI allows correction of the haemostatic abnormalities exhibited by patients who suffer from von Willebrand factor deficiency (von Willebrand's di­sease) at two levels: –     VEYVONDI re-establishes platelet adhesion to the vascular sub-endothelium at the site of

vascular damage (as it binds both to the vascular sub-endothelium matrix (e.g. collagen) 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.

• – VEYVONDI produces delayed correction of the associated factor VIII deficiency. Administered intravenously, VEYVONDI 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 VEYVONDI restores the FVIII:C level to normal as a secondary effect after the first infusion Administration of the FVIII:C rises above 40% within 6 hours and peaks within 24 hours in a majority of patients, depending on the baseline FVIII:C level.

VEYVONDI is a rVWF that contains ultra-large multimers in addition to all of the multimers found in plasma as it is not exposed to proteolysis by ADAMTS13 during the manufacturing process.

Clinical efficacy and safety

The clinical safety, efficacy and PK data were assessed in 3 completed trials, (070701, 071001 and 071101) which enrolled patients with VWD. A total of 92 unique subjects (80 unique subjects with VWD in studies 070701, 071001 and 071101 and 12 subjects with Haemophilia A in study 071104) were exposed to VEYVONDI during clinical development.

The European Medicines Agency has deferred the obligation to submit the results of studies with VEYVONDI in all subsets of the paediatric population in the treatment of von Willebrand Disease (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetics (PK) of VEYVONDI were determined in three clinical studies by assessing the plasma levels of VWF:RCo, von Willebrand Factor Antigen (VWF:Ag), and von Willebrand Collagen Binding Activity (VWF:CB). In all three studies, subjects were evaluated in the non-bleeding state. Sustained increase of FVIII:C was observed by six hours after a single infusion of VEYVONDI.

Table 6 summarizes the PK of VEYVONDI after 50 IU/kg VWR:RCo (PK50) or 80 IU/kg VWF:RCo (PK80) infusions. The mean duration of infusion was 16.5 minutes (SD ± 3.51 minutes) for 50 IU/kg (PK50) and 11.8 minutes (± 2.86 minutes) for 80 IU/kg VWF:RCo (PK80).

a[hours], b[dL/kg/hours], c[(IU/dL)/(U VWF­:RCo/kg)] d[(h*IU/dL)] e[(h*IU/dL)/(IU VWF:RCo/kg)] f[VWF:RCo assays with different sensitivity and working ranges were used: Phase 1: automated assay 0.08 –1.50 lU/mL and sensitive manual assay 0.01 – 0.08 lU/mL; Phase 3: automated assay 0.08 – 1.50 lU/mL gThis trial was done using ADVATE, a recombinant factor VIII

An exploratory analysis of combined data from studies 070701 and 071001 indicated a statistically significantly (at the 5% level) longer mean residence time, a statistically significantly (at the 5% level) longer terminal half-life and statistically significantly (at the 5% level) larger AUC0-inf regarding VWF:RCo following administration with VEYVONDI (50 IU/kg VWF:RCo) and combined administration of VEYVONDI and octocog alfa (50 IU/kg VWF:RCo and 38.5 IU/kg rFVIII) than after administration of pdVWF and pdFVIII (50 IU/kg pdVWF:RCo and 38.5 IU/kg pdFVIII).

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

No investigations on carcinogenicity, fertility impairment and fetal development have been conducted. In a human ex vivo placenta perfusion model, it has been demonstrated that VEYVONDI does not cross the human placenta barrier.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Powder

Sodium citrate

Glycine

Trehalose dihydrate

Mannitol

Polysorbate 80

Solvent

Water for injections

6.2 Incompatibilities

Clinical and compatibility studies were conducted to administer vonicog alfa (human von Willebrand factor) with octocog alfa (human coagulation factor) in the same syringe. The rVWF and rFVIII can be pre-mixed in a single syringe to achieve the appropriate dose (see section 4.2 for mode of administration). This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6

6.3 Shelf life

Unopened vial

• 3 years.

Shelf-life after reconstitution:

Chemical and physical in-use stability has been demonstrated for 3 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 and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Powder

Do not store above 30°C.

Do not freeze.

Store in the original package in order to protect from light.

After reconstitution

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

6.6   Special precautions for disposal and other handling

7. MARKETING AUTHORISATION HOLDER

Baxalta Innovations GmbH

Industriestraße 67

1221 Vienna

Austria

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1298/001

EU/1/18/1298/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 31 August 2018