Leaflet VEYVONDI 650UI powder+solvent for injection

VEYVONDI 650 IU powder and solvent for solution for injection

VEYVONDI 1 300 IU powder and solvent for solution for injection

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/mLvonicog alfa.

VEYVONDI 1 300 IU powder and solvent for solution for injection

Each vial of powder contains nominally 1 300 International Units (IU) vonicog alfa.

After reconstitution with the 10 mL solvent provided, VEYVONDI contains approximately 130 IU/mLvonicog 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 activityassay (VWF:RCo). The ristocetin cofactor activity of recombinant human von Willebrand factor wasdetermined against the International Standard for von Willebrand factor concentrate (WHO).

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

Each 650 IU powder vial contains 5.2 mg sodium and 0.5 mg of polysorbate 80.

Each 1 300 IU powder vial contains 10.4 mg sodium and 1.0 mg of polysorbate 80.

For the full list of excipients, see section 6.1.

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.

Prevention and treatment of haemorrhage or surgical bleeding in adults (aged 18 years and older) withvon Willebrand disease (VWD), when desmopressin (DDAVP) treatment alone is ineffective orcontraindicated.

Treatment of haemorrhage in children (aged less than 18 years) with von Willebrand disease (VWD),when desmopressin (DDAVP) treatment alone is ineffective or contraindicated.

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

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

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

Generally, 1 IU/kg (VWF:RCo/VEYVONDI/vonicog alfa) raises the plasma VWF:RCo by0.02 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 ofrVWF will, in a majority of patients, lead to an increase above 40% in endogenous FVIII:C activitywithin 6 hours and will result in sustaining this level up to 72 hours post infusion. The dose andduration of the treatment depend on the clinical status of the patient, the type and severity of thebleeding, 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 toadminister a recombinant factor VIII product with the first infusion of VEYVONDI, in order toachieve 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 sufficientto ensure haemostasis, the physician may decide to omit the co-administration of rFVIII at the firstinfusion with VEYVONDI.

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

Treatment of bleeding episodes (on-demand treatment) in adults and children

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 guidelinesfor 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%, orare unknown, to control bleeding. The rFVIII dose should be calculated according to the differencebetween the patient’s baseline plasma FVIII:C level, and the desired peak FVIII:C level to achieve anappropriate 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 body weight [kg]

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

Based on experience from clinical trials, once VWF has been replaced, endogenous FVIII levels willremain 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

Initial dosea

Haemorrhage Subsequent dose(IU VWF:RCo/kg body weight)

Minor 40 to 50 IU/kg every 8 to(e.g. epistaxis, oral bleeding, 40 to 50 IU/kg 24 hours (or as long as deemedmenorrhagia) clinically necessary)

Majorb(e.g. severe or refractory40 to 60 IU/kg every 8 toepistaxis, menorrhagia,24 hours for approximatelygastrointestinal bleeding, 50 to 80 IU/kg2-3 days (or as long as deemedcentral nervous systemclinically necessary)trauma, haemarthrosis, ortraumatic haemorrhage)a If rFVIII is administered, see rFVIII package insert for reconstitution and administration instructions.b A bleed could be considered major if red blood cell transfusion is either required or potentially indicated or ifbleeding occurs in a critical anatomical site (e.g., intracranial or gastrointestinal haemorrhage).

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

Prior to surgery

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

For prevention of excessive bleeding in case of elective surgery, within 3 hours prior to initiation ofany surgical procedure, the FVIII:C levels should be assessed. If the FVIII:C levels are at therecommended 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 inaddition to vonicog alfa to raise VWF:RCo and FVIII:C, within 1 hour prior to the procedure. Pleaserefer to Table 2 for FVIII:C recommended target levels. The dose depends on VWF and FVIII levelsof 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 achievedprior to surgery for the prevention of excessive bleeding during and after surgery

VWF:RCo target FVIII:C target Calculation of rVWF dose (to be

Type ofpeak plasma peak plasma administered within 1 hour prior tosurgerylevel levela surgery) (IU VWF:RCo required)

Minor 0.50 - 0.60 IU/mL 0.40 - 0.50 IU/mL ∆b VWF:RCo x BW (kg) /IRc

Major 1 IU/mL 0.80 - 1 IU/mL ∆b VWF:RCo x BW (kg) /IRca Additional rFVIII may be required to attain the recommended FVIII:C target peak plasma levels. Dosingguidance should be done based on the IR.

b ∆ = Target peak plasma VWF:RCo - baseline plasma VWF:RCoc IR = Incremental Recovery as measured in the subject. If the IR is not available, assume an IR of0.02 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 bemonitored and the intra- and post-operative substitution regimen should be individualised according tothe pharmacokinetics (PK) results, intensity and duration of the haemostatic challenge, and theinstitution’s standard of care. In general, the frequency of VEYVONDI dosing for post-operativesubstitution should range from twice a day to every 48 hours. Please refer to Table 3 for treatmentrecommendations for subsequent maintenance doses.

Table 3. Recommended target trough plasma levels of VWF:RCo and FVIII:C and minimumduration of treatment for subsequent maintenance doses for the prevention of excessive bleeding aftersurgery

VWF:RCo FVIII:Ctarget trough plasma level target trough plasma level Minimum

Type of Frequency of

After Up to After duration ofsurgery Up to 72 hours dosing72 hours post 72 hours post 72 hours post treatmentpost surgerysurgery surgery surgery

Every 12-24 hrs

Minor ≥ 0.30 IU/mL - > 0.40 IU/mL - 48 hours/every otherday

Every 12-24 hrs

Major > 0.50 IU/mL > 0.30 IU/mL > 0.50 IU/mL > 0.40 IU/mL 72 hours/every otherday

Prophylactic treatment in adults

For initiation of long-term prophylaxis against bleeds in patients with VWD, doses of 40 to 60 IU/kgof VEYVONDI administered twice weekly should be considered. Depending on the patient’scondition and clinical response, including breakthrough bleeds, higher doses (not exceeding 80 IU/kg)and/or an increased dose frequency (up to three times per week) may be required.

The safety and efficacy of VEYVONDI in children aged less than 18 years have been established forthe treatment of haemorrhage. Dosing is based on the same guidelines as for adults and should beadjusted to the clinical condition of the patient, as well as their VWF:RCo and FVIII:C plasma levels.

In younger patients, shorter dose intervals or higher doses may be necessary (see section 5.2). Thesafety and efficacy of VEYVONDI for prophylactic treatment or the prevention or treatment ofsurgical bleeding have not yet been established in children aged less than 18 years.

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

The rate of administration should be slow enough to ensure the comfort of the patient, up to amaximum 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 ofinfusion should be reduced or stopped as required by the clinical condition of the patient.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

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

Known allergic reaction to mouse or hamster proteins.

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

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

Hypersensitivity reactions (including anaphylaxis) have occurred. Patients and/or their caregiversshould be informed of the early signs of hypersensitivity reactions, which may include but are notlimited 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 medicaltreatment for shock should be implemented.

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

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

VEYVONDI contains trace amounts of mouse immunoglobulin G and hamster proteins (less than orequal to 2 ng/IU VEYVONDI). Patients treated with this product may develop hypersensitivityreactions to these non-human mammalian proteins. VEYVONDI contains trace amounts ofrecombinant coagulation factor VIII.

Thrombosis and embolism

There is a risk of occurrence of thrombotic events, particularly in patients with known clinical orlaboratory risk factors for thrombosis including low ADAMTS13 levels. Therefore, patients at riskhave to be monitored for early signs of thrombosis, and prophylaxis measures againstthromboembolism 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 level for FVIII:C activity should be monitored to avoid sustained excessive FVIII:C plasmalevel, which may increase the risk of thrombotic events.

Any FVIII that would be administered along with VEYVONDI should be a pure FVIII product. Acombination with a FVIII product containing VWF would pose an additional risk of thromboticevents.

Neutralising antibodies (inhibitors)

Patients with VWD, especially type 3, may develop neutralising antibodies (inhibitors) to von

Willebrand factor. If the expected plasma level of (VWF:RCo) is not attained, or if bleeding is notcontrolled 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 neutralising antibodies,von Willebrand factor therapy may not be effective and other therapeutic options should be consideredto establish haemostasis.

Treatment of VWD patients who have high-titer binding antibodies [due to previous treatment withplasma derived von Willebrand factor (pdVWF)] may require a higher dose to overcome the bindingantibody effect and such patients could be managed clinically by administration of higher doses ofvonicog 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 each1 300 IU vial, equivalent to 2.2% of the WHO recommended maximum daily intake of 2 g sodium foran adult, assuming a body weight of 70 kg and a dose of 80 IU/kg body weight. This is to be taken intoconsideration by patients on a controlled sodium diet.

Polysorbate content

This medicinal product contains 0.5 mg of polysorbate 80 in each 650 IU vial or 1.0 mg ofpolysorbate 80 in each 1 300 IU vial, which is equivalent to 0.1 mg/mL. Polysorbates may causeallergic reactions.

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

Animal reproduction studies have not been conducted with VEYVONDI.

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

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

The effects of VEYVONDI on fertility have not been established.

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

During treatment with VEYVONDI the following adverse reactions may occur: hypersensitivity orallergic reactions, thromboembolic events, inhibitor formation against VWF.

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: verycommon (≥ 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). Withineach frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 4. Summary of adverse reactions reported in clinical trials, post-authorisation safetystudies or post-marketing with VEYVONDI in von Willebrand disease

MedDRA system organ Frequency category

Adverse reaction by preferred term (PT)class (SOC) by subject

Immune system disorders Anaphylactic reaction* Not known

Headache Very common

Dizziness Common

Nervous system disorders Vertigo Common

Dysgeusia Uncommon

Tremor Uncommon

Cardiac disorders Tachycardia Uncommon

Hypertension Common

Vascular disorders Deep venous thrombosis Uncommon

Hot flush Uncommon

Vomiting Common

Nausea Common

Skin and subcutaneous

Pruritus generalised Commontissue disorders

Chest discomfort Uncommon

General disorders and Infusion site paraesthesia Uncommonadministration site Infusion-related reaction (includingconditions tachycardia, flushing, rash, dyspnea, blurred Not knownvision)*

Electrocardiogram T wave inversion Uncommon

Heart rate increased Uncommon

* Adverse reactions identified during post-marketing surveillance.

There is a possibility of developing hypersensitivity or allergic reactions (which may includeangioedema, burning and stinging at the infusion site, chills, flushing, rhinoconjunctivitis, generalisedurticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of thechest, tingling, vomiting, wheezing) which may in some cases progress to anaphylaxis (includingshock).

Patients with VWD, especially type 3, may very rarely develop neutralising antibodies (inhibitors) tovon Willebrand factor. If such inhibitors occur, the condition may manifest itself as an inadequateclinical response. Such antibodies may occur in close association with hypersensitivity or anaphylacticreactions. Therefore, patients experiencing hypersensitivity or anaphylactic reactions should be testedand 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 orlaboratory risk factors including low ADAMTS13 levels. Therefore, patients at risk have to bemonitored for early signs of thrombosis, and prophylaxis measures against thromboembolism shouldbe instituted according to current recommendations and standard of care.

The immunogenicity of VEYVONDI was assessed in clinical trials by monitoring the development ofneutralising 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 ofneutralising antibodies against human VWF or neutralising antibodies against human rFVIII wasobserved. One of the 132 subjects who received VEYVONDI peri-operatively in clinical trialsdeveloped treatment-emergent binding antibodies against VWF following a surgery for whom noadverse events or lack of haemostatic efficacy has been reported. Binding antibodies against impuritiessuch as rFurin, CHO-protein or mouse IgG were not observed after treatment with VEYVONDI.

The frequency, type and severity of adverse reactions in children receiving VEYVONDI for thetreatment of haemorrhage are expected to be the same as in adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factors, ATC code: B02BD10

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

Administration of VEYVONDI allows correction of the haemostatic abnormalities exhibited bypatients 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 ofvascular damage (as it binds both to the vascular sub-endothelium matrix (e.g. collagen) and tothe platelet membrane), providing primary haemostasis as shown by the shortening of thebleeding time. This effect occurs immediately and is known to depend to a large extent on thelevel of polymerisation of the protein.

- VEYVONDI produces delayed correction of the associated factor VIII deficiency. Administeredintravenously, VEYVONDI binds to endogenous factor VIII (which is produced normally by thepatient), 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. Afterthe first infusion, the FVIII:C level is expected to rise above 40% within 6 hours and to peakwithin 24 hours in most 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 inplasma as it is not exposed to proteolysis by ADAMTS13 during the manufacturing process.

The clinical safety, efficacy and PK data were assessed in 5 completed trials in adults and childrenwith VWD (070701, 071001, 071101, 071301 and SHP677-304) and in one ongoing trial in childrenwith VWD (071102). A total of 144 unique subjects (103 unique adult subjects with VWD, 29 uniquepaediatric subjects with VWD, 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 one or more subsets of the paediatric population in the treatment of von Willebrand

Disease (see section 4.2 for information on paediatric use).

The pharmacokinetics (PK) of VEYVONDI were determined in three clinical trials in adults byassessing 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 thenon-bleeding state. Sustained increase of FVIII:C was observed by six hours after a single infusion of

VEYVONDI.

Table 5 summarizes the PK of VEYVONDI in adults 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) for50 IU/kg (PK50) and 11.8 minutes (± 2.86 minutes) for 80 IU/kg VWF:RCo (PK80).

Table 5. Pharmacokinetic assessment of VWF:RCoa in adults

Parameter Phase 1 PK50 Phase 3 PK50 Phase 3 PK80 Surgery PK50

VEYVONDI with VEYVONDI VEYVONDI VEYVONDIoctocog alfag (Study 071001) (Study 071001) (Study 071101)(Study 070701)

Mean (95% CI) Mean (95% CI) Mean (95% CI)

Mean (95% CI) SD SD SD

SD

T b1/2 19.3 (14.3; 24.3) 22.6 (19.5; 25.7) 19.1 (16.7; 21.5) 17.8 (12.9; 22.8)10.99 5.34 4.32 7.34

Clc 0.04 (0.03; 0.05) 0.02 (0.02; 0.03) 0.03 (0.02; 0.03) 0.03 (0.02; 0.04)0.028 0.005 0.009 0.011

IR at 1.7 (1.4; 2.0) 1.9 (1.6; 2.1) 2.0 (1.7; 2.2) 2.0 (1.7; 2.3)

C dmax 0.62 0.41 0.39 0.45

AUC e0-inf 1541.4 (1295.7; 1787.2) 2105.4 (1858.6; 2352.3) 2939.0 (2533.2; 3344.8) 1834.4 (1259.0; 2409.7)554.31 427.51 732.72 856.45

AUC0- 33.4 (27.2; 39.5) 42.1 (37.3; 46.9) 36.8 (31.8; 41.8) 37.5 (25.3; 49.7)inf/Dosef 13.87 8.31 8.97 18.14a [VWF:RCo assays with different sensitivity and working ranges were used: Phase 1: automated assay0.08 - 1.50 IU/mL and sensitive manual assay 0.01 - 0.08 IU/mL; Phase 3: automated assay 0.08 - 1.50 IU/mL.b [hours]c [dL/kg/hours]d [(IU/dL)/(IU VWF:RCo/kg)]e [(h*IU/dL)]f [(h*IU/dL)/(IU VWF:RCo/kg)]g This trial was done using ADVATE, a recombinant factor VIII.

An exploratory analysis of combined data from studies 070701 and 071001 indicated a statisticallysignificantly (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 combinedadministration of VEYVONDI and octocog alfa (50 IU/kg VWF:RCo and 38.5 IU/kg rFVIII) thanafter administration of pdVWF and plasma derived factor VIII (pdFVIII) (50 IU/kg pdVWF:RCo and38.5 IU/kg pdFVIII).

In addition, full PK assessments of VEYVONDI were performed following single and multiple dosingin study 071301, which investigated long-term prophylactic treatment in a total of 23 adult subjectswith severe VWD (N=3 type 1, N=1 type 2A, N=1 type 2B, N=18 type 3). PK parameters derivedfrom these assessment confirmed the results of previous trials (see Table 5 above) and a statisticalcomparison of key VWF PK parameters between initiation and month 12 of prophylactic treatment didnot reveal any significant differences.

PK data of VWF (N=134) across 6 studies were evaluated using a population PK modelling andsimulation approach. These results confirmed that the PK of VWF:RCo is both dose-independent(range: 2.0 to 80 IU/kg) and time-independent (up to 4.3 years). Covariate evaluations indicated noclinically meaningful effect of gender, race or VWD type on VWF:RCo PK; body weight and agewere identified as significant covariates.

PK of VWF in 24 paediatric patients with VWD were estimated based on population PK modellingusing sparse PK samples collected during a paediatric study across three age groups (less than 6 yearsold [N=5], 6 years to less than 12 years old [N=10], and 12 years to less than 18 years old [N=9]) afterreceiving a single infusion of 50 ± 5 IU/kg rVWF:RCo (see Table 6).

Table 6. Pharmacokinetic assessment of VWF:RCo in paediatric subjectsa

PK50 VEYVONDI

Parameter (Study 071102)

Mean (95% CI)

SD< 6 yrs 6 yrs to < 12 yrs 12 yrs to < 18 yrs Total

Age range(n=5) (n=10) (n=9) (n=24)b 12.4 (9.91; 15.0) 14.5 (13.6; 15.4) 15.1 (14.2; 16.1) 14.3 (13.5; 15.1)

T1/22.90 1.47 1.50 2.03c 0.082 (0.047; 0.118) 0.051 (0.041; 0.061) 0.043 (0.038; 0.048) 0.055 (0.045; 0.065)

CL0.041 0.016 0.007 0.025d 1.25 (0.92; 1.58) 1.54 (1.30; 1.77) 1.58 (1.43; 1.72) 1.49 (1.36; 1.63)

IR at Cmax0.378 0.378 0.225 0.339e 1260 (690; 1840) 1630 (1080; 2170) 1600 (1140; 2060) 1540 (1240; 1840)

AUC0-inf654 882 704 757f 25.6 (14.4; 36.9) 32.5 (21.3; 43.7) 32.6 (23.2; 41.9) 31.1 (25.0; 37.2)

AUC0-inf/Dose12.8 18.1 14.3 15.3a Data represent 4 sparse PK samples collected in each subject during paediatric study 071102 and population PKmodeling resultsb [hours]c [dL/kg/hours]d [(IU/dL)/(IU VWF:RCo/kg)]e [(h*IU/dL)]f [(h*IU/dL)/(IU VWF:RCo/kg)]

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand 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 notcross the human placenta barrier.

Sodium citrate (E 331)

Glycine (E 640)

Trehalose dihydrate

Mannitol (E 421)

Polysorbate 80 (E 433)

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial3 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 usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user.

Store below 30 °C.

Do not freeze.

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

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

VEYVONDI 650 IU powder and solvent for solution for injection

Each pack contains:

- powder in a vial (type I glass), with a butyl rubber stopper

- 5 mL of solvent in a vial (type I glass), with a rubber stopper (chlorobutyl or bromobutyl)

- one reconstitution device (Mix2Vial)

VEYVONDI 1 300 IU powder and solvent for solution for injection

Each pack contains:

- powder in a vial (type I glass), with a butyl rubber stopper

- 10 mL of solvent in a vial (type I glass), with a rubber stopper (bromobutyl)

- one reconstitution device (Mix2Vial)

General instructions

- Check the expiry date, and ensure that the VEYVONDI powder and water for injections(solvent) are at room temperature prior to preparation. Do not use after the expiry date stated onthe labels and carton.

- Use antiseptic technique (clean and low-germ conditions) and a flat work surface during thereconstitution procedure. Wash your hands and put on clean exam gloves (the use of gloves isoptional).

- Use the reconstituted product (after mixing the powder with the supplied water) as soon aspossible and within three hours. You can store the reconstituted product at room temperature notto exceed 25 °C for up to three hours.

- Ensure that the VEYVONDI powder vial and the water for injections (solvent) are at roomtemperature prior to preparation.

- Use plastic syringes with this product because proteins in the product tend to stick to the surfaceof glass syringes.

- Do not mix VEYVONDI with other medicinal products except for octocog alfa (ADVATE).

Instructions for reconstitution and application

Steps Image example1 Remove the caps from the VEYVONDI powder and solventvials to expose the centre of the rubber stoppers.

2 Disinfect each stopper with a separate sterile alcohol swab (orother suitable sterile solution suggested by your doctor orhaemophilia treatment centre) by wiping the stopper forseveral seconds. Allow the rubber stopper to dry. Place thevials on a flat surface.

3 Open the Mix2Vial device package by completely peelingaway the lid, without touching the inside of the package. Do NAnot remove the Mix2Vial device from the package.

Steps Image example4 Turn the package with the Mix2Vial device upside down andplace it over the top of the solvent vial. Firmly insert the blueplastic spike of the device into the centre of the solvent vialstopper by pushing straight down. Grip the package at its edgeand lift it off the Mix2Vial device. Be careful not to touch theclear plastic spike. The solvent vial now has the Mix2Vialdevice connected to it and is ready to be connected to the

VEYVONDI vial.

5 To connect the solvent vial to the VEYVONDI vial, turn thesolvent vial over and place it on top of the vial containing

VEYVONDI powder. Fully insert the clear plastic spike intothe VEYVONDI vial stopper by firmly pushing straight down.

This should be done right away to keep the liquid free ofgerms. The solvent will flow into the VEYVONDI vial byvacuum. Check that all the solvent has transferred. Do not useif the vacuum has been lost and the solvent does not flow intothe VEYVONDI vial.

6 Gently and continuously swirl the connected vials or allow thereconstituted product to stand for 5 minutes then gently swirlto ensure the powder is completely dissolved. Do not shake.

Shaking will adversely affect the product. Do not refrigerateafter reconstitution.

7 Disconnect the two sides of the Mix2Vial from each other byholding the clear plastic side of the Mix2Vial device attachedto the VEYVONDI vial with one hand and the blue plasticside of the Mix2Vial device attached to the solvent vial withthe other hand. Turn the blue plastic side counterclockwiseand gently pull the two vials apart. Do not touch the end of theplastic connector attached to the VEYVONDI vial containingthe dissolved product. Place the VEYVONDI vial on a flatwork surface. Discard the empty solvent vial.

8 Draw air into the empty, sterile disposable plastic syringe bypulling back on the plunger. The amount of air should equalthe amount of reconstituted VEYVONDI that you willwithdraw from the vial.

9 Leaving the VEYVONDI vial (containing the reconstitutedproduct) on your flat work surface, connect the syringe to theclear plastic connector and turn the syringe clockwise.

Steps Image example10 Hold the vial with one hand and use the other hand to push allthe air from the syringe into the vial.

11 Flip connected syringe and VEYVONDI vial so the vial is ontop. Be sure to keep the syringe plunger pressed in. Draw the

VEYVONDI into the syringe by pulling plunger back slowly.

12 Do not push and pull solution back and forth between syringeand vial. Doing so may harm the medicine. When ready toinfuse, disconnect the syringe by turning it counterclockwise.

Inspect the syringe visually for particulate matter; the solutionshould be clear and colourless. If flakes or particles are seen,do not use the solution and notify your doctor.

13 If you need more than one vial of VEYVONDI to make upyour dose:

- Leave the syringe attached to the vial until anadditional vial is prepared.

- Use the reconstitution steps above (2 to 8) to preparethe additional vial of VEYVONDI using a fresh

Mix2Vial device for each vial.

14 The contents of two vials may be drawn into a single syringe.

NOTE: When pushing air into a second vial of VEYVONDIto be pooled into a syringe, position the vial and connectedsyringe so that the vial is on top.

Instructions for administration

Inspect the prepared solution in the syringe for particulate matter and discolouration prior toadministration (the solution should be clear, colourless and free from particles). It is not uncommonfor a few flakes or particles to remain in the product vial after reconstitution. The filter included inthe Mix2Vial device removes those particles completely. Filtration does not influence dosecalculations. The solution in the syringe should not be used if it is cloudy or contains flakes orparticles after filtration.

1. Attach the infusion needle to a syringe containing VEYVONDI solution. For comfort, a winged(butterfly) infusion set is preferred. Point the needle up and remove any air bubbles by gentlytapping the syringe with your finger and slowly and carefully pushing air out of the syringe andneedle.

2. Apply a tourniquet and get the infusion site ready by wiping the skin well with a sterile alcoholswab (or other suitable sterile solution suggested by your doctor or haemophilia treatmentcentre).

3. Insert the needle into the vein and remove the tourniquet. Slowly infuse VEYVONDI. Do notinfuse any faster than 4 mL per minute. Disconnect the empty syringe. If your dose requiresmultiple syringes, attach and administer each additional syringe of VEYVONDI one at a time.

Note:

Do not remove butterfly needle until all syringes have been infused and do not touch the Luerport that connects to the syringe.

If recombinant factor VIII has been prescribed, administer recombinant factor VIII within10 minutes after infusion of VEYVONDI has been completed.

4. Take the needle out of the vein and use sterile gauze to put pressure on the infusion site forseveral minutes.

In case large volumes of VEYVONDI are required, it is possible to pool two vials of VEYVONDItogether. The contents of each reconstituted product of VEYVONDI can be drawn in a single syringe.

However, in these cases the initially reconstituted solution of VEYVONDI should not be diluted anyfurther.

The solution should be slowly administered intravenously (see section 4.2) not exceeding 4 mL/min.

Do not recap the needle. Place the needle, syringe, and empty VEYVONDI and solvent vial(s) in ahard-walled sharps container for proper disposal. Do not dispose of these supplies in ordinaryhousehold trash.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Baxalta Innovations GmbH

Industriestrasse 671221 Vienna

AustriamedinfoEMEA@takeda.com

EU/1/18/1298/001

EU/1/18/1298/002

Date of first authorisation: 31 August 2018

Date of latest renewal: 23 June 2023

Detailed information on this medicinal product is available on the website of the European

Medicines Agency https://www.ema.europa.eu.