Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: CSL Behring GmbH, Emil-von-Behring-Str. 76, 35041 Marburg, Germany
Voncento can be used for all age groups.
Prophylaxis and treatment of haemorrhage or surgical bleeding in patients with VWD, when desmopressin (DDAVP) treatment alone is ineffective or contraindicated.
Prophylaxis and treatment of bleeding in patients with haemophilia A.
Treatment of VWD and haemophilia A should be supervised by a physician experienced in the treatment of haemostatic disorders.
The decision on the use of the product at home for patients with VWD and with haemophilia A should be made by the treating physician who should ensure that appropriate training is provided and the use is reviewed at intervals.
The ratio between FVIII:C and VWF:RCo in a vial is approximately 1:2.4.
During the course of treatment, appropriate determination of factor VIII levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their response to factor VIII, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable.
It is important to calculate the dose using the number of IU of VWF:RCo specified. Generally, 1 IU/kg VWF:RCo raises the circulating level of VWF:RCo by 0.02 IU/ml (2%).
Levels of VWF:RCo of >0.6 IU/ml (60%) and of FVIII:C of >0.4 IU/ml (40%) should be achieved.
Usually 40-80 IU/kg of von Willebrand factor (VWF:RCo) corresponding to 20-40 IU FVIII:C/kg of body weight (BW) are recommended to achieve haemostasis.
An initial dose of 80 IU/kg VWF:RCo may be required, especially in patients with type 3 VWD where maintenance of adequate levels may require greater doses than in other types of VWD.
For prevention of excessive bleeding during or after surgery the application should start 1-2 hours before the surgical procedure.
An appropriate dose should be re-administered every 12-24 hours. The dose and duration of the treatment depend on the clinical status of the patient, the type and severity of the bleeding, and both VWF:RCo and FVIII:C levels.
When using a FVIII-containing VWF product, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII:C. After 24-48 hours of treatment, in order to avoid an excessive rise in FVIII:C, reduced doses and/or prolongation of the dose interval or the use of a VWF product containing a low level of FVIII should be considered (see section 5.2).
For long term prophylaxis in patients with VWD, a dose of 25-40 IU VWF:RCo/kg body weight should be considered at a frequency of 1 to 3 times per week. In patients with gastrointestinal bleeds or menorrhagia, shorter dose intervals or higher doses may be necessary. The dose and duration of treatment will depend on the clinical status of the patient, as well as their VWF:RCo and FVIII:C plasma levels.
Treatment of bleeding:
Usually 40-80 IU/kg of von Willebrand factor (VWF:RCo) corresponding to 20-40 IU FVIII:C/kg of body weight (BW) are recommended in paediatric patients to treat a bleed.
Prophylaxis treatment:
Patients aged 12 to 18 years old: Dosing is based on the same guidelines as for adults.
Patients aged <12 years old: Based on results from a clinical trial in which paediatric patients under 12 years of age were shown to have lower exposure of VWF, a prophylactic dose range of 40–80 IU VWF:RCo/kg body weight 1 to 3 times a week should be considered. (see Section 5.2).
The dose and duration of treatment will depend on the clinical status of the patient, as well as their VWF:RCo and FVIII:C plasma levels.
It is important to calculate the dose using the number of IU of FVIII:C specified.
The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and on the patient’s clinical condition.
The number of units of factor VIII administered is expressed in International Units (IU), which is related to the current WHO concentrate standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or preferably in International Units (relative to an International Standard for factor VIII in plasma).
1 IU of factorVIII activity is equivalent to that quantity of factor VIII in 1 ml of normal human plasma.
The calculation of the required dose of factor VIII is based on the empirical finding that 1 International Unit (IU) factor VIII per kg body weight raises the plasma factor VIII activity by about 2% of normal activity (in vivo recovery 2 IU/dl). The required dose is determined using the following formula:
Required units = body weight [kg] x desired factor VIII rise [% or IU/dl] x 0.5.
The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case.
In the case of the following haemorrhagic events, the factor VIII activity should not fall below the given plasma activity level (in % of normal or IU/dl) within the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:
| Degree of haemorrhage / Type of surgical procedure | Factor VIII level required (% or IU/dl) | Frequency of doses (hours) / Duration of therapy (days) |
|---|---|---|
| Haemorrhage | ||
| Early haemarthrosis, muscle bleeding or oral bleeding | 20-40 | Repeat infusion every 12-24 hours for at least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved. |
| More extensive haemarthrosis, muscle bleeding or haematoma | 30-60 | Repeat infusion every 12-24 hours for 3-4 days or more until pain and acute disability are resolved. |
| Life-threatening haemorrhages | 60-100 | Repeat infusion every 8-24 hours until threat is resolved. |
| Surgery | ||
| Minor surgery including tooth extraction | 30-60 | Repeat infusion every 24 hours for at least 1 day, until healing is achieved. |
| Major surgery | 80-100 (pre- and postoperative) | Repeat infusion every 8-24 hours until adequate wound healing, then continue therapy for at least another 7 days to maintain a factor VIII activity of 30% - 60% (IU/dl). |
For long term prophylaxis in patients with severe haemophilia A, the usual dose is 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. In some cases, especially in younger patients, shorter dose intervals or higher doses may be necessary.
Dosing in haemophilia A in children and adolescents aged ˂18 years old is based on body weight and is therefore generally based on the same guidelines as for adults. In some cases shorter dose intervals or higher doses may be necessary. The frequency of administration should always be oriented to the clinical effectiveness in the individual case.
Currently available data are described in Sections 4.8and 5.2.
No dose adjustment is necessary for the older people.
For intravenous use.
For instructions on reconstitution of the medicinal product before administration, see section 6.6. The reconstituted preparation should be injected/infused slowly intravenously at a rate comfortable for the patient.
The injection/infusion rate should not exceed 6 ml per minute. The patient should be observed for any immediate reaction. If any reaction takes place that might be related to the administration of Voncento, the rate of injection should be decreased or the application should be stopped, as required by the clinical condition of the patient (see also section 4.4).
Five cases of overdose have been reported from clinical trials. No adverse reactions have been associated with these reports.
The risk of thromboembolic events cannot be excluded in case of major overdose, especially in patients with VWD.
3 years.
Chemical and physical in-use stability has been demonstrated for 8 hours at room temperature (below 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.
Do not store above 25°C.
Do not freeze. Keep vials in the outer carton in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
Powder (250 IU/600 IU) in a vial (type I glass), with a stopper (rubber) a disc (plastic) and a cap (aluminium).
5 ml of solvent in a vial (type I glass), with a stopper (rubber) a disc (plastic) and a cap (aluminium).
One pack contains:
1 vial with powder
1 vial with 5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 10 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster
Powder (500 IU/1200 IU) in a vial (type I glass), with a stopper (rubber) a disc (plastic) and a cap (aluminium).
10 ml of solvent in a vial (type I glass), with a stopper (rubber) a disc (plastic) and a cap (aluminium).
One pack contains:
1 vial with powder
1 vial with 10 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 10 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster
Powder (500 IU/1200 IU) in a vial (type I glass), with a stopper (rubber) a disc (plastic) and a cap (aluminium).
5 ml of solvent in a vial (type I glass), with a stopper (rubber) a disc (plastic) and a cap (aluminium).
One pack contains:
1 vial with powder
1 vial with 5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 10 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster
Powder (1000 IU/2400 IU) in a vial (type I glass), with a stopper (rubber) a disc (plastic) and a cap (aluminium).
10 ml of solvent in a vial (type I glass) with a stopper (rubber) a disc (plastic) and a cap (aluminium).
One pack contains:
1 vial with powder
1 vial with 10 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 10 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster
Not all pack sizes may be marketed.
General instructions:
The solution should be clear or slightly opalescent. After filtering/withdrawal (see below) the reconstituted product should be inspected visually for particulate matter and discoloration prior to administration. Do not use visibly cloudy solutions or solutions still containing flakes or particles. Reconstitution and withdrawal must be carried out under aseptic conditions.
Reconstitution:
Bring the solvent to room temperature. Ensure powder and solvent vial flip caps are removed and the stoppers are treated with an antiseptic solution and allowed to dry prior to opening the Mix2Vial package.
1. Open the Mix2Vial package by peeling off the lid. Do not remove the Mix2Vial from the blister package!
2. Place the solvent vial on an even, clean surface and hold the vial tight. Take the Mix2Vial together with the blister package and push the spike of the blue adapter end straight down through the solvent vial stopper.
3. Carefully remove the blister package from the Mix2Vial set by holding at the rim, and pulling vertically upwards. Make sure that you only pull away the blister package and not the Mix2Vial set.
4. Place the product vial on an even and firm surface. Invert the solvent vial with the Mix2Vial set attached and push the spike of the transparent adapter end straight down through the product vial stopper. The solvent will automatically flow into the product vial.
5. With one hand grasp the product-side of the Mix2Vial set and with the other hand grasp the solvent-side and unscrew the set carefully counterclockwise into two pieces to avoid excessive build-up of foam when dissolving the product. Discard the solvent vial with the blue Mix2Vial adapter attached.
6. Gently swirl the product vial with the transparent adapter attached until the substance is fully dissolved. Do not shake.
7. Draw air into an empty, sterile syringe. While the product vial is upright, connect the syringe to the Mix2Vial´s Luer Lock fitting by screwing clockwise. Inject air into the product vial.
Withdrawal and application:
8. While keeping the syringe plunger pressed, turn the system upside down and draw the solution into the syringe by pulling the plunger back slowly.
9. Now that the solution has been transferred into the syringe, firmly hold on to the barrel of the syringe (keeping the syringe plunger facing down) and disconnect the transparent Mix2Vial adapter from the syringe by unscrewing counterclockwise.
For injection of Voncento only the provided administration sets should be used because treatment failure can occur as a consequence of FVIII adsorption to the internal surfaces of some injection/infusion equipment.
In case large volumes of Voncento are required, it is possible to pool several vials of Voncento via a commercially available infusion set (e.g. a syringe pump for intravenous application of medicinal products). However, in these cases the initially reconstituted solution of Voncento should not be diluted any further.
Administer the solution slowly intravenously (see section 4.2), taking care to ensure that no blood enters the syringe filled with product.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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