VONCENTO Powder and solvent for solution for injection/infusion Ref.[108425] Active ingredients: Coagulation factor VIII Von Willebrand factor

Traceability

It is strongly recommended that every time that Voncento is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Hypersensitivity

Allergic type hypersensitivity reactions are possible. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. In case of shock, the current medical standards for shock treatment should be observed.

Virus safety

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non-enveloped hepatitis A virus (HAV).

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

Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia).

Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma-derived factor VIII/VWF products.

von Willebrand disease

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 thromboembolism should be instituted, according to the current recommendations.

When using a FVIII-containing VWF product, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII:C. In patients receiving FVIII-containing VWF products, plasma levels of FVIII:C should be monitored to avoid sustained excessive FVIII:C plasma levels which may increase the risk of thrombotic events, and antithrombotic measures should be considered (see also section 5.2).

Patients with VWD, especially type 3 patients, may develop neutralising antibodies (inhibitors) to VWF. If the expected VWF:RCo activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an appropriate assay should be performed to determine if a VWF inhibitor is present. In patients with high levels of inhibitor, therapy may not only be ineffective but also lead to anaphylactoid reactions and other therapeutic options should be considered.

Haemophilia A

Inhibitors

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per ml of plasma, using the modified assay. The risk of developing inhibitors is correlated to the severity of the disease as well as exposure to factor VIII, this risk being highest within the first 50 exposure days but continues throughout life although the risk is uncommon.

The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre posing less of a risk of insufficient clinical response than high titre inhibitors. In general, all patients treated with coagulation factor VIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for FVIII inhibitor presence should be performed. In patients with high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of haemophilia and factor VIII inhibitors.

Cardiovascular events

In patients with existing cardiovascular risk factors, substitution therapy with FVIII may increase the cardiovascular risk.

Catheter-related complications

If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteremia and catheter site thrombosis should be considered.

Sodium content

Presentations with 250 IU FVIII/600 IU VWF (5 ml solvent) and 500 IU FVIII/1200 VWF IU (5 ml solvent): contain up to 14.75 mg (0.64 mmol) sodium per vial, equivalent to 0.74% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Presentations with 500 IU FVIII/1200 IU VWF (10 ml solvent) and 1000 IU FVIII/2400 IU VWF (10 ml solvent): contain up to 29.50 mg (1.28 mmol) sodium per vial, equivalent to 1.48% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Paediatric population

The listed warnings and precautions apply both to adults and paediatrics.

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

Animal reproduction studies have not been conducted with Voncento.

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

Haemophilia A: Based on the rare occurrence of haemophilia A in women, experience regarding the treatment during pregnancy and breastfeeding is not available.

Therefore, Voncento should be used during pregnancy and breast-feeding only if clearly indicated.

Fertility

There are no data on fertility available.

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

Summary of the safety profile

During treatment with Voncento the following adverse reactions may occur: Hypersensitivity or allergic reactions, thromboembolic events, pyrexia, headache, dysgeusia and abnormal liver function test levels. Furthermore patients may develop inhibitors to FVIII and VWF.

Tabulated list of adverse reactions

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

Frequencies have been evaluated according to the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

^* Adverse events assessed as related to administration of the Voncento
^** Frequency is based on studies with all FVIII products which included patients with severe haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients.
^*** Observed during postmarketing surveillance, not observed in clinical trials.

Description of selected adverse reactions

Hypersensitivity (allergic reactions)

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest (including chest pain and chest discomfort), back pain, tingling, vomiting, wheezing) have been observed, and may in some cases progress to severe anaphylaxis (including shock).

FVIII inhibition

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with Voncento. If such inhibitors occur, the condition may manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.

VWF inhibition

Patients with VWD, especially type 3 patients, may develop neutralising antibodies (inhibitors) to VWF. If such inhibitors occur, the condition will manifest itself as an inadequate clinical response. Such antibodies are precipitating and may occur concomitantly to anaphylactic reactions. Therefore, patients experiencing an anaphylactic reaction should be evaluated for the presence of an inhibitor. In all such cases, it is recommended that a specialised haemophilia centre be contacted.

Thromboembolic events

In patients with VWD, there is a risk of occurrence of thromboembolic events, particularly in patients with known clinical or laboratory risk factors. In patients receiving FVIII-containing VWF products, sustained excessive FVIII:C plasma levels may increase the risk of thromboembolic events (see also section 4.4).

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

Paediatric population

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

Reporting of suspected adverse reactions

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

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products, diluents or solvents except those mentioned in section 6.1.