CEVENFACTA Powder and solvent for solution for injection Ref.[50508] Active ingredients: Coagulation factor VIIa

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.

Thrombosis

There is limited information about the safety of this medicinal product in patients with a history of arterial or venous thromboembolic disease, because such patients were excluded from CEVENFACTA clinical studies. Such reactions have been reported in clinical studies and post-marketing surveillance with eptacog alfa and aPCC/PCC (activated or non-activated prothrombin complex).

The following patients may be at an increased risk of thromboembolic events with use of this medicinal product:

• History of congenital or acquired haemophilia receiving concomitant treatment with aPCC/PCC or other haemostatic agents (see section 4.5);
• History of atherosclerosis, coronary artery disease, cerebrovascular disease, crush injury, septicaemia, or thromboembolism.

Patients receiving this medicinal product should be monitored for the development of signs and symptoms of activation of the coagulation system or thrombosis. When there is laboratory confirmation of intravascular coagulation or presence of clinical thrombosis, the dose of this medicinal product should be reduced or treatment should be stopped, depending on the patient’s condition.

Hypersensitivity reactions

Hypersensitivity reactions, including anaphylaxis, may occur with this medicinal product. Symptoms may include hives, itching, rash, difficulty breathing, swelling around the mouth and throat, tightness of the chest, wheezing, dizziness or fainting, and low blood pressure. In the event of hypersensitivity reactions, patients should discontinue treatment and seek immediate medical attention.

Patients with known IgE-based hypersensitivity to casein may be at a higher risk of hypersensitivity reactions. Should signs or symptoms of hypersensitivity occur, treatment should be discontinued. Subsequent treatment with this medicinal product should be based on a thorough assessment of the risks and benefits.

Neutralising antibodies

Neutralising antibodies may occur with the use of this medicinal product. If treatment with this medicinal product does not result in adequate haemostasis, then the development of neutralising antibodies should be suspected as the possible cause and, as clinically indicated, testing should be performed.

Neutralising antibodies to other Factor VIIa-containing products have been observed in congenital Factor VII-deficient patients, an unapproved indication for eptacog beta (activated).

Elderly

The safety and efficacy of this medicinal product have not yet been established in elderly patients. No data are available.

Patients with renal or hepatic impairment

The safety and efficacy of this medicinal product have not yet been established in patients with renal or hepatic impairment. No data are available.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per injection, that is to say essentially ‘sodium free’.

No interaction studies have been conducted with this medicinal product.

Clinical experience with pharmacologic use of other FVIIa-containing products indicates an elevated risk of thrombotic events when used simultaneously with activated prothrombin complex concentrates (see section 4.4). Based on a non-clinical study with eptacog alfa it is also not recommended to combine rFVIIa and rFXIII. There are no clinical data available on the interaction between rFVIIa and rFXIII.

Pregnancy

There are no data on the use of eptacog beta (activated) in pregnant women. As a precautionary measure, it is preferable to avoid the use of this medicinal product during pregnancy.

Breast-feeding

It is unknown whether eptacog beta (activated) is excreted in human milk. No studies have been conducted to assess the impact of eptacog beta (activated) on milk production or its presence in breast milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from CEVENFACTA therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Animal studies do not indicate direct or indirect harmful effect on male fertility. No fertility data are available in humans. Thus, the effect of eptacog beta (activated) on male and female fertility is unknown.

The active substance eptacog beta (activated) may have a minor influence on the ability to drive and use machines. Dizziness may occur following administration of the active substance eptacog beta (see section 4.8).

Summary of the safety profile

A total of 103 patients received at least one dose of eptacog beta (activated). The overall safety population used for the integrated analysis (see Table 3) comprised 75 unique patients, in four clinical studies, exposed to 3 418 injections in a total of 1 117 treatment episodes. The most frequently reported adverse reactions were infusion site discomfort (1.3%), infusion site haematoma (1.3%), postprocedural haematoma (1.3%), infusion-related reaction (1.3%), body temperature increased (1.3%), dizziness (1.3%) and headache (1.3%). Twenty-eight (28) other patients received a single intravenous bolus dose of eptacog beta (activated) in a fifth clinical study (Study LFB-FVIIA-009-19): a summary of the safety data from study LFB-FVIIA-009-19 is presented hereafter.

Paediatric population

Of the 75 patients included in the integrated analysis of safety, 34 were adolescents and children: 13 (17%) were aged <6 years, 15 (20%) were from 6 to less than 12 years and 6 (8%) were <18 years.

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

Tabulated list of adverse reactions

In this section, the following categories of frequency have been used: 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.

Table 3 lists the adverse reactions.

Table 3. Adverse reactions from pooled clinical studies:

In study LFB-FVIIa-009-19, only one mild episode of headache (in the 75 µg/kg group) was assessed as related to eptacog beta (activated) and was resolved by the end of the study. There was no SAE. Overall, the safety data from Study 009-19 did not alter the CEVENFACTA safety profile described above.

Description of selected adverse reactions

Immunogenicity

In the pooled safety data for the three pivotal PerSept clinical studies, 5 out of 60 patients had a positive screening assay for anti-CEVENFACTA antibodies at baseline (prior to exposure to this medicinal product) and at follow-up visits. Two patients had transient anti-CEVENFACTA antibodies with an additional confirmatory test for anti-CEVENFACTA antibodies; these were confirmed as nonneutralising antibodies. No patient developed anti-rabbit milk protein antibodies during treatment with this medicinal product. Still, as with all therapeutic proteins, there is the potential for immunogenicity.

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.