CEVENFACTA is indicated in adults and adolescents (12 years of age and older) for the treatment of bleeding episodes and for the prevention of bleeding in those undergoing surgery or invasive procedures in the following patient groups: • in patients with congenital haemophilia with high-responding inhibitors to coagulation factors VIII or IX (i.e. =5 Bethesda Units (BU)); • in patients with congenital haemophilia with low titre inhibitors (BU <5), but expected to have a high anamnestic response to factor VIII or factor IX administration or expected to be refractory to increased dosing of FVIII or FIX.

Treatment should be initiated and supervised by a physician experienced in the treatment of haemophilia and/or bleeding disorders. Posology The dose and duration of treatment depend on the location and severity of the bleeding or the type of surgery/procedure, the need for urgent haemostasis, the frequency of administration, and the known patient responsiveness to FVIIa- containing bypassing agents during prior bleeding events. The results of laboratory assessment(s) of coagulation (prothrombin time (PT)/international normalised ratio (INR), activated partial thromboplastin time (aPTT), FVII coagulation activity (Clotting time) (FVII:C)) do not necessarily correlate with or predict the haemostatic effectiveness of this medicinal product. The dose, frequency, and duration of CEVENFACTA therapy should be based on the patient’s clinical response and haemostasis evaluation. Maximum tolerated doses have not been determined for this medicinal product and cumulative daily doses greater than 1 025 µg/kg have not been studied. Treatment of bleeding episodes Treatment with this medicinal product should be initiated as soon as a bleeding event occurs. The recommended initial dose should be adjusted based on the criteria provided in Table 1. For mild to moderate bleeding episodes, the duration of home therapy should not exceed 24 hours. Only after consultation with the haemophilia treatment centre can continued home treatment be considered. If signs or symptoms of severe bleeding occur in the home setting, immediate medical care should be sought by patients. In the meantime, to avoid any treatment delay, an initial dose can be administered at home. In all situations, if an adequate haemostatic response is not achieved (e.g., within 24 hours of the first administration of CEVENFACTA for mild and moderate bleeding episodes), alternative therapies should be considered. Table 1: Dosing for the treatment of bleeding episodes Type of bleeding Dosing regimen recommendation Duration of therapy Mild and moderate Joint, superficial muscle, soft tissue, and mucous membranes. 75 µg/kg repeated every 3 hours until haemostasis is achieved. or Initial dose of 225 µg/kg. If haemostasis is not achieved within 9 hours, additional 75 µg/kg doses may be administered every 3 hours as needed to achieve haemostasis. The following factors should be considered when choosing the initial dose of this medicinal product: The severity and site of bleeding and need for urgent haemostasis Frequency of administration Known patient responsiveness to FVIIa- containing bypassing agents during prior bleeding events Continue therapy to support healing and prevent recurrent haemorrhage after haemostasis to maintain the haemostatic plug. The site and severity of bleeding should determine therapy duration. Severe Life or limb threatening haemorrhage, iliopsoas and deep muscle with neurovascular injury, retroperitoneum, intracranial, or 225 µg/kg initially, followed if necessary 6 hours later with 75 µg/kg every 2 hours until haemostasis is achieved. Subsequent dosing: After achieving haemostasis, the decision for dosing should be based on the clinical assessment and the type of bleeding bearing in mind relevant warning and precautions (see section 4.4). Continue therapy to support healing and prevent recurrent haemorrhage. The site and severity of bleeding and the use of other procoagulant therapies should determine therapy duration. gastrointestinal. There was limited experience with severe bleedings in the PerSept 1 clinical study. Prevention of bleeding during surgical or invasive procedures CEVENFACTA dosing for the prevention of bleeding during surgical or invasive procedures (perioperative management) is provided in Table 2. Table 2: Dosing for perioperative management of bleeding Type of surgical procedure Dosing regimen recommendation Duration of therapy Minor Including uncomplicated tooth extraction, peripheral central catheter insertion, Port-a- Cath placement, etc. Initial dose: 75 µg/kg immediately before surgery or start of invasive procedure; then Subsequent doses: 75 µg/kg repeated every 2 hours for the first 48 hours following the initial dose. Most minor procedures should be treated for 48 hours to achieve haemostasis. At the discretion of the clinician, this medicinal product may be administered less frequently than every 2 hours and/or for less than 48 hours. Major Pre-operative and operative doses: 200 µg/kg immediately before the surgery, followed by 75 µg/kg every 2 hours for the duration of the surgery The following post-operative doses may be administered: • First 48 hours: 75 µg/kg every 2 hours • Days 3-4: 75 µg/kg every 2 to 4 hours • Days 5-6: 75 µg/kg every 2 to 6 hours • Days 7-10: 75 µg/kg every 2 to 8 hours • Day 11 onwards: 75 µg/kg every 2 to 12 hours The dose and dosing intervals may be adjusted by the healthcare provider based on the clinical assessment and known patient responsiveness to FVIIa-containing bypassing agents. Following the surgery, CEVENFACTA (75 This medicinal product should be administered for a minimum of 5 postoperative days (120 hours) and for as long as necessary to achieve haemostasis and support wound healing. µg/kg) is also recommended prior to drain or suture removal or physical therapy. Close follow-up is important for early detection of potential postoperative bleeding events that may require adjustment of the dosing intervals. Special population The dosing regimen in elderly patients and in patients with renal or hepatic impairment has not yet been established (see sections 4.4 and 5.2). Paediatric population The efficacy of CEVENFACTA in children <12 years has not been established. Currently available data are described in sections 4.8 and 5.1 but no recommendation on a posology can be made. In line with the European Medicines Agency recommendations, there is no relevant use of CEVENFACTA for the treatment of congenital haemophilia in the paediatric population from birth to less than 6 months. Method of administration For instructions on reconstitution of the medicinal product before administration, see section 6.6. Administer the solution as an intravenous bolus injection over 2 minutes or less.

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

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

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%), post-procedural 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 System Organ Class Adverse Reactions (Preferred Term) Frequency Dizziness Common Nervous system disorders Headache Common Injection site discomfort Common General disorders and administration site conditions Injection site haematoma Common Investigations Body temperature increased Common Post-procedural haematoma Common Injury, poisoning and procedural complications Injection related reaction Common 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 non-neutralising 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 Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

There is no experience of in clinical studies. The dosing schedule should not be intentionally increased above the recommended doses due to the absence of information on the additional risk that may be incurred.

Pharmacotherapeutic group: Blood coagulation factors, ATC code: B02BD08 Mechanism of action In normal conditions, FVIIa is the factor initiating coagulation following its

The pharmacokinetic evaluation was conducted in clinical study LFB-FVIIA-009-19 in 28 patients with haemophilia A, with or without inhibitors to FVIII (mean age 37.2 (median of 15.1 (range 19-70 years)) who received a single dose of eptacog beta (activated) (either 75 µg/kg or 225 µg/kg). This medicinal product displayed a pharmacokinetic profile comparable to other rhFVIIa products with an increase in plasma levels shortly after injection followed by a biexponential decay from the maximal concentration to return to baseline approximately 8-12 hours post-administration. Data were analysed using noncompartmental analysis (NCA). Results of pharmacokinetic analysis after a single bolus intravenous administration of either 75 µg/kg or 225 µg/kg of this medicinal product in 28 adult patients are presented in Table 6. Table 6: Pharmacokinetic parameters of CEVENFACTA (Geometric Mean [CV%]) in adults Parameter (Geometric Mean (CV%)) Cmax (ng/mL) Clearance (L/h) Vd (L) AUC0-inf (ng*h/mL) t1/2 (h) 75 µg/kg (n=14) 938 (37) 5.1 (37) 8.2 (37) 1 008 (47) 2.3 (16) 225 µg/kg (n=14) 3 211 (23) 4.5 (20) 7 (22) 3 571 (26) 2.0 (8) Cmax= maximum plasma concentration; AUC0-inf = Area under the curve from time 0 to infinity; t½= terminal half-life; Vd= Volume of distribution Non-compartmental analysis showed approximate dose proportionality between 75 µg/kg and 225 µg/kg of eptacog beta (activated), with the geometric mean AUC0-inf and Cmax increasing 3.5- and 3.4-fold, respectively, for the 3.0-fold dose increment. It should be noted that higher exposure (AUC and Cmax) was observed for increasing body weight (especially relevant for obese subjects) for either of the available doses (75µg/kg and 225µg/kg). It is recognised that data in this subgroup is currently limited, but potential dosing recommendations will be updated once sufficient data will become available. Limited pharmacokinetic data exist in the elderly: 3 elderly patients, from PK study LFB-FVIIA-009-19, were included in the clinical studies, 1 aged 70 years in the 75 µg/kg single intravenous dose arm, and 2 (the oldest aged 67 years) in the 225 µg/kg single intravenous dose arm. No pharmacokinetic data in both renally-impaired and hepatically-impaired patients are available. No clinical studies with this medicinal product to evaluate mass balance have been performed. Still, metabolism is expected to occur via proteolysis in the liver and excretion occurs in urine and faeces (amino acids) based on the available literature.

All findings in the preclinical safety programme were related to the pharmacological effect of rFVIIa.

Powder Arginine hydrochloride Isoleucine Trisodium citrate dihydrate Glycine Lysine hydrochloride Polysorbate 80 Hydrochloric acid (for pH adjustment) Solvent Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

3 years. After reconstitution, the product must be stored below 30 °C in the original vial and administered within 4 hours. Do not freeze. Any unused solution should be discarded 4 hours after reconstitution. For more information on instructions for reconstitution please refer to section 6.6.

Store below 30 °C. Do not freeze. Keep the vial in the outer carton in order to protect from light. For storage conditions of the reconstituted medicinal product, see section 6.3.

Each pack contains: - 1 glass vial with powder (5 mg) for solution for injection, - 1 sterile vial adapter for reconstitution equipped with a 5 µm filter, - 1 prefilled syringe of water for injections (5.2 mL), - 1 plunger rod and backstop.

After reconstitution with the supplied set, the solution appears as a clear to slightly turbid colourless liquid free of foreign particles. The reconstituted medicinal product should be inspected visually for particulate matter prior to administration. Do not use solutions that are cloudy or have deposits. Instructions for reconstitution Aseptic technique and a flat work surface should always be used during the reconstitution procedure. 1. CEVENFACTA powder vial and pre-filled syringe with solvent should be at room temperature (between 15 °C and 25 °C) at reconstitution. 2. Remove the plastic cap from the vial (Fig A). If the cap is lost or missing, do not use the vial. 3. Wipe the rubber stopper on the vial with an alcohol swab. Allow the alcohol to dry. After cleaning with the swab, do not touch the rubber stopper with your fingers and don’t allow it to touch any other object until you attach the vial adapter, as this can transfer germs (Fig B). B A 4. Open the vial adapter package by peeling off the protective paper cover, without touching the inside. Do not remove the vial adapter from the package. The spike of the adapter should line up with the middle of the grey rubber stopper (Fig C). 5. Turn the package over. Firmly press down to fully insert the vial adapter spike through the rubber stopper of the vial (Fig D). 6. Lightly squeeze the plastic cover and lift up to remove it from the vial adapter. Do not touch the exposed spike of the vial adapter (Fig E). 7. Remove the syringe cap from the pre-filled syringe by holding the syringe body with one hand and using the other hand to unscrew the syringe cap (turn to the left). Do not touch the syringe tip. Do not use the prefilled syringe if the syringe cap is lost or missing (Fig F). C D E F 8. While holding the edges of the vial adapter screw on the prefilled syringe (turn to the right) a few turns until it starts to tighten. Be careful not to overtighten as you will need to remove the syringe later (Fig G). 9. Hold the plunger rod by the wide top end in one hand and the syringe body using your other hand. Insert the plunger rod into the syringe, and then screw a few turns (turn to the right) so that the plunger rod is attached to the grey rubber stopper in the syringe (Fig H). 10. Very slowly push the plunger rod down to the bottom of the syringe, in order to transfer all of the liquid from the syringe into the vial. Do not push too quickly as it can result in excess foam in the vial (Fig I). 11. Swirl the vial gently or roll between hands until all powder is dissolved. Do not shake the vial as this creates foam (Fig J). G H I J 12. Without withdrawing any medicinal product back into the syringe, unscrew the syringe from the vial adapter (turn to the left) until it is completely detached. Don’t remove the vial adapter from the vial (Fig K). 13. Withdraw the liquid medicinal product from the vial(s), using a syringe provided by your specialty pharmacy that is large enough to hold your prescribed dose. If your dose requires more than one vial, repeat the above steps with additional kits until you have reached your required dose. Instructions for administration The medicinal product must be administered within 4 hours of reconstitution. The medicinal product can be administered as an intravenous bolus injection over 2 minutes or less. Instructions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

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