CEVENFACTA (Eptacog Beta Activated)

What Is CEVENFACTA and What Is It Used For?

CEVENFACTA (eptacog beta activated) is a recombinant coagulation factor VIIa used to treat and control bleeding episodes in patients with hemophilia A or B who have developed inhibitors (neutralizing antibodies) against their usual clotting factor replacement therapy. It works by activating the extrinsic coagulation pathway at the site of vascular injury.

Hemophilia A and hemophilia B are inherited bleeding disorders caused by deficiencies in coagulation factor VIII and factor IX, respectively. Treatment typically involves replacing the missing factor through intravenous infusions. However, approximately 25–30% of patients with severe hemophilia A and 3–5% of those with hemophilia B develop inhibitors — antibodies that neutralize the infused clotting factor and render standard replacement therapy ineffective.

For patients with inhibitors, bypassing agents are essential. These medications promote blood clotting through alternative pathways that do not depend on the inhibited factors. CEVENFACTA belongs to this class of bypassing agents. Its active substance, eptacog beta activated, is a recombinant form of human coagulation factor VIIa produced using a unique transgenic technology in which the protein is expressed in the milk of genetically modified rabbits.

When injected intravenously, eptacog beta binds to tissue factor (TF) exposed at sites of vascular injury. This TF-FVIIa complex activates factor X to factor Xa on the surface of activated platelets, leading to a burst of thrombin generation that is sufficient to convert fibrinogen to fibrin and form a stable hemostatic clot. This mechanism effectively bypasses the need for factor VIII or factor IX in the coagulation cascade.

CEVENFACTA received marketing authorization from the European Medicines Agency (EMA) and approval from the U.S. Food and Drug Administration (FDA) for the treatment of bleeding episodes in adults and children (aged 1 year and older) with hemophilia A or B with inhibitors. It was developed by Laboratoire français du Fractionnement et des Biotechnologies (LFB), a French biopharmaceutical company specializing in plasma-derived and recombinant therapeutic proteins.

How does CEVENFACTA differ from other factor VIIa products?

CEVENFACTA is distinguished from other recombinant factor VIIa products primarily by its production method. While other rFVIIa products are manufactured using baby hamster kidney (BHK) cell lines, CEVENFACTA is produced in the mammary glands of transgenic rabbits. This results in a protein with a distinct post-translational modification profile, including differences in glycosylation patterns. These structural differences may influence the pharmacokinetic and pharmacodynamic properties of the molecule.

Clinical studies have demonstrated that CEVENFACTA is effective in achieving hemostasis in the majority of bleeding episodes, with treatment success rates comparable to existing bypassing agents. The pivotal PERSEPT 1 trial showed that 86% of mild to moderate bleeding episodes and 78% of severe bleeding episodes were successfully treated within 12 hours.

What Should You Know Before Taking CEVENFACTA?

Before using CEVENFACTA, inform your doctor about all medical conditions, particularly any history of blood clots, cardiovascular disease, liver disease, or disseminated intravascular coagulation (DIC). CEVENFACTA is contraindicated in patients with known hypersensitivity to rabbits or rabbit proteins.

Contraindications

CEVENFACTA must not be used in the following situations:

• Known hypersensitivity to the active substance (eptacog beta activated), to rabbit proteins, or to any of the excipients listed in the product composition
• Known allergy to rabbits or rabbit-derived products: Because CEVENFACTA is produced in transgenic rabbits, patients with known rabbit allergy may be at risk of severe hypersensitivity reactions including anaphylaxis

Your physician will perform appropriate allergy testing if there is any suspicion of rabbit protein sensitivity before initiating treatment. Patients who develop hypersensitivity reactions during infusion should have the treatment stopped immediately and receive appropriate medical management.

Warnings and Precautions

Several important warnings and precautions must be considered before and during treatment with CEVENFACTA:

• Thrombotic events: CEVENFACTA, like other bypassing agents, carries a risk of thromboembolic complications including deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke. The risk may be elevated in patients with pre-existing cardiovascular disease, obesity, diabetes, recent surgery, immobilization, or advanced age
• Disseminated intravascular coagulation (DIC): Patients receiving CEVENFACTA should be monitored for signs and symptoms of DIC, including unexplained bleeding from multiple sites, consumption of coagulation factors, and thrombocytopenia
• Hypersensitivity reactions: Allergic-type hypersensitivity reactions, including anaphylaxis, are possible. Early signs may include hives, chest tightness, wheezing, low blood pressure, and anaphylaxis. If such reactions occur, treatment should be discontinued immediately
• Neutralizing antibodies: As with all protein-based therapeutic products, there is a potential for immunogenicity. Patients may develop antibodies against eptacog beta that could reduce its clinical effectiveness
• Laboratory monitoring: Conventional coagulation tests such as aPTT and PT do not reliably correlate with clinical hemostatic response to CEVENFACTA. Clinical assessment of bleeding is the primary method for evaluating treatment efficacy

Pregnancy and Breastfeeding

There is limited clinical data on the use of CEVENFACTA during pregnancy and breastfeeding. Hemophilia A and B are X-linked recessive disorders and predominantly affect males. However, female carriers may occasionally require treatment for bleeding episodes.

Animal reproduction studies with eptacog beta have not shown direct harmful effects on embryo-fetal development. However, as a precautionary measure, CEVENFACTA should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. The decision to use CEVENFACTA during breastfeeding should take into account the benefit of therapy for the mother and the potential risks for the nursing infant.

Women of childbearing potential who may require treatment with CEVENFACTA should discuss family planning considerations with their hematologist.

How Does CEVENFACTA Interact with Other Drugs?

CEVENFACTA may interact with other hemostatic agents, particularly activated prothrombin complex concentrates (aPCC), emicizumab, and antifibrinolytic agents such as tranexamic acid. Concurrent use of these agents may increase the risk of thrombotic events and should be carefully managed by a specialist.

Drug interactions with CEVENFACTA are primarily pharmacodynamic in nature, meaning they relate to the combined effects on the coagulation system rather than to metabolic interactions. Because factor VIIa operates within the coagulation cascade, co-administration with other pro-hemostatic agents can produce additive or synergistic effects that increase thrombotic risk.

The following table summarizes the clinically significant interactions:

Major Interactions

The most clinically significant interactions involve co-administration with other bypassing agents, particularly activated prothrombin complex concentrates (aPCC) such as FEIBA. When two or more pro-hemostatic agents are used together, the combined effect on thrombin generation may overwhelm the body's natural anticoagulant mechanisms, leading to disseminated intravascular coagulation (DIC) or localized thromboembolic events.

The interaction with emicizumab is of particular importance given the increasing use of this bispecific antibody for routine prophylaxis in hemophilia A patients with inhibitors. When patients on emicizumab experience breakthrough bleeding and require treatment with a bypassing agent, CEVENFACTA may be preferred over aPCC, but should still be used at the lowest effective dose and for the shortest duration necessary. The treating physician at the hemophilia treatment center should provide individualized guidance.

Minor Interactions

Antifibrinolytic agents such as tranexamic acid and aminocaproic acid are frequently used as adjunctive therapy in hemophilia patients to stabilize clots, particularly for mucosal bleeding (e.g., dental procedures, epistaxis). These agents can generally be used in combination with CEVENFACTA, but patients should be monitored for signs of thrombotic complications, especially in the postoperative setting.

No formal drug-drug interaction studies with common medications such as antibiotics, analgesics, or antihypertensives have shown clinically relevant interactions. However, as with any intravenous protein therapeutic, CEVENFACTA should not be mixed with other medicinal products in the same syringe or infusion line.

What Is the Correct Dosage of CEVENFACTA?

The recommended initial dose of CEVENFACTA is 75 micrograms per kilogram of body weight, administered as a slow intravenous injection. Additional doses of 75 mcg/kg may be given every 2–3 hours until hemostasis is achieved. Treatment should be initiated as early as possible after the onset of a bleeding episode.

Dosing of CEVENFACTA is weight-based and should be individualized according to the type and severity of the bleeding episode, the patient's clinical response, and the treating physician's clinical judgment. The following guidelines are based on the approved prescribing information and international consensus recommendations.

Adults

The number of doses required depends on the bleeding episode's severity and the patient's individual response. In the PERSEPT 1 clinical trial, most mild to moderate bleeding episodes were controlled within 1–3 doses, while severe episodes sometimes required additional doses administered over a longer period. Clinical assessment of hemostasis, rather than laboratory testing, should guide decisions about repeat dosing.

Children

Pharmacokinetic studies in pediatric patients have shown that younger children tend to have faster clearance of recombinant factor VIIa compared to adults. This may necessitate more frequent dosing in some pediatric patients. The treating physician should carefully assess the clinical response and adjust the dosing interval accordingly. CEVENFACTA has not been studied in neonates (under 1 year of age).

Elderly

There is limited clinical experience with CEVENFACTA in elderly patients (aged 65 years and older). Elderly patients may be at increased risk of thromboembolic events due to age-related cardiovascular comorbidities. The dose of CEVENFACTA in elderly patients is the same as in younger adults (75 mcg/kg), but particular attention should be paid to monitoring for thrombotic complications. The treating physician should carefully weigh the benefits and risks in this population.

Missed Dose

CEVENFACTA is used on demand for the treatment of acute bleeding episodes rather than on a regular prophylactic schedule. Therefore, the concept of a "missed dose" does not apply in the traditional sense. However, if a planned repeat dose is delayed, it should be administered as soon as possible if bleeding has not yet been adequately controlled. Do not administer a double dose to compensate for a delayed dose. Consult your healthcare provider for guidance on resuming the dosing schedule.

Overdose

There is limited data on overdose with CEVENFACTA. As with other factor VIIa products, overdose may result in an increased risk of thromboembolic complications. If overdose is suspected, the patient should be closely monitored for signs and symptoms of thrombosis, including deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke. Treatment should be discontinued and appropriate supportive care initiated. There is no specific antidote for CEVENFACTA overdose.

What Are the Side Effects of CEVENFACTA?

The most common side effects of CEVENFACTA include headache, dizziness, injection site reactions, fever, and nausea. Serious but less frequent adverse events include thromboembolic complications (deep vein thrombosis, pulmonary embolism) and hypersensitivity reactions including anaphylaxis.

Like all medicines, CEVENFACTA can cause side effects, although not everyone experiences them. The safety profile of CEVENFACTA has been characterized through clinical trials (PERSEPT program) and post-marketing surveillance. The following frequency classification is based on the convention used by the European Medicines Agency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), and rare (<1/1,000).

The risk of thromboembolic events is of particular clinical importance. These events are more likely in patients with predisposing risk factors such as advanced age, obesity, diabetes mellitus, recent surgery, prolonged immobilization, central venous catheter use, or a personal history of thromboembolic disease. Healthcare providers should carefully assess the risk-benefit ratio before initiating treatment and monitor patients throughout the treatment course.

Immunogenicity is another important consideration. Patients may develop antibodies against eptacog beta that could diminish its hemostatic efficacy. If a patient's expected clinical response is not achieved despite appropriate dosing, testing for neutralizing antibodies should be considered. In clinical trials, the incidence of neutralizing antibody development was low.

How Should You Store CEVENFACTA?

Store unopened CEVENFACTA in a refrigerator at 2–8°C. The product may be stored at room temperature (up to 25°C) for a single period of up to 12 months. After reconstitution, use immediately or within 4 hours at room temperature. Do not freeze.

Proper storage of CEVENFACTA is essential to maintain the product's stability, potency, and safety. As a biologic product consisting of a lyophilized protein, it is sensitive to temperature extremes, light exposure, and physical agitation. The following storage guidelines should be strictly followed:

• Unopened vials (refrigerated): Store in a refrigerator at 2–8°C (36–46°F). Keep the vial in the outer carton to protect from light
• Room temperature storage: The unopened product may be stored at room temperature (up to 25°C / 77°F) for a single period not exceeding 12 months. Once removed from the refrigerator, do not return it to refrigerated storage. Record the date of removal from the refrigerator on the outer carton
• After reconstitution: The reconstituted solution should be used immediately. If not used immediately, it may be stored at room temperature (up to 25°C) for a maximum of 4 hours. Do not refrigerate or freeze the reconstituted solution
• Do not freeze: Freezing may damage the protein structure and reduce efficacy
• Do not shake: Gently swirl the vial during reconstitution to dissolve the powder. Do not shake vigorously, as this may cause foaming and protein denaturation
• Protect from light: Keep the vial in its original outer carton until ready for use
• Do not use after expiry date: Check the expiry date printed on the carton and vial label. Do not use after this date

When traveling with CEVENFACTA, use an insulated container with a cool pack to maintain appropriate temperature. Airlines typically allow passengers to carry medical supplies in their hand luggage with a physician's letter. Patients should carry their hemophilia treatment center contact details and an emergency treatment plan when traveling.

Dispose of any unused product or waste material in accordance with local requirements. Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer need.

What Does CEVENFACTA Contain?

The active substance in CEVENFACTA is eptacog beta activated (recombinant human coagulation factor VIIa). Each vial contains 1 mg of eptacog beta activated. The powder is reconstituted with a provided solvent before intravenous injection.

CEVENFACTA is supplied as a white to slightly yellow lyophilized (freeze-dried) powder with a separate solvent for reconstitution. The complete composition of the product is as follows:

Active substance

• Eptacog beta activated: 1 mg per vial (corresponding to approximately 45,000 IU after reconstitution). This is a recombinant human coagulation factor VIIa produced in the milk of transgenic rabbits by recombinant DNA technology

Excipients in the powder

• L-arginine hydrochloride
• L-isoleucine
• Trisodium citrate dihydrate
• Polysorbate 80
• Hydrochloric acid and/or sodium hydroxide (for pH adjustment)

Solvent

• Water for injections (1 mL)

After reconstitution with the provided solvent, each mL of solution contains 1 mg of eptacog beta activated. The reconstituted solution should be clear to slightly opalescent and colorless to slightly yellow. Do not use if the solution is cloudy, contains particulate matter, or shows any discoloration.

CEVENFACTA does not contain any preservatives. It does not contain any components derived from human blood or plasma, which eliminates the risk of transmission of human blood-borne pathogens such as HIV, hepatitis B, or hepatitis C. However, as the product is derived from transgenic rabbit milk, the theoretical risk of transmission of rabbit-specific infectious agents cannot be entirely excluded, although manufacturing processes include viral inactivation and removal steps.

The product is supplied in a single-use Type I glass vial with a bromobutyl rubber stopper and an aluminum seal with a plastic flip-off cap. The solvent is provided in a pre-filled syringe. A vial adapter and an infusion needle are also included in the pack.

Frequently Asked Questions About CEVENFACTA