Recombinant factor VIIa

Recombinant factor VIIa, also known as eptacog alfa (INN), and sold under the brand name Novoseven, among others, is a form of blood factor VII that has been manufactured via recombinant technology.[4][5] It is administered via an injection into a vein.[6][4][5]

Recombinant factor VIIa
INN: Eptacog alfa
Clinical data
Trade namesNovoseven, Sevenfact, others
Other namesrFVIIa, Coagulation factor VIIa (recombinant), Coagulation factor VIIa (recombinant)-jncw
BiosimilarsAryoseven
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: B1
Routes of
administration		Intravenous injection
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG

The most common side effects with Novoseven include venous thromboembolic events (problems caused by blood clots in the veins), rash, pruritus (itching), urticaria (hives), fever and reduced effectiveness of treatment.[4] The most common side effects with Cevenfacta include injection site discomfort and hematoma (a collection of blood under the skin) as well as injection-related reactions, an increase in body temperature, dizziness and headache.[5]

Novoseven was approved for medical use in the European Union in February 1996,[4] and in the United States in March 1999.[7] Novoseven RT was approved for medical use in the US in May 2008.[6]

Medical uses

Novoseven is indicated for the treatment of bleeding episodes and for the prevention of bleeding in surgical interventions or invasive procedures in people with acquired hemophilia.[7][8]

Novoseven RT is indicated for the treatment of bleeding episodes and peri-operative management in adults and children with hemophilia A or B with inhibitors, congenital factor VII deficiency, and Glanzmann's thrombasthenia with refractoriness to platelet transfusions, with or without antibodies to platelets and for the treatment of bleeding episodes and peri-operative management in adults with acquired hemophilia.[6][2]

Sevenfact [coagulation factor VIIa (recombinant)-jncw] is approved for use in the United States and is indicated for the treatment and control of bleeding episodes occurring in adults and adolescents twelve years of age and older with hemophilia A or B with inhibitors (neutralizing antibodies).[9][10][3]

As of 2012, recombinant factor VIIa is not supported by the evidence for treating most cases of major bleeding.[11] There is a significant risk of arterial thrombosis with its use and thus, other than in those with factor VII deficiency, it should only be given in clinical trials.[11] Recombinant human factor VII, while initially looking promising in intracerebral hemorrhage, failed to show benefit following further study and is no longer recommended.[12][13]

In people with hemophilia type A and B who have a deficiency of factors VIII and IX, these two factors are administered for controlling bleeding or as prophylaxis medication before starting surgeries. However, in some cases they subsequently develop neutralizing antibodies, called inhibitors, against the drug. These inhibitors often increase over time and inhibit the action of coagulation in the body. Recombinant factor VIIa, which is an activated form of factor VII, bypasses factors VIII and IX and causes coagulation without the need for factors VIII and IX. It can't be given without inhibitor. It is important for some patients to shift to proper blood factors according to their inhibitor titer. Other indications include use for patients with acquired hemophilia, people born with a deficiency of factor VII, and people with Glanzmann's thrombasthenia.[6]

Pharmacology

Mechanism of action

This treatment results in activation of the extrinsic pathway of blood coagulation.[6]

Coagulation factor VIIa (recombinant)-jncw

Coagulation factor VIIa (recombinant)-jncw (Sevenfact) is expressed in the mammary gland of genetically engineered rabbits and secreted into the rabbits' milk. During purification and processing of the milk, FVII is converted into activated FVII (FVIIa).[9] The recombinant DNA (rDNA) construct in the genetically engineered rabbits used for the production of Sevenfact was approved by the FDA's Center for Veterinary Medicine.[9]

The safety and efficacy of coagulation factor VIIa (recombinant)-jncw were determined using data from a clinical study that evaluated 27 patients with hemophilia A or B with inhibitors, which included treatment of 465 mild or moderate, and three severe bleeding episodes.[9] The study assessed the efficacy of treatment twelve hours after the initial dose was given.[9] The proportion of mild or moderate bleeding episodes treated successfully both with the lower dose of 75mcg/kg and higher dose of 225 mcg/kg (requiring no further treatment for the bleeding episode, no administration of blood products and no increase in pain beyond 12 hours from initial dose) was approximately 86%.[9] The study also included three severe bleeding episodes that were treated successfully with the higher dose.[9]

Another study evaluated the safety and pharmacokinetics of three escalating doses of coagulation factor VIIa (recombinant)-jncw in 15 subjects with severe hemophilia A or B with or without inhibitors.[9] Results from this study were used to select the two doses, 75mcg/kg and 225 mcg/kg, that were evaluated in the study described above.[9]

The most common side effects of coagulation factor VIIa (recombinant)-jncw are headache, dizziness, infusion site discomfort, infusion related reaction, infusion site hematoma and fever.[9]

Coagulation factor VIIa (recombinant)-jncw is contraindicated in those with known allergy or hypersensitivity to rabbits or rabbit proteins.[9]

Society and culture

Novoseven was approved for use in the United States in March 1999 and indicated for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX.[7] It was approved in October 2006 and indicated for the treatment of bleeding episodes and for the prevention of bleeding in surgical interventions or invasive procedures in patients with acquired hemophilia.[7]

Novoseven RT was approved for use in the United States in May 2008 as a room-temperature stable formulation.[6] In January 2010, the label was updated to include a boxed warning on serious thrombotic adverse events associated with the use of Novoseven RT outside labeled indications.[6][2]

In April 2020, coagulation factor VIIa (recombinant)-jncw (Sevenfact) was approved for use in the United States.[10][9]

On 19 May 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Cevenfacta, intended for the treatment of bleeding episodes.[14] The applicant for this medicinal product is Laboratoire français du Fractionnement et des Biotechnologies (LFB).[14] The active substance of Cevenfacta is eptacog beta (activated), a blood coagulation factor (ATC code: B02BD08).[14] Eptacog beta is almost identical to, and functions like, coagulation factor VII.[14] It activates factor X, which starts the clotting process and thereby provides control of the bleeding.[14] Because factor VII acts directly on factor X, independently from factors VIII and IX, Cevenfacta can be used to restore haemostasis in their absence or in the presence of inhibitors.[14] Cevenfacta was approved for medical use in the European Union in July 2022.[5][15]

Military use

rFVIIa was used routinely in severely wounded American troops during the Iraq War, credited with saving many lives but also resulting in a high number of deep venous thromboses and pulmonary emboli, as well as unexpected strokes, heart attacks, and deaths.[16][17]

References
  1. "NovoSeven 1 mg (50KIU) powder and solvent for solution for injection - Summary of Product Characteristics (SmPC)". (emc). 21 November 2019. Archived from the original on 15 January 2021. Retrieved 1 April 2020.
  2. "NovoSeven RT (coagulation factor viia- recombinant kit". DailyMed. Novo Nordisk. Archived from the original on 25 March 2021. Retrieved 1 April 2020.
  3. "Sevenfact- coagulation factor viia recombinant human kit". DailyMed. 12 April 2020. Retrieved 3 March 2023.
  4. "NovoSeven EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 27 February 2023.
  5. "Cevenfacta EPAR". European Medicines Agency (EMA). 17 May 2022. Retrieved 3 March 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. "NovoSeven RT". U.S. Food and Drug Administration (FDA). 22 July 2017. Archived from the original on 17 December 2019. Retrieved 1 April 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  7. "NovoSeven". U.S. Food and Drug Administration (FDA). 1 October 2017. Archived from the original on 20 October 2020. Retrieved 1 April 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  8. "NovoSeven Coagulation Factor VIIa (Recombinant) For Intravenous Use Only" (PDF). U.S. Food and Drug Administration (FDA). Novo Nordisk. Archived from the original on 14 December 2019. Retrieved 2 April 2020.
  9. "FDA Approves Additional Treatment for Adults and Adolescents with Hemophilia A or B and Inhibitors". U.S. Food and Drug Administration (FDA) (Press release). 1 April 2020. Archived from the original on 2 April 2020. Retrieved 1 April 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  10. "Sevenfact coagulation factor VIIa (recombinant)-jncw". U.S. Food and Drug Administration (FDA). 1 April 2020. Archived from the original on 1 April 2020. Retrieved 2 April 2020.
  11. Simpson E, Lin Y, Stanworth S, Birchall J, Doree C, Hyde C (March 2012). "Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia". The Cochrane Database of Systematic Reviews. 3 (3): CD005011. doi:10.1002/14651858.CD005011.pub4. hdl:10871/13808. PMID 22419303.
  12. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, et al. (February 2005). "Recombinant activated factor VII for acute intracerebral hemorrhage". The New England Journal of Medicine. 352 (8): 777–785. doi:10.1056/NEJMoa042991. PMID 15728810.
  13. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, et al. (May 2008). "Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage". The New England Journal of Medicine. 358 (20): 2127–2137. doi:10.1056/NEJMoa0707534. hdl:10067/688040151162165141. PMID 18480205.
  14. "Cevenfacta: Pending EC decision". European Medicines Agency (EMA). 19 May 2022. Archived from the original on 20 May 2022. Retrieved 20 May 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  15. "Cevenfacta Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  16. Little R (19 November 2006). "Dangerous Remedy". The Baltimore Sun. Archived from the original on 2 April 2020. Retrieved 1 April 2020.
  17. Hodgetts TJ, Kirkman E, Mahoney PF, Russell R, Thomas R, Midwinter M (December 2007). "UK defence medical services guidance for the use of recombinant factor VIIa (rFVIIa) in the deployed military setting". Journal of the Royal Army Medical Corps. 153 (4): 307–309. doi:10.1136/jramc-153-04-18. PMID 18619169. S2CID 10776054.

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