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. It is administered intravenously (IV).[2]

Recombinant factor VIIa
INN: Eptacog alfa
Clinical data
Trade namesNovoSeven, AryoSeven, Sevenfact, others
Other namesrFVIIa, Coagulation factor VIIa (recombinant), Coagulation factor VIIa (recombinant)-jncw
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: B1
Routes of
administration		Intravenous injection
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only) [1]
  • US: ℞-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Excretion 
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG


Medical uses

NovoSeven is approved for use in the United States and is indicated for the treatment of bleeding episodes and for the prevention of bleeding in surgical interventions or invasive procedures in patients with acquired hemophilia.[3][4]

NovoSeven RT is approved in the United States and 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 (FVII) 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.[2][5]

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).[6][7][8]

As of 2012, recombinant factor VIIa is not supported by the evidence for treating most cases of major bleeding.[9] 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.[9] Recombinant human factor VII, while initially looking promising in intracerebral hemorrhage, failed to show benefit following further study and is no longer recommended.[10][11]

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.[2]

Pharmacology

Mechanism of action

This treatment results in activation of the extrinsic pathway of blood coagulation.[2]

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).[6] 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.[6]

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.[6] The study assessed the efficacy of treatment twelve hours after the initial dose was given.[6] 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%.[6] The study also included three severe bleeding episodes that were treated successfully with the higher dose.[6]

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.[6] 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.[6]

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.[6]

Coagulation factor VIIa (recombinant)-jncw is contraindicated in those with known allergy or hypersensitivity to rabbits or rabbit proteins.[6]

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.[12] 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.[12]

NovoSevenRT was approved for use in the United States in May 2008, as a room temperature stable formulation.[13] In January 2010, the label was updated to include a black box warning on serious thrombotic adverse events associated with the use of NovoSeven RT outside labeled indications.[13][5]

In April 2020, coagulation factor VIIa (recombinant)-jncw (Sevenfact) was approved for use in the United States.[7][6]

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]

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.[15][16]

References
  1. "NovoSeven 1 mg (50KIU) powder and solvent for solution for injection - Summary of Product Characteristics (SmPC)". (emc). 21 November 2019. Retrieved 1 April 2020.
  2. "NovoSeven RT". U.S. Food and Drug Administration (FDA). 22 July 2017. Retrieved 1 April 2020. This article incorporates text from this source, which is in the public domain.
  3. "NovoSeven". U.S. Food and Drug Administration (FDA). 1 October 2017. Retrieved 1 April 2020. This article incorporates text from this source, which is in the public domain.
  4. "NovoSeven Coagulation Factor VIIa (Recombinant) For Intravenous Use Only" (PDF). U.S. Food and Drug Administration (FDA). Novo Nordisk.
  5. "NovoSeven RT (coagulation factor viia- recombinant kit". DailyMed. Novo Nordisk. Retrieved 1 April 2020.
  6. "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. Retrieved 1 April 2020. This article incorporates text from this source, which is in the public domain.
  7. "Sevenfact coagulation factor VIIa (recombinant)-jncw". U.S. Food and Drug Administration (FDA). 1 April 2020. Retrieved 2 April 2020.
  8. "Sevenfact [coagulation factor VIIa (recombinant)-jncw] Lyophilized Powder for Solution, for Intravenous Use" (PDF). U.S. Food and Drug Administration (FDA). Laboratoire Francais du Fractionnement et des Biotechnologies S.A.
  9. Simpson, E; Lin, Y; Stanworth, S; Birchall, J; Doree, C; Hyde, C (14 March 2012). "Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia" (PDF). Cochrane Database of Systematic Reviews. 3 (3): CD005011. doi:10.1002/14651858.CD005011.pub4. hdl:10871/13808. PMID 22419303.
  10. Mayer S, Brun N, Begtrup K, Broderick J, Davis S, Diringer M, Skolnick B, Steiner T (2005). "Recombinant activated factor VII for acute intracerebral hemorrhage". N. Engl. J. Med. 352 (8): 777–85. doi:10.1056/NEJMoa042991. PMID 15728810.
  11. Mayer SA, Brun NC, Begtrup K, et al. (May 2008). "Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage". N. Engl. J. Med. 358 (20): 2127–37. doi:10.1056/NEJMoa0707534. hdl:10067/688040151162165141. PMID 18480205.
  12. "NovoSeven". U.S. Food and Drug Administration (FDA). 23 December 2014. Archived from the original on 1 November 2017. Retrieved 1 April 2020.{{cite web}}: CS1 maint: unfit URL (link) This article incorporates text from this source, which is in the public domain.
  13. "NovoSevenRT". U.S. Food and Drug Administration (FDA). 26 February 2015. Archived from the original on 22 July 2017. Retrieved 1 April 2020.{{cite web}}: CS1 maint: unfit URL (link) This article incorporates text from this source, which is in the public domain.
  14. "Cevenfacta: Pending EC decision". European Medicines Agency. 19 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. Little R (19 November 2006). "Dangerous Remedy". The Baltimore Sun. Retrieved 1 April 2020.
  16. 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. ISSN 0035-8665. PMID 18619169. S2CID 10776054.

Further reading
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