Products Licensed for the Treatment of Hemophilia and Other Bleeding Disorders
Publication Date: April 27, 2022
Last Updated: May 2, 2022
Summary of Recommendations
Recommendations for Healthcare Providers and Physicians Treating Patients with Hemophilia A and B, von Willebrand Disease, and other Congenital Bleeding Disorders
Treatment of Hemophilia A
- Recombinant Factor VIII Concentrates
- Recombinant (r) FVIII is often produced by two well-established hamster cell lines, baby hamster kidney (BHK) and Chinese hamster ovary (CHO), that have been transfected with the gene for human FVIII (F8). (1, 2) Two newer rFVIII products are produced in human embryonic kidney (HEK) cell lines. In some products, the rFVIII is full length, while in other products the B-domain is largely deleted. Either 14 amino acids (Xyntha, Eloctate), 16 amino acids (Nuwiq), or 21 amino acids (NovoEight) of the B-domain remain in the rFVIII. (3)
- First generation rFVIII contains animal and/or human plasma-derived proteins in the cell culture medium and in the final formulation vial. Second generation rFVIII contains animal or human plasma-derived proteins in the culture medium but not in the final formulation vial. Third generation rFVIII does not contain any animal or human plasma-derived proteins in the culture medium or in the final formulation vial.
- One third generation recombinant Factor VIII product that is fused to the Fc fragment of human IgG (rFVIIIFc) inhibits lysosomal degradation of rFVIII by reticuloendothelial cells, thus prolonging FVIII half-life in the circulation. This product is made in HEK cells. No additives of human or animal origin are used in the production of this product. (4)
- Three other third generation recombinant FVIII products, two produced in CHO and one in BHK cells, are PEGylated to delay degradation and thereby prolong their half-lives. No additives of human or animal origin are used in the production of these products.
- The risk of human viral contamination associated with recombinant FVIII is exceedingly low. No seroconversions to human immunodeficiency virus (HIV), hepatitis B (HBV) or hepatitis C (HCV) have been reported with any of the currently available rFVIII products.
- Recombinant factor VIII products are the recommended treatment of choice for patients with hemophilia A. A possible exception to this recommendation is a newly diagnosed individual, who should also consider with their healthcare providers initiating treatment with a plasma-derived factor VIII / von Willebrand Factor (VWF) product (see MASAC Recommendation on SIPPET, Document #243). (Table I.A.)
- Plasma-Derived Factor VIII Concentrates
- Improved viral-depleting processes and donor screening practices have resulted in plasma-derived (pd) FVIII products that have greatly reduced risk for transmission of HIV, HBV, and HCV. No seroconversions to HIV, HBV, or HCV have been reported with any of the pdFVIII products currently marketed in the United States, including products that are dry-heated, heated in aqueous solution (pasteurized), solvent-detergent treated, and/or immunoaffinity purified. Thus, each of these methods appears to have greatly reduced the risk of viral transmission compared to older methods of viral inactivation (5-7).
- There remains the slight possibility of HIV, HBV, or HCV transmission with the use of currently marketed, viral-inactivated, plasma-derived products. The non-lipid enveloped viruses human parvovirus B19 and hepatitis A virus were also previously transmitted by pdFVIII (8-10); however, additional steps such as nanofiltration have been added to the manufacturing process to reduce risks of these viral infections as well. (Table I.B., Table I.C.)
- Bispecific Antibody for Hemophilia A
- Hemlibra (emicizumab-kxwh)
- Emicizumab is a humanized, bispecific, monoclonal antibody that binds to FIX / FIXa and FX / FXa, thereby standing in for the missing FVIII to prevent or reduce the occurrence of bleeding in patients with hemophilia A. It was shown in phase 3 clinical trials to be safe and effective in adults, adolescents, children, and infants with hemophilia A with and without inhibitors (11-13). Subcutaneous administration of emicizumab is often viewed as being easier and/or less time consuming compared to intravenous administration of FVIII. Dosing intervals are also much longer than FVIII, with prophylaxis regimens for emicizumab with weekly, every 2 weeks, or every 4 weeks dosing. In those undergoing major surgery, preliminary experience suggests standard preoperative dose FVIII and tapering postoperative doses may be safe and effective, while in some minor surgeries, low or no FVIII may be appropriate. (14) (Table IV.C.)
- Hemlibra (emicizumab-kxwh)
- Cryoprecipitate Not Recommended for Hemophilia A
- FVIII products are available that are manufactured by recombinant technology and thus theoretically do not transmit human viruses. Moreover, methods of viral inactivation (dry heat, pasteurization, solvent-detergent treatment, immunoaffinity purification) have resulted in a reduced risk of HIV, HBV and HCV transmission with plasma-derived factor VIII concentrates (6-7, 15-17).
- Despite donor screening by nucleic acid testing (NAT) for HIV, HBV, and HCV, cryoprecipitate might still be infectious. The current estimate for the risk of HIV or HCV infection from a single unit of blood is approximately one in 1,000,000 donations. (18)
- For these reasons, cryoprecipitate, which has not had any viral elimination steps applied, should not be used as a treatment alternative for hemophilia A unless there is a risk to loss of life or limb and no FVIII concentrate is available.
- Treatment of Mild Hemophilia A
- Desmopressin (DDAVP) may be used for patients with mild hemophilia A who have been documented by a DDAVP trial to have a clinically significant rise in FVIII. DDAVP is available in both a parenteral form (DDAVP Injection) and a highly concentrated intranasal spray formulation (Stimate Nasal Spray for Bleeding). (19) (Table I.D.)
- Desmopressin should not be used in certain categories of patients:
- 1. Children under the age of 2 years and
- 2. Patients with mild hemophilia A in whom desmopressin does not provide adequate FVIII levels for the specific intended treatment purpose.
- These patients should be treated as per section I.A.1 or I.A.2 above.
- Desmopressin should be used with caution in pregnant women during labor and delivery. (20)
- In all patients, careful attention should be paid to fluid restriction, since excessive water intake can lead to hyponatremia and seizures.
Recommendations Concerning Products Licensed for the Treatment of Hemophilia and Other Bleeding Disorders