Introduction

1. Hemophilia A is a factor VIII [factor 8] deficiency and hemophilia B is a factor IX [factor 9] deficiency that both result in lifelong bleeding disorders.
2. Plasma-derived Factor Concentrates and Recombinant Factor Concentrates are the two main types of clotting factor concentrates available. Products are classified by properties such as purity and half-life. Some recombinant factor products have extended half-life.
3. Products are further characterized by their generation from first to fourth generation. This classification reflects the cell line used to make the product and the addition of or exposure to human and/or animal protein in the final product
4. Patients with Hemophilia A and B without inhibitors (antibodies) presenting with severe bleeding should receive 50units/kg FACTOR VIII (Hemophilia A) and 100-140 units/kg FACTOR IX (for hemophilia B)for a factor replacement level of 80 – 100%. 
5. Patients with Hemophilia A or B with inhibitors presenting with life threatening bleed should receive factor VIIa at 90mcg/kg or aPCC*(FEIBA) at a dose of 75-100units/kg. 

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Pharmacology

	Factor VIII Products	Factor IX Products	Factor VII (Novoseven)	aPCC* (FEIBA)
Dose	25 -50 units/kg a	50 – 140 units/kgb	90mcg/kg/dosec	50 to 100 units/kgd
Administration	Brand dependent	Brand dependent	IV bolus over 2 – 5minutes or Continuous infusion for perioperative management of major bleeding.	IV injection/infusion over a max rate of 2units/kg/minute. Complete infusion within 3 hours.
PK/PD	MOA: Factor VIII replacement, necessary for clot formation and maintenance of hemostasis. It activates factor X in conjunction with activated factor IX; activated factor X converts prothrombin to thrombin, which converts fibrinogen to fibrin, and with factor XIII forms a stable clot. T1/2: See table below	MOA: Replaces deficient clotting factor IX. Factor IX is activated by factor XIa in the intrinsic coagulation pathway. Activated factor IX (IXa) in combination with factor VII activates factor X to Xa, resulting ultimately in the conversion of prothrombin to thrombin and the formation of a fibrin clot. The infusion of exogenous factor IX to replace the deficiency present in hemophilia B temporarily restores hemostasis. T1/2: See table below	MOA: Recombinant factor VIIa, promotes hemostasis by activating the extrinsic pathway of the coagulation cascade. It replaces deficient activated coagulation factor VII, which complexes with tissue factor and may activate coagulation factor X to Xa and factor IX to IXa. When complexed with other factors, coagulation factor Xa converts prothrombin to thrombin, leading to the formation of a fibrin-platelet hemostatic plug. T1/2: 3.2 ±0.3hours	MOA: Anti-inhibitor coagulant complex (Human) contains mainly non-activated therapeutic levels of factors II, IX, and X and mainly activated factor VII. Provides coagulation factors to restore hemostasis in patients with inhibitors.  T1/2: 4 to 7 hours (based on thrombin generation)
Adverse Effects	Antibody Formation, headache, hypersensitivity reaction	Antibody Formation, headache, dizziness, hypersensitivity reaction	Thrombosis, dizziness, headache, hypertension	Nausea, vomiting, hypersensitivity reaction, bronchospasm
Drug Interactions and warnings	Emicizumab and Factor VIIa	Antifibrinolytics (Aminocaproic acid, tranexamic acid) and Factor VIIa	Factor VIII, Emicizumab, Factor IX, Factor XIII, PCC(Human)	Antifibrinolytics (Aminocaproic acid, tranexamic acid) Emicizumab and Factor VIIa
Compatibility	No information available	No information available	Normal SalineDo not mix with other infusions	No information available
Comments	rFVIIa is recommended over FEIBA for acute bleeding events or procedures in hemophilia A inhibitor patients on emicizumab prophylaxis as aPCCs may cause thrombosis or thrombotic microangiopathy in those receiving emicizumab and should be avoided. In factor IX patients with a history of inhibitors and anaphylaxis, factor IX-containing products, including FEIBA should be avoided.

 

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	Overview of Evidence
Author, year	Design/ sample size	Intervention & Comparison	Outcome
Schneiderman2004	Retrospective chart review(n=5 patients with HA and HB,170 hospital days, 91days of sequential therapy)	Patients who did not respond to initial outpatient therapy of either APCC or rFVIIa received sequential therapy with both within 6hours of each other. Doses of aPCC ranged from 35 to 80units/kg/dose with a mean of 55units/kg/dose). Doses of rFVIIa ranged from 80 to 225 mcg/kg/dose with a mean of 164 mcg/kg/dose.	There was no clinical or laboratory evidence of thrombosis, thrombocytopenia, or disseminated intravascular coagulation (DIC). Combination therapy with aPCC and rFVIIa for refractory bleeds is safe when given in the inpatient setting with careful monitoring of the physical examination and frequent laboratory screening
Astermark2007	A prospective, open-label randomized, crossover(n=66 HA patients, 96 bleeding episodes)	One dose of FEIBA (75-100units/kg body weight; target dose, 85units/kg)OR Two doses of NovoSeven (90-120 mcg/kg body weight; target dose, 105mcg/kg) administered intravenously at two hour interval.  Patients switched to the other product for the next bleeding episode.  Patients were instructed to initiate treatment within 4 hours bleeding episode and record hemostatic effect at 2 (before the second dose of NovoSeven), 6, 12, 24, 36, and 48 hours in terms of whether the patient thought the treatment was effective, partially effective, poorly effective, or not effective, and whether the bleeding had stopped.	At six hours post-bleeding, the overall efficacy of FEIBA and rFVIIa were similar (81.3% and 78.1% respectively)Other time points and efficacy measures did not show one product to be clearly superior however some patients derived greater efficacy from one product or the other, especially during the first 12 hours.
Young2008	Randomized, multicentre, cross-over, double-blind study(n=42 HA and HB patients)	270 mcg/kg) of rFVIIa at hour 0 followed by placebo at hours 3 and 6, OR90 mcg/kg) of rFVIIa at hours 0, 3 and 6, OR75units/kg of aPCC at hour 0. Patients with Hemophilia A or B inhibitors with a history of two or more joint bleeds within 12months received all three treatments with a different treatment for each bleeding episode. Patients were assessed for 9hours after dosing based on	A one time 270mcg/kg/dose was as safe and effective as three dose of 90mcg/kg/dose for the management of joint bleeding in patients with haemophilia and inhibitorsA dose of 270mcg/kg of rFVIIa significantly reduces the need for rescue medications compared to aPCC suggesting it to be potentially more effective treatment option than aPCC
Borg2015	Non-interventional restrospective review(n=34, 50 bleeding episodes) of patients with AHA	Mean initial FEIBA dose was 75.4units/kg with (SD, 7units/kg) with mean total daily dose of 155units/kg (SD, 52units/kg).  Dosing interval were once daily (20%),  every 12 h (52% of patients) and three times daily (28% of patients).	Overall efficacy of FEIBA in resolving the bleeding episodes was 88.0% (95% CI, 75.8– 94.5%).5 patients encountered thrombosis related adverse effects
Olivieri2020	Cohort Analysis(n=221)	Male patients using one of five recombinant FVIII product as prophylaxis for greater than 8weeks were included in the analysis.  Dosing frequency, bleeding rate and factor consumption was compared between long acting rVIII-SingleChain (AFSTYLA) and four other rFVII products (long acting rFVIIIFc, standard acting octocog alfa and moroctocog alfa)	Patients treated with rVIII-SingleChain had the lowest factor consumption in comparison to other FVIII products.Bleeding rates was comparable between all FVIII productsPatients who switched to rVIII-SingleChain were able to be dosed less frequently at two times weekly.
Yan 2020	Retrospective Review (n=240)	Patient’s annualized bleeding rates (ABRs), dosing frequency, and factor consumption was compared between three standard Factor VIII products (Advate,Kogenate and Kovaltry) and three long acting products (AFSTYLA, Eloctate and Adynovate).	Long-acting products sustained effectiveness at reduced dosing frequency compared with standard-acting products.  All six products showed statistically equivalent ABRs and percentage of Patients with 0 bleeds including those with severe disease. rVIII-SingleChain (AFSTYLA) demonstrated lowest mean consumption for all patients,as well as for patients with severe hemophilia A, which may lead to potential savings in health care costs.
Davis2019	Systematic literature review	Comparison between rFIX products (IDELVION, ALPROLIX and REFIXIA) and standard-acting products (Benefix, Rixubis and Ixinity).  Annualized bleeding rate (ABR), spontaneous ABR (AsBR), and joint ABR (AjBR) data were extracted from seven articles in a literature review of Phase III trials of prophylactic rFIX treatment in previously treated hemophilia B patients aged ≥ 12 years.	Treatment with rIX-FP (IDELVION) in general compares favorably vs other rFIX products for prophylactic treatment of hemophilia B in adult patients rIX-FP 7-day prophylaxis displayed significantly lower ABR than most other rFIX products AsBR and AjBR also showed statistical significance or trending in favor of rIX-FP
Shapiro2005	Multicenter, open label, single cohort study(n=63)	rFIX was administered at a dose of 50units/kg to patients in a non-bleeding state on day 1 as an intravenous infusion. Thereafter it was administered either for on-demand therapy of a bleeding episode or as a prophylactic treatment to prevent bleeding.  Plasma rFIX activity was measured prior to rFIX infusion, as soon as possible after infusion (preferably within 30 minutes of infusion),  4 and 24 hours after infusion.	Bleeding was well controlled, with 75% of hemorrhages requiring only one rFIX infusion. Effective hemostasis was achieved in 32 PUPs receiving rFIX for routine prophylaxis rFIX administered for 30 surgical procedures in 23 PUPs achieved hemostasis for all rated procedures rFIX was well tolerated, with no associated thrombotic events or evidence of viral transmission. rFIX showed to be safe and effective treatment for PUPs with hemophilia B

 

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Conclusions

1. Patients with Hemophilia A or B are managed with the use of either a standard-acting or long-acting product. 
2. Factor VIII products show comparable bleeding rates however the long acting products have added advantage of being dosed less frequently. 
3. Recombinant Factor IX is safe and effective for HB patients. A long acting product such as IDELVION had a lower annual bleeding rate in comparison to other Factor IX replacement product. 
4. Patients develop antibodies (inhibitors) to factor products over time leading to the need for the administration of a bypassing agent such as Factor VIIa or aPCC.  
5. Bypassing agents have shown to be safe and effective at controlling bleeds when given either as a bolus injection or an infusion. Both agents can also be administered sequentially in patients with refractory bleeds to one product. 

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References

1. Center for Disease Control and Prevention.1600 Clifton Road, Atlanta, GA 30329. Retrieved February 19, 2021 from https://www.cdc.gov/ncbddd/hemophilia/treatment.html
2. Uptodate [Electronic version]. Retrieved February 22, 2021, from http://www.uptodate.com/
3. Clinical Pharmacology [Electronic version]. Elsevier, 302 Knights Run Ave., Suite 800, Tampa, FL 33602. Retrieved February 22, 2021, from http://www.clinicalpharmacology-ip.com/
4. https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/masac-documents/masac-document-257-guidelines-for-emergency-department-management-of-individuals-with-hemophilia-and-other-bleeding-disorders
5. National Hemophilia Foundation [Electronic version]. 7 Penn Plaza Suite 1204, New York, NY 10001, United States. Retrieved February 19 2021 from https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/products-licensed-in-the-us#1
6. Schneiderman J, Nugent DJ, Young G. Sequential therapy with activated prothrombin complex concentrate and recombinant factor VIIa in patients with severe haemophilia and inhibitors. Haemophilia. 2004;10(4):347-351. 
7. Astermark J, Donfield SM, DiMichele DM, et al. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. Blood. 2007;109(2):546-551. 
8. Young G, Shafer FE, Rojas P, Seremetis S. Single 270 microg kg(-1)-dose rFVIIa vs. standard 90 microg kg(-1)-dose rFVIIa and APCC for home treatment of joint bleeds in haemophilia patients with inhibitors: a randomized comparison. Haemophilia. 2008;14(2):287-294. 
9. Borg JY, Négrier C, Durieu I, et al. FEIBA in the treatment of acquired haemophilia A: results from the prospective multicentre French ‘FEIBA dans l’hémophilie A acquise’ (FEIBHAC) registry. Haemophilia. 2015;21(3):330-337. 
10. Olivieri M, Sommerer P, Maro G, Yan S. Assessing prophylactic use and clinical outcomes in hemophilia A patients treated with rVIII-SingleChain and other common rFVIII products in Germany. Eur J Haematol. 2020;104(4):310-317. 
11. Yan S, Maro GS, Desai V, Simpson ML. A Real-World Analysis of Commonly Prescribed FVIII Products Based on U.S. Medical Charts: Consumption and Bleeding Outcomes in Hemophilia A Patients. J Manag Care Spec Pharm. 2020;26(10):1258-1265. 
12. Davis J, Yan S, Matsushita T, Alberio L, Bassett P, Santagostino E. Systematic review and analysis of efficacy of recombinant factor IX products for prophylactic treatment of hemophilia B in comparison with rIX-FP. J Med Econ. 2019;22(10):1014-1021. 
13. Shapiro AD, Di Paola J, Cohen A, et al. The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe hemophilia B. Blood. 2005;105(2):518-525. 
14. Srivastava A, Santagostino E, Dougall A, et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020;26 Suppl 6:1-158.