Therapeutic options for patients with hemophilia have improved greatly during the past decades. Initially, therapy was limited to whole blood transfusion. Therapy then progressed to the administration of freeze-dried plasma concentrates of coagulation factor VIII (FVIII) for hemophilia A and prothrombin complex containing factors II, VII, IX, and X for hemophilia B; these became available commercially in the 1970s. Recombinant DNA technology led to still further advances in replacement therapy and prophylaxis in the 1990s.1

Replacement therapy is currently the predominant form of approved therapy for hemophilia. Replacement factors have been modified to increase their plasma half-life and thus lengthen the intervals between injections. In some cases, antibodies against coagulation factors develop, so that patients do not respond to replacement therapy. For these patients, bypassing products have been developed that do not rely on the missing factor but can still induce blood clotting. In another method of treatment, anticoagulant inhibitors are used to increase the formation of defective thrombin. Therapeutic options continue to be developed and refined to address the challenges and limitations of standard treatments.1

Advate

Advate® (octocog alfa; antihemophilic factor [recombinant]) is a recombinant treatment for hemophilia A designed to replace FVIII. It was originally developed and produced by Shire and was subsequently acquired by Takeda Pharmaceuticals.2,3 Advate was the first recombinant FVIII made without the use of human or animal proteins to be approved for use in adults and children; initial approval was in 2003. After extensive and lengthy study, Advate is now indicated for the on-demand, perioperative, or prophylactic treatment of hemophilia A.2,4 The most common adverse reactions to Advate include pyrexia, headache, cough, nasopharyngitis, arthralgia, vomiting, upper respiratory tract infection, limb injury, nasal congestion, and diarrhea.2

Adynovate

Adynovate® (rurioctocog alfa pegol; antihemophilic factor [recombinant], PEGylated) is a recombinant FVIII for the on-demand, perioperative, or prophylactic treatment of hemophilia A in children and adults. Previously known as BAX 855, it was originally approved in 2015. Adynovate is based on the Advate molecule but with the addition of polyethylene glycol (PEG). This modification allows it to remain in the circulation longer by reducing binding to the physiological FVIII clearance receptor (LRP1).5 Because of the increased time it remains in the plasma, Adynovate has to be injected only twice a week for prophylaxis. Like Advate, 2*Adynovate was originally developed by Shire and is now distributed by Takeda. The most common adverse events reported during clinical trials include headache, diarrhea, rash, nausea, dizziness, and urticaria.5

Afstyla

Afstyla® (lonoctocog alfa; antihemophilic factor [recombinant], single chain) is another recombinant FVIII for the on-demand, perioperative, or prophylactic treatment of hemophilia A in children and adults. It was originally approved in 2016 and is distributed by CSL Behring. Unlike Advate, Afstyla is a single-chain recombinant FVIII with a truncated B-domain that allows covalent bonding of the light and heavy chains.6,7 This modification increases its affinity for von Willebrand factor (VWF), which stabilizes and protects it from degradation.6,7 The most common adverse reactions to Afstyla (occurring in 0.5% or more of patients) are dizziness and hypersensitivity.6

Alphanate

Alphanate® (beroctocog alfa; antihemophilic factor/von Willebrand factor complex [human]) is a mixture of both FVIII and von Willebrand factor (VWF) that is indicated for the control and prevention of bleeding in patients with hemophilia A.8 It is also indicated for patients with von Willebrand disease who are undergoing invasive or surgical procedures and for whom desmopressin is ineffective or contraindicated.8 Alphanate should not be given to patients with von Willebrand disease type 3 who are undergoing major surgery.8 Alphanate is derived from pooled human plasma that has been filtered and processed to isolate FVIII and VWF and reduce the risk for transmission of infection.8 The VWF in Alphanate binds to FVIII and increases its half-life by protecting it from proteases and endocytosis.9 The VWF also helps to carry FVIII to the site of bleeding for effective hemostasis.8,9 The most frequent side effects reported with Alphanate infusions are pruritus, headache, back pain, paresthesia, respiratory distress, facial edema, pain, rash, and chills.8 Alphanate was originally approved in 1978 and is still available today from Grifols.8

AlphaNine SD

AlphaNine SD® (coagulation factor IX [human]) is a purified, virus-filtered, solvent detergent-treated preparation of coagulation factor IX (FIX) used in the treatment and control of bleeding in patients with hemophilia B.10 Factor IX is isolated from pooled human plasma; small amounts of factors II, VII, and X may also be present. AlphaNine SD was originally developed by Alpha Therapeutic Corporation and approved by the Food and Drug Administration (FDA) in 1996 before being acquired by Grifols in 2003.11,12 Adverse reactions to AlphaNine SD infusions may include allergic reactions at the infusion site as well as thrombosis or disseminated intravascular coagulation.10

Alprolix

Alprolix® (eftrenonacog alfa; coagulation factor IX [recombinant], Fc fusion protein) is approved for the perioperative management, prophylaxis, and control of bleeding in patients with hemophilia B. Alprolix is a recombinant FIX manufactured by Bioverativ Therapeutics that was originally approved by the FDA in 2014. The drug is a fusion protein that contains the Fc region of immunoglobulin G1 (IgG1); this binds to the neonatal Fc receptor, prolonging the half-life of the factor as the protein is cycled back into the circulation. The most common adverse reactions vary depending on the patient’s treatment status. Headache, oral paresthesia, and obstructive uropathy have occurred in 1% or more of previously treated patients. FIX inhibition, injection site erythema, and hypersensitivity have occurred in 1% or more of previously untreated patients.13

Amicar

Amicar® (aminocaproic acid) is a fibrinolysis inhibitor that can be given to patients to enhance hemostasis.14 It can be used off label to prevent bleeding in patients with hemophilia A who are undergoing dental procedures.15 Amicar works by competitively binding to plasminogen and preventing it from binding to and degrading fibrin.15 Three administration options are available for Amicar: oral tablets, oral solution, and intravenous (IV) injection.15 Amicar is generally well tolerated, but the most common adverse effects include malaise, myalgias, renal impairment, seizures, hypotension, bradycardia, thrombosis, edemas, and injection site reactions.15 Less common adverse events include gastrointestinal symptoms such as diarrhea and nausea.15

BeneFix

BeneFix® (nonacog alfa; coagulation factor IX [recombinant]) is another recombinant FIX treatment that was originally approved in 1997. It is manufactured by Pfizer and is now FDA-approved for the on-demand and perioperative treatment of adults and children with hemophilia B and for prophylaxis in patients 16 of age and older. The most common adverse events with incidence rates above 5% are fever, cough, nausea, injection site reaction, injection site pain, headache, dizziness, and rash.16

Cyklokapron

Cyklokapron® (tranexamic acid) is an antifibrinolytic that is FDA-approved for short-term use to reduce or prevent hemorrhage in patients who have hemophilia or who require replacement therapy during and after tooth extractions. It was originally approved in 1986. Cyklokapron is believed to act by inhibiting the lysine receptor-binding sites of plasmin, thereby preventing it from binding to fibrin and breaking down the fibrin matrix. The most common adverse reactions include nausea, vomiting, diarrhea, allergic dermatitis, giddiness, hypotension, and thromboembolic events.17

DDAVP

DDAVP® (desmopressin acetate) is a synthetic version of the antidiuretic hormone produced by the pituitary gland, called 8-arginine vasopressin or antidiuretic hormone.18 DDVAP is approved for on-demand and perioperative use in patients with hemophilia A and von Willebrand disease type 1. In addition to its antidiuretic properties, DDAVP induces the release of VWF and FVIII from storage sites, along with Weibel-Palade bodies and alpha granules of platelets, which aid in clotting.19 DDAVP is available as an IV or subcutaneous injection, intranasal spray, or a dissolvable sublingual strip.19 Adverse events following DDAVP administration include hyponatremia, headache, tachycardia, and facial flushing.19 In rare cases, the administration of DDAVP may also lead to seizure, stroke, or myocardial infarction.19

Eloctate

Eloctate® (efmoroctocog alfa; antihemophilic factor [recombinant], Fc fusion protein) is a recombinant FVIII that has been fused with the Fc region of IgG1 to prolong the half-life of the factor. It is approved as an IV injection for the perioperative, on-demand, and prophylactic treatment of episodes of bleeding in adults and children with hemophilia A. Eloctate was originally approved in 2014 and is manufactured by Bioverativ, a subsidiary of Sanofi Genzyme. The most commonly reported adverse events in previously treated patients include arthralgia, malaise, myalgia, headache, and rash. In previously untreated patients, the most common reactions include FVIII inhibition, device-related thrombosis, and papular rash.20

Esperoct 

Esperoct® (turoctocog alfa pegol; antihemophilic factor [recombinant], glycopegylated-exei) is another recombinant FVIII, in this case attached to a 40-kDa PEG molecule to increase its half-life and decrease its clearance. Esperoct, manufactured by Novo Nordisk, has been approved since 2019 for the on-demand treatment, perioperative management, and routine prophylaxis of hemophilia A in children and adults. The most common side effects reported during clinical trials were rash, redness, itching, and injection site reactions.21

Feiba 

Feiba® (anti-inhibitor coagulant complex) is a mixture of clotting factors approved for the on-demand, perioperative, and prophylactic management of bleeding in patients who have hemophilia A or hemophilia B with inhibitors. Feiba is a mixture of non-activated factors II, IX, and X as well as activated factor VII (FVII); these interact with other coagulation factors and platelets to increase thrombin generation. Feiba is manufactured from pools of human plasma that have been tested and treated to reduce the risk for viral transmission. The drug was originally approved in the United States in 1986, but its indications have been updated over the years to include prophylaxis. The most frequent adverse reactions to Feiba include anemia, diarrhea, hemarthrosis, nausea, vomiting, and positivity for hepatitis B surface antibodies.22

Hemlibra

Hemlibra® (emicizumab-kxwh) is a humanized bispecific antibody approved by the FDA for the prophylactic treatment of hemophilia A in patients of any age with or without FVIII inhibitors.23 Hemlibra mimics FVIIIa and works as a cofactor to bring factor IXa (FIXa) and factor X (FX) antigens appropriately close together to allow the FIXa-catalyzed activation of FX.24 Hemlibra was originally developed by Chugai Pharmaceuticals and is now manufactured by Genentech, both members of the Roche Group. The most common adverse reactions to Hemlibra, occurring in 10% or more of patients, include injection site reactions, headache, and arthralgia.23

Hemofil M

Hemofil® M (antihemophilic factor, human) is a FVIII preparation created from pooled human plasma.25 In the preparation process, murine monoclonal antibodies to FVIII undergo immunoaffinity chromatography followed by ion exchange chromatography.25 Hemofil M is further processed with viral inactivation detergent and nanofiltration to reduce the risk for disease transmission. Hemofil M was originally approved by the FDA in 1966 and is produced by Baxalta, a subsidiary of Shire/Takeda.25,26 The most frequently reported adverse reactions to Hemofil M (occurring in 0.8% or more of patients) include FVIII inhibition, infusion site inflammation, dizziness, headache, dysgeusia, and pyrexia.25

Humate-P

Humate-P® (antihemophilic factor/von Willebrand factor [human]) is a combination of FVIII and VWF indicated for the treatment and prevention of bleeding in patients with hemophilia A. It is also approved for the treatment of spontaneous or trauma-induced bleeding and the perioperative prevention of excessive bleeding in patients with von Willebrand disease in whom desmopressin is known or suspected to be inadequate. Like other human hemophilia products, Humate-P is made from pooled plasma that has been purified and tested for a number of viruses, including the hepatitis A, B, and C viruses as well as human immunodeficiency virus 1. Humate-P combines FVIII and VWF to improve hemostasis and increase the half-life of FVIII. Humate-P was originally approved in the United States in 1986 and is produced by CSL Behring.27

Idelvion 

Idelvion® (albutrepenonacog alfa; coagulation factor IX [recombinant], albumin fusion protein) is a recombinant fusion protein (FIX and albumin) for the on-demand, perioperative, and prophylactic management of patients with hemophilia B. Joining FIX and albumin extends the half-life of FIX, while FIX can be separated from the albumin through cleavage of a linker derived from the endogenous activation peptide in native FIX. Idelvion is produced by CSL Behring and was approved by the FDA in 2016. The most common adverse event, occurring in 1% or more of patients, is headache.28

Ixinity 

Ixinity® (trenonacog alfa; coagulation factor IX [recombinant]) is a recombinant FIX that was approved in the United States in 2015 for the on-demand treatment and perioperative management of bleeding in adults and children age 12 and older with hemophilia B. In adults only, Ixinity is also approved for routine prophylaxis. The most commonly observed adverse reaction in clinical trials, occuring in more than 2% of patients, was headache. Ixinity is manufactured by Aptevo BioTherapeutics.29

Jivi 

Jivi® (damoctocog alfa pegol; antihemophilic factor [recombinant] PEGylated-aucl) is a recombinant FVIII indicated for the on-demand, perioperative, and prophylaxis treatment of patients with hemophilia A age 12 and older who have previously been treated. Jivi is not indicated for patients younger than 12 because of an increased risk for hypersensitivity reactions. Jivi is created by conjugating recombinant FVIII produced from Baby Hamster Kidney (BHK) cells with a branched PEG moiety. PEG binding to the A3 domain of FVIII extends the half-life of the molecule by reducing the binding of FVIII clearance receptors. Adverse reactions occurring in 5% or more of patients during clinical trials were headache, cough, nausea, and fever. Jivi was approved by the FDA in 2018 and is manufactured and distributed by Bayer.30

Koāte

Koāte® (antihemophilic factor [human]), also known as Koāte-DVI, is a human plasma-derived FVIII indicated for the treatment and prevention of episodes of bleeding in patients with hemophilia A.31 Initially approved in the United States in 1974, the processing methods have been updated over the years to make the product safer from viral contamination.31 The Koāte manufacturing process now includes the double viral inactivation (DVI) steps of solvent/detergent treatment followed by heat treatment at 80°C for 72 hours.31,32 Most recently, a PEG precipitation/depth filtration step has been added to increase safety further.33 Koāte is manufactured by Grifols Therapeutics for Kedrion Biopharma.31 The most common adverse events reported in clinical trials include nervousness, headache, abdominal pain, nausea, paresthesia, and blurred vision.31

Kogenate FS 

Kogenate® FS (octocog alfa; antihemophilic factor [recombinant]) is a recombinant FVIII indicated for the perioperative and on-demand treatment and the prophylaxis of episodes of bleeding in patients with hemophilia A. Kogenate FS temporarily replaces the missing or defective FVIII required for hemostasis. It contains an unmodified, full-length version of endogenous FVIII that is produced with BHK cells and formulated with sucrose. A number of adverse reactions were reported in 4% or more of patients during clinical trials, including inhibitor formation in patients previously untreated or minimally treated, skin-associated hypersensitivity reactions, infusion site reactions, and infections related to central venous access devices. Kogenate FS was initially approved by the FDA in 1993 and is produced by Bayer.34

Kovaltry

Kovaltry® (octocog alfa; antihemophilic factor [recombinant]) is a next-generation recombinant FVIII.35,36 It has the same protein backbone as Kogenate FS, but in a modified production process, no human- or animal-derived raw materials are added.35,36 Furthermore, the gene coding for human heat shock protein 70 (HSP70) is introduced into the BHK cells together with the gene coding for human FVIII.35,36 HSP70 induces proper folding of the FVIII protein and also may increase its half-life.35,36 Kovaltry is produced by Bayer and was approved in 2016 for the on-demand treatment, perioperative management, and routine prophylaxis of bleeding in adults and children with hemophilia A.35 The most commonly reported adverse events in clinical trials were inhibitor formation in previously untreated or minimally treated patients as well as headache, pyrexia, and pruritus.35

Novoeight

Novoeight® (turoctocog alfa; antihemophilic factor [recombinant]) is a recombinant FVIII produced by Novo Nordisk. It was originally approved in the United States in 2013 and is indicated for the on-demand treatment, perioperative management, and routine prophylaxis of bleeding in adults and children with hemophilia A. The most frequently reported side effects include inhibitor formation in previously untreated patients, injection site reactions, and pyrexia.37

NovoSeven RT

NovoSeven® RT (eptacog alfa activated; coagulation factor VIIa [recombinant]) is a recombinant coagulation factor VIIa (FVIIa). It is indicated for perioperative management and the treatment of episodes of bleeding in adults and children with several different bleeding disorders, including hemophilia A and B with inhibitors, congenital FVII deficiency, and Glanzmann thrombasthenia with refractoriness to platelet transfusions, with or without antibodies to platelets. NovoSeven RT is also approved for adults with acquired hemophilia. NovoSeven RT helps to activate FX to FXa and FIX to FIXa, needed for the conversion of prothrombin to thrombin and of fibrinogen to fibrin to induce local hemostasis. NovoSeven RT is produced by Novo Nordisk and was originally approved in 1999. The most commonly reported adverse events during clinical trials of NovoSeven RT were thrombotic events, which occurred in 4% of patients with acquired hemophilia and 0.2% of patients with congenital hemophilia.38

Nuwiq 

Nuwiq® (simoctocog alfa; antihemophilic factor [recombinant]) is a recombinant FVIII initially approved in the United States in 2015. It is indicated for the on-demand treatment, routine prophylaxis, and perioperative management of bleeding in adults and children with hemophilia A. Unlike other recombinant FVIII products, Nuwiq is produced from human embryonic kidney cells rather than hamster cells. No animal- or human-derived materials are used in the manufacturing process after translation. The most common adverse reactions, occurring in more than 5% of patients during clinical trials of Nuwiq, include upper respiratory tract infection, headache, fever, cough, lower respiratory tract infection, rhinitis, chills, abdominal pain, arthralgia, anemia, and pharyngitis. Nuwiq was developed and is manufactured by Octapharma.39

Obizur

Obizur® (antihemophilic factor [recombinant], porcine sequence) is a recombinant analogue of porcine FVIII produced in BHK cells. Obizur is indicated for the on-demand treatment and control of episodes of bleeding in adult patients with acquired hemophilia A. It was initially approved in 2014. According to clinical trial data, the most common adverse reaction was the development of inhibitors to the porcine FVIII. Obizur is manufactured by Baxalta.40

Profilnine

Profilnine® (factor IX complex) is a complex containing FIX, factor II (FII), FX, and small amounts of FVII derived from pooled human plasma.41 The most recent iteration, labeled Profilnine SD, has been treated with a mixture of the organic solvent tri(n-butyl)phosphate 9*(TNBP) and the nonionic detergent polysorbate 80 to reduce the risk for the transmission of virus from pooled human plasma.41 Profilnine SD is indicated for the prevention and control of bleeding in patients with hemophilia B.41 Profilnine was initially approved in 1981 and is produced by Grifols.26,41 The adverse reactions that have been reported for Profilnine SD include urticaria, pyrexia, chills, nausea, vomiting, headache, somnolence, lethargy, flushing, and tingling.41

Rebinyn/Refixia 

Rebinyn® (nonacog beta pegol; coagulation factor IX [recombinant], glycoPEGylated) is indicated for the on-demand treatment and control, as well as the perioperative management, of bleeding in adults and children with hemophilia B. Rebinyn is a recombinant FIX protein that has been conjugated to a 40-kDa PEG group to slow its removal from the circulation. The most common adverse effects experienced by 1% or more of patients in clinical trials include itching and injection site reactions. Rebinyn was approved in the United States in 2017 and is produced by Novo Nordisk.42 Rebinyn is known as Refixia® in Europe.

Recombinate 

Recombinate™ (octocog alfa; antihemophilic factor [recombinant]) is a recombinant FVIII initially approved for use in the United States in 1992.26 Recombinate is indicated for the perioperative management, prevention, and control of episodes of bleeding in patients with hemophilia A. It is produced in culture from the Chinese Hamster Ovary (CHO) cell line before being processed and purified. The most common drug reactions include chills, flushing, rash, and epistaxis. Recombinate is manufactured by Baxalta.43

Rixubis

Rixubis® (coagulation factor IX [recombinant]) is a recombinant FIX produced by Baxalta and initially approved in 2013 by the FDA. It is indicated for the on-demand treatment and control of episodes of bleeding, the perioperative management of bleeding, and the routine prophylaxis of episodes of bleeding in patients with hemophilia B. The most common adverse reactions (>1%) seen in clinical trials include dysgeusia, extremity pain, and positivity for furin antibodies. Rixubis is produced in genetically modified CHO cells, and no human or animal proteins are added during manufacturing.44

Sevenfact

Sevenfact® (coagulation factor VIIa [recombinant]-jncw) is the most recently FDA-approved therapy (2020) for patients with hemophilia. Sevenfact is a recombinant FVIIa indicated for use in adults and adolescents age 12 and older who have hemophilia A or B with inhibitors. Sevenfact utilizes new recombinant DNA technology to produce FVII from genetically engineered rabbits. The rabbits are engineered to produce FVII in their mammary glands and secrete it in their milk. The milk is then processed to isolate the FVII and enzymatically convert it to FVIIa. Because of this process, Sevenfact is contraindicated in patients who are allergic to rabbits or rabbit proteins. Adverse events that occurred in 1% or more of patients during clinical trials include headache, dizziness, infusion site discomfort, infusion site hematoma, infusion related reaction, and fever. Sevenfact was developed by HEMA Biologics.45

Wilate 

Wilate® (von Willebrand factor/coagulation factor VIII complex [human]) is a combination of VWF and FVIII created from large pools of human plasma. Wilate is purified, doubly virus-inactivated, treated with a solvent/detergent mixture, and heat-treated to reduce the risk for infection. Wilate is produced by Octapharma and was FDA-approved in 2009. It is indicated for the on-demand treatment and control of bleeding and perioperative management in children and adults with von Willebrand disease. Wilate is also indicated for the routine prophylaxis or on-demand treatment and control of episodes of bleeding in adolescent and adult patients with hemophilia A. The most common adverse reactions to Wilate include hypersensitivity reactions, urticaria, and dizziness.46

Xyntha

Xyntha® (antihemophilic factor [recombinant]) is a recombinant factor VIII indicated for the on-demand treatment, perioperative management, and routine prophylaxis of bleeding in patients with hemophilia A. Xyntha temporarily replaces FVIII in patients with hemophilia A to aid in hemostasis. Xyntha is produced from genetically modified CHO cells before being processed and purified to remove any viruses or materials derived from animal or human sources. Xyntha was initially approved by the FDA in 2008 and is developed and distributed by Wyeth Biopharma, a subsidiary of Pfizer. The most frequent adverse reactions experienced by previously treated patients during clinical trials of Xyntha include headache, arthralgia, pyrexia, and cough.47

References

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Reviewed by Harshi Dhingra, MD, on 8/30/2021.