Antihemophilic Factor (Recombinant)

Class: Hemostatics
VA Class: BL500
CAS Number: 9001-27-8
Brands: Advate, Helixate FS, Kogenate FS, Recombinate, ReFacto, Xyntha

Introduction

Biosynthetic preparation (recombinant DNA origin) of antihemophilic factor (blood coagulation factor VIII).1 2 7 8 10 11 40 120 121 122 151 Structurally similar to endogenous human factor VIII and produces the same biologic effects as plasma-derived antihemophilic factor (human).1 2 3 4 7 8 9 10 40 49 50 69 77 120 121 122 151

Uses for Antihemophilic Factor (Recombinant)

Hemophilia A

Prevention and control of hemorrhagic episodes in patients with a deficiency of coagulation factor VIII (antihemophilic factor) associated with hemophilia A (congenital factor VIII deficiency; classic hemophilia);1 2 3 4 5 9 23 24 40 41 47 48 55 56 68 69 73 74 76 79 114 120 121 122 126 151 designated an orphan drug by FDA for this use.114

Maintenance of hemostasis in patients with hemophilia A undergoing minor surgery (e.g., tooth extraction, elective circumcision) or major surgery (e.g., bilateral osteotomies, thoracotomy, liver transplant, joint replacement, laparotomy, prostatectomy, lumbar puncture, bilateral inguinal herniorrhaphy).1 2 76 120 121 122 151

Because of a decreased risk of transmission of human viruses (e.g., HIV, hepatitis A virus [HAV], hepatitis B virus [HBV], hepatitis C virus [HCV]) and other transmissible disease agents (e.g., agents for Creutzfeldt-Jakob disease [CJD], variant CJD [vCJD]) compared with plasma-derived antihemophilic factor (human), the National Hemophilia Foundation’s Medical and Scientific Advisory Council (MASAC) and other experts recommend antihemophilic factor (recombinant) as the preferred preparation when antihemophilic factor therapy is indicated in patients with hemophilia A.3 4 8 9 14 40 49 52 55 69 73 76 79 110 Recombinant and plasma-derived preparations of antihemophilic factor are similar and produce comparable hemostatic effects.3 8 9 14 40 47 48 49 69 73 76

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Herbal and Dietary Supplements Deserve Your Attention

Antihemophilic factor replacement therapy generally is required in patients with mild to moderate hemophilia A who do not respond adequately to desmopressin or those with moderate to severe hemophilia A and factor VIII levels <5% of normal.56 68 74 79 95 96 126

Effective in the management of spontaneous or traumatic bleeding episodes (e.g., hemarthrosis, IM hematoma, soft tissue hemorrhage) or acute bleeding events (e.g., GI, retroperitoneal, tonsillar, ocular) in patients with hemophilia A.1 3 5 47 48 76

Has been used for routine prophylaxis (i.e., administration at regular intervals) to prevent or reduce joint hemorrhage in individuals with severe hemophilia A.2 120 121 126 135 136 139 140 143 151 Helixate FS and Kogenate FS are indicated for routine prophylaxis in children with no preexisting joint damage.120 121 MASAC recommends prophylaxis in patients with severe hemophilia A (factor VIII activity <1%) after careful consideration of risks versus benefits.129

Not indicated for treatment of von Willebrand disease.1 2 119 120 121 122 151

Hemophilia A with Inhibitors to Antihemophilic Factor

Prevention and treatment of bleeding in patients with hemophilia A who have developed relatively low levels of inhibitor antibodies (alloantibodies) to factor VIII.1 2 27 55 85 120 121 122 126 142 (See Development of Inhibitors to Antihemophilic Factor under Cautions.) May be effective in those who are low responders and whose inhibitor levels have historically remained <5–10 Bethesda units/mL.26 67 74 77 79 85 95 106 120 121 122 Some manufacturers state that antihemophilic factor may be effective in patients with inhibitor levels ≤10 Bethesda units/mL;122 other clinicians recommend use of these preparations in those with inhibitor levels <5 Bethesda units/mL.126 149 150

Has been used to induce immune tolerance as a long-term strategy to eradicate or suppress further inhibitor production.95 99 100 101 102 106 141 Such therapy eliminates risk of anamnesis with continued use of antihemophilic factor.95 99 100 101 102 While some experts state there is insufficient evidence to recommend use of immune tolerance therapy in patients with antihemophilic factor inhibitors, MASAC recommends such therapy for eradication of high-titer inhibitors.79

Generally should not be used for treatment of minor hemorrhage (e.g., cutaneous) in patients with inhibitors and a history of anamnestic response.95 106 108

Other therapeutic options for patients with inhibitors include bypassing agents such as anti-inhibitor coagulant complex (activated prothrombin complex concentrate [APCC]), factor VIIa (recombinant), or certain factor IX complex preparations (prothrombin complex concentrates [PCCs]).26 55 61 62 67 73 74 77 78 79 95 97 127 128 131 141 149 MASAC currently recommends use of a bypassing agent in hemophilia A patients with inhibitors to prevent or control bleeding in settings where antihemophilic factor preparations would otherwise be used, including before and after surgery and physical therapy.131

Management of hemophilia A in patients with inhibitors may be difficult and consultation with a hemophilia treatment center is strongly recommended.55 74 79 85 95 126

Acquired Hemophilia

Has been used to control bleeding in patients without hemophilia A who spontaneously acquire inhibitors (autoantibodies) to factor VIII.1 85 93 106 Autoantibodies are similar to but more heterogeneous than the alloantibodies that develop in patients with hemophilia A.28 31 55 61 67 88 90 93

Management of acquired hemophilia not well established.27 28 33 55 61 62 67 74 85 86 87 88 90 92 93 106 Antihemophilic factor (recombinant or human) may be effective in patients with low levels (e.g., ≤10 Bethesda units/mL) of acquired inhibitors.1 78 85 88 92 95 Other treatment options include immunosuppressive therapy, desmopressin, or bypassing agents.27 30 31 33 55 61 62 67 77 85 86 88 92 93 94 95 106 124 125

Antihemophilic Factor (Recombinant) Dosage and Administration

General

  • Initiate therapy under supervision of a clinician experienced in treating hemophilia A.1 2 120 121 122 151

  • Confirm deficiency of factor VIII prior to initiating therapy.1

  • Monitor factor VIII levels when clinically indicated to individualize dosage and assess response to therapy.1 2 120 121 122 126 151 (See Laboratory Monitoring under Cautions.)

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by slow IV injection or IV infusion over several minutes.1 2 3 4 120 121 122 151

Has been given as a continuous infusion.144 145 146

May be self-administered in medically supervised home treatment programs for hemophilia A.4 23 24 55 56 74 96 106 (See Advice to Patients.)

Instructions on reconstitution, dilution, and administration vary according to preparation; consult manufacturers’ labeling for specific information on each antihemophilic factor (recombinant) product.1 2 120 121 122 151

Reconstitution

Prior to reconstitution, warm lyophilized powders and diluents supplied by the manufacturers to room temperature (do not exceed 37°C).1 2 108 120 121 122 151

Reconstitute and administer drug using tubing, administration sets, vial adapters, and transfer devices provided by manufacturer.1 2 120 121 122 151 Use plastic syringes only; proteins such as antihemophilic factor may adhere to glass.1 122

Gently swirl solution to dissolve powder completely; do not shake vigorously.1 2 120 121 122 151

Keep reconstituted solutions at room temperature and administer within 3 hours after reconstitution.1 2 121 122 151

The surfactant (polysorbate 80) contained in reconstituted Xyntha solutions is known to increase the rate of extraction of diethylhexylphthalate (DEHP) from PVC containers and administration sets.151 The manufacturer states that this should be considered during preparation and administration of the drug, including storage time elapsed in a PVC container following reconstitution.151

Rate of Administration

Individualize infusion rates according to patient response.1 2 120 121 122 151 Monitor pulse before and during infusion.1 120 121 122 Slow infusion rate or temporarily discontinue therapy if there is a substantial increase in pulse rate.1 2 120 121 122

Advate: Administer over 5 minutes or less.122

Helixate FS, Kogenate FS: Administer over 1–15 minutes.120 121

Recombinate: Administer at a rate that ensures patient’s comfort; rates of ≤10 mL/minute suggested.1

ReFacto, Xyntha: Administer over several minutes; determine rate of administration by patient’s comfort level.2 151

Dosage

Dosage expressed in terms of international units (IU, units).1 2 120 121 122 151 One unit is approximately equivalent to amount of factor VIII activity in 1 mL of fresh pooled normal human plasma.72 95 120 121 122 151

Individualize dosage and duration of therapy based on degree of factor VIII deficiency, desired factor VIII levels, patient weight, type and severity of bleeding, and clinical response.1 2 55 120 121 122 151

Use the following calculations and dosage guidelines (based on the degree of hemorrhage or type of surgery) for administering the drug.1 2 106 120 121 122 151 These calculations and suggested dosage regimens are only approximations and should not preclude appropriate clinical monitoring and laboratory determinations of factor VIII levels.1 2 55 120 121 122 151 Perform serial assays of factor VIII (e.g., with one-stage clotting assay) at suitable intervals when clinically indicated to ensure that adequate levels have been attained and maintained.1 2 120 121 122 (See Laboratory Monitoring under Cautions.)

Careful control of the dose is especially important in cases of life-threatening bleeding or major surgery.1 120 121 122 If recommended dosage is ineffective in achieving expected factor VIII levels or if bleeding is not controlled, consider the possibility that inhibitors to antihemophilic factor may have developed.1 120 121 122 (See Development of Inhibitors to Antihemophilic Factor under Cautions.) Some patients with inhibitors (e.g., those with low-titer inhibitors) may require higher dosages.1 2 120 122 151

Administration of 1 unit/kg antihemophilic factor (recombinant) generally increases factor VIII activity by approximately 2%.2 48 55 74 126 151

Dosage required to achieve desired factor VIII levels:1 2 120 121 122 151

Dose (in units) = body weight (in kg) × 0.5 × desired factor VIII increase (in % of normal)

Approximate % increase in factor VIII levels expected from a given dosage:1 120 121 122

Expected factor VIII increase (in % of normal) = [dose (in units)/body weight (in kg)] × 2

Pediatric Patients

Hemophilia A
Advate
IV

Children ≤16 years of age with early hemarthrosis, mild muscle hemorrhage, or mild oral bleeding: Initially, 10–20 units/kg to achieve a peak postinfusion plasma factor VIII level of 20–40% of normal; repeat every 12–24 hours (8–24 hours for patients <6 years of age) for 1–3 days until bleeding episode resolves (indicated by pain relief) or healing achieved.122

Children ≤16 years of age with moderate bleeding into muscles, bleeding into oral cavity, definite hemarthrosis, or known trauma: Initially, 15–30 units/kg to achieve a peak postinfusion plasma factor VIII level of 30–60% of normal; repeat every 12–24 hours (8–24 hours for patients <6 years of age) for ≥3 days until bleeding episode resolves (indicated by pain relief) or healing achieved.122

Children ≤16 years of age with substantial GI bleeding; intracranial, intra-abdominal, or intrathoracic bleeding; CNS bleeding; bleeding in the retropharyngeal or retroperitoneal spaces or iliopsoas sheath; fractures; or head trauma: Initially, 30–50 units/kg to achieve a peak postinfusion plasma factor VIII level of 60–100% of normal; repeat every 8–24 hours (6–12 hours for patients <6 years of age) until bleeding episode resolves.122

Children ≤16 years of age undergoing minor surgery (e.g., tooth extraction): Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 60–100% of normal.122 Single bolus infusion of 30–50 units/kg is given within 1 hour of surgery.122 Infusions may be repeated every 12–24 hours as needed to control bleeding.122 Consider adjunctive therapy for dental procedures.122

Children ≤16 years of age undergoing major surgery (intracranial, intra-abdominal, or intrathoracic surgery; joint replacement): Initially, 40–60 units/kg to achieve pre- and postoperative factor VIII levels of 80–120% of normal (must verify 100% factor activity prior to surgery).122 Repeat dose every 8–24 hours (6–24 hours for patients <6 years of age) to desired factor VIII activity and state of wound healing.122

Helixate FS and Kogenate FS
IV

Children of any age with minor hemorrhage (e.g., early hemarthrosis, minor muscle or oral bleeding): Initially, 10–20 units/kg to achieve a plasma factor VIII level of 20–40% of normal; repeat if bleeding continues.120 121

Children of any age with moderate hemorrhage (bleeding into muscles or oral cavity, definite hemarthroses, known trauma): Initially, 15–30 units/kg to achieve a plasma factor VIII level of 30–60% of normal; repeat every 12–24 hours until bleeding resolves.120 121

Children of any age with majorhemorrhage (intracranial, intra-abdominal, or intrathoracic hemorrhages; GI bleeding; CNS bleeding; bleeding in retropharyngeal or retroperitoneal spaces or iliopsoas sheath), fractures, head trauma: Initially, 40–50 units/kg to achieve a plasma factor VIII level of 80–100% of normal; give additional doses of 20–25 units/kg every 8–12 hours until bleeding resolves.120 121

Children of any age undergoing minor surgery (e.g., tooth extraction): Initially, 15–30 units/kg to achieve a plasma factor VIII level of 30–60% of normal; repeat every 12–24 hours until bleeding resolves.120 121

Children of any age undergoing major surgery (e.g., tonsillectomy, inguinal herniotomy, synovectomy, total knee replacement, craniotomy, osteosynthesis, trauma): Initially, 50 units/kg preoperatively to achieve a plasma factor VIII level of 100% of normal (must verify 100% factor activity prior to surgery); may repeat after 6–12 hours initially, and for 10–14 days until healing complete.120 121

Recombinate
IV

Children of any age with early hemarthrosis, muscle hemorrhage, or oral bleeding: Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 20–40% of normal; repeat every 12–24 hours for 1–3 days until bleeding resolves (indicated by pain relief) or healing occurs.1

Children of any age with more extensive hemarthrosis, muscle hemorrhage, or hematoma: Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 30–60% of normal; repeat every 12–24 hours for ≥3 days until pain and disability resolve.1

Children of any age with life-threatening bleeding (e.g., head injury, throat bleeding, severe abdominal pain): Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 60–100% of normal; repeat every 8–24 hours until bleeding resolves.1

Children of any age undergoing minor surgery (including tooth extraction): Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 60–80% of normal.1 A single infusion in conjunction with oral antifibrinolytic therapy within 1 hour usually sufficient in about 70% of patients.1

Children of any age undergoing major surgery: Use appropriate dosage to achieve plasma pre- and postoperative factor VIII levels of 80–100% of normal.1 Repeat dose every 8–24 hours to desired factor VIII activity and state of wound healing.1

ReFacto and Xyntha
IV

Children of any age with minor hemorrhage (early hemarthrosis, minor muscle hemorrhage, oral bleeding): Use appropriate dosage to achieve a plasma factor VIII level of 20–40% of normal; repeat every 12–24 hours as needed until bleeding resolves.2 151 Give at least 1 day of therapy (depending on the severity of hemorrhage).2 151

Children of any age with moderate hemorrhage (muscle hemorrhage, mild trauma capitis, hemorrhage into oral cavity): Use appropriate dosage to achieve a plasma factor VIII level of 30–60% of normal; repeat infusions every 12–24 hours for 3–4 days until local hemostasis achieved.2 151

Children of any age with major hemorrhage (GI, intracranial, intra-abdominal, or intrathoracic hemorrhages) or fractures: Use appropriate dosage to achieve a plasma factor VIII level of 60–100% of normal; repeat every 8–24 hours until bleeding resolves.2 151

Children of any age undergoing minor surgery (e.g., tooth extraction): Use appropriate dosage to achieve a plasma factor VIII level of 30–60% of normal; repeat infusions every 12–24 hours for 3–4 days until local hemostasis achieved.2 151 For tooth extraction, a single infusion in conjunction with oral antifibrinolytic therapy within 1 hour may be sufficient.2 151

Children of any age undergoing major surgery: Use appropriate dosage to achieve a plasma factor VIII level of 60–100% of normal; repeat every 8–24 hours until local hemostasis and/or wound healing is achieved.2 151

Routine Prophylaxis
IV

Various dosing regimens have been recommended; optimal dosage remains to be established.120 121 126 129 136 139 Dosages of 25–40 units/kg every other day (minimum 3 times a week) usually recommended.120 121 126 136 139 151 MASAC states that an antihemophilic factor dosage of 25–50 units/kg 3 times a week or every other day usually is sufficient to maintain trough factor VIII concentrations >1% in between infusions.129 136

Institute prophylactic therapy early (e.g., 1–2 years of age) prior to onset of frequent bleeding.129 139

Evaluate patients periodically to determine continued need for prophylaxis.129

Adults

Hemophilia A
Advate
IV

Early hemarthrosis, mild muscle hemorrhage, or mild oral bleeding: Initially, 10–20 units/kg to achieve a peak postinfusion plasma factor VIII level of 20–40% of normal; repeat every 12–24 hours for 1–3 days until bleeding resolves (indicated by pain relief) or healing achieved.122

Moderate bleeding into muscles, bleeding into oral cavity, definite hemarthrosis, or known trauma: Initially, 15–30 units/kg to achieve a peak postinfusion plasma factor VIII level of 30–60% of normal; repeat every 12–24 hours for ≥3 days until bleeding resolves (indicated by pain relief) or healing achieved.122

Substantial GI bleeding; intracranial, intra-abdominal, intrathoracic, or CNS bleeding; bleeding in the retropharyngeal spaces or iliopsoas sheath; fractures; or head trauma: Initially, 30–50 units/kg to achieve a peak postinfusion plasma factor VIII level of 60–100% of normal; repeat every 8–24 hours until bleeding resolves.122

Minor surgery (e.g., tooth extraction): Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 60–100% of normal within 1 hour of surgery.122 Single bolus infusion of 30–50 units/kg is given within 1 hour of surgery.122 Infusions may be repeated every 12–24 hours as needed to control bleeding.122 Consider adjunctive therapy for dental procedures.122

Major surgery (intracranial, intra-abdominal, or intrathoracic surgery; joint replacement): Initially, 40–60 units/kg to achieve pre- and postoperative plasma factor VIII levels of 80–120% of normal (must verify 100% factor activity prior to surgery).122 Repeat dose every 8–24 hours to desired factor VIII activity and state of wound healing.122

Helixate FS and Kogenate FS
IV

Minor hemorrhage (e.g., early hemarthrosis, minor muscle or oral bleeding): Initially, 10–20 units/kg to achieve factor VIII level of 20–40% of normal; repeat if bleeding continues.120 121

Moderate hemorrhage (bleeding into muscles or oral cavity, definite hemarthroses, known trauma): Initially, 15–30 units/kg to achieve a factor VIII level of 30–60% of normal; repeat every 12–24 hours until bleeding resolves.120 121

Major hemorrhage (intracranial, intra-abdominal, or intrathoracic hemorrhages; GI or CNS bleeding; bleeding in retropharyngeal or retroperitoneal spaces or iliopsoas sheath), fractures, head trauma: Initially, 40–50 units/kg to achieve a plasma factor VIII level of 80–100% of normal; give additional doses of 20–25 units/kg every 8–12 hours until bleeding resolves.120 121

Minor surgery (including tooth extraction): Initially, 15–30 units/kg to achieve a plasma factor VIII level of 30–60% of normal; repeat every 12–24 hours until bleeding resolves.120 121

Major surgery (e.g., tonsillectomy, inguinal herniotomy, synovectomy, total knee replacement, craniotomy, osteosynthesis, trauma): Initially, 50 units/kg preoperatively to achieve a factor VIII level of 100% of normal (must verify 100% factor activity prior to surgery); may repeat every 6–12 hours initially, and for 10–14 days until healing complete.120 121

Recombinate
IV

Early hemarthrosis, muscle hemorrhage, or oral bleeding: Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 20–40% of normal; repeat every 12–24 hours for 1–3 days until bleeding resolves (indicated by pain relief) or healing occurs.1

More extensive hemarthrosis, muscle hemorrhage, or hematoma: Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 30–60% of normal; repeat every 12–24 hours for ≥3 days until pain and disability resolve.1

Life-threatening bleeding (e.g., head injury, throat bleeding, severe abdominal pain): Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 60–100% of normal; repeat every 8–24 hours until bleeding resolves.1

Minor surgery (including tooth extraction): Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 60–80% of normal.1 A single infusion in conjunction with oral antifibrinolytic therapy within 1 hour usually sufficient in about 70% of patients.1

Major surgery: Use appropriate dosage to achieve pre- and postoperative plasma factor VIII levels of 80–100% of normal.1 Repeat dose every 8–24 hours to desired factor VIII level and state of wound healing.1

ReFacto and Xyntha
IV

Minor hemorrhage (early hemarthrosis, minor muscle hemorrhage, oral bleeding): Use appropriate dosage to achieve a plasma factor VIII level of 20–40% of normal; repeat every 12–24 hours until bleeding resolves.2 151 Give at least 1 day of therapy (depending on the severity of hemorrhage).2 151

Moderate hemorrhage (muscle hemorrhage, mild trauma capitis, hemorrhage into oral cavity): Use appropriate dosage to achieve a plasma factor VIII level of 30–60% of normal; administer infusions every 12–24 hours for 3–4 days until local hemostasis achieved.2 151

Major hemorrhage (GI, intracranial, intra-abdominal, or intrathoracic hemorrhages), fractures: Use appropriate dosage to achieve a plasma factor VIII level of 60–100% of normal; repeat every 8–24 hours until local hemostasis achieved.2 151

Minor surgery (e.g., tooth extraction): Use appropriate dosage to achieve a plasma factor VIII level of 30–60% of normal; administer infusions every 12–24 hours for 3–4 days until local hemostasis achieved.2 151 For tooth extraction, a single infusion in conjunction with oral antifibrinolytic therapy within 1 hour may be sufficient.2 151

Major surgery: Use appropriate dosage to achieve a factor VIII level of 60–100% of normal; repeat every 8–24 hours until local hemostasis and wound healing achieved.2 151

Routine Prophylaxis
IV

Various dosing regimens have been recommended; optimal dosage remains to be established.120 121 126 129 136 139 Dosages of 25–40 units/kg every other day (minimum 3 times a week) usually recommended.120 121 126 136 139 151 MASAC states that an antihemophilic factor dosage of 25–50 units/kg 3 times a week or every other day usually is sufficient to maintain trough factor VIII concentrations >1% in between infusions.129 136

Evaluate patients periodically to determine continued need for prophylaxis.129

Prescribing Limits

Pediatric Patients

Hemophilia A
IV

Maximum infusion rate of 10 mL/minute.1 122

Adults

Hemophilia A
IV

Maximum infusion rate of 10 mL/minute.1 122

Cautions for Antihemophilic Factor (Recombinant)

Contraindications

  • Known hypersensitivity to antihemophilic factor (recombinant) or any ingredient in the formulation.1 120 121 122

  • Known hypersensitivity to murine or hamster proteins (Advate, Helixate FS, KogenateFS, Recombinate, ReFacto)1 2 120 121 122 or bovine proteins (Recombinate).1

  • Although the manufacturer of Xyntha states that there are no known contraindications to use of the drug, patients receiving this drug may develop hypersensitivity to hamster protein, which is present in trace amounts in the preparation.151 (See Antibody Formation to Trace Animal Proteins under Cautions.)

Warnings/Precautions

Warnings

Development of Inhibitors to Antihemophilic Factor

Risk of development of inhibitors (alloantibodies) to factor VIII following antihemophilic factor therapy.1 2 4 5 13 29 39 46 69 76 89 120 121 122 126 142 151 Inhibitors reported in about 10–30% of patients with hemophilia A receiving factor concentrates.1 4 5 120 121 122 126 136

Risk of inhibitor development appears to correlate with the severity of hemophilia A and extent of exposure to the drug.1 27 57 59 61 62 89 95 98 101 102 104 Other genetic factors also may play a role.1 26 27 46 55 58 59 61 62 95

Inhibitors usually identified in patients <20 years of age; those <10 years of age appear to be at greatest risk.27 57 58 59 62 63 95 98 104 106 Probability of developing inhibitors is highest during the first 20 days of exposure to the drug.1 106 Inhibitors more common in previously untreated patients, but also reported in previously treated patients.120 121 122 151 Inhibitors may diminish or neutralize response to therapy.1 2 142 Anamnestic response and increased levels of inhibitor possible with continued use of drug.1

Monitor for development of inhibitors during treatment with clinical observation and appropriate laboratory tests.1 2 27 28 55 65 67 74 91 95 120 121 122 151 Perform quantitative test (e.g., Bethesda assay) for inhibitors routinely (e.g., every 3–6 months) and immediately prior to surgery.23 55 56 60 66 74 106 126 The World Federation of Hemophilia recommends that children be screened every 3–12 months or every 10–20 days following drug exposure, whichever occurs first.126 Consider possibility that inhibitors may have developed in patients who fail to respond to adequate dosages of antihemophilic factor (recombinant) or those with unusually prolonged aPTT.1 27 61 65 74 95 120 121 122 142 151

Consider several factors (e.g., severity and location of bleeding, type [low- or high-responding] and titer of inhibitors, history of anamnestic antibody response, previous response to these preparations) when treating patients with inhibitors.26 27 55 62 67 74 77 79 85 95 126 127 Consultation with a hemophilia treatment center strongly recommended.79 126 Carefully monitor such patients, especially when surgical procedures indicated.1 55 60 74 79 85 95 126 Higher than recommended dosages may be required to achieve hemostasis in patients with inhibitors.1 2 120 121 122 151

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., hives, generalized urticaria, tightness of the chest, wheezing, hypotension, dizziness, rash, flushing, anaphylaxis) reported with antihemophilic factor (recombinant) preparations.1 120 121 122 Systemic hypersensitivity reactions, including bronchospastic reactions, hypotension, shock, and/or anaphylaxis, reported with Advate, Helixate FS, Kogenate FS, and Recombinate.1 120 121 122

If hypersensitivity reaction occurs, discontinue drug immediately and initiate appropriate therapy (e.g., epinephrine, oxygen).1 2 120 121 122 151

Antibody Formation to Trace Animal Proteins

Some preparations of antihemophilic factor (recombinant) contain trace amounts of animal proteins (Advate, Helixate FS, Kogenate FS, Recombinate, ReFacto, Xyntha), which may stimulate antibody production and cause hypersensitivity reactions.1 2 120 121 122 151 Antibodies to such animal proteins reported in a few patients; effect on clinical response not fully elucidated.40 45

Latex Sensitivity

Packaging components for some preparations (e.g., Recombinate) may contain natural latex proteins; take appropriate precautions if injection is handled by or administered to individuals with a history of natural latex sensitivity.1 147 148

General Precautions

Risk of Transmissible Agents

Since antihemophilic factor (recombinant) preparations are not prepared using pooled human plasma, they are associated with a decreased risk of transmission of human viruses compared with plasma-derived antihemophilic factor (human).3 4 8 9 14 40 49 52 55 69 73 76 79 110

Theoretical but remote risk of transmitting other viruses (e.g., those associated with mammalian cell cultures employed in manufacturing).40 49 79 106 108 110 No such transmission reported to date.79 110

Laboratory Monitoring

Monitor plasma factor VIII levels when clinically indicated to guide dosing and ensure adequate therapeutic response.1 2 55 120 121 122 151

Monitor for development of factor VIII inhibitors during treatment, prior to surgery, and when switching between different factor VIII preparations.1 27 28 55 65 67 74 91 95 122 126 If expected plasma factor VIII levels are not attained or bleeding is not controlled with an expected dose, perfom appropriate laboratory test (Bethesda assay) to detect and measure concentrations of factor VIII inhibitors.1 120 121 122 (See Development of Inhibitors to Antihemophilic Factor under Cautions.)

Sucrose Content

Helixate FS (250-, 500-, and 1000-unit vials) and Kogenate FS (250-, 500-, and 1000-unit vials) contain 28 mg of sucrose per vial, while Helixate FS (2000- and 3000-unit vials) and Kogenate FS (2000- and 3000-unit vials) contain 52 mg of sucrose.120 121 The manufacturers state that IV administration of these injections will not affect blood glucose concentrations.120 121

Specific Populations

Pregnancy

Category C.1 2 120 121 122 151

Lactation

Not known whether antihemophilic factor (recombinant) is distributed into human milk.1 120 121 122 151 Use only if clinically indicated.2 120 121

Pediatric Use

Helixate FS, Kogenate FS, Recombinate, ReFacto: Have been used in children of all ages without any unusual adverse effects.1 2 4 5 47 120 121 122 Helixate FS and Kogenate FS also indicated for routine prophylactic treatment in pediatric patients with no preexisting joint damage.120 121

Advate: Indicated for use in children 0–16 years of age.122

Xyntha: Has been evaluated in a small number of previously treated pediatric patients 12–16 years of age with hemophilia A; pharmacokinetic parameters in these patients appeared to be similar to those obtained in adults.151 A study in previously treated patients <6 years of age is ongoing.151

Infusion-related reactions (e.g., urticaria, flushing, erythema) have occurred rarely in previously untreated neonates and children following administration of recombinant factor VIII.5 106 108

Clearance of factor VIII is higher in children than in adults, resulting in shorter half-life and lower recovery of factor VIII; consider these pharmacokinetic differences when selecting dosage or monitoring factor VIII levels in pediatric patients.120 121 122

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.2 120 121 122 151 Individualize dosage.2 120 121 122 151

Common Adverse Effects

Advate: Development of inhibitors (reported mainly in previously untreated patients), nausea, vomiting, diarrhea, constipation, nasal congestion, rhinorrhea, sinusitis, sore throat, upper respiratory infection, earache, ear infection, nasopharyngitis, pharyngolaryngeal pain, flu-like symptoms, chest discomfort/pain, fever, accident and injury (limb), falling, joint sprain and swelling, joint pain/swelling, extremity pain, headache, fatigue/malaise, limb injury, cough, procedural pain.122

Helixate FS, Kogenate FS: Development of inhibitors (reported in previously untreated or minimally treated patients), skin-related hypersensitivity reactions (e.g., rash, pruritus, urticaria), infusion site reactions (e.g., inflammation, pain), infection associated with a central venous access device.120 121

Recombinate: Chills, flushing, rash, epistaxis.1

Refacto: Development of inhibitors (reported in previously untreated patients), headache, nausea, dyspnea, pruritus, fever.2

Xyntha: Headache, nausea, diarrhea, asthenia, pyrexia, vomiting.151

Interactions for Antihemophilic Factor (Recombinant)

No formal drug interaction studies to date.122 133 134 137 138 No known drug interactions reported to date with Advate or Xyntha.122 151

Antihemophilic Factor (Recombinant) Pharmacokinetics

Absorption

Bioavailability

Following IV administration, peak plasma concentrations generally occur 10–15 minutes after end of infusion; may occur up to 1–2 hours later.132

Plasma Concentrations

Following IV infusion over 5–15 minutes, plasma concentrations of factor VIII increase by approximately 0.02–0.025 unit/mL per unit/kg administered.132

Distribution

Extent

Circulates in plasma; minimally distributed (about 14%) outside the vascular system.132

Plasma Binding

Binds noncovalently to von Willebrand factor; stabilizes and protects factor VIII from degradation.132

Elimination

Metabolism

Metabolic fate not fully determined.43 48

Elimination Route

May be partly eliminated via reticuloendothelial system.132

Half-life

Approximately 8–15 hours.1 2 120 121 122 151

Special Populations

Compared with adults, children have higher clearance, lower recovery of factor VIII, and a shorter factor VIII half-life; more frequent or larger doses may be necessary to adjust for these pharmacokinetic differences.120 121 122

Stability

Storage

Parenteral

Powder for IV Infusion

Advate: 2–8°C (avoid freezing to prevent damage to the diluent vial).122 May store at room temperature ≤30°C up to 6 months; do not return drug to refrigerator after storage at room temperature.122 Do not use beyond expiration date.122 Do not refrigerate after reconstitution; use solution within 3 hours of reconstitution.122 Discard any unused portion of the drug.122

Helixate FS: 2–8°C (avoid freezing); may store at room temperature ≤25°C up to 3 months.121 Do not return to refrigerator after storage at room temperature.121 Do not use beyond expiration date.121 Protect from extreme exposure to light and store lyophilized powder in the carton prior to use.121 Use solution within 3 hours of reconstitution.121

Kogenate FS: 2–8°C (avoid freezing); may store at room temperature ≤25°C up to 3 months.120 Do not return to refrigerator after storage at room temperature.120 Do not use beyond expiration date.120 Protect from extreme exposure to light and store lyophilized powder in the carton prior to use.120 Use solution within 3 hours of reconstitution.120

Recombinate: 2–8°C (avoid freezing to prevent damage to the diluent vial); may store at room temperature ≤30°C.1 Do not use beyond expiration date.1 Do not refrigerate after reconstitution; use solution within 3 hours of reconstitution.1

ReFacto: 2–8°C (avoid freezing to prevent damage to the diluent vial); may store at room temperature ≤25°C up to 3 months.2 Do not use beyond expiration date.2 Protect from extreme exposure to light.2 Use solution within 3 hours of reconstitution.2

Xyntha: 2–8°C; may store at room temperature ≤25°C up to 3 months.151 Do not return to refrigerator after storage at room temperature.151 Do not use beyond expiration date.151 May store prefilled diluent syringe at 2–25°C (avoid freezing to prevent damage).151 Protect from prolonged exposure to light.151 Use solution within 3 hours of reconstitution.151

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Formal compatibility studies have not been performed; manufacturer states antihemophilic factor (recombinant) should not be administered in the same tubing or container with other drugs.2 134 138 151

Actions

  • Antihemophilic factor (recombinant) is structurally similar to and appears to produce the same pharmacologic effects as endogenous human blood coagulation factor VIII.1 3 4 7 8 9 10 12 40 49 50 69 77

  • Factor VIII is essential for blood clotting and maintenance of hemostasis.12 23 24 73 74 82 95 96 151

  • Patients with hemophilia A have decreased levels of endogenous factor VIII or dysfunctional factor VIII, resulting in a hemorrhagic tendency and clinical manifestations such as bleeding into soft tissues, muscles, and weight-bearing joints.1 4 12 23 24 41 69 73 95 96 151 Therefore, replacement therapy with exogenous antihemophilic factor is necessary.151

  • Clinical severity and frequency of bleeding in patients with hemophilia A correlate with the degree of deficiency of factor VIII activity.23 24 41 73 74 Patients with mild hemophilia A generally have >5% of normal activity, those with moderate disease generally have 1–5% of normal activity, and those with severe disease have <1% of normal activity.23 24 95

  • Administration of antihemophilic factor (recombinant) to patients with hemophilia A results in increased plasma levels of factor VIII and temporarily corrects the coagulation defect in these patients.1 2 5 9 40 47 55 68 69 73 120 121 122 151

  • Although similar in structure and pharmacologic effects to plasma-derived human factor VIII,1 2 3 4 7 8 9 10 40 49 50 69 77 120 121 122 antihemophilic factor (recombinant) is associated with substantially reduced risk of transmission of blood-borne human viruses (e.g., HIV, HAV, HBV, HCV).3 4 8 9 14 40 49 50 68 69 73 76 79 110 122

  • Prepared by recombinant DNA technology in a mammalian cell expression system using different methods to express, isolate, harvest, and purify factor VIII.1 2 7 8 10 11 40 120 121 122 151

Advice to Patients

  • Importance of reading manufacturer’s patient information prior to therapy.1

  • Risk of developing inhibitors to factor VIII; importance of patients informing clinician if they experience a lack of clinical response to antihemophilic factor replacement therapy, which may be a sign of inhibitor development.1 2 120 121 122 151

  • Importance of discontinuing therapy and immediately seeking emergency supportive or resuscitative treatment if hives, rash, urticaria, chest tightness, hypotension, wheezing, anaphylaxis, or other manifestations of hypersensitivity reactions develop.1 2 120 121 122 151

  • Importance of consulting clinician prior to travel; advise patients to bring an adequate supply of antihemophilic factor (recombinant) with them while traveling.120 121 122

  • Importance of initiating self-administration only after appropriate training is provided by a clinician or hemophilia center.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 2 120 121 122 151

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 2 120 121 122 151

  • Importance of informing patients of other important precautionary information.1 2 120 121 122 151 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Antihemophilic Factor (Recombinant)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use

number of units indicated on label

Advate Plasma/Albumin Free Method (with sterile water for injection diluent; available with needleless transfer device)

Baxter

Helixate FS (with sucrose and sterile water for injection diluent; available with transfer and filter needles and an administration set)

CSL Behring, (manufactured by Bayer)

Kogenate FS (with sucrose and sterile water for injection diluent; available with transfer and filter needles and an administration set)

Bayer

Recombinate (with albumin [human] and sterile water for injection diluent; available with transfer and filter needles)

Baxter

ReFacto (with albumin [human] and sodium chloride for injection diluent; available with alcohol swabs, transfer and filter needles, and an administration set)

Wyeth

Xyntha (with 4 mL prefilled syringe containing 0.9% sodium chloride diluent; available with vial adapter, alcohol swabs, bandage, gauze, and an administration set)

Wyeth

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions April 6, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Baxter Healthcare Corporation. Recombinate antihemophilic factor (recombinant) prescribing information. Westlake Village, CA; 2010 Marl.

2. Wyeth. ReFacto antihemophilic factor (recombinant) prescribing information. Philadelphia, PA; 2007 Dec.

3. White GC II, McMillan CW, Kingdon HS et al. Use of recombinant antihemophilic factor in the treatment of two patients with classic hemophilia. N Engl J Med. 1989; 320:166-70. [IDIS 249928] [PubMed 2492083]

4. Schwartz RS, Abildgaard CF, Aledort LM et al and the Recombinant Factor VIII Study Group. Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med. 1990; 323:1800-5. [IDIS 275524] [PubMed 2123300]

5. Lusher JM, Arkin S, Abildgaard CF et al and the Kogenate Previously Untreated Patient Study Group. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A: safety, efficacy, and development of inhibitors. N Engl J Med. 1993; 328:453-9. [IDIS 309583] [PubMed 8421474]

7. Kaufman RJ. Insight into the structure, function, and biosynthesis of factor VIII through recombinant DNA technology. Ann Hematol. 1991; 63:155-65. [PubMed 1932292]

8. Bray GL. Recent advances in the preparation of plasma-derived and recombinant coagulation factor VIII. J Pediatr. 1990; 117:503-7. [IDIS 302270] [PubMed 2118176]

9. Sharrer I. Current status of a recombinant antihemophilic factor VIII clinical trial organized by Baxter. Ann Hematol. 1991; 63:172-6. [PubMed 1932294]

10. Griffith M, Kingdon H, Liu SL et al. In-process controls and characterization of recombinate antihemophilic factor (recombinant). Ann Hematol. 1991; 63:166-71. [PubMed 1932293]

11. Kaufman RJ, Wasley LC, Dorner AJ. Synthesis, processing, and secretion of recombinant human factor VIII expressed in mammalian cells. J Biolog Chem. 1988; 263:6352-62.

12. White GC II, Shoemaker CB. Factor VIII gene and hemophilia A. Blood. 1989; 73:1-12. [PubMed 2491949]

13. Cohen A, Butler R. Recombinant factor VIII in hemophilia. N Engl J Med. 1991; 324:1515-6. [PubMed 1902552]

14. Walker I, Poon MC. Recombinant factor VIII concentrate. Lancet. 1992; 339:61-2. [IDIS 290656] [PubMed 1345984]

15. Gjerset GF, Mosley JW. Safety of factor VIII. Ann Intern Med. 1991; 114:171. [IDIS 276613] [PubMed 1898586]

16. Normann A, Graff J, Gerritzen A et al. Detection of hepatitis A virus RNA in commercially available factor VIII preparation. Lancet. 1992; 340:1232. [IDIS 305121] [PubMed 1359306]

17. Gerritzen A, Schneweis KE, Brackmann HH et al. Acute hepatitis A in haemophiliacs. Lancet. 1992; 340:1231-2. [IDIS 305120] [PubMed 1359305]

18. Schulman S, Lindgren AC, Petrini P et al. Transmission of hepatitis C with pasteurised factor VIII. Lancet. 1992; 340:305-6. [IDIS 300223] [PubMed 1353214]

19. Wyld PJ, Dawson KP. The management of patients with bleeding disorders. N Z Med J. 1984; 97:118-9. [IDIS 182865] [PubMed 6424072]

20. Pierce GF, Lusher JM, Brownstein AP et al. The use of purified clotting factor concentrates in hemophilia: influence of viral safety, cost, and supply on therapy. JAMA. 1989; 261:3434-8. [IDIS 255548] [PubMed 2498537]

21. Brettler DB, Levine PH. Factor concentrates for treatment of hemophilia: which one to choose? Blood. 1989; 73:2067-73.

22. Roberts HR. The treatment of hemophilia: past tragedy and future promise. N Engl J Med. 1989; 321:1188-90. [IDIS 259995] [PubMed 2507918]

23. Handin RI. Disorders of coagulation and thrombosis. In: Isselbacher KJ, Braunwald E, Wilson JD et al, eds. Harrison’s principles of internal medicine, 13th ed. New York: McGraw-Hill, Inc.; 1994:1804-8.

24. Mosher DF. Disorders of blood coagulation. In: Wyngaarden JB, Smith LH Jr, Bennett JC, eds. Cecil textbook of medicine. Philadelphia: WB Saunders Company, 1988:1060-9.

25. Cohen H, Kernoff PBA. Plasma, plasma products, and indications for their use. Br Med J. 1990; 300:803-6.

26. Anon. Anti-factor-VIII inhibitors in haemophilia Lancet. 1989; 2:363-4.

27. Kasper CK. Treatment of factor VIII inhibitors. In: Coller BS, ed. Progress in hemostasis and thrombosis, Vol. 9. Philadelphia: WB Saunders Company, 1989:57-86.

28. Kessler CM. An introduction to factor VIII inhibitors: the detection and quantitation. Am J Med. 1991; 91(Suppl 5A):1-5S. [IDIS 285702] [PubMed 1858817]

29. Fulcher CA. Immunochemistry of factor VIII:C inhibitor antibodies. Am J Med. 1991; 91(Suppl 5A):6-8S.

30. Hultin MB. Acquired inhibitors in malignant and nonmalignant disease states. Am J Med. 1991; 91(Suppl 5A):9-13S.

31. Green D. Cytotoxic suppression of acquired factor VIII:C inhibitors. Am J Med. 1991; 91(Suppl 5A):14-19S.

32. Hoyer LW. Future approaches to factor VIII inhibitor therapy. Am J Med. 1991; 91(Suppl 5A):40-4S.

33. Kessler CM. Conclusion. Am J Med. 1991; 91(Suppl 5A):45-7S. [PubMed 1858828]

34. Bergman GE. Factor VIII inhibitors. Lancet. 1993; 342:1109. [PubMed 8105322]

35. Addiego JE. Factor VIII inhibitors. Lancet. 1993; 342:1109.

36. Allard S, Philpott N, Bevan DH. Factor VIII inhibitors. Lancet. 1993; 342:1109-10. [IDIS 321641] [PubMed 8105323]

37. Ghirardini A, Schinaia N. Factor VIII inhibitors. Lancet. 1993; 342:1110. [IDIS 321642] [PubMed 8105325]

38. Peerlinck K, Vermylen J, Rosendaal F et al. Factor VIII inhibitors. Lancet. 1993; 342:1110. [IDIS 321643] [PubMed 8105324]

39. Schwartz R. Recombinant factor VIII in hemophilia. N Engl J Med. 1991; 324:1516. [PubMed 2023617]

40. Mannucci PM. Modern treatment of hemophilia: from the shadows towards the light. Thromb Haemost. 1993; 70:17-23. [PubMed 8236096]

41. Büchel KH. Recombinant factor VIII: an introduction. Semin Hematol. 1991; 28(Suppl 1):1-4.

42. Fournel MA. Preclinical and in vitro studies of recombinant factor VIII. Semin Hematol. 1991; 28(Suppl 1):22-6. [PubMed 1908122]

43. Harrison JFM, Bloom AL, Abildgaard CF for the rFactor VIII Clinical Trial Group. The pharmacokinetics of recombinant factor VIII. Semin Hematol. 1991; 28(Suppl 1):29-35. [PubMed 1908124]

44. Brackman HH, Egli JE, Van Loo B for the rFactor VIII Clinical Trial Group. Clinical safety of recombinant factor VIII. Semin Hematol. 1991; 28(Suppl 1):37-42. [PubMed 1908125]

45. Abildgaard CF for the rFactor VIII Clinical Trial Group. Immunologic safety of recombinant factor VIII. Semin Hematol. 1991; 28(Suppl 1):44.

46. Brettler DB. Comments on the development of inhibitor antibodies in patients using recombinant factor VIII concentrates. Semin Hematol. 1991; 28(Suppl 1):45-6. [PubMed 1908128]

47. Arkin S, Rose E, Forster A for the rFactor VIII Clinical Trial Group. Clinical efficacy of recombinant factor VIII. Semin Hematol. 1991; 28(Suppl 1):47-51. [PubMed 1908129]

48. Schwartz RS, Rousell RH. A summary of the world-wide clinical investigations of recombinant factor VIII. Semin Hematol. 1991; 28(Suppl 1):53-4. [PubMed 1908130]

49. Aronson DL. The current status of recombinant human factor VIII. Semin Hematol. 1991; 28(Suppl 1):55-6. [PubMed 1908131]

50. Klein U. Production and characterization of recombinant factor VIII. Semin Hematol. 1991; 28(Suppl 1):17-21. [PubMed 1908121]

51. Chan SY, Lembach KJ. Genetic characterization of recombinant BHK-21 cells expressing factor VIII. Semin Hematol. 1991; 28(Suppl 1):10-6. [PubMed 1908120]

52. Hilgartner MW. The need for recombinant factor VIII: historical background and rationale. Semin Hematol. 1991; 28(Suppl 1):6-9. [PubMed 1908132]

53. Brackmann HH, Egli H. Acute hepatitis B infection after treatment with heat-inactivated factor VIII concentrate. Lancet. 1988; 2:967. [IDIS 247324] [PubMed 2902416]

54. Robinson SM, Schwinn H, Smith A. Clotting factors and hepatitis A. Lancet. 1992; 340:1465. [IDIS 307252] [PubMed 1360575]

55. Ratnoff OD, Forbes CD, eds. Disorders of hemostasis. Philadelphia: WB Saunders Company; 1991:164-266.

56. Lusher JM. The hemophilias. In: Brain MC, Carbone PP, eds. Current therapy in hematology-oncology. 4th ed. Philadelphia: BC Decker; 1992:93-100.

57. Ehrenforth S, Kreuz W, Scharrer I et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet. 1992; 339:594-8. [PubMed 1347102]

58. Peerlinck K, Arnout J, Gilles JG et al. A higher than expected incidence of factor VIII inhibitors in multitransfused haemophilia A patients treated with an intermediate purity pasteurized factor VIII concentrate. Thromb Haemost. 1993; 69:115-8. [PubMed 8456422]

59. McMillan CW, Shapiro SS, Whitehurst D et al and the Hemophilia Study Group. The natural history of factor VIII:C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors. Blood. 1988; 71:344-8. [PubMed 3122859]

60. Rosendaal FR, Hieuwenhuis HK, van den Berg HM et al. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in the Netherlands. Blood. 1993; 81:2180-6. [PubMed 8471777]

61. Lusher JM. Factor VIII inhibitors: etiology, characterization, natural history, and management. Ann N Y Acad Sci. 1987; 509:89-101. [PubMed 3122623]

62. Kasper CK. Complications of hemophilia A treatment: factor VIII inhibitors. Ann N Y Acad Sci. 1991; 614:97-105. [PubMed 1902643]

63. Schwarzinger I, Pabinger I, Korninger C et al. Incidence of inhibitors in patients with severe and moderate hemophilia A treated with factor VIII concentrates. Am J Hematol. 1987; 24:241-5. [PubMed 3103425]

64. Aledort LM. World registry on factor VIII inhibitor patients: why? Semin Hematol. 1993; 30(Suppl 1):7-9.

65. Goldsmith JC. Diagnosis of factor VIII versus nonspecific inhibitors. Semin Hematol. 1993; 30(Suppl 1):3-6. [PubMed 8480195]

66. Goldsmith JC. Introduction: the challenges of inhibitor patient care. Semin Hematol. 1993; 30(Suppl 1):1-2. [PubMed 8480191]

67. Macik BG. Treatment of factor VIII inhibitors: products and strategies. Semin Thromb Hemost. 1993; 19:13-24. [PubMed 8456320]

68. Gill JC. Therapy of factor VIII deficiency. Semin Thromb Hemost. 1993; 19:1-12. [PubMed 8456319]

69. Limentani SA, Roth DA, Furie BC et al. Recombinant blood clotting proteins for hemophilia therapy. Semin Thromb Hemost. 1993; 19:62-72. [PubMed 8456325]

70. Fricke WA, Lamb MA. Viral safety of clotting factor concentrates. Semin Thromb Hemost. 1993; 19:54-61. [PubMed 8456324]

71. Scott JP, Montgomery RR. Therapy of von Willebrand disease. Semin Thromb Hemost. 1993; 19:37-47. [PubMed 8456322]

72. Barrowcliffe TW. Standardization and assay. Semin Thromb Hemost. 1993; 19:73-9. [PubMed 8456326]

73. Lusher JM, Warrier I. Hemophilia and related conditions. In: Rakel RE, ed. Conn’s current therapy. Philadelphia: WB Saunders Company; 1994:361-72.

74. Hemostatics. In: Drug Evaluations Annual 1994. Chicago: American Medical Association:777-801.

75. Mannucci PM, Brettler DB, Aledort LM et al. Immune status of human immunodeficiency virus seropositive and seronegative hemophiliacs infused for 3.5 years with recombinant factor VIII. Blood. 1994; 83:1958-62. [IDIS 327577] [PubMed 7908234]

76. Bray GL, Gomperts ED, Courter S et al and the Recombinant Study Group. A multicenter study of recombinant factor VIII (Recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood. 1994; 83:2428-35. [IDIS 328696] [PubMed 8167332]

77. Nabi. Autoplex T anti-inhibitor coagulant complex heat treated prescribing information. Glendale, CA; 1998 Apr.

78. Speywood. Hyate:C antihemophilic factor (porcine) prescribing information. Milford, MA; 1998 Mar.

79. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders (revised April 2010). MASAC recommendation #195. From National Hemophilia Foundation website ().Accessed 14 August 2010.

82. Zimmerman TS. Factor VIII/von Willebrand factor: structure and function. Ann N Y Acad Sci. 1991; 614:53-9.

83. Hilgartner MW. Changes in CD4 count relative to product usage: findings from the transfusion safety study. Semin Hematol. 1993; 30:7-9. [PubMed 7903481]

84. Seremetis SV for the Monoclate Study Group. Very-high-purity versus intermediate-purity factor VIII in human immunodeficiency virus-positive hemophiliacs: conclusions of a prospective 3-year study. Semin Hematol. 1993; 30(Suppl 5):10-3.

85. Kessler CM. Factor VIII inhibitor—an algorithmic approach to treatment. Semin Hematol. 1994; 31(Suppl 4):33-6. [PubMed 7939771]

86. Morrison AE, Ludlam CA, Kessler C. Use of porcine factor VIII in the treatment of patients with acquired hemophilia. Blood. 1993; 81:1513-20. [IDIS 312029] [PubMed 8453098]

87. Lottenberg R, Kentro TB, Kitchens CS. Acquired hemophilia: a natural history study of 16 patients with factor VIII inhibitors receiving little or no therapy. Arch Intern Med. 1987; 147:1077-81. [PubMed 3109341]

88. Ludlam CA, Morrison AE, Kessler C. Treatment of acquired hemophilia. Semin Hematol. 1994; 31(Suppl 4):16-9. [PubMed 7939767]

89. Briët E, Rosendaal FR. Inhibitors in hemophilia: are some products safer? Semin Hematol. 1994; 31(Suppl 4):11-5.

90. Hoyer LW, Scandella D. Factor VIII inhibitors: structure and function in autoantibody and hemophilia A patients. Semin Hematol. 1994; 31(Suppl 4):1-5. [PubMed 7524160]

91. White GC II. Factor VIII inhibitor assay: quantitative and qualitative assay limitations and development needs. Semin Hematol. 1994; 31(Suppl 4):6-10. [PubMed 7939779]

92. Kessler CM, Ludlam CA for the International Acquired Hemophilia Study Group. The treatment of acquired factor VIII inhibitors: worldwide experience with porcine factor VIII concentrate. Semin Hematol. 1993; 30(Suppl 1):22-7.

93. Lusher JM. Perspectives on the use of factor IX complex concentrates in the treatment of bleeding in persons with acquired factor VIII inhibition. Am J Med. 1991; 91(Suppl 5A):30-4S. [IDIS 285704] [PubMed 1858826]

94. Green D. Immunosuppression of factor VIII inhibitors in nonhemophilic patients. Semin Hematol. 1993; 30(Suppl 1):28-31. [PubMed 8480194]

95. Hoffman R, Benz EJ Jr, Shattil SJ et al, eds. Hematology: basic principles and practice. New York: Churchill Livingstone; 1991:1276-1308,1380-2.

96. Lee GR, Bithell TC, Foerster J et al. Wintrobe’s clinical hematology. 9th ed. Philadelphia: Lea & Febiger; 1993.

97. Eyster ME, Spero JA, Catalano PM et al. Inhibitor treatment using unactivated prothrombin complex concentrates: the Pennsylvania experience—1978-1982. Prog Clin Biol Res. 1984; 150:309-22. [PubMed 6431435]

98. Sultan Y. Prevalence of inhibitors in a population of 3435 hemophilia patients in France. French Hemophilia Study Group. Thromb Haemost. 1992; 67:600-2. [PubMed 1509398]

99. Nilsson IM. Immune tolerance. Semin Hematol. 1994; 31(Suppl 4):44-8. [PubMed 7939775]

100. Mariani G, Scheibel E, Nogao T et al. Immunetolerance [sic] as treatment of alloantibodies to factor VIII in hemophilia. Semin Hematol. 1994(Suppl 4):62-4.

101. Nilsson IM, Berntorp E, Zettervall O. Induction of immune tolerance in patients with hemophilia and antibodies to factor VIII by combined treatment with intravenous IgG, cyclophosphamide, and factor VIII. N Engl J Med. 1988; 318:947-50. [IDIS 240457] [PubMed 3127711]

102. Ewing NP, Sanders NL, Dietrich SL et al. Induction of immune tolerance to factor VIII in hemophiliacs with inhibitors. JAMA. 1988; 259:65-8. [IDIS 236187] [PubMed 3119878]

103. Roberts HR. Induction of immune tolerance to factor VIII: a plea for caution. JAMA. 1988; 259:84-5. [IDIS 236190] [PubMed 3119879]

104. Ehrenforth S, Kreuz W, Scharrer I et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet. 1992; 339:594-8. [PubMed 1347102]

106. Reviewers’ comments (personal observations).

107. Seremetis SV, Aledort LM, Gergman GE et al. Three-year randomised study of high-purity or intermediate-purity factor VIII concentrates in symptom-free HIV-seropositive haemophiliacs: effects on immune status. Lancet. 1993; 342:700-3. [IDIS 320107] [PubMed 8103820]

108. Baxter Healthcare Corporation, Glendale, CA; personal communication.

109. Hironaka T, Furakawa K, Esmon PC et al. Comparative study of the sugar chains of factor VIII purified from human plasma and from the culture media of recombinant baby hamster kidney cells. J Biol Chem. 1992; 267:8012-20. [PubMed 1569060]

110. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations regarding the use of recombinant clotting factor products with respect to pathogen transmission (June 3, 2006). MASAC recommendation #169. From National Hemophilia Foundation website ().

111. DeHart WP (Alpha Therapeutic Corporation). Dear Doctor letter. 1995 Dec 8.

112. Mannucci PM, Gdovin S, Gringeri A et al. Transmission of hepatitis A to patients with hemophilia by factor VIII concentrates treated with organic solvent and detergent to inactivate viruses. Ann Intern Med. 1994; 120:107.

113. National Hemophilia Foundation. Initiation of voluntary withdrawal of Baxter plasma derivatives (Medical Bulletin No. 230). New York, NY: National Hemophilia Foundation; July 21 1995.

114. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.

115. Anon. Hepatitis A among persons with hemophilia who received clotting factor concentrate—United States, September-December 1995. MMWR Morb Mortal Wkly Rep. 1996; 45:29-32. [IDIS 359576] [PubMed 8531917]

116. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations regarding exposure to blood product derivatives and potential risk of vCJD (November 7, 2004). MASAC recommendation #158. From National Hemophilia Foundation website ().

117. Naoumov NV, Petrova EP, Thomas MG et al. Presence of a newly described human DNA virus (TTV) in patients with liver disease. Lancet. 1998; 352:195-7. [PubMed 9683209]

118. Simmonds P, Davidson F, Lycett C et al. Detection of a novel DNA virus (TTV) in blood donors and blood products. Lancet. 1998; 352:191-5. [PubMed 9683208]

119. Phillips MD, Santhouse A. von Willebrand disease: recent advances in pathophysiology and treatment. Am J Med Sci. 1998; 316:77-86. [IDIS 412301] [PubMed 9704661]

120. Bayer HealthCare. Kogenate FS antihemophilic factor (recombinant) formulated with sucrose prescribing information. Tarrytown, NY; 2009 July.

121. CSL Behring. Helixate FS antihemophilic factor (recombinant) formulated with sucrose prescribing information. Kankakee, IL; 2009 Aug.

122. Baxter Healthcare Corporation. Advate antihemophilic factor (recombinant) plasma/albumin-free method prescribing information. Westlake Village, CA; 2010 Mar.

123. Kasper CK, Brooker M. Registry of clotting factor concentrates. Seventh ed. World Federation of Hemophilia; Montreal, Quebec. 2006.

124. NovoNordisk. NovoSeven (coagulation factor VIIa [recombinant]) prescribing information. Princeton, NJ; 2006 13 Oct.

125. Giangrande P. Acquired hemophilia. Treatment of Hemophilia. 2005. From World Federation of Hemophilia website (). Accessed 2006 Nov 16.

126. World Federation of Hemophilia. Guidelines for the management of hemophilia. 2005. From World Federation of Hemophilia website (). Accessed 2006 Nov 16.

127. Kulkarni R, Aledort LM, Berntorp E et al. Therapeutic choices for patients with hemophilia and high-titer inhibitors. Am J Hematol. 2001; 67:240-6. [PubMed 11443636]

128. Makris M. Systematic review of the management of patients with haemophilia A and inhibitors. Blood Coagul Fibrinolysis. 2004; 15(Suppl 1):S25-7. [PubMed 15166930]

129. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations concerning prophylaxis (regular administration of clotting factor concentrate to prevent bleeding) (November 4, 2007). MASAC recommendation #179. From National Hemophilia Foundation website ().

130. Hewitt PE, Llewelyn CA, Mackenzie J et al. Creutzfeldt-Jakob disease and blood transfusion: result of the UK transfusion medicine epidemiological review study. Vox Sang. 2006; 91:221-30. [PubMed 16958834]

131. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations regarding the use of bypassing agents in patients with hemophilia A or B and inhibitors) (June 3, 2006). MASAC recommendation #167. From National Hemophilia Foundation website ().

132. Björkman S, Berntorp E. Pharmacokinetics of coagulation factor: clinical relevance for patients with haemophilia. Clin Pharmacokinet. 2001; 40: 815-32.

133. Bayer HealthCare , Tarrytown, NY: Personal communication.

134. Wyeth Pharmaceuticals, Philadelphia, PA: Personal communication.

135. Stobart K, Iorio A, Wu JK for the Cochrane Collaboration. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B (review). Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD003429. DOI: 10.1002/14651858.CD003429.pub3.

136. Manco-Johnson MJ, Abshire TC, Shapiro AD et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007; 357:535-44.

137. Baxter Healthcare Corporation, Westlake Village, CA: Personal communication.

138. ZLB Behring, Kankakee, IL: Personal communication.

139. Carcao MD, Aledort L. Prophylactic factor replacement in hemophilia. Blood Rev. 2004; 18:101-13. [PubMed 15010149]

140. Nilsson IM, Berntorp E, Löfqvist T et al. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J Intern med. 1992; 232:25-32. [PubMed 1640190]

141. Dimichele D. Immune tolerance therapy for factor VIII inhibitors: moving from empiricism to an evidence-based approach. J Throm Haemost. 2007; 5 (Suppl 1):143-50.

142. World Federation of Hemophilia. Diagnosis and management of inhibitors to factors VIII and IX: an introductory discussion for physicians. 2004. From World Federation of Hemophilia website (). Accessed 2007 Sept 19.

143. Hoots KW, Nugent DJ. Evidence for the benfits of prophylaxis in the management of hemophilia A. J Throm Haemost. 2006; 96:433-40.

144. Batorova A, Martinowitz U. Continuous infusion of coagulation factors: current opinion. Curr Opin Hematol. 2006; 13:308-15. [PubMed 16888434]

145. Batorova A, Martinowitz U. Continuous infusion of coagulation factors. Haemophil. 2002; 8:170-7.

146. Stachnik JM, Gabay MP. Continuous infusion of coagulation factor products. Ann Pharmacother. 2002; 36:882-91. [PubMed 11978168]

147. Food and Drug Administration. Amended economic impact analysis of final rule requiring use of labeling on natural rubber containing devices; 21 CFR Part 801. Final rule. (Docket No. 96N-0119) Fed Regist. 1998; 63:50660-704.

148. Food and Drug Administration. Latex-containing devices; user labeling. 21 CFR Part 801. Proposed rule. (Docket No. 96N-0119) Fed Regist. 1996; 61:32617-21.

149. Mathew P. Current opinion on inhibitor treatment options. Semin Hematol. 2006; 43 (Suppl 4):S8-13. [PubMed 16690374]

150. White GC II, Rosendaal F, Aledort LM et al. Definitions in hemophilia: recommendations of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the international society on thrombosis and haemostasis. Thromb Haemost. 2001; 85:560. [PubMed 11307831]

151. Wyeth. Xyntha antihemophilic factor (recombinant), plasma/albumin-free prescribing information. Philadelphia, PA; 2008 Apr.

152. Baxter Healthcare Corporation. Recombinate antihemophilic factor (recombinant) prescribing information. Westlake Village, CA; 2005 Oct.

153. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations regarding factor concentrate prescriptions and formulary development and restrictions (March 12, 2005). MASAC recommendation #159. From National Hemophilia Foundation website ().

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