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Antihemophilic Factor (Recombinant)

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

Introduction

Biosynthetic (recombinant DNA origin) preparation of antihemophilic factor (blood coagulation factor VIII).1 2 7 8 10 11 40 120 121 122 151 153 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 77 120 121 122 151 153

Uses for Antihemophilic Factor (Recombinant)

Hemophilia A

Prevention and control of bleeding episodes in patients 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 76 114 120 121 122 151 153 215 246 designated an orphan drug by FDA for this use.114

Maintenance of hemostasis in patients with hemophilia A undergoing surgery (i.e., perioperative management).1 2 76 120 121 122 151 153

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 95 96 215 246

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

Also used for routine prophylaxis (i.e., administration at regular intervals) to prevent or reduce frequency of bleeding events.2 120 121 122 135 136 143 151 153 215 224 231 Such prophylaxis considered the current standard of care for patients with hemophilia A.215 218 Decreases frequency of spontaneous musculoskeletal bleeding, preserves joint function, and improves quality of life.215 224 231

Several antihemophilic factor concentrates are currently available in the US, including a variety of recombinant and plasma-derived preparations; the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation recommends preferential use of recombinant antihemophilic factor preparations because of their potentially superior safety profile with respect to pathogen transmission.218 246 247 Other experts (e.g., World Federation of Hemophilia) state that choice of preparation should be determined by local criteria.215 When selecting an appropriate antihemophilic factor preparation, consider characteristics of each clotting factor concentrate, individual patient variables, patient/provider preference, and emerging data.215 243 246 247

Has been used for treatment of bleeding in patients with hemophilia A who have developed relatively low levels of neutralizing antibodies (alloantibodies; inhibitors) to factor VIII.1 2 27 55 85 120 121 122 142 215 (See Neutralizing Antibodies to Factor VIII under Cautions.)

Not indicated for treatment of von Willebrand disease; does not contain appreciable amounts of von Willebrand factor.1 2 119 120 121 122 151 153

Acquired Hemophilia A

Has been used to control bleeding in patients with acquired hemophilia A (i.e., spontaneous development of antibodies to factor VIII [autoantibodies] in patients who do not have congenital hemophilia A).85 93 106 251 253

Although antihemophilic factor (recombinant) therapy may be effective in some patients with low levels of acquired factor VIII inhibitors when given in high doses,85 93 106 251 bypassing agents are substantially more effective and are considered the treatment of choice.214 251 253

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

  • Individualize dosage and duration of therapy based on severity of factor VIII deficiency, location and extent of bleeding, and patient's clinical and pharmacokinetic (e.g., in vivo recovery, half-life) response.1 2 55 120 121 122 151 153

  • Monitor factor VIII levels when clinically indicated to individualize dosage and assess response to therapy.1 2 120 121 122 151 215 Careful control is especially important in cases of life-threatening bleeding or major surgery.1 120 121 122 153 (See Laboratory Monitoring under Cautions.)

Administration

IV Administration

Administer by slow IV injection or IV infusion over several minutes.1 2 3 4 120 121 122 151 153

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 2 120 121 122 151 153

Reconstitution

Prior to reconstitution, warm lyophilized powders and diluents supplied by the manufacturers to room temperature.1 2 108 120 121 122 151 153

Reconstitute and administer drug using tubing, administration sets, vial adapters, and transfer devices provided by manufacturer.1 2 120 121 122 151 153 Some manufacturers recommend use of plastic syringes only since proteins such as antihemophilic factor may adhere to glass.1 122

Following addition of diluent, gently swirl solution to dissolve powder completely; do not shake.1 2 120 121 122 151 153

Keep reconstituted solutions at room temperature.1 2 121 122 151 153 Administer Advate, Helixate FS, Kogenate FS, Recombinate, ReFacto, and Xyntha within 3 hours of reconstitution, and Novoeight within 4 hours of reconstitution.1 2 121 122 151 153

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 a period of ≤5 minutes (up to a maximum of 10 mL/minute).122

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

Novoeight: Administer over 2–5 minutes.153

Recombinate: Administer at a rate that ensures patient’s comfort; generally can be administered over a period of up to 1 minute.1 152

ReFacto: Administer over several minutes based on patient’s comfort level.2

Xyntha: Administer over several minutes based on patient’s comfort level.151

Dosage

Dosage expressed in terms of international units (IU, units).1 2 120 121 122 151 153 One unit is approximately equivalent to amount of factor VIII activity in 1 mL of fresh pooled normal human plasma.72 95 120 121 122 151 153

Administration of 1 unit/kg antihemophilic factor (recombinant) generally increases factor VIII activity by approximately 2%.2 48 55 74 151 153 215

Dose required to achieve desired factor VIII levels:1 2 120 121 122 151 153

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

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

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

Determine desired factor VIII level by clinical situation and severity of bleeding.1 2 120 121 122 151 153 (For recommendations on target factor VIII levels, see the individual preparation-specific dosage sections below.) 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 55 120 121 122 151 153 Perform serial assays of factor VIII (usually with one-stage clotting assay) at suitable intervals to ensure that adequate levels have been attained and maintained.1 2 120 121 122 153 (See Laboratory Monitoring under Cautions.)

If recommended dosage is ineffective in achieving expected factor VIII levels or if bleeding is not controlled, consider possibility of inhibitor development.1 120 121 122 153 (See Neutralizing Antibodies to Factor VIII under Cautions.) Some patients with inhibitors may require higher dosages.1 2 120 122 151

Consult manufacturers’ prescribing information for specific dosage recommendations for each antihemophilic factor (recombinant) preparation.1 2 120 121 122 151 153

Pediatric Patients

Prevention and Control of Bleeding Episodes in Hemophilia A
Advate
IV

Minor bleeding (e.g., early hemarthrosis, mild muscle bleeding, mild oral bleeding): Initially, 10–20 units/kg to achieve a plasma factor VIII level of 20–40% or more of normal; repeat every 12–24 hours for patients ≥6 years of age or every 8–24 hours for patients <6 years of age for approximately 1–3 days to maintain desired factor VIII levels until bleeding episode resolves (indicated by pain relief) or healing achieved.122

Moderate bleeding (e.g., bleeding into muscles, bleeding into oral cavity, definite hemarthrosis, known trauma): Initially, 15–30 units/kg to achieve a plasma factor VIII level of 30–60% or more of normal; repeat every 12–24 hours for patients ≥6 years of age or every 8–24 hours for patients <6 years of age for approximately 3 days or longer to maintain desired factor VIII levels until bleeding episode resolves (indicated by pain relief) or healing achieved.122

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

Minor surgery (e.g., tooth extraction): Administer a single dose of 30–50 units/kg within 1 hour of surgery to achieve plasma factor VIII levels of 60–100% or more of normal.122 Repeat every 12–24 hours as needed to maintain desired factor VIII levels and control bleeding.122 Consider adjunctive therapy for dental procedures.122

Major surgery (e.g., intracranial, intra-abdominal, or intrathoracic surgery; joint replacement): 40–60 units/kg to achieve pre- and postoperative factor VIII levels of 80–120% or more of normal.122 A preoperative dose to achieve 100% activity is recommended.122 Repeat every 8–24 hours for patients ≥6 years of age or every 6–24 hours for patients <6 years of age depending on desired level of factor VIII and state of wound healing.122

Helixate FS and Kogenate FS
IV

Minor bleeding (e.g., early hemarthrosis, minor muscle or oral bleeding): Initially, 10–20 units/kg to achieve a plasma factor VIII level of 20–40% or more of normal; repeat dose to maintain desired factor VIII levels until bleeding resolves.120 121

Moderate bleeding (e.g., 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% or more of normal; repeat every 12–24 hours to maintain desired factor VIII levels until bleeding resolves.120 121

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

Minor surgery (e.g., tooth extraction): Initially, 15–30 units/kg to achieve a plasma factor VIII level of 30–60% or more of normal; repeat every 12–24 hours to maintain desired factor VIII levels 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 plasma factor VIII level of 100% of normal; repeat every 6–12 hours as necessary to maintain factor VIII levels in the desired range until healing complete.120 121

Novoeight
IV

Minor bleeding (e.g., early hemarthrosis, minor muscle or oral bleeding): Administer appropriate dose to increase factor VIII levels to at least 20–40% of normal.153 Repeat every 12–24 hours to maintain desired factor VIII levels for at least 1 day until bleeding episode resolves.153

Moderate bleeding (e.g., muscle bleeding, mild head trauma, bleeding into oral cavity): Administer appropriate dose to increase factor VIII levels to at least 30–60% of normal.153 Repeat every 12–24 hours to maintain desired factor VIII levels for approximately 3–4 days until pain and acute disability resolve.153

Major bleeding (e.g., life- or limb-threatening; GI, intracranial, intra-abdominal, or intrathoracic bleeding; fractures): Administer appropriate dose to increase factor VIII levels to at least 60–100% of normal.153 Repeat every 8–24 hours to maintain desired factor VIII levels for approximately 7–10 days until bleeding resolves.153

Minor surgery (e.g., tooth extraction): Administer appropriate dose to increase factor VIII levels to at least 30–60% of normal.153 Repeat every 24 hours to maintain desired factor VIII levels until healing is achieved; at least 1 day of treatment recommended.153

Major surgery (e.g., intracranial, intra-abdominal, intrathoracic, joint replacement surgery): Administer appropriate dose to achieve preoperative and postoperative factor VIII levels of at least 80–100% of normal.153 Repeat every 8–24 hours to maintain desired factor VIII levels until adequate wound healing occurs; at least 7 days of treatment recommended to maintain factor VIII levels at 30–60%.153

Recombinate
IV

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

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

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

Minor surgery (e.g., tooth extraction): Administer appropriate dose 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: Administer appropriate dose to achieve plasma preoperative and postoperative factor VIII levels of 80–100% of normal.1 Repeat every 8–24 hours to maintain desired factor VIII activity and state of wound healing.1

ReFacto
IV

Minor bleeding (e.g., early hemarthrosis, minor muscle bleeding, oral bleeding): Administer appropriate dose to achieve a plasma factor VIII level of 20–40% of normal; repeat every 12–24 hours as needed to maintain desired factor VIII levels until bleeding resolves.2 Give at least 1 day of therapy (depending on severity of bleeding).2

Moderate bleeding (e.g., muscle bleeding, mild head trauma, bleeding into oral cavity): Administer appropriate dose to achieve a plasma factor VIII level of 30–60% of normal; repeat every 12–24 hours for 3–4 days or until local hemostasis achieved.2

Major bleeding (e.g., GI, intracranial, intra-abdominal, or intrathoracic bleeding; fractures): Administer appropriate dose to achieve a plasma factor VIII level of 60–100% of normal; repeat every 8–24 hours to maintain desired factor VIII levels until bleeding resolves.2

Minor surgery (e.g., tooth extraction): Administer appropriate dose to achieve a plasma factor VIII level of 30–60% of normal; repeat every 12–24 hours for 3–4 days or 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

Major surgery: Administer appropriate dose to achieve a plasma factor VIII level of 60–100% of normal; repeat every 8–24 hours to maintain desired factor VIII levels until local hemostasis and/or wound healing is achieved.2

Xyntha
IV

Minor bleeding (e.g., early hemarthrosis, minor muscle bleeding, oral bleeding): Administer appropriate dose to achieve a plasma factor VIII level of at least 20–40% of normal; repeat every 12–24 hours as needed to maintain desired factor VIII levels until bleeding resolves.151 Give at least 1 day of therapy (depending on severity of bleeding).151

Moderate bleeding (e.g., muscle bleeding, mild head trauma, bleeding into oral cavity): Administer appropriate dose to achieve a plasma factor VIII level of at least 30–60% of normal; repeat every 12–24 hours for 3–4 days or until local hemostasis achieved.151

Major bleeding (e.g., GI, intracranial, intra-abdominal, or intrathoracic bleeding; fractures): Administer appropriate dose to achieve a plasma factor VIII level of at least 60–100% of normal; repeat every 8–24 hours to maintain desired factor VIII levels until bleeding resolves.151

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

Major surgery: Administer appropriate dose to achieve a plasma factor VIII level of at least 60–100% of normal; repeat every 8–24 hours to maintain desired factor VIII levels until local hemostasis and/or wound healing is achieved.151

Routine Prophylaxis of Bleeding Episodes in Hemophilia A
IV

Various dosing regimens have been recommended.120 121 136 215 218 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.218

MASAC states that prophylaxis should be instituted at an early age (e.g., 1–2 years) prior to the onset of frequent bleeding; however, optimum duration of prophylaxis not known.218

Individualize prophylactic regimens; evaluate patients periodically to determine continued need for prophylaxis.122 218

Advate
IV

Manufacturer recommends 20–40 units/kg every other day (3–4 times a week); alternatively, may administer a dose every third day to achieve factor VIII levels of ≥1%.122

Helixate FS and Kogenate FS
IV

Manufacturer recommends 25 units/kg every other day.120 121

Novoeight
IV

Children <12 years of age: 25–60 units/kg 3 times a week of 25–50 units/kg every other day.153

Adolescents ≥12 years of age: 20–50 units/kg 3 times a week or 20–40 units/kg every other day.153

ReFacto
IV

Manufacturer recommends that a prophylactic dose be administered at least twice weekly.2 In pediatric patients, shorter dosage intervals or higher doses may be necessary.2 Some evidence suggests that a 3-times-weekly regimen may be associated with lower bleeding risk than twice-weekly dosing.2 In clinical studies, mean dose administered for routine prophylaxis was 29 units/kg in previously treated pediatric patients ≥8 years of age and 53 units/kg in previously untreated pediatric patients ≤52 months of age.2

Xyntha
IV

Manufacturer does not provide specific dosage recommendations; in clinical studies, prophylactic dosage of 25–35 units/kg 3 times a week was administered.151

Adults

Prevention and Control of Bleeding Episodes in Hemophilia A
Advate
IV

Minor bleeding (e.g., early hemarthrosis, mild muscle bleeding, mild oral bleeding): Initially, 10–20 units/kg to achieve a factor VIII level of 20–40% or more of normal; repeat every 12–24 hours to maintain desired factor VIII levels for approximately 1–3 days until bleeding resolves (indicated by pain relief) or healing achieved.122

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

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

Minor surgery (e.g., tooth extraction): Administer single dose of 30–50 units/kg within 1 hour of surgery to achieve factor VIII levels of 60–100% or more of normal.122 Repeat every 12–24 hours as needed to maintain desired factor VIII levels and control bleeding.122 Consider adjunctive therapy for dental procedures.122

Major surgery (e.g., intracranial, intra-abdominal, or intrathoracic surgery; joint replacement): 40–60 units/kg to achieve pre- and postoperative plasma factor VIII levels of 80–120% or more of normal.122 A preoperative dose to achieve 100% activity is recommended.122 Repeat every 8–24 hours depending on desired level of factor VIII activity and state of wound healing.122

Helixate FS and Kogenate FS
IV

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

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

Major bleeding (e.g., GI, intracranial, intra-abdominal, intrathoracic, 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% or more of normal; give additional doses of 20–25 units/kg every 8–12 hours to maintain desired factor VIII levels until bleeding resolves.120 121

Minor surgery (e.g., tooth extraction): Initially, 15–30 units/kg to achieve a plasma factor VIII level of 30–60% or more of normal; repeat every 12–24 hours to maintain desired factor VIII levels 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; repeat as necessary every 6–12 hours to maintain factor VIII levels in the desired range until healing complete.120 121

Novoeight
IV

Minor bleeding (e.g., early hemarthrosis, minor muscle or oral bleeding): Administer appropriate dose to increase factor VIII levels to at least 20–40% of normal.153 Repeat every 12–24 hours to maintain desired factor VIII levels for at least 1 day until bleeding episode resolves.153

Moderate bleeding (e.g., muscle bleeding, mild head trauma, bleeding into oral cavity): Administer appropriate dose to increase factor VIII levels to at least 30–60% of normal.153 Repeat every 12–24 hours to maintain desired factor VIII levels for approximately 3–4 days until pain and acute disability resolve.153

Major bleeding (e.g., life- or limb-threatening; GI, intracranial, intra-abdominal, or intrathoracic bleeding; fractures): Administer appropriate dose to increase factor VIII levels to at least 60–100% of normal.153 Repeat every 8–24 hours to maintain desired factor VIII levels for approximately 7–10 days until bleeding resolves.153

Minor surgery (e.g., tooth extraction): Administer appropriate dose to increase factor VIII levels to at least 30–60% of normal.153 Repeat every 24 hours to maintain desired factor VIII levels until healing is achieved; at least 1 day of treatment recommended.153

Major surgery (e.g., intracranial, intra-abdominal, intrathoracic, joint replacement surgery): Administer appropriate dose to achieve preoperative and postoperative factor VIII levels of at least 80–100% of normal.153 Repeat every 8–24 hours to maintain desired factor VIII levels until adequate wound healing occurs; at least 7 days of treatment recommended to maintain factor VIII levels at 30–60%.153

Recombinate
IV

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

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

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

Minor surgery (e.g., tooth extraction): Administer appropriate dose 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: Administer appropriate dose to achieve preoperative and postoperative plasma factor VIII levels of 80–100% of normal.1 Repeat every 8–24 hours to maintain desired factor VIII level and state of wound healing.1

ReFacto
IV

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

Moderate bleeding (muscle bleeding, mild head trauma, bleeding into oral cavity): Administer appropriate dose to achieve a plasma factor VIII level of 30–60% of normal; repeat every 12–24 hours for 3–4 days or until local hemostasis achieved.2

Major bleeding (GI, intracranial, intra-abdominal, or intrathoracic bleeding; fractures): Administer appropriate dose to achieve a plasma factor VIII level of 60–100% of normal; repeat every 8–24 hours to maintain desired factor VIII levels until local hemostasis achieved.2

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

Major surgery: Administer appropriate dose to achieve a factor VIII level of 60–1 00% of normal; repeat every 8–24 hours to maintain desired factor VIII levels until local hemostasis and wound healing achieved.2

Xyntha
IV

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

Moderate bleeding (muscle bleeding, mild trauma capitis, bleeding into oral cavity): Administer appropriate dose to achieve a plasma factor VIII level of at least 30–60% of normal; repeat every 12–24 hours for 3–4 days or until local hemostasis achieved.151

Major bleeding (GI, intracranial, intra-abdominal, or intrathoracic bleeding; fractures): Administer appropriate dose to achieve a plasma factor VIII level of at least 60–100% of normal; repeat every 8–24 hours to maintain desired factor VIII levels until bleeding is resolved.151

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

Major surgery: Administer appropriate dose to achieve a factor VIII level of at least 60–100% of normal; repeat every 8–24 hours to maintain desired factor VIII levels until local hemostasis and wound healing achieved.151

Routine Prophylaxis of Bleeding Episodes in Hemophilia A
IV

Various dosing regimens have been recommended.120 121 136 215 218 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.136 218

Individualize prophylactic regimens; evaluate patients periodically to determine continued need for prophylaxis.122 218

Advate
IV

Manufacturer recommends prophylactic dosage of 20–40 units/kg every other day (3–4 times a week); alternatively, may administer a dose every third day to achieve factor VIII levels of ≥1%.122

Helixate FS and Kogenate FS
IV

Manufacturer recommends 25 units/kg 3 times a week.120 121

Novoeight
IV

20–50 units/kg 3 times a week or 20–40 units/kg every other day.153

ReFacto
IV

Manufacturer recommends that a prophylactic dose be administered at least twice weekly.2 In some patients (e.g., children), shorter dosage intervals or higher doses may be necessary.2 Some evidence suggests that a 3-times-weekly regimen may be associated with lower bleeding risk than twice-weekly dosing.2 In clinical studies in previously treated adults ≤73 years of age, mean dose of ReFacto administered for routine prophylaxis was 29 units/kg.2

Xyntha
IV

Manufacturer does not provide specific dosage recommendations for routine prophylaxis; in clinical studies, prophylactic dosage of 25–35 units/kg 3 times a week was administered.151

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, including murine, hamster, or bovine proteins that may be present.1 120 121 122 151 153

Warnings/Precautions

Warnings

Neutralizing Antibodies to Factor VIII

Risk of development of neutralizing antibodies (inhibitors) to factor VIII following treatment with any antihemophilic factor preparation.1 2 4 5 13 29 39 46 69 76 89 120 121 122 142 151 153 215 250 255 Reported to occur in approximately 20–30% of patients with severe hemophilia A and 5–10% of those with mild to moderate disease.215 255

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 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 (e.g., Bethesda assay).1 2 27 28 55 65 67 74 91 95 120 121 122 151 153 Consider possibility of inhibitors in patients who fail to respond to adequate dosages of antihemophilic factor (recombinant), particularly in those who previously achieved a response.1 27 61 65 74 95 120 121 122 142 151 153

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., hives, generalized urticaria, tightness of the chest, wheezing, hypotension, dizziness, rash, flushing, anaphylaxis) reported.1 120 121 122 153 (See Contraindications under Cautions.)

If hypersensitivity reaction occurs, patient should discontinue drug immediately and seek immediate treatment.1 2 120 121 122 151 153

Antibodies to Nonmammalian Proteins

All currently available preparations of antihemophilic factor (recombinant) contain trace amounts of animal proteins, which may stimulate antibody production and cause hypersensitivity reactions.1 2 120 121 122 151 153 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

Potential 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 76 110 246

Theoretical but remote risk of transmitting other viruses (e.g., those associated with mammalian cell cultures employed in manufacturing).40 49 106 108 110 246 No such transmission reported to date.110 246

Laboratory Monitoring

Monitor plasma factor VIII levels when clinically indicated to guide dosing and ensure adequate therapeutic response.1 2 55 120 121 122 151 153

Monitor for development of factor VIII inhibitors during treatment.1 27 28 55 65 67 74 91 95 122 153 215 If expected plasma factor VIII levels are not attained or bleeding is not controlled with an expected dose, perform appropriate laboratory test (Bethesda assay) to detect and measure concentrations of factor VIII inhibitors.1 120 121 122 153 (See Neutralizing Antibodies to Factor VIII 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 2 120 121 122 151 153

Lactation

Not known whether antihemophilic factor (recombinant) is distributed into human milk.1 120 121 122 151 153 Use with caution and only if clinically indicated.2 120 121 153

Pediatric Use

Has been used in pediatric patients of all ages for treatment of hemophilia A; adverse effects reported in pediatric patients generally are similar to those reported in adults.2 4 5 47 120 121 153

Infusion-related reactions (e.g., urticaria, flushing, erythema) have occurred rarely in previously untreated neonates and children following administration of the drug.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.1 120 121 122 151 153

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.2 120 121 122 151 153 Individualize dosage.2 120 121 122 151

Common Adverse Effects

Advate: Development of inhibitors (reported mainly in previously untreated patients), pyrexia, headache, cough, nasopharyngitis, vomiting, arthralgia, limb injury.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), infections associated with a central venous access device.120 121

Novoeight: Injection site reactions, hepatic enzyme elevations, pyrexia.153

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, arthralgia, cough.151

Interactions for Antihemophilic Factor (Recombinant)

No formal drug interaction studies to date.133 134 137 138

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 7–17 hours depending on patient age, sampling time, specific assay, and other factors.1 2 120 121 122 151 153

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.120 121 122 153

Stability

Storage

Parenteral

Powder for IV Infusion

Advate: 2–8°C (avoid freezing).122 May store at room temperature of ≤30°C for up to 6 months; do not return drug to refrigerator after storage at room temperature.122

Helixate FS/Kogenate FS: 2–8°C (avoid freezing); may store at room temperature of ≤25°C for up to 12 months.120 121 Do not return to refrigerator after storage at room temperature.120 121 Protect from extreme exposure to light and store lyophilized powder in the carton prior to use.120 121

Novoeight: 2–8°C (avoid freezing) for up to 30 months; may store at room temperature of ≤30°C for up to 12 months within this period.153 Do not return to refrigerator after storage at room temperature.153 Store in original container to protect from light.153

Recombinate: 2–8°C (avoid freezing); may store at room temperature of ≤30°C.1

ReFacto: 2–8°C (avoid freezing); may store at room temperature of ≤25°C for up to 3 months.2 Do not use beyond expiration date.2 Protect from extreme exposure to light.2

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

Store reconstituted solutions at room temperature; use within 3 hours (Advate, Helixate FS, Kogenate FS, Recombinate, ReFacto, Xyntha) or 4 hours (Novoeight) of reconstitution.1 2 120 121 122 151 153

Actions

  • 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 bleeding tendency and clinical manifestations such as bleeding into soft tissues, muscles, and 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 generally correlate with 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) increases plasma levels of factor VIII and temporarily corrects the coagulation defect in patients with hemophilia A.1 2 5 9 40 47 55 68 69 73 120 121 122 151 153

  • 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 76 110 122 246

  • 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 40 120 121 122 151 153

Advice to Patients

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

  • Risk of developing neutralizing antibodies (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 2 120 121 122 151 153

  • 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 2 120 121 122 151 153

  • Importance of consulting clinician prior to travel; advise patients to bring an adequate supply of antihemophilic factor (recombinant) with them while traveling.120 121 122 153

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

  • Importance of adhering to proper storage conditions for the drug.153

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 2 120 121 122 151 153

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 2 120 121 122 151 153

  • Importance of informing patients of other important precautionary information.1 2 120 121 122 151 153 (See Cautions.)

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Antihemophilic Factor (Recombinant)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use

number of units indicated on label

Advate (with sterile water for injection diluent; available with administration set)

Baxter

Helixate FS (with sterile water for injection diluent; available with filter transfer device)

Bayer

Kogenate FS (with sterile water for injection diluent; available with transfer and filter needles or alternative needleless transfer systems, and administration set)

Bayer

Novoeight (with prefilled syringe containing 0.9% sodium chloride diluent; available with vial adapter)

Novo Nordisk

Recombinate (with sterile water for injection diluent; available with needleless transfer device)

Baxter

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

Wyeth

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

Wyeth

AHFS DI Essentials. © Copyright 2017, Selected Revisions February 27, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

References

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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.

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120. Bayer HealthCare. Kogenate FS antihemophilic factor (recombinant) formulated with sucrose prescribing information. Tarrytown, NY; 2014 May.

121. Baxter. Helixate FS antihemophilic factor (recombinant) formulated with sucrose prescribing information. Kankakee, IL; 2014 May.

122. Baxter. Advate antihemophilic factor (recombinant) prescribing information. Westlake Village, CA; 2014 April.

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.

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]

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.

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