Introduction

Biosynthetic (recombinant DNA origin) preparation of blood coagulation factor VIII covalently linked to the Fc domain of human IgG₁.

Uses for Antihemophilic Factor (recombinant), Fc Fusion Protein

Hemophilia A

On-demand treatment and control of bleeding episodes in patients with hemophilia A (congenital factor VIII deficiency; classic hemophilia).

Maintenance of hemostasis in patients with hemophilia A undergoing surgery (i.e., perioperative management of bleeding).

Routine prophylaxis (i.e., administration at regular intervals) to reduce frequency of bleeding events. Such prophylaxis considered the current standard of care for patients with hemophilia A. Decreases frequency of spontaneous musculoskeletal bleeding, preserves joint function, and improves quality of life.

Designated an orphan drug by FDA for treatment of hemophilia A.

Half-life of antihemophilic factor (recombinant), Fc fusion protein is longer than that of conventional preparations of recombinant antihemophilic factor; may allow for less frequent dosing and possibly improve patient compliance with prophylactic regimens.

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. Other experts (e.g., World Federation of Hemophilia) state that choice of preparation should be determined by local criteria. When selecting an appropriate antihemophilic factor preparation, consider characteristics of each clotting factor concentrate, individual patient variables, patient/provider preference, and emerging data.

Not indicated for the treatment of von Willebrand disease.

Antihemophilic Factor (recombinant), Fc Fusion Protein Dosage and Administration

General

• Monitor factor VIII activity to individualize dosage and assess response to therapy. (See Laboratory Monitoring under Cautions.) Ensure that adequate levels are attained and maintained. Careful control is especially important in cases of life-threatening bleeding or major surgery.

Administration

IV Administration

Administer by slow IV injection. (See Rate of Administration under Dosage and Administration.)

Reconstitution

Reconstitute with sterile water for injection (supplied by manufacturer). Allow drug vial and prefilled diluent syringe to warm to room temperature prior to reconstitution. Gently swirl vial until powder is completely dissolved; do not shake. Resultant solution should be clear to slightly opalescent and colorless; do not use if cloudy, discolored, or particulate matter observed.

Administer immediately or within 3 hours after reconstitution; do not refrigerate reconstituted solution.

Do not administer reconstituted solution in the same tubing or container with other drugs.

Consult manufacturer's labeling for specific instructions on reconstitution and preparation of antihemophilic factor (recombinant), Fc fusion protein.

Rate of Administration

Administer over a period of several minutes; determine administration rate by patient's comfort level (not to exceed 10 mL/minute).

Dosage

Dosage and potency expressed in terms of international units (IU, units) of antihemophilic factor activity. Potency is determined by a chromogenic substrate assay; however, both chromogenic assays and one-stage clotting assays are routinely used in US clinical laboratories for measurement of plasma factor VIII activity. In general, administration of 1 unit/kg of antihemophilic factor (recombinant), Fc fusion protein increases circulating factor VIII levels by approximately 2 units/dL (2%).

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. Estimate dose required to achieve a particular percentage increase in plasma factor VIII with the following formula:

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

Determine desired factor VIII level by the clinical situation and severity of bleeding. For recommendations on target factor VIII levels for a given clinical situation, see the specific dosage sections for various types of uses below. These calculations and suggested dosage regimens are only approximations and should not preclude appropriate clinical monitoring and individualization of dosage based on the hemostatic requirements of patients. Measure patient's factor VIII activity after a dose is given to verify calculated dose.

If calculated dose is ineffective in achieving appropriate factor VIII levels, consider possibility of inhibitor development. (See Neutralizing Antibodies to Factor VIII under Cautions.)

Pediatric Patients

Hemophilia A

Higher doses or more frequent dosing may be required in patients <6 years of age because of increased clearance and shorter half-life. Dosage requirements in patients ≥6 years of age generally similar to those in adults.

On-Demand Treatment and Control of Bleeding

Minor or moderate bleeding (e.g., joint, superficial muscle [except iliopsoas] without neurovascular compromise, deep laceration and renal, superficial soft tissue, mucous membranes): Initial dose of 20–30 units/kg to achieve a factor VIII level of at least 40–60% of normal; repeat dose every 12–24 hours for patients <6 years of age or every 24–48 hours for patients ≥6 years of age until bleeding resolves.

Major bleeding (e.g., life- or limb-threatening, iliopsoas and deep muscle with neurovascular injury, GI, retroperitoneal, intracranial): Initial dose of 40–50 units/kg to achieve a factor VIII level of at least 80–100% of normal; repeat dose every 8–24 hours for patients <6 years of age or every 12–24 hours for patients ≥6 years of age until bleeding resolves (approximately 7–10 days).

Perioperative Hemostasis

Minor surgery (e.g., uncomplicated dental extraction): Initial dose of 25–40 units/kg to achieve a factor VIII level of 50–80% of normal. Repeat dose every 12–24 hours for patients <6 years of age or every 24 hours for patients ≥6 years of age for at least 1 day until healing is achieved.

Major surgery (e.g., intracranial, intra-abdominal, joint replacement): Initial preoperative dose of 40–60 units/kg to achieve a factor VIII level of at least 80–120% of normal. Repeat with dose of 40–50 units/kg after 6–24 hours for patients <6 years of age or every 8–24 hours for patients ≥6 years of age, then every 24 hours thereafter to maintain factor VIII levels within target range. Once adequate wound healing achieved, continue therapy for at least 7 days to maintain target factor VIII levels.

Routine Prophylaxis of Bleeding

Children ≥6 years of age: Manufacturer recommends initial dosage of 50 units/kg every 4 days. Adjust dosage to 25–65 units/kg every 3–5 days based on response.

Children <6 years of age: Manufacturer recommends initial dosage of 50 units/kg twice weekly. More frequent or higher doses up to 80 units/kg may be required. Adjust dosage to 25–65 units/kg every 3–5 days based on response.

MASAC states that prophylactic therapy 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.

Individualize prophylactic dosage regimens; evaluate patients periodically to determine continued need for prophylaxis. Optimum duration of prophylaxis unknown.

Adults

Hemophilia A

On-Demand Treatment and Control of Bleeding

Minor or moderate bleeding (e.g., joint, superficial muscle [except iliopsoas] without neurovascular compromise, deep laceration and renal, superficial soft tissue, mucous membranes): Initial dose of 20–30 units/kg to achieve a factor VIII level of at least 40–60% of normal; repeat dose every 24–48 hours until bleeding resolves.

Major bleeding (e.g., life- or limb-threatening, iliopsoas and deep muscle with neurovascular injury, GI, retroperitoneal, intracranial): Initial dose of 40–50 units/kg to achieve a factor VIII level of at least 80–100% of normal; repeat dose every 12–24 hours until bleeding resolves (approximately 7–10 days).

Perioperative Hemostasis

Minor surgery (e.g., uncomplicated dental extraction): Initial dose of 25–40 units/kg to achieve a factor VIII level of at least 50–80% of normal. Repeat dose every 24 hours for at least 1 day until healing is achieved.

Major surgery (e.g., intracranial, intra-abdominal, joint replacement): Initial preoperative dose of 40–60 units/kg to achieve a factor VIII level of at least 80–120% of normal. Repeat with dose of 40–50 units/kg after 8–24 hours, then every 24 hours thereafter to maintain factor VIII levels within target range. Once adequate wound healing achieved, continue therapy for at least 7 days to maintain target factor VIII levels.

Routine Prophylaxis of Bleeding

Manufacturer recommends initial dosage of 50 units/kg every 4 days. Adjust dosage within range of 25–65 units/kg every 3–5 days based on patient response.

Individualize prophylactic dosage regimens; evaluate patients periodically to determine continued need for prophylaxis. Optimum duration of prophylaxis unknown.

Contraindications

• Life-threatening hypersensitivity reactions (e.g., anaphylaxis) to antihemophilic factor (recombinant), Fc fusion protein or other components of the preparation.

Warnings/Precautions

Neutralizing Antibodies to Factor VIII

Risk for development of neutralizing antibodies (inhibitors) to factor VIII following treatment with any antihemophilic factor preparation. Reported to occur in approximately 20–30% of patients with severe hemophilia A and 5–10% of those with mild to moderate disease.

Monitor patients for development of inhibitors using appropriate clinical observation and laboratory tests. (See Laboratory Monitoring under Cautions.) Suspect presence of inhibitors if expected factor VIII levels not achieved or bleeding not controlled with recommended dose, particularly in those who previously achieved a response.

Laboratory Monitoring

Monitor factor VIII levels using a validated test (e.g., one-stage clotting assay) to guide dosing and assess therapeutic response. Important to achieve and maintain adequate levels of factor VIII for effective hemostatic control during an acute bleeding episode or during surgery.

Monitor for development of inhibitors. Perform appropriate laboratory test (i.e., Bethesda assay) to confirm presence of inhibitors. (See Neutralizing Antibodies to Factor VIII under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Potential risk of hypersensitivity reactions, including anaphylaxis. If a hypersensitivity reaction occurs, discontinue drug immediately and initiate appropriate therapy.

Specific Populations

Pregnancy

Not known whether drug can cause fetal harm or affect reproductive capacity; use during pregnancy only when clearly needed.

Lactation

Not known whether distributed into human milk. Consider known benefits of breast-feeding; mother's clinical need for antihemophilic factor (recombinant), Fc fusion protein; and any potential adverse effects of the drug or disease on infant.

Pediatric Use

Safety and efficacy evaluated in previously treated adolescents 12–18 years of age in principal efficacy study.

In a separate pediatric study evaluating patients <12 years of age, antihemophilic factor (recombinant), Fc fusion protein half-life was shorter and body weight-adjusted clearance was substantially higher in children 1–5 years of age than in older pediatric patients.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.

Common Adverse Effects

Arthralgia, malaise, myalgia, headache, rash.

General

• Monitor factor VIII activity to individualize dosage and assess response to therapy. (See Laboratory Monitoring under Cautions.) Ensure that adequate levels are attained and maintained. Careful control is especially important in cases of life-threatening bleeding or major surgery.

Administration

IV Administration

Administer by slow IV injection. (See Rate of Administration under Dosage and Administration.)

Reconstitution

Reconstitute with sterile water for injection (supplied by manufacturer). Allow drug vial and prefilled diluent syringe to warm to room temperature prior to reconstitution. Gently swirl vial until powder is completely dissolved; do not shake. Resultant solution should be clear to slightly opalescent and colorless; do not use if cloudy, discolored, or particulate matter observed.

Administer immediately or within 3 hours after reconstitution; do not refrigerate reconstituted solution.

Do not administer reconstituted solution in the same tubing or container with other drugs.

Consult manufacturer's labeling for specific instructions on reconstitution and preparation of antihemophilic factor (recombinant), Fc fusion protein.

Rate of Administration

Administer over a period of several minutes; determine administration rate by patient's comfort level (not to exceed 10 mL/minute).

Dosage

Dosage and potency expressed in terms of international units (IU, units) of antihemophilic factor activity. Potency is determined by a chromogenic substrate assay; however, both chromogenic assays and one-stage clotting assays are routinely used in US clinical laboratories for measurement of plasma factor VIII activity. In general, administration of 1 unit/kg of antihemophilic factor (recombinant), Fc fusion protein increases circulating factor VIII levels by approximately 2 units/dL (2%).

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. Estimate dose required to achieve a particular percentage increase in plasma factor VIII with the following formula:

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

Determine desired factor VIII level by the clinical situation and severity of bleeding. For recommendations on target factor VIII levels for a given clinical situation, see the specific dosage sections for various types of uses below. These calculations and suggested dosage regimens are only approximations and should not preclude appropriate clinical monitoring and individualization of dosage based on the hemostatic requirements of patients. Measure patient's factor VIII activity after a dose is given to verify calculated dose.

If calculated dose is ineffective in achieving appropriate factor VIII levels, consider possibility of inhibitor development. (See Neutralizing Antibodies to Factor VIII under Cautions.)

Pediatric Patients

Hemophilia A

Higher doses or more frequent dosing may be required in patients <6 years of age because of increased clearance and shorter half-life. Dosage requirements in patients ≥6 years of age generally similar to those in adults.

On-Demand Treatment and Control of Bleeding

Minor or moderate bleeding (e.g., joint, superficial muscle [except iliopsoas] without neurovascular compromise, deep laceration and renal, superficial soft tissue, mucous membranes): Initial dose of 20–30 units/kg to achieve a factor VIII level of at least 40–60% of normal; repeat dose every 12–24 hours for patients <6 years of age or every 24–48 hours for patients ≥6 years of age until bleeding resolves.

Major bleeding (e.g., life- or limb-threatening, iliopsoas and deep muscle with neurovascular injury, GI, retroperitoneal, intracranial): Initial dose of 40–50 units/kg to achieve a factor VIII level of at least 80–100% of normal; repeat dose every 8–24 hours for patients <6 years of age or every 12–24 hours for patients ≥6 years of age until bleeding resolves (approximately 7–10 days).

Perioperative Hemostasis

Minor surgery (e.g., uncomplicated dental extraction): Initial dose of 25–40 units/kg to achieve a factor VIII level of 50–80% of normal. Repeat dose every 12–24 hours for patients <6 years of age or every 24 hours for patients ≥6 years of age for at least 1 day until healing is achieved.

Major surgery (e.g., intracranial, intra-abdominal, joint replacement): Initial preoperative dose of 40–60 units/kg to achieve a factor VIII level of at least 80–120% of normal. Repeat with dose of 40–50 units/kg after 6–24 hours for patients <6 years of age or every 8–24 hours for patients ≥6 years of age, then every 24 hours thereafter to maintain factor VIII levels within target range. Once adequate wound healing achieved, continue therapy for at least 7 days to maintain target factor VIII levels.

Routine Prophylaxis of Bleeding

Children ≥6 years of age: Manufacturer recommends initial dosage of 50 units/kg every 4 days. Adjust dosage to 25–65 units/kg every 3–5 days based on response.

Children <6 years of age: Manufacturer recommends initial dosage of 50 units/kg twice weekly. More frequent or higher doses up to 80 units/kg may be required. Adjust dosage to 25–65 units/kg every 3–5 days based on response.

MASAC states that prophylactic therapy 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.

Individualize prophylactic dosage regimens; evaluate patients periodically to determine continued need for prophylaxis. Optimum duration of prophylaxis unknown.

Adults

Hemophilia A

On-Demand Treatment and Control of Bleeding

Minor or moderate bleeding (e.g., joint, superficial muscle [except iliopsoas] without neurovascular compromise, deep laceration and renal, superficial soft tissue, mucous membranes): Initial dose of 20–30 units/kg to achieve a factor VIII level of at least 40–60% of normal; repeat dose every 24–48 hours until bleeding resolves.

Major bleeding (e.g., life- or limb-threatening, iliopsoas and deep muscle with neurovascular injury, GI, retroperitoneal, intracranial): Initial dose of 40–50 units/kg to achieve a factor VIII level of at least 80–100% of normal; repeat dose every 12–24 hours until bleeding resolves (approximately 7–10 days).

Perioperative Hemostasis

Minor surgery (e.g., uncomplicated dental extraction): Initial dose of 25–40 units/kg to achieve a factor VIII level of at least 50–80% of normal. Repeat dose every 24 hours for at least 1 day until healing is achieved.

Major surgery (e.g., intracranial, intra-abdominal, joint replacement): Initial preoperative dose of 40–60 units/kg to achieve a factor VIII level of at least 80–120% of normal. Repeat with dose of 40–50 units/kg after 8–24 hours, then every 24 hours thereafter to maintain factor VIII levels within target range. Once adequate wound healing achieved, continue therapy for at least 7 days to maintain target factor VIII levels.

Routine Prophylaxis of Bleeding

Manufacturer recommends initial dosage of 50 units/kg every 4 days. Adjust dosage within range of 25–65 units/kg every 3–5 days based on patient response.

Individualize prophylactic dosage regimens; evaluate patients periodically to determine continued need for prophylaxis. Optimum duration of prophylaxis unknown.