Antihemophilic Factor (recombinant), Fc Fusion Protein

Biosynthetic (recombinant DNA origin) preparation of blood coagulation factor VIII covalently linked to the Fc domain of human IgG1.1 7 9 16

General

• Monitor factor VIII activity to individualize dosage and assess response to therapy.1 6 (See Laboratory Monitoring under Cautions.) Ensure that adequate levels are attained and maintained.1 Careful control is especially important in cases of life-threatening bleeding or major surgery.1

Administration

IV Administration

Administer by slow IV injection.1 (See Rate of Administration under Dosage and Administration.)

Reconstitute with sterile water for injection (supplied by manufacturer).1 Allow drug vial and prefilled diluent syringe to warm to room temperature prior to reconstitution.1 Gently swirl vial until powder is completely dissolved; do not shake.1 Resultant solution should be clear to slightly opalescent and colorless; do not use if cloudy, discolored, or particulate matter observed.1

Administer immediately or within 3 hours after reconstitution; do not refrigerate reconstituted solution.1

Do not administer reconstituted solution in the same tubing or container with other drugs.1

Consult manufacturer's labeling for specific instructions on reconstitution and preparation of antihemophilic factor (recombinant), Fc fusion protein.1

Administer over a period of several minutes; determine administration rate by patient's comfort level (not to exceed 10 mL/minute).1 2

Dosage

Dosage and potency expressed in terms of international units (IU, units) of antihemophilic factor activity.1 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.1 5 6 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%).1

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.1 215 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.1 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.1 Measure patient's factor VIII activity after a dose is given to verify calculated dose.1 215

If calculated dose is ineffective in achieving appropriate factor VIII levels, consider possibility of inhibitor development.1 215 (See Neutralizing Antibodies to Factor VIII under Cautions.)

Pediatric Patients

Higher doses or more frequent dosing may be required in patients <6 years of age because of increased clearance and shorter half-life.1 256 Dosage requirements in patients ≥6 years of age generally similar to those in adults.1

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.1

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).1

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.1 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.1

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.1 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.1 Once adequate wound healing achieved, continue therapy for at least 7 days to maintain target factor VIII levels.1

Children ≥6 years of age: Manufacturer recommends initial dosage of 50 units/kg every 4 days.1 Adjust dosage to 25–65 units/kg every 3–5 days based on response.1

Children <6 years of age: Manufacturer recommends initial dosage of 50 units/kg twice weekly.1 More frequent or higher doses up to 80 units/kg may be required.1 Adjust dosage to 25–65 units/kg every 3–5 days based on response.1

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.218

Individualize prophylactic dosage regimens; evaluate patients periodically to determine continued need for prophylaxis.1 218 Optimum duration of prophylaxis unknown.218

Adults

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.1

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).1

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.1 Repeat dose every 24 hours for at least 1 day until healing is achieved.1

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.1 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.1 Once adequate wound healing achieved, continue therapy for at least 7 days to maintain target factor VIII levels.1

Manufacturer recommends initial dosage of 50 units/kg every 4 days.1 Adjust dosage within range of 25–65 units/kg every 3–5 days based on patient response.1

Individualize prophylactic dosage regimens; evaluate patients periodically to determine continued need for prophylaxis.1 218 Optimum duration of prophylaxis unknown.218

Contraindications

• Life-threatening hypersensitivity reactions (e.g., anaphylaxis) to antihemophilic factor (recombinant), Fc fusion protein or other components of the preparation.1

Warnings/Precautions

Neutralizing Antibodies to Factor VIII

Risk for development of neutralizing antibodies (inhibitors) to factor VIII following treatment with any antihemophilic factor preparation.1 215 250 255 Reported to occur in approximately 20–30% of patients with severe hemophilia A and 5–10% of those with mild to moderate disease.215

Monitor patients for development of inhibitors using appropriate clinical observation and laboratory tests.1 215 (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.1 215

Laboratory Monitoring

Monitor factor VIII levels using a validated test (e.g., one-stage clotting assay) to guide dosing and assess therapeutic response.1 6 215 Important to achieve and maintain adequate levels of factor VIII for effective hemostatic control during an acute bleeding episode or during surgery.1 6 215

Monitor for development of inhibitors.1 Perform appropriate laboratory test (i.e., Bethesda assay) to confirm presence of inhibitors.1 215 (See Neutralizing Antibodies to Factor VIII under Cautions.)

Sensitivity Reactions

Potential risk of hypersensitivity reactions, including anaphylaxis.1 If a hypersensitivity reaction occurs, discontinue drug immediately and initiate appropriate therapy.1

Specific Populations

Not known whether drug can cause fetal harm or affect reproductive capacity; use during pregnancy only when clearly needed.1

Not known whether distributed into human milk.1 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.1

Safety and efficacy evaluated in previously treated adolescents 12–18 years of age in principal efficacy study.1

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.1 256

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1

Common Adverse Effects

Arthralgia, malaise, myalgia, headache, rash.1

• Biosynthetic (recombinant DNA origin) preparation of blood coagulation factor VIII covalently linked to the Fc domain of IgG1.1 7 9 16 Fc portion prolongs half-life of factor VIII through interaction with the Fc neonatal receptor.1 7 8 9 Factor VIII portion is similar in structure and function to endogenous factor VIII.1

• Patients with hemophilia A have decreased levels of endogenous factor VIII, resulting in a hemorrhagic tendency and clinical manifestations such as bleeding into soft tissues, muscles, joints, and internal organs.1 215 Clinical severity and frequency of bleeding generally correlate with degree of deficiency of factor VIII activity.215 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.215

• Administration of antihemophilic factor (recombinant), Fc fusion protein increases plasma levels of factor VIII and temporarily corrects coagulation defect in patients with hemophilia A.1 215 Also may shorten aPTT, which is typically prolonged in such patients.1

• Produced by recombinant DNA technology in a human embryonic kidney (HEK) cell line; undergoes several purification processes (e.g., filtration, chromatography, detergent treatment) and is manufactured without proteins from human or animal sources.1 7 9

• Importance of advising patients to read the manufacturer-provided patient information and instructions for use.1 2

  Importance of patients reporting to their clinician any adverse reactions or other issues following administration of the drug.1

• Importance of advising patients to immediately contact a clinician or proceed to an emergency room if a hypersensitivity reaction occurs; early signs of such hypersensitivity include rash, urticaria, pruritus, chest tightness, wheezing, or swelling of the face.1

• Possible development of neutralizing antibodies (inhibitors); advise patients to inform clinician if they experience a lack of response to therapy.1

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

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

• Importance of informing patients of other important precautionary information.1 (See Cautions.)