Introduction

Biosynthetic (recombinant DNA origin) preparation of antihemophilic factor (blood coagulation factor VIII) conjugated to polyethylene glycol (PEG).

Uses for Antihemophilic Factor (recombinant), PEGylated

Hemophilia A

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

Perioperative management of bleeding in adults and children with hemophilia A undergoing surgery.

Routine prophylaxis (i.e., administration at regular intervals) in adults and children with hemophilia A to reduce frequency of bleeding episodes.

Prophylactic therapy with antihemophilic factor concentrates or other non-factor replacement product is considered the current standard of care for patients with severe hemophilia A (factor VIII activity <1%). Prophylaxis also may be considered in patients with mild or moderate hemophilia A depending on their risk of bleeding. Episodic (“on-demand”) clotting factor therapy may be associated with a higher risk of musculoskeletal damage and other bleeding-related complications and is no longer recommended as a long-term treatment option.

Individualize specific treatment strategy based on patient's age at the time of prophylaxis initiation, bleeding phenotype, joint status, individual pharmacokinetics, lifestyle, and preference for choice of therapy.

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. Recombinant preparations include standard half-life and extended half-life products such as antihemophilic factor (recombinant), PEGylated. Extended half-life products provide longer lasting therapy, reducing treatment burden and optimizing prophylaxis.

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 treatment of von Willebrand disease.

Antihemophilic Factor (recombinant), PEGylated Dosage and Administration

General

Patient Monitoring

• Monitor factor VIII activity using a one-stage clotting assay to individualize dosage and assess response to therapy. Adequate levels of factor VIII should be attained and maintained during therapy. Careful control of the dose is especially important in cases of life-threatening bleeding or major surgery.

• Carefully monitor patients for development of factor VIII inhibitors using appropriate clinical observations and laboratory tests.

• Monitor patients for signs and symptoms of hypersensitivity (e.g., chest or throat tightness, dizziness, mild hypotension, nausea).

Administration

IV Administration

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

Must reconstitute lyophilized powder prior to administration.

Reconstitution

Reconstitute with diluent (sterile water for injection) supplied by manufacturer.

Prior to reconstitution, allow the drug vial and diluent to warm to room temperature; after warming to room temperature, do not place the products back into the refrigerator.

After addition of diluent, gently swirl vial until powder is completely dissolved; do not shake.

Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration. The resulting solution should be clear and colorless; discard the product if particulate matter or discoloration is observed.

Administer as soon as possible following reconstitution. If not used immediately, store at room temperature for up to 3 hours and protect from light.

Consult manufacturer's labeling for additional instructions on reconstitution and preparation of antihemophilic factor (recombinant), PEGylated.

Rate of Administration

Administer over a period of ≤5 minutes (maximum infusion rate of 10 mL/minute).

Dosage

Dosage expressed in terms of international units (IU, units) of antihemophilic factor activity; one IU corresponds to the activity of factor VIII contained in one milliliter of normal human plasma.

Administration of 1 unit/kg antihemophilic factor (recombinant), PEGylated generally increases factor VIII activity by approximately 2%.

Individualize dosage and duration of treatment based on the severity of factor VIII deficiency, location and extent of bleeding, and the patient's clinical condition. The dosage required to establish hemostasis will vary with each patient since there is considerable variability among patients in their pharmacokinetic and clinical response.

Estimate required dose for on-demand treatment and control of bleeding and perioperative management using the following formula:

Required dose (IU) = body weight (kg) × desired factor VIII rise (% of normal or IU/dL) × 0.5 IU/kg per IU/dL)

Estimate expected in vivo peak increase using the following formula:

Estimated increment of factor VIII (IU/dL or % of normal) = [Total dose (IU)/body weight (kg)] × 2 (IU/dL per IU/kg)

Desired factor VIII level is determined 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.

Pediatric Patients

Hemophilia A

Because of increased clearance, dosage adjustment may be required in children <12 years of age.

On-Demand Treatment and Control of Bleeding Episodes

Minor bleeding episodes (e.g., early hemarthroses, mild muscle bleeding, mild oral bleeds): Initial dose of 10–20 units/kg recommended to achieve a factor VIII level of 20–40% of normal; repeat dose every 12–24 hours until bleeding resolves.

Moderate bleeding (e.g., muscle bleeding, moderate bleeding into the oral cavity, definite hemarthrosis, known trauma): Initial dose of 15–30 units/kg recommended to achieve factor VIII levels of 30–60% of normal; repeat dose every 12–24 hours until bleeding resolves.

Major significant bleeding (e.g., GI, intracranial, intra-abdominal or intrathoracic bleeding, CNS bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath, fractures, head trauma): Initial dose of 30–50 units/kg recommended to achieve a factor VIII level of 60–100% of normal; repeat dose every 8–24 hours until bleeding resolves.

Perioperative Hemostasis

Minor surgery (e.g., dental extraction): Initial dose of 30–50 units/kg recommended within 1 hour prior to surgery to increase factor VIII level to 60–100% of normal. Repeat dose after 24 hours as necessary until bleeding is resolved.

Major surgery (e.g., intracranial, intra-abdominal, intrathoracic, or joint replacement): Initial dose of 40–60 units/kg recommended within 1 hour prior to surgery to achieve 100% factor VIII activity. Repeat dose every 8–24 hours (6–24 hours for children <12 years of age) to maintain factor VIII levels within the range of 80–120% until adequate wound healing is achieved.

Routine Prophylaxis of Bleeding Episodes

Children <12 years of age: Initially, 55 units/kg twice weekly (up to a maximum of 70 units/kg). Adjust subsequent dose and dosing intervals based on patient response.

Adolescents ≥12 years of age: Initially 40–50 units/kg twice weekly. Adjust subsequent dose and dosing intervals based on patient response.

Adults

Hemophilia A

On-Demand Treatment and Control of Bleeding Episodes

Minor bleeding episodes (e.g., early hemarthroses, mild muscle bleeding, mild oral bleeds): Initial dose of 10–20 units/kg recommended to achieve a factor VIII level of 20–40% of normal; repeat dose every 12–24 hours until bleeding resolves.

Moderate bleeding (e.g., muscle bleeding, moderate bleeding into the oral cavity, definite hemarthrosis, known trauma): Initial dose of 15–30 units/kg recommended to achieve factor VIII levels of 30–60% of normal; repeat dose every 12–24 hours until bleeding resolves.

Major significant bleeding (e.g., GI, intracranial, intra-abdominal or intrathoracic bleeding, CNS bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath, fractures, head trauma): Initial dose of 30–50 units/kg recommended to achieve a factor VIII level of 60–100% of normal; repeat dose every 8–24 hours until bleeding resolves.

Perioperative Hemostasis

IV

Minor surgery (e.g., dental extraction): Initial dose of 30–50 units/kg recommended within 1 hour prior to surgery to increase factor VIII level to 60–100% of normal. Repeat dose after 24 hours as necessary until bleeding is resolved.

Major surgery (e.g., intracranial, intra-abdominal, intrathoracic, or joint replacement): Initial dose of 40–60 units/kg recommended within 1 hour prior to surgery to achieve 100% factor VIII activity. Repeat dose every 8–24 hours to maintain factor VIII levels within the range of 80–120% until adequate wound healing is achieved.

Routine Prophylaxis of Bleeding Episodes

IV

Initially 40–50 units/kg twice weekly. Adjust subsequent dose and dosing intervals based on patient response.

Prescribing Limits

Pediatric Patients

Hemophilia A

IV

Maximum infusion rate of 10 mL/minute.

Adults

Hemophilia A

IV

Maximum infusion rate of 10 mL/minute.

Contraindications

• History of anaphylactic reaction to antihemophilic factor (recombinant), PEGylated, the parent molecule (antihemophilic factor [recombinant]), or any ingredient in the formulation including murine or hamster protein.

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions are possible. Allergic-type hypersensitivity reactions, including anaphylaxis, reported with other recombinant antihemophilic factor VIII products, including the parent molecule, antihemophilic factor (recombinant).

Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus. If a hypersensitivity reaction occurs, immediately discontinue administration and initiate appropriate treatment.

Immunogenicity

Formation of neutralizing antibodies (inhibitors) to factor VIII can occur.

Monitor patients regularly for the development of factor VIII inhibitors by appropriate clinical observation and laboratory tests. Perform an assay that measures factor VIII inhibitor concentration if plasma factor VIII level fails to increase as expected, or if bleeding not controlled with expected dose.

Laboratory Monitoring

Monitor plasma factor VIII activity by performing a validated one-stage clotting assay to confirm that adequate factor VIII levels have been achieved and maintained.

Monitor for development of factor VIII inhibitors. Perform the Bethesda inhibitor assay to determine if factor VIII inhibitor is present. If expected factor VIII activity plasma levels are not attained, or if bleeding not controlled with expected dose, determine inhibitor levels using Bethesda Units (BU).

Specific Populations

Pregnancy

Not known whether drug can cause fetal harm or affect reproductive capacity.

Lactation

Not known whether distributed into human milk or whether the drug affects the breastfed infant or milk production.

Consider known benefits of breastfeeding along with mother's clinical need for antihemophilic factor (recombinant), PEGylated and any potential adverse effects on the breastfed infant from the drug or disease.

Pediatric Use

Evaluated in 91 previously treated pediatric patients 1 year to <18 years of age in clinical studies. Safety and efficacy in routine prophylaxis and treatment of bleeding episodes were comparable between children and adults.

Higher clearance, shorter half-life, and lower incremental recovery of factor VIII demonstrated in children <12 years of age compared with adults. Dose adjustment or more frequent dosing based on body weight may be needed in this pediatric population.

Geriatric Use

Clinical studies did not include patients ≥65 years of age.

Common Adverse Effects

Most common adverse reactions (≥1%): Headache, diarrhea, rash, nausea, dizziness, urticaria.

General

Patient Monitoring

• Monitor factor VIII activity using a one-stage clotting assay to individualize dosage and assess response to therapy. Adequate levels of factor VIII should be attained and maintained during therapy. Careful control of the dose is especially important in cases of life-threatening bleeding or major surgery.

• Carefully monitor patients for development of factor VIII inhibitors using appropriate clinical observations and laboratory tests.

• Monitor patients for signs and symptoms of hypersensitivity (e.g., chest or throat tightness, dizziness, mild hypotension, nausea).

Administration

IV Administration

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

Must reconstitute lyophilized powder prior to administration.

Reconstitution

Reconstitute with diluent (sterile water for injection) supplied by manufacturer.

Prior to reconstitution, allow the drug vial and diluent to warm to room temperature; after warming to room temperature, do not place the products back into the refrigerator.

After addition of diluent, gently swirl vial until powder is completely dissolved; do not shake.

Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration. The resulting solution should be clear and colorless; discard the product if particulate matter or discoloration is observed.

Administer as soon as possible following reconstitution. If not used immediately, store at room temperature for up to 3 hours and protect from light.

Consult manufacturer's labeling for additional instructions on reconstitution and preparation of antihemophilic factor (recombinant), PEGylated.

Rate of Administration

Administer over a period of ≤5 minutes (maximum infusion rate of 10 mL/minute).

Dosage

Dosage expressed in terms of international units (IU, units) of antihemophilic factor activity; one IU corresponds to the activity of factor VIII contained in one milliliter of normal human plasma.

Administration of 1 unit/kg antihemophilic factor (recombinant), PEGylated generally increases factor VIII activity by approximately 2%.

Individualize dosage and duration of treatment based on the severity of factor VIII deficiency, location and extent of bleeding, and the patient's clinical condition. The dosage required to establish hemostasis will vary with each patient since there is considerable variability among patients in their pharmacokinetic and clinical response.

Estimate required dose for on-demand treatment and control of bleeding and perioperative management using the following formula:

Required dose (IU) = body weight (kg) × desired factor VIII rise (% of normal or IU/dL) × 0.5 IU/kg per IU/dL)

Estimate expected in vivo peak increase using the following formula:

Estimated increment of factor VIII (IU/dL or % of normal) = [Total dose (IU)/body weight (kg)] × 2 (IU/dL per IU/kg)

Desired factor VIII level is determined 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.

Pediatric Patients

Hemophilia A

Because of increased clearance, dosage adjustment may be required in children <12 years of age.

On-Demand Treatment and Control of Bleeding Episodes

Minor bleeding episodes (e.g., early hemarthroses, mild muscle bleeding, mild oral bleeds): Initial dose of 10–20 units/kg recommended to achieve a factor VIII level of 20–40% of normal; repeat dose every 12–24 hours until bleeding resolves.

Moderate bleeding (e.g., muscle bleeding, moderate bleeding into the oral cavity, definite hemarthrosis, known trauma): Initial dose of 15–30 units/kg recommended to achieve factor VIII levels of 30–60% of normal; repeat dose every 12–24 hours until bleeding resolves.

Major significant bleeding (e.g., GI, intracranial, intra-abdominal or intrathoracic bleeding, CNS bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath, fractures, head trauma): Initial dose of 30–50 units/kg recommended to achieve a factor VIII level of 60–100% of normal; repeat dose every 8–24 hours until bleeding resolves.

Perioperative Hemostasis

Minor surgery (e.g., dental extraction): Initial dose of 30–50 units/kg recommended within 1 hour prior to surgery to increase factor VIII level to 60–100% of normal. Repeat dose after 24 hours as necessary until bleeding is resolved.

Major surgery (e.g., intracranial, intra-abdominal, intrathoracic, or joint replacement): Initial dose of 40–60 units/kg recommended within 1 hour prior to surgery to achieve 100% factor VIII activity. Repeat dose every 8–24 hours (6–24 hours for children <12 years of age) to maintain factor VIII levels within the range of 80–120% until adequate wound healing is achieved.

Routine Prophylaxis of Bleeding Episodes

Children <12 years of age: Initially, 55 units/kg twice weekly (up to a maximum of 70 units/kg). Adjust subsequent dose and dosing intervals based on patient response.

Adolescents ≥12 years of age: Initially 40–50 units/kg twice weekly. Adjust subsequent dose and dosing intervals based on patient response.

Adults

Hemophilia A

On-Demand Treatment and Control of Bleeding Episodes

Minor bleeding episodes (e.g., early hemarthroses, mild muscle bleeding, mild oral bleeds): Initial dose of 10–20 units/kg recommended to achieve a factor VIII level of 20–40% of normal; repeat dose every 12–24 hours until bleeding resolves.

Moderate bleeding (e.g., muscle bleeding, moderate bleeding into the oral cavity, definite hemarthrosis, known trauma): Initial dose of 15–30 units/kg recommended to achieve factor VIII levels of 30–60% of normal; repeat dose every 12–24 hours until bleeding resolves.

Major significant bleeding (e.g., GI, intracranial, intra-abdominal or intrathoracic bleeding, CNS bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath, fractures, head trauma): Initial dose of 30–50 units/kg recommended to achieve a factor VIII level of 60–100% of normal; repeat dose every 8–24 hours until bleeding resolves.

Perioperative Hemostasis

IV

Minor surgery (e.g., dental extraction): Initial dose of 30–50 units/kg recommended within 1 hour prior to surgery to increase factor VIII level to 60–100% of normal. Repeat dose after 24 hours as necessary until bleeding is resolved.

Major surgery (e.g., intracranial, intra-abdominal, intrathoracic, or joint replacement): Initial dose of 40–60 units/kg recommended within 1 hour prior to surgery to achieve 100% factor VIII activity. Repeat dose every 8–24 hours to maintain factor VIII levels within the range of 80–120% until adequate wound healing is achieved.

Routine Prophylaxis of Bleeding Episodes

IV

Initially 40–50 units/kg twice weekly. Adjust subsequent dose and dosing intervals based on patient response.

Prescribing Limits

Pediatric Patients

Hemophilia A

IV

Maximum infusion rate of 10 mL/minute.

Adults

Hemophilia A

IV

Maximum infusion rate of 10 mL/minute.

No formal drug interaction studies to date.