Antihemophilic Factor (Recombinant), Fc-VWF-XTEN Fusion Protein-ehtl (Monograph)

Drug class: Hemostatics

Medically reviewed by Drugs.com on Mar 10, 2024. Written by ASHP.

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Introduction

Biosynthetic (recombinant DNA origin) preparation of blood coagulation factor VIII consisting of a single chain B-domain-deleted factor VIII covalently linked to the Fc domain of human immunoglobulin G (IgG), the FVIII-binding D'D3 domain of human von Willebrand factor (VWF), and 2 XTEN polypeptides.

Uses for Antihemophilic Factor (Recombinant), Fc-VWF-XTEN Fusion Protein-ehtl

Hemophilia A

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

On-demand treatment and control of bleeding episodes in adults and children with hemophilia A.

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

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

Compared with other standard or extended half-life factor VIII products, circulating half-life of antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl is approximately 3- to 4-fold longer.

The World Federation of Hemophilia and Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation published guidelines on the management of hemophilia. Guidelines generally support the use of factor VIII products for prophylaxis and treatment of bleeding in patients with hemophilia A.

Several antihemophilic factor concentrates are currently available in the US; these include a variety of recombinant and plasma-derived preparations. When selecting an appropriate antihemophilic factor preparation, consider patient- and drug-specific factors in addition to emerging data.

Not indicated for the treatment of von Willebrand disease.

Antihemophilic Factor (Recombinant), Fc-VWF-XTEN Fusion Protein-ehtl Dosage and Administration

General

Patient Monitoring

• Monitor factor VIII activity to individualize dosage and assess response to therapy. Ensure that adequate levels are attained and maintained.

• Monitor for the development of factor VIII inhibitors. Perform a Bethesda inhibitor assay if expected plasma factor VIII levels are not attained or bleeding is not controlled with recommended dosages.

Administration

Administer by slow IV injection.

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

Reconstitution

Reconstitute using the prefilled diluent syringe supplied by the manufacturer (containing 3 mL of sterile water for injection). Reconstitution of more than one vial of drug may be necessary to obtain the required dose.

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. Consult manufacturer's labeling for specific instructions on reconstitution and preparation.

Rate of Administration

Adults and adolescents >12 years of age: Determine rate of administration by the patient's comfort level, but do not exceed 1-2 minutes per vial.

Children <12 years of age: Do not exceed rate of 2–3 minutes per vial in those with body weight ≥20 kg; do not exceed rate of >6 minutes per vial in those with body weight <20 kg.

Dosage

Dosage and potency expressed in terms of international units (IU, units) of antihemophilic factor activity; one unit is equivalent to the amount of factor VIII activity in 1 mL of normal human plasma. Potency is determined by an activated partial thromboplastin time (aPTT)-based one-stage clotting assay. In general, the antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl factor VIII activity level is overestimated by the assay by approximately 2.5-fold.

Individualize dosage and duration of therapy based on the severity of factor VIII deficiency, location and extent of bleeding, and the patient's clinical and pharmacokinetic (e.g., half-life, in vivo recovery) response.

Estimate dosage required to achieve a particular percentage increase in plasma factor VIII with the following formula: Dosage (in units) = Body Weight (kg) × Desired Factor VIII Increase (IU/dL or % of normal) × 0.5 (IU/kg per IU/dL).

Determine the 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 the patient's factor VIII activity after a dose to verify calculated doses.

If the calculated dose is ineffective in achieving appropriate factor VIII levels, consider the possibility of neutralizing antibody (inhibitor) development.

Pediatric Patients

Hemophilia A

On Demand Treatment and Control of Bleeding Episodes

IV

For on-demand treatment and control of bleeding episodes, see Table 1 for recommended dosages.

When resuming prophylaxis (if applicable) after treatment of a bleed, it is recommended to allow an interval of at least 72 hours between the last 50 IU/kg dose for treatment of a bleed and resumption of prophylaxis dosing. Continue prophylaxis as usual based on the patient's regular schedule.

Perioperative Hemostatsis

IV

For perioperative hemostatsis, see recommended dosing in Table 2.

Routine Prophylaxis

IV

Initially, 50 IU/kg administered once weekly.

MASAC states that prophylactic therapy should be instituted at an early age (e.g., 1–2 years) prior to the onset of frequent bleeding. Evaluate patients periodically to determine continued need for such therapy.

Adults

Hemophilia A

On Demand Treatment and Control of Bleeding Episodes

IV

For on-demand treatment and control of bleeding episodes in adults, see Table 1 above for recommended dosages.

For resumption of prophylaxis (if applicable) after treatment of a bleed, it is recommended to allow an interval of at least 72 hours between the last 50 IU/kg dose for treatment of a bleed and resumption of prophylaxis dosing. Continue prophylaxis as usual on the patient's regular schedule.

Perioperative Hemostasis

IV

For perioperative hemostatsis in adults, see Table 2 above for recommended dosages.

Routine Prophylaxis

IV

Initially, 50 IU/kg administered once weekly.

MASAC states that prophylactic therapy should be instituted at an early age (e.g., 1–2 years) prior to the onset of frequent bleeding. Evaluate patients periodically to determine continued need for such therapy.

Cautions for Antihemophilic Factor (Recombinant), Fc-VWF-XTEN Fusion Protein-ehtl

Contraindications

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

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, are possible. Although not reported in the principal clinical study of the drug, consider the possibility of such reactions. If symptoms of a hypersensitivity reaction occur, discontinue drug immediately and initiate appropriate therapy.

Neutralizing Antibodies

Risk for development of neutralizing antibodies (inhibitors) to factor VIII following treatment with any antihemophilic factor preparation.

Monitor patients for development of inhibitors using appropriate clinical observation and laboratory tests. 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 activity with a validated test (e.g., one-stage clotting assay) to guide dosing and assess therapeutic response to therapy. 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. 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.

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 or if drug has any effects on breastfed infant or milk production. Consider known benefits of breast-feeding along with mother's need for antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl and any potential adverse effects of the drug or disease on the infant.

Pediatric Use

Safety and efficacy evaluated in previously treated pediatric patients <18 years of age.

Geriatric Use

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

Common Adverse Effects

Most common adverse effects (≥10%): headache, arthralgia.

Antihemophilic Factor (Recombinant), Fc-VWF-XTEN Fusion Protein-ehtl Pharmacokinetics

Distribution

Extent

Not known whether antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl is distributed into milk.

Elimination

Half-life

Following administration of a single 50-unit/kg dose given as an IV injection in adults and adolescents with hemophilia A, terminal half-life of the drug was approximately 48.2 and 44.6 hours in adults and adolescents (>12 to 18 years of age), respectively.

In children 6 to <12 years of age and children 1 to <6 years of age, the terminal half-life of the drug was approximately 42.4, and 39.9 hours, respectively, following administration of a single 50-unit/kg dose of the drug.

Average time to reach mean factor VIII activity of more than 40 IU/dL was approximately 4 days in adults and 3.6 days in adolescents.

FVIII activity over 10 IU/dL was maintained in 83.5% of adults and adolescents throughout the study.

In children <12 years of age, normal to near normal (>40 IU/dL) FVIII activity was maintained for 2 to 3 days and >10 IU/dL FVIII activity was maintained for approximately 6 to 7 days. The majority of children <12 years of age maintained FVIII activity in mild hemophilia range (>5 IU/dL) 7 days after dosing.

Stability

Storage

Parenteral

Powder for Injection

2–8°C in original package; do not freeze or expose to direct sunlight.

May store drug and diluent syringe at room temperature (≤30°C) for a single period of up to 6 months or until expiration date. Do not return product to refrigerator after storage at room temperature.

Reconstituted Solution

May store at room temperature (≤30°C); protect from direct sunlight. Use within 3 hours of reconstitution.

Actions

• Biosynthetic (recombinant DNA origin) preparation of blood coagulation factor VIII consisting of a single molecule of B-domain-deleted human coagulation factor VIII covalently linked to the Fc domain of human immunoglobulin G₁ (IgG₁), the FVIII-binding D'D3 domain of human von Willebrand factor (VWF), and 2 XTEN polypeptides.

• 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. Clinical severity and frequency of bleeding generally correlate with degree of deficiency of factor VIII activity. 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.

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

• Produced by recombinant DNA technology in a human embryonic kidney (HEK) cell line and undergoes a series of purification and viral inactivating/removal processes.

Advice to Patients

• Advise patients to read the manufacturer-provided patient information and instructions for use.

• Advise patients to report any adverse reactions or other issues following administration of antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl to their clinician.

• Advise 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.

• Inform patients of the possible development of neutralizing antibodies (inhibitors); advise patients to inform clinician if they experience a lack of response to antihemophilic factor (recombinant), Fc fusion protein-ehtl therapy.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

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