AHFS Class:

• Hemostatics 20:28.16

Generic Name(s):

• Antihemophilic Factor (recombinant), PEGylated

Antihemophilic factor (recombinant) pegylated is a biosynthetic (recombinant DNA origin) preparation of blood coagulation factor VIII consisting of full-length antihemophilic factor conjugated to polyethylene glycol (PEG).1

Hemophilia A

Antihemophilic factor (recombinant), PEGylated is used in adults and children with hemophilia A (congenital factor VIII deficiency; classic hemophilia) for the on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis (i.e., administration at regular intervals on an ongoing basis) to reduce the frequency of bleeding episodes.1

Antihemophilic factor (recombinant), PEGylated is not indicated for the treatment of von Willebrand disease.1

Antihemophilic factor (recombinant), PEGylated was evaluated in a multicenter, open-label, prospective, non-randomized clinical trial that compared hemostatic efficacy and safety of a twice-weekly prophylactic treatment regimen to on-demand treatment with the drug.1,2 A total of 137 previously treated male patients (12-65 years of age) with severe hemophilia A received at least one infusion with antihemophilic factor (recombinant), PEGylated in the study.1,2 Patients received either prophylactic treatment with the drug at a dosage of 40-50 IU/kg twice weekly or on-demand treatment at a dose of 10-60 IU/kg.1

A total of 591 bleeding episodes were treated with antihemophilic factor (recombinant), PEGylated (361 bleeding episodes in the on-demand group and 230 bleeding episodes in the routine prophylaxis group).1 Approximately 96% of bleeding episodes were successfully treated with 1 or 2 infusions of antihemophilic factor (recombinant), PEGylated in both the on-demand and prophylaxis groups, with hemostatic efficacy ratings of excellent (full relief of pain and objective signs of bleeding cessation) or good (definite pain relief and/or improvement in signs of bleeding).1,2 A total of 38% of patients experienced no bleeding episodes and 57% experienced no joint bleeding episodes in the prophylaxis arm.1 Prophylaxis with the drug resulted in a significantly lower annualized bleed rate compared with on-demand treatment.3 The mean annualized bleed rate in patients who received on-demand treatment was 40.8 compared to a mean annualized bleed rate of 4.7 in those who received routine prophylaxis with antihemophilic factor (recombinant), PEGylated.1

Effective prophylaxis with antihemophilic factor (recombinant), PEGylated in pediatric patients <12 years of age with severe hemophilia A was demonstrated in a separate pediatric trial.1 Patients received a prophylactic regimen of 40-60 IU/kg of antihemophilic factor (recombinant), PEGylated twice a week for 6 months.1 Among 66 patients who were treated with the drug (32 patients <6 years of age and 34 patients 6 to <12 years of age), 25 (38%) experienced no bleeding episodes, 44 (67%) experienced no spontaneous bleeding episodes, and 48 (73%) experienced no joint bleeding episodes.1 Of the 70 bleeding episodes during the pediatric trial, 91.4% were controlled with 1 or 2 infusions.1 Control of bleeding was rated excellent or good in 90% of bleeding episodes.1

Safety and efficacy of antihemophilic factor (recombinant), PEGylated during major surgical procedures (7 non-orthopedic surgeries, 14 orthopedic surgeries, 5 additional minor surgeries) were evaluated in 21 patients.1 Overall perioperative hemostatic efficacy was rated as excellent (blood loss less than or equal to that expected for the same type of procedure performed in a non-hemophilic patient) for all procedures with available assessments.1,3

Clinical Perspective

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 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%).215,218 Prophylaxis also may be considered in patients with mild or moderate hemophilia A depending on their risk of bleeding.215,218 Routine administration of coagulation factor concentrates has been shown to decrease the frequency of spontaneous musculoskeletal bleeding, preserve joint function, and improve quality of life.215 Episodic (“on-demand”) clotting factor therapy is no longer considered a long-term treatment option because it has not been shown to alter the natural history of hemophilia with regard to musculoskeletal damage and other bleeding-related complications.215

Prophylactic therapy should be instituted at an early age (ideally before 3 years of age) prior to the onset of frequent bleeding.218 Once prophylaxis is initiated, such therapy may need to be continued indefinitely, unless the patient develops neutralizing antibodies (inhibitors) to factor VIII and/or there is a lack of response to the drug.1,218 When making decisions regarding long-term prophylaxis, the risks and benefits should be evaluated and thoroughly discussed with the patient and/or their caregiver.218 The specific treatment strategy should be individualized based on the patient's age at the time of prophylaxis initiation, bleeding phenotype, joint status, individual pharmacokinetics, lifestyle, and preference for choice of therapy.215,218

Several antihemophilic factor concentrates are currently available in the US for the treatment of hemophilia A; these include a variety of plasma-derived and recombinant preparations.1,215,246 Among the commercially available factor VIII concentrates, the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation recommends preferential use of recombinant preparations because of their potentially superior safety profile with respect to pathogen transmission.218,246,247 Recombinant preparations include standard half-life and extended half-life products such as antihemophilic factor (recombinant), PEGylated.1,218 The extended half-life products were designed to provide longer lasting therapy, thus reducing treatment burden and maintaining higher factor trough levels to optimize prophylaxis.215 When selecting an appropriate antihemophilic factor preparation, consider characteristics of each clotting factor concentrate, individual patient variables, patient/provider preference, and emerging data.215,246,247

General

Patient Monitoring

• Monitor factor VIII activity using a one-stage clotting assay to individualize dosage and assess response to therapy.1 Adequate levels of factor VIII should be attained and maintained during therapy.1 Careful control of the dose is especially important in cases of life-threatening bleeding or major surgery.1
• Carefully monitor patients for development of factor VIII inhibitors using appropriate clinical observations and laboratory tests.1
• Monitor patients for signs and symptoms of hypersensitivity (e.g., chest or throat tightness, dizziness, mild hypotension, nausea).1

Administration

IV Administration

Antihemophilic factor (recombinant), PEGylated is administered by slow IV injection or IV infusion.1 (See Rate of Administration under Dosage and Administration.)

Store vials of antihemophilic factor (recombinant), PEGylated in their original container at 2-8°C prior to use; do not freeze and protect the drug from extreme exposure to light.1 The drug may be stored at room temperature (not to exceed 30°C) for a period of up to 3 months not to exceed the expiration date printed on the label.1 Record the date that the product was removed from refrigeration on the carton.1 After storage at room temperature, the product should not be returned to the refrigerator.1

Reconstitution

Prior to administration, antihemophilic factor (recombinant), PEGylated lyophilized powder must be reconstituted using the diluent (sterile water for injection) supplied by the manufacturer.1 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.1 After addition of the diluent, gently swirl the vial until the powder is completely dissolved; do not shake the vial.1 Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration.1 The resulting solution should be clear and colorless; discard the product if particulate matter or discoloration is observed.1

Following reconstitution, antihemophilic factor (recombinant), PEGylated should be administered as soon as possible.1 If not used immediately, the reconstituted solution should be stored at room temperature (protected from light) for up to 3 hours.1

Consult manufacturer's labeling for additional instructions on reconstitution and preparation of antihemophilic factor (recombinant), PEGylated.1

Rate of Administration

Administer antihemophilic factor (recombinant), PEGylated by slow IV injection or IV infusion over a period of ≤5 minutes (maximum infusion rate of 10 mL/minute).1

Dosage

Dosage and potency of antihemophilic factor (recombinant), PEGylated are 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.1 Calculation of the required dose of factor VIII is based on the empirical finding that 1 IU of factor VIII per kg body weight increases the plasma factor VIII level by 2 IU/dL.1

Hemophilia A

Individualize dosage and duration of antihemophilic factor (recombinant), PEGylated treatment based on the severity of factor VIII deficiency, location and extent of bleeding, and the patient's clinical condition.1 The dosage required to establish hemostasis will vary with each patient since there is considerable variability among patients in their pharmacokinetic and clinical responses.1 Because of increased clearance, dosage adjustment may be needed in children <12 years of age.1

Estimate the dose of antihemophilic factor (recombinant), PEGylated required for on-demand treatment and control of bleeding and perioperative management using the following formula:1

Required dose (IU) = body weight (kg) × desired factor VIII rise (% of normal or IU/dL) × 0.5 IU/kg per IU/dL)1

Estimate the expected in vivo peak increase using the following formula:1

Estimated increment of factor VIII (IU/dL or % of normal) = [Total dose (IU)/body weight (kg)] × 2 (IU/dL per IU/kg)1

The desired factor VIII level is determined 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 The patient's factor VIII activity should be measured after a dose to verify calculated doses.1 If the calculated dose is ineffective in achieving appropriate factor VIII levels, consider the possibility of neutralizing antibody (inhibitor) development.1

On-Demand Treatment and Control of Bleeding Episodes

For the on-demand treatment and control of minor bleeding episodes (e.g., early hemarthroses, mild muscle bleeding, mild oral bleeds) in adults and children with hemophilia A, an initial dose of 10-20 units/kg of antihemophilic factor (recombinant), PEGylated is recommended to achieve a factor VIII level of 20-40% of normal; doses should be repeated every 12-24 hours until bleeding resolves.1

For the on-demand treatment and control of moderate bleeding (e.g., muscle bleeding, moderate bleeding into the oral cavity, definite hemarthrosis, known trauma) in adults and children with hemophilia A, an initial dose of 15-30 units/kg of antihemophilic factor (recombinant), PEGylated is recommended to achieve factor VIII levels of 30-60% of normal; doses should be repeated every 12-24 hours until bleeding resolves.1

For the on-demand treatment and control of 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) in adults and children with hemophilia A, an initial dose of 30-50 units/kg of antihemophilic factor (recombinant), PEGylated is recommended to achieve a factor VIII level of 60-100% of normal; doses should be repeated every 8-24 hours until bleeding resolves.1

Perioperative Hemostasis

In adults and children with hemophilia A undergoing minor surgery (e.g., dental extraction), an initial dose of 30-50 units/kg of antihemophilic factor (recombinant), PEGylated is recommended within 1 hour prior to surgery to increase factor VIII level to 60-100% of normal.1 Doses should be repeated as needed until bleeding is resolved.1 Doses can be repeated after 24 hours if necessary.1

In adults and children with hemophilia A undergoing major surgery (e.g., intracranial, intra-abdominal, intrathoracic, or joint replacement), an initial antihemophilic factor (recombinant), PEGylated dose of 40-60 units/kg is recommended within 1 hour prior to surgery to achieve 100% factor VIII activity.1 Doses should be repeated every 8-24 hours (6-24 hours for patients <12 years of age) to maintain factor VIII levels within the range of 80-120% until adequate wound healing is achieved.1

Routine Prophylaxis of Bleeding Episodes

For routine prophylaxis of bleeding episodes in adults and adolescents ≥12 years of age with hemophilia A, the manufacturer recommends an initial antihemophilic factor (recombinant), PEGylated dosage of 40-50 units/kg twice weekly.1 In children <12 years of age, a dosage of 55 units/kg twice weekly is recommended up to a maximum of 70 units/kg.1 Adjust subsequent dose and dosing intervals based on patient response.1

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.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions are possible with antihemophilic factor (recombinant) pegylated.1 Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with other recombinant antihemophilic factor VIII products, including the parent molecule, antihemophilic factor (recombinant).1 Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus.1 If a hypersensitivity reaction occurs during treatment with antihemophilic factor (recombinant), PEGylated, immediately discontinue administration and initiate appropriate treatment.1

Immunogenicity

Formation of neutralizing antibodies (inhibitors) to factor VIII can occur following administration of antihemophilic factor (recombinant), PEGylated.1 Monitor patients regularly for the development of factor VIII inhibitors by appropriate clinical observation and laboratory tests.1 Perform an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected, or if bleeding is not controlled with the expected dose.1

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.1

Monitor for the development of factor VIII inhibitors.1 Perform the Bethesda inhibitor assay to determine if factor VIII inhibitor is present.1 If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with the expected dose of antihemophilic factor (recombinant), PEGylated, determine inhibitor levels using Bethesda Units (BU).1

Specific Populations

Pregnancy

There are no data with antihemophilic factor (recombinant), PEGylated use in pregnant women to inform a drug-associated risk.1 Animal reproduction studies have not been conducted with the drug.1 It is not known whether antihemophilic factor (recombinant), PEGylated can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.1

Lactation

It is not known whether antihemophilic factor (recombinant), PEGylated distributes into human milk; the effects of the drug on the breastfed infant or on milk production also are not known.1

Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for antihemophilic factor (recombinant), PEGylated and any potential adverse effects on the breastfed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of antihemophilic factor (recombinant), PEGylated have been evaluated in 91 previously treated pediatric patients 1 year to <18 years of age who received at least one dose of antihemophilic factor (recombinant), PEGylated as part of routine prophylaxis, on-demand treatment of bleeding episodes, or perioperative management.1 Adolescents 12 to <18 years of age were enrolled in the adult and adolescent safety and efficacy trial, and children <12 years of age were enrolled in a pediatric trial.1 The safety and efficacy of antihemophilic factor (recombinant), PEGylated in routine prophylaxis and the treatment of bleeding episodes were comparable between children and adults.1

Pharmacokinetic studies in children (<12 years) have demonstrated higher clearance, shorter half-life, and lower incremental recovery of factor VIII compared to adults.1 Because clearance (based on body weight per kg) has been demonstrated to be higher in children (<12 years), dose adjustment or more frequent dosing based on body weight may be needed in this population.1

Geriatric Use

Clinical studies of antihemophilic factor (recombinant), PEGylated did not include patients ≥65 years of age.1

Common Adverse Effects

The most common adverse reactions reported in ≥1% of patients in clinical studies were headache, diarrhea, rash, nausea, dizziness, and urticaria.1

Description

Antihemophilic factor (recombinant), PEGylated is a third-generation recombinant DNA-derived, factor VIII concentrate that temporarily replaces the missing coagulation factor VIII in patients with hemophilia A.1,246 Full-length human coagulation factor VIII is conjugated with one or more molecules of polyethylene glycol (PEG).1 Pegylation of the parent molecule reduces binding to the physiological factor VIII clearance receptor and prolongs half-life of the drug.1 The elimination half-life of antihemophilic factor (recombinant), PEGylated is 14.7 hours compared to an average half-life of 8-12 hours in non-fusion protein plasma-derived or other recombinant factor VIII products.3

Coagulation factor VIII is essential for blood clotting and maintenance of hemostasis.1,215 Administration of antihemophilic factor (recombinant), PEGylated to patients with hemophilia A results in increased plasma levels of factor VIII and temporarily corrects the coagulation defect in these patients.1 When antihemophilic factor (recombinant), PEGylated is used for replacement therapy, administration of 1 unit/kg generally increases plasma factor VIII activity by approximately 2 IU/dL.1 Treatment with antihemophilic factor (recombinant), PEGylated normalizes the activated partial thromboplastin time (aPTT), which is prolonged in patients with hemophilia A.1

Antihemophilic factor (recombinant), PEGylated is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell lines.1 The cell line used to produce the factor product does not contain any proteins derived from animal or human sources.1 Compared with plasma-derived antihemophilic factor preparations, recombinant preparations of antihemophilic factor are associated with a substantially reduced risk of transmission of bloodborne human viruses (e.g., human immunodeficiency virus [HIV], hepatitis A virus [HAV], hepatitis B virus [HBV], hepatitis C virus [HCV]).246,247

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.

1. Baxalta US. Adynovate^® antihemophilic factor (recombinant) PEGylated prescribing information. Lexington, MA; 2021 Jul.

2. Konkle BA, Stasyshyn O, Chowdary P et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood. 2015 Aug 27;126(9):1078-85. Epub 2015 Jul 8. [PubMedCentral][PubMed 26157075]

3. US Food and Drug Administration. Center for Drug Evaluation and Research. BLA supplement: clinical review for antihemophilic Factor (Recombinant), PEGylated. From FDA website. [Web]

215. World Federation of Hemophilia. Guidelines for the management of hemophilia 2nd edition. 2012. From the World Federation of Hemophilia website. [Web]

218. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendation concerning prophylaxis for hemophilia A and B with and without inhibitors (revised April 27, 2022). MASAC recommendation #267. From National Hemophilia Foundation website. [Web]

246. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders (revised March 2022). MASAC recommendation #272. From National Hemophilia Foundation website. [Web]

247. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendation regarding the use of recombinant clotting factor products with respect to pathogen transmission (May 6, 2014). MASAC recommendation #226. From National Hemophilia Foundation website. [Web]