Antihemophilic Factor (recombinant), PEGylated-aucl (Monograph)

Brand name: Jivi
Drug class: Hemostatics
VA class: BL500

Medically reviewed by Drugs.com on Dec 23, 2022. Written by ASHP.

Introduction

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

Uses for Antihemophilic Factor (recombinant), PEGylated-aucl

Hemophilia A

On-demand treatment and control of bleeding episodes in previously treated adults and adolescents ≥12 years of age with hemophilia A (congenital factor VIII deficiency; classic hemophilia).

Perioperative management of bleeding in previously treated adults and adolescents ≥12 years of age with hemophilia A undergoing surgery.

Routine prophylaxis (i.e., administration at regular intervals) in previously treated adults and adolescents ≥12 years of age 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 the 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-aucl. The extended half-life products provide longer lasting therapy, thus reducing treatment burden and maintaining higher factor trough levels to optimize 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 in pediatric patients <12 years of age because of the greater risk of hypersensitivity reactions.

Not indicated in previously untreated patients with hemophilia A.

Not indicated for the treatment of von Willebrand disease.

Related/similar drugs

tranexamic acid, desmopressin, Cyklokapron, DDAVP, Hemlibra, antihemophilic factor

Antihemophilic Factor (recombinant), PEGylated-aucl Dosage and Administration

General

Patient Monitoring

• Monitor factor VIII activity to individualize dosage and assess response to therapy. Use a validated chromogenic substrate assay or a selected validated one-stage clotting assay to monitor factor VIII activity. If a validated one-stage clotting or chromogenic assay is not available locally, then use of a reference laboratory is recommended. 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 episodes 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 IV infusion.

Must reconstitute lyophilized powder prior to administration.

Reconstitution

Reconstitute with diluent syringe supplied by the manufacturer (contains sterile water for injection). Allow drug vial and prefilled diluent syringe to warm to room temperature prior to reconstitution. After addition of the diluent, gently swirl vial until powder is completely dissolved; do not shake. Filter reconstituted product using vial adapter provided by manufacturer to remove potential particulate matter in the solution. Discard resulting solution if it is cloudy or contains particulate matter.

Administer immediately after reconstitution; if not used immediately, may store at room temperature for up to 3 hours.

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

Rate of Administration

Administer by IV infusion over a period of 1–15 minutes; the rate of administration may be adjusted based on the patient's response (not to exceed 2.5 mL/minute).

Dosage

Dosage expressed in terms of international units (IU, units). One IU is defined by the current World Health Organization (WHO) international standard for factor VIII concentrate.

Administration of 1 unit/kg antihemophilic factor (recombinant), PEGylated-aucl 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) × reciprocal of expected recovery (or observed recovery, if available) (e.g., 0.5 for a recovery of 2 IU/dL per IU/kg)

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)

Total recommended maximum dose per infusion is approximately 6000 IU (rounded to vial size).

Pediatric Patients

Hemophilia A

Dosage requirements in adolescent patients ≥12 years of age generally similar to those in adults.

On-Demand Treatment and Control of Bleeding

IV

Adolescents ≥12 years of age: Minor bleeding (e.g., early hemarthroses, minor muscle bleeding, oral bleeds): 10–20 units/kg to achieve a factor VIII level of 20–40% of normal; repeat dose every 24–48 hours until bleeding resolves.

Adolescents ≥12 years of age: Moderate bleeding (e.g., more extensive hemarthroses, muscle bleeding, hematoma): 15–30 units/kg to achieve factor VIII levels of 30–60% of normal; repeat dose every 24–48 hours until bleeding resolves.

Adolescents ≥12 years of age: Major bleeding (e.g., intracranial, intra-abdominal or intrathoracic hemorrhages, GI bleeding, CNS bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, iliopsoas sheath, or life- or limb-threatening hemorrhage): 30–50 units/kg to achieve factor VIII levels of 60–100% of normal; repeat dose every 8–24 hours until bleeding resolves.

Perioperative Hemostasis

IV

Adolescents ≥12 years of age: Minor surgery (e.g., dental extraction): 15–30 units/kg to achieve a pre- and post-operative factor VIII level of 30–60% of normal; repeat dose every 24 hours for at least 1 day until healing achieved.

Adolescents ≥12 years of age: Major surgery (e.g., intracranial, intra-abdominal, intrathoracic, or joint replacement): 40–50 units/kg to achieve a pre- and post-operative factor VIII level of 80–100% of normal. Repeat dose of 40–50 units/kg every 12–24 hours to maintain factor VIII levels within target range. Once adequate wound healing achieved, continue therapy for at least another 7 days to maintain a factor VIII level of 30–60% of normal.

Routine Prophylaxis of Bleeding Episodes

IV

Adolescents ≥12 years of age: Manufacturer recommends initial dosage of 30–40 units/kg twice weekly. May adjust dosage to 45–60 units/kg every 5 days based on response. Individualize prophylactic regimen; may further adjust dosage regimen to less or more frequent dosing based on bleeding episodes.

Adults

Hemophilia A

On-Demand Treatment and Control of Bleeding

IV

Minor bleeding (e.g., early hemarthroses, minor muscle bleeding, oral bleeds): 10–20 units/kg to achieve a factor VIII level of 20–40% of normal; repeat dose every 24–48 hours until bleeding resolves.

Moderate bleeding (e.g., more extensive hemarthroses, muscle bleeding, hematoma): 15–30 units/kg to achieve factor VIII levels of 30–60% of normal; repeat dose every 24–48 hours until bleeding resolves.

Major bleeding (e.g., intracranial, intra-abdominal or intrathoracic hemorrhages, GI bleeding, CNS bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, iliopsoas sheath, or life- or limb-threatening hemorrhage): 30–50 units/kg to achieve factor VIII levels of 60–100% of normal; repeat dose every 8–24 hours until bleeding resolves.

Perioperative Hemostasis

IV

Minor surgery (e.g., dental extraction): 15–30 units/kg to achieve a pre- and post-operative factor VIII level of 30–60% of normal; repeat dose every 24 hours for at least 1 day until healing is achieved.

Major surgery (e.g., intracranial, intra-abdominal, intrathoracic, or joint replacement): 40–50 units/kg to achieve a pre- and post-operative factor VIII level of 80–100% of normal. Repeat dose of 40–50 units/kg every 12–24 hours to maintain factor VIII levels within target range. Once adequate wound healing achieved, continue therapy for at least another 7 days to maintain a factor VIII level of 30–60% of normal.

Routine Prophylaxis of Bleeding Episodes

IV

Manufacturer recommends initial dosage of 30–40 units/kg twice weekly. May adjust dosage to 45–60 units/kg every 5 days based on response. Individualize prophylactic regimen; may further adjust dosage regimen to less or more frequent dosing based on bleeding episodes.

Prescribing Limits

Pediatric Patients

Hemophilia A

IV

Adolescents ≥12 years of age: Maximum infusion rate of 2.5 mL/minute.

Adults

Hemophilia A

IV

Maximum infusion rate of 2.5 mL/minute.

Cautions for Antihemophilic Factor (recombinant), PEGylated-aucl

Contraindications

• Known hypersensitivity to antihemophilic factor (recombinant) or any ingredient in the formulation, including polyethylene glycol (PEG), or murine or hamster protein.

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions, including severe allergic reactions, reported. Early signs of hypersensitivity reactions (e.g., chest or throat tightness, dizziness, mild hypotension, nausea) can progress to anaphylaxis.

Monitor patients for symptoms of hypersensitivity reactions.

If a hypersensitivity reaction occurs, immediately discontinue drug and initiate appropriate treatment.

May contain trace amounts of murine and hamster proteins; possibility of hypersensitivity reactions to these non-human mammalian proteins.

Hypersensitivity reactions also may be related to antibodies against polyethylene glycol (PEG).

Immunogenicity

Neutralizing antibodies (inhibitors) against factor VIII detected in patients receiving factor VIII preparations. Presence of inhibitory antibodies may manifest as inadequate response to treatment.

Carefully monitor patients for possible development of factor VIII inhibitors using appropriate clinical observation and laboratory tests. If expected plasma factor VIII activity levels not attained or if bleeding not controlled as expected with administered dose, measure factor VIII inhibitory antibody concentrations and suspect the presence of an inhibitor.

Immune Response to PEG

Clinical immune response associated with IgM anti-PEG antibodies, manifested as transient symptoms of acute hypersensitivity and/or loss of drug effect, observed primarily in pediatric patients <6 years of age. Anti-PEG IgM titers decreased over time to undetectable levels. No immunoglobulin class switching observed.

If loss of drug effect suspected, conduct testing for factor VIII inhibitors and factor VIII recovery.

A low post-infusion factor VIII level in the absence of detectable factor VIII inhibitors indicates that loss of drug effect is probably due to anti-PEG antibodies. If this occurs, discontinue antihemophilic factor (recombinant), PEGylated-aucl and switch to a previously effective factor VIII product.

Laboratory Monitoring

Monitor plasma factor VIII activity level with a validated chromogenic assay or a selected validated one-stage clotting assay. If a validated one-stage clotting or chromogenic assay is not available locally, use a local reference laboratory. Certain silica-based one-stage assays may underestimate factor VIII activity from antihemophilic factor (recombinant), PEGylated-aucl and some reagents (e.g., kaolin-based activators) may overestimate activity.

If bleeding is not uncontrolled or expected peak plasma factor VIII activity levels not attained, perform appropriate laboratory test (Bethesda inhibitor assay) to detect and measure concentrations of factor VIII inhibitors.

Specific Populations

Pregnancy

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

Lactation

Not known whether distributed into human milk. Consider known benefits of breastfeeding; mother's clinical need for antihemophilic factor (recombinant); and any potential adverse effects of the drug or underlying maternal condition on infant.

Pediatric Use

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

Manufacturer states safety and efficacy in pediatric patients <12 years of age not established. Use of the drug not indicated in this age group because of an increased risk of hypersensitivity reactions. Use also not indicated in previously untreated pediatric patients.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients. Other reported clinical experience has not identified differences in responses between geriatric and younger patients.

In general, use caution with dosage selection in geriatric patients, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, and of concomitant disease and other drug therapy.

Common Adverse Effects

Most common adverse reactions (greater than or equal to sign 5%): headache, cough, nausea, fever.

Drug Interactions

No formal drug interaction studies to date.

Antihemophilic Factor (recombinant), PEGylated-aucl Pharmacokinetics

Absorption

Plasma Concentrations

Following administration of single 25- and 60-unit/kg doses based on chromogenic assay, peak plasma concentrations of approximately 64.2 and 167 IU/dL, respectively, achieved.

Distribution

Extent

Not known whether distributed into human milk.

Elimination

Half-life

17.4–21.4 hours depending on specific assay following administration of single 25- and 60-unit/kg doses.

Stability

Storage

Parenteral

2–8°C in original package; do not freeze and protect from extreme exposure to light.

May store at room temperature (≤25°C) for a single period of up to 6 months or until expiration date on label, whichever is earlier. Do not place back into refrigerator after storage at room temperature.

Reconstituted solution: May store at room temperature for no longer than 3 hours.

Actions

• A third-generation recombinant DNA-derived, factor VIII concentrate that temporarily replaces the missing coagulation factor VIII in patients with hemophilia A.

• Active protein is a B-domain-deleted human coagulation factor VIII conjugated in a site-specific manner to a single (dual-branched) polyethylene glycol (PEG) molecule.

• Site-specific PEGylation reduces binding to the physiological factor VIII clearance receptors, and prolongs half-life of the drug.

• Produced by recombinant DNA technology in baby hamster kidney cells and manufactured without proteins from human or animal sources.

Advice to Patients

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

• Risk of hypersensitivity reactions (e.g., tightness of chest or throat, dizziness, mild hypotension, nausea). Advise patients of the early signs of hypersensitivity that can progress to anaphylaxis. If these symptoms occur, advise patients to discontinue the drug and seek immediate emergency treatment with resuscitative measures such as the administration of epinephrine and oxygen.

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

• Allergic reactions to polyethylene glycol (PEG), a component of antihemophilic factor (recombinant), PEGylated-aucl, are possible; advise patients to inform their clinician or treatment center if they experience a lack of clinical response from their usual dose.

• Advise patients to discard all equipment, including any unused product, in an appropriate container.

• Importance of consulting clinician prior to travel; advise patients to bring an adequate supply of antihemophilic factor (recombinant), PEGylated-aucl with them while traveling.

• 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. (See Cautions.)

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.

Reload page with references included

Medical Disclaimer