Coagulation Factor IX (recombinant), Glycopegylated (Monograph)

Drug class: Hemostatics

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

Introduction

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

Uses for Coagulation Factor IX (recombinant), Glycopegylated

Hemophilia B

Routine prophylaxis to reduce the frequency of bleeding episodes in adults and children with hemophilia B (congenital factor IX deficiency; Christmas disease). Designated an orphan drug by FDA for such use.

Also used as on-demand treatment and control of bleeding episodes in patients with hemophilia B and for the maintenance of hemostasis in such patients undergoing surgery.

Compared with other preparations of recombinant factor IX, coagulation factor IX (recombinant), glycoPEGylated is conjugated to a 40-kDa polyethylene glycol molecule, which slows down its removal from circulation and prolongs the drug's half-life.

Several factor IX 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 Bleeding Disorders Foundation recommends preferential use of recombinant factor IX preparations because of their potentially superior safety profile with respect to pathogen transmission. Other experts (e.g., World Federation of Hemophilia) state that choice of preparation should be determined by local criteria. When selecting an appropriate factor IX preparation, consider characteristics of each clotting factor concentrate, individual patient variables, patient/provider preference, and emerging data.

Not indicated for induction of immune tolerance in patients with hemophilia B.

Coagulation Factor IX (recombinant), Glycopegylated Dosage and Administration

General

Patient Monitoring

Monitor factor IX activity by the one-stage clotting assay to individualize dosage and assess response to therapy.
Monitor for the development of inhibitors with clinical observation and appropriate laboratory tests during factor IX replacement therapy.

Other General Considerations

Initiate therapy under supervision of a clinician experienced in the treatment of hemophilia B.

Administration

IV Administration

Administer by slow IV injection.

Must reconstitute prior to use.

Reconstitution

Reconstitute lyophilized powder with contents of prefilled diluent syringe provided by manufacturer.

Allow drug vial and prefilled diluent syringe to warm to room temperature prior to reconstitution.

Add the diluent to drug vial, using the vial adapter, according to the instructions provided in the packaging. After addition of diluent, gently swirl vial to dissolve powder completely.

Administer immediately after reconstitution. If not used immediately after reconstitution, store solution in the vial with the vial adapter and the syringe attached, at room temperature (≤30°C). Discard unused solution >4 hours after reconstitution.

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

Rate of Administration

Administer by slow IV injection over 1–4 minutes.

Dosage

Dose (potency) expressed in terms of international units (IU) of factor IX activity. Potency is determined by a one-stage clotting assay calibrated against World Health Organization (WHO) standard. Each vial states the actual factor IX potency in IU on the label.

Dosage and duration of therapy required to establish hemostasis will vary with each patient based on the location and extent of bleeding and clinical condition. Carefully individualize dosage and monitor factor IX levels frequently during therapy.

Pediatric Patients

Hemophilia B

Prevention and Control of Bleeding

Dosing for on-demand treatment and control of bleeding episodes is provided in Table 1.

Table 1. Coagulation Factor IX (Recombinant) GlycoPEGylated Dosing for On-demand Treatment and Control of Bleeding Episodes1
Type of bleeding	Recommended dose (IU/kg body weight)	Additional Information
Minor and moderate (e.g., uncomplicated joint bleeds, minor muscular bleeds, mucosal or subcutaneous bleeds)	40	A single dose should be sufficient for minor and moderate bleeds; additional doses of 40 IU/kg can be given.
Major (e.g., intracranial, retroperitoneal, iliopsoas and neck bleeds, muscle bleeds with compartment syndrome, and bleeds associated with a significant decrease in the hemoglobin level)	80	Additional doses of 40 IU/kg can be given.

Perioperative Hemostasis

Dosing for perioperative management is provided in Table 2.

Table 2. Coagulation Factor IX (Recombinant) GlycoPEGylated Dosing for Perioperative Hemostasis1
Type of surgical procedure	Recommended dose (IU/kg body weight)	Additional Information
Minor (e.g., implanting pumps in subcutaneous tissue, skin biopsies, or simple dental procedures)	40	A single pre-operative dose should be sufficient; additional doses can be given if needed.
Major(e.g., body cavity is entered, mesenchymal barrier is crossed, fascial plane is opened, organ is removed, normal anatomy is operatively altered)	80 as a pre-operative dose, then 40 as clinically needed for management of bleeding.	Repeated doses of 40 IU/kg (in 1-3 day intervals) within the first week after major surgery may be administered; due to the long half-life of coagulation factor IX (recombinant), glycoPEGylated, the frequency of dosing in the post-surgical setting may be extended to once weekly after the first week until bleeding stops and healing is achieved.

Routine Prophylaxis

Recommended dose is 40 IU/kg body weight once weekly.

Adjust dosing regimen based on individual patient’s bleeding pattern and physical activity.

Adults

Hemophilia B

Prevention and Control of Bleeding

Dosing for on-demand treatment and control of bleeding episodes is provided in Table 1 above.

Perioperative Hemostasis

Dosing for perioperative management is provided in Table 2 above.

Routine Prophylaxis

Recommended dose is 40 IU/kg body weight once weekly.

Adjust dosing regimen based on individual patient’s bleeding pattern and physical activity.

Special Populations

Geriatric Patients

No specific dosage recommendations.

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Cautions for Coagulation Factor IX (recombinant), Glycopegylated

Contraindications

Patients who have known sensitivity to the drug or its components (including hamster proteins).

Warnings/Precautions

Hypersensitivity Reactions

Allergic-type hypersensitivity reactions, including anaphylaxis, have occurred. May contain traces of hamster proteins, which in some patients may cause allergic reactions. Early manifestations of hypersensitivity reactions, which can progress to anaphylaxis, may include angioedema, chest tightness, difficulty breathing, wheezing, urticaria, and itching.

Observe patients for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of exposure to the product. Discontinue use if allergic- or anaphylactic-type reactions occur, and initiate appropriate treatment. Evaluate any patient who experiences a hypersensitivity reaction for the presence of inhibitors.

Inhibitors

Risk of developing neutralizing antibodies to factor IX.

Measure factor IX inhibitor concentration if expected plasma factor IX activity levels are not attained or if bleeding is not controlled as expected with the administered dose.

Monitor patients regularly for development of inhibitors using clinical observations and laboratory tests.

Patients who develop inhibitors to factor IX may be at increased risk of anaphylaxis following re-exposure to the drug.

Thrombotic Events

Thromboembolic complications (e.g., DVT, PE, arterial thrombosis) reported.

Monitor for early signs of thrombotic and consumptive coagulopathy when administering to patients with liver disease, postoperative patients, newborn infants, or patients at risk of thrombosis or disseminated intravascular coagulation (DIC).

Weigh risk of thromboembolic complications against benefits of therapy in patients with (or at risk of) DIC or thromboembolism.

Nephrotic Syndrome

Nephrotic syndrome reported following immune tolerance induction therapy with factor IX products in hemophilia B patients who have factor IX inhibitors and a history of allergic reactions to factor IX.

Safety and efficacy of for immune tolerance induction not established.

Laboratory Tests

Use a chromogenic assay or selected one-stage clotting assay validated for use with coagulation factor IX (recombinant), glycoPEGylated. The one-stage clotting assay results can be significantly affected by the type of activated partial thromboplastin time (aPTT) reagent used, which can result in over- or underestimation of factor IX activity. Avoid the use of silica-based reagents, as some may overestimate the activity. Use a reference laboratory, if a validated one-stage clotting or chromogenic assay is not available locally.

Monitor for development of inhibitors with clinical observation and appropriate laboratory tests during factor IX replacement therapy. Perform the appropriate laboratory test (Bethesda assay) to detect the presence of factor IX inhibitors if expected plasma factor IX levels are not attained or bleeding is not controlled with the recommended dose.

Specific Populations

Pregnancy

Not known if the drug can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.

Lactation

No information regarding presence in human milk, effect on the breastfed infant, or effect on milk production.

Pediatric Use

Safety and efficacy evaluated in pediatric patients. Body weight-adjusted clearance observed to be higher for pediatric subjects than for adult subjects. However, in clinical trials no dose adjustment was needed in pediatric subjects who received a fixed dose of 40 IU/kg every week for routine prophylaxis.

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether or not they respond differently than younger subjects.

No adverse neurologic effects of PEG have been reported in adults who received the drug in clinical trials; however, use in older adults with baseline cognitive dysfunction not fully evaluated.

Common Adverse Effects

Previously treated patients (≥1%): itching and injection site reactions.

Previously untreated patients (≥1%): itching, injection site reactions, rash, factor IX inhibition, hypersensitivity, anaphylactic reactions.

Coagulation Factor IX (recombinant), Glycopegylated Pharmacokinetics

Absorption

Plasma Concentrations

At steady state, the mean peak level % of factor IX was 97.9 for adults, 82.8 for adolescents 13-17 years of age, 71.4 for children 7-12 years of age, and 65.5 for children ≤6 years of age. The trough level % of factor IX at steady state was 29.3, 23.7, 18.7, and 15.4 for these respective age groups.

Elimination

Elimination Route

Children have lower plasma levels compared with adults and adolescents due to increased clearance.

Half-life

The half life after a single dose of 40 IU/kg is 83 hours in adults, 89.4 hours in children 13 to 17 years of age, 76.3 hours in children 7 to 12 years of age, and 69.6 hours in children ≤6 years of age. At steady state for doses of 40 IU/kg given once weekly, the half-life is 114.9 hours for adults and 103.1 hours for children 13 to 17 years of age.

Stability

Storage

Parenteral

Powder for Infusion

Store vials and diluent syringes in their original package at 2–8°C prior to use for up to 24 months from the date of manufacture until the expiration date on the label. Do not freeze.

Store drug and diluent syringe at room temperature (not to exceed 30°C) for a single period of up to 6 months within the expiration date printed on the label. Record the date that the product was removed from refrigeration on the carton in the area provided. After storage at room temperature, do not place back into the refrigerator. Do not use drug and diluent beyond expiration date on the vial or 6 months after the date recorded on the carton, whichever is earlier.

Reconstituted Solution

If not used immediately after reconstitution, store the reconsituted solution in the vial, with the vial adapter and the syringe attached, at room temperature (≤30° C). Do not store for longer than 4 hours; discard any unused solution after this time.

Actions

Preparation of blood coagulation factor IX produced by recombinant DNA technology.
A purified recombinant human factor IX (rFIX) with a 40 kilodalton (kDa) polyethylene-glycol (PEG) conjugated to the protein. Once activated, the resulting rFIX has structural and functional properties similar to those of endogenous activated factor IX.
Increases plasma levels of factor IX and can temporarily correct the coagulation defect in hemophilia B patients.

Advice to Patients

Advise patients to read the FDA-approved patient labeling containing information and instructions for use.
Inform patients of the early signs of hypersensitivity reactions including rash, hives, itching, facial swelling, tightness of the chest, and wheezing. Advise patients to discontinue use of the product and contact their healthcare provider if these symptoms occur.
Advise patients to contact their healthcare provider for further treatment and/or assessment if they experience a lack of clinical response to coagulation factor IX therapy, as in some cases this may be a manifestation of an inhibitor.
Advise patients to contact their healthcare provider if they experience any thrombotic complications.
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 breastfeed.
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.

Coagulation Factor IX (Recombinant), glycoPEGylated
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV use	number of units indicated on label (nominally 500, 1000, 2000, 3000 international units [IU])	Rebinyn (supplied with prefilled diluent syringe and vial adapter)	Novo Nordisk