Factor IX (Recombinant) (Monograph)

Brand names: BeneFIX, Rixubis
Drug class: Hemostatics
VA class: BL500
Chemical name: Blood-coagulation factor IX (synthetic human)
CAS number: 181054-95-5

Medically reviewed by Drugs.com on Jan 16, 2024. Written by ASHP.

Introduction

Biosynthetic (recombinant DNA origin) preparation of blood coagulation factor IX.

Uses for Factor IX (Recombinant)

Hemophilia B

Prevention and control of bleeding episodes in patients with hemophilia B (congenital factor IX deficiency or Christmas disease).

Maintenance of hemostasis in patients with hemophilia B undergoing surgery.

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

Also used for routine prophylaxis (i.e., administration at regular intervals) to prevent or reduce frequency of bleeding events. Such prophylactic therapy currently considered the standard of care for patients with hemophilia B. Decreases frequency of spontaneous musculoskeletal hemorrhage, preserves joint function, and improves quality of 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 Hemophilia 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 the treatment of other coagulation factor deficiencies (e.g., factors II, VII, VIII, X) or for management of hemophilia A in patients with inhibitors to factor VIII.

Not indicated for reversal of coumarin-induced anticoagulation or for treatment of bleeding associated with low levels of liver-dependent coagulation factors.

Safety and efficacy of factor IX (recombinant) for induction of immune tolerance in patients with hemophilia B not established.

Factor IX (Recombinant) Dosage and Administration

General

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

• Individualize dosage and duration of therapy based on patient's age, severity and location of bleeding, degree of factor IX deficiency, desired factor IX levels, presence of factor IX inhibitors, and clinical and pharmacokinetic (e.g., half-life, incremental recovery) response. (See Laboratory Monitoring under Cautions.)

• Monitor factor IX activity (by one-stage clotting assay) to individualize dosage and assess response to therapy. (See Laboratory Monitoring under Cautions.)

Administration

IV Administration

Administer by slow (over several minutes) IV injection.

Has been given by continuous infusion^{† [off-label]}; however, manufacturers state that safety and efficacy of continuous infusions of factor IX (recombinant) not established. Thromboembolic events reported in some patients receiving continuous infusion of factor IX (recombinant). (See Thromboembolic Events under Cautions and also see Pediatric Use under Cautions.)

Consult manufacturers' labeling for specific information on reconstitution and administration of factor IX (recombinant) preparations.

Reconstitution and Administration of BeneFIX

Reconstitute lyophilized powder with prefilled diluent syringe (containing sodium chloride 0.234%) provided by manufacturer.

Prior to reconstitution, allow drug vial and prefilled diluent syringe to warm to room temperature.

After addition of diluent, gently swirl vial to dissolve powder completely.

Administer within 3 hours of reconstitution; discard any unused solution after this time.

The surfactant (polysorbate 80) contained in the reconstituted solution is known to increase the rate of extraction of diethylhexylphthalate (DEHP) from PVC; manufacturer states that this should be considered during the preparation and administration of the drug, including consideration of storage time elapsed in a PVC container following reconstitution.

Administer using the infusion set tubing and diluent syringe provided by the manufacturer, or a single sterile disposable plastic syringe. To minimize risk of RBC agglutination, administer carefully to prevent blood from entering tubing and syringe. If agglutination occurs, discard administration set, syringe, and remaining drug solution; resume administration using new materials.

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

For additional details on reconstitution and preparation, consult manufacturer's labeling.

Reconstitution and Administration of Rixubis

Reconstitute lyophilized powder with sterile water for injection provided by manufacturer.

Prior to reconstitution, allow drug vial and diluent to warm to room temperature.

After addition of diluent, gently swirl vial to dissolve powder completely.

Administer within 3 hours of reconstitution; discard any unused solution after this time.

For additional details on reconstitution and preparation, consult manufacturer's labeling.

Rate of Administration

Administer IV over several minutes.

BeneFIX: Individualize infusion rates based on patient response and comfort; slow infusion rate or discontinue therapy if any adverse reaction occurs.

Rixubis: Inject slowly; do not exceed rate of 10 mL/minute.

Dosage

Dose (potency) expressed in terms of international units (IU, units) of factor IX activity. Potency is determined by an aPTT-based one-stage clotting assay calibrated against a WHO standard.

Estimate initial dose using the following formula:

Dose (units) = body weight (in kg) x reciprocal of observed recovery (in units/kg per units/dL) × desired factor IX increase (in % of normal or units/dL)

Determine desired factor IX level by the clinical situation and severity of bleeding. For recommendations on target factor IX levels for a given clinical situation, see the specific dosage sections below. Incremental recovery should be based on patient's individual recovery determined by serial factor IX activity assays; however, an initial dose may be calculated empirically based on expected recovery values observed in clinical trials. In clinical trials, administration of 1 unit/kg BeneFIX generally increased factor IX levels by approximately 0.8% in adults and 0.7% in children <15 years of age; administration of 1 unit/kg Rixubis generally increased factor IX levels by approximately 0.9% in adults and adolescents ≥12 years of age and 0.7% in children <12 years of age.

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. Perform serial assays of factor IX activity (by the one-stage clotting assay) whenever possible to ensure that adequate levels of factor IX have been attained and maintained.

Adjust subsequent dosage based on individual clinical and pharmacokinetic (e.g., half-life, incremental recovery) response.

If calculated dose is ineffective in achieving appropriate factor IX levels, consider possibility that inhibitors may have developed. (See Development of Inhibitors to Factor IX under Cautions.)

When switching from plasma-derived preparations of factor IX to factor IX (recombinant), it may be necessary to increase dose of factor IX (recombinant). (See Plasma Concentrations under Pharmacokinetics.) Patients at the low end of the observed factor IX recovery may require an increase in dose (e.g., to as much as twice the initial empirically calculated dose according to the manufacturer of BeneFIX) to achieve intended increase in factor IX activity.

Pediatric Patients

Hemophilia B

BeneFIX

IV

Minor bleeding (e.g., uncomplicated hemarthroses, superficial muscle, soft tissue): Administer appropriate dose to achieve factor IX levels of 20–30% of normal; repeat every 12–24 hours for 1–2 days.

Moderate bleeding (e.g., intramuscular, soft tissue with dissection, mucous membranes, tooth extraction, hematuria): Administer appropriate dose to achieve factor IX levels of 25–50% of normal; repeat every 12–24 hours until bleeding resolves and healing begins, about 2–7 days.

Major bleeding (e.g., pharyngeal, retropharyngeal, retroperitoneal, CNS): Administer appropriate dose to achieve factor IX levels of 50–100% of normal; repeat every 12–24 hours for 7–10 days.

Patients undergoing surgery associated with moderate bleeding (e.g., dental extractions): Administer appropriate dose to achieve factor IX levels of 25–50% of normal; repeat every 12–24 hours until bleeding resolves and healing begins, about 2–7 days.

Patients undergoing surgery associated with major bleeding: Administer appropriate dose to achieve factor IX levels of 50–100% of normal; repeat every 12–24 hours for 7–10 days.

Routine prophylaxis: Manufacturer does not provide specific dosage regimen; however, in clinical studies, mean dose of 40.3 units/kg (given an average of twice a week) was administered in previously treated patients and mean dose of 73.3 units/kg (given at least once or twice weekly) was administered in previously untreated patients for primary or secondary prophylaxis. Individualize prophylactic regimens; evaluate patients periodically to determine continued need for prophylaxis.

Rixubis

IV

Minor bleeding (e.g., uncomplicated hemarthroses, superficial muscle, soft tissue): Administer appropriate dose to achieve target factor IX levels of 20–30% of normal; repeat every 12–24 hours for at least 1 day until healing is achieved.

Moderate bleeding (e.g., intramuscular, soft tissue with dissection, mucous membranes, hematuria): Administer appropriate dose to achieve a factor IX level of 25–50% of normal; repeat every 12–24 hours for 2–7 days until bleeding resolves and healing is achieved.

Major bleeding (e.g., pharyngeal, retropharyngeal, retroperitoneal, CNS): Administer appropriate dose to achieve a factor IX level of 50–100% of normal; repeat every 12–24 hours for 7–10 days until bleeding resolves and healing is achieved.

Patients undergoing minor surgery (e.g., dental extractions): Administer appropriate dose to achieve a factor IX level of 30–60% of normal; repeat dose every 24 hours for at least 1 day until healing is achieved.

Patients undergoing major surgery (e.g., intracranial, intraabdominal, intrathoracic, joint replacement): Administer appropriate dose to achieve a target factor IX level of 80–100%; repeat every 8–24 hours for 7–10 days until bleeding resolves and healing is achieved.

Routine prophylaxis in previously treated patients: In adolescents ≥12 years of age, manufacturer recommends initial dosage of 40–60 units/kg twice weekly. In pediatric patients <12 years of age, manufacturer recommends initial dosage of 60–80 units/kg twice weekly. Adjust dosage based on patient's age, bleeding pattern, and physical activity. Individualize prophylactic regimens; evaluate patients periodically to determine continued need for prophylaxis.

Adults

Hemophilia B

BeneFIX

IV

Minor bleeding (e.g., uncomplicated hemarthroses, superficial muscle, soft tissue): Administer appropriate dose to achieve factor IX levels of 20–30% of normal; repeat every 12–24 hours for 1–2 days.

Moderate bleeding (e.g., intramuscular, soft tissue with dissection, mucous membranes, dental extractions, hematuria): Administer appropriate dose to achieve factor IX levels of 25–50% of normal; repeat every 12–24 hours until bleeding resolves and healing begins, about 2–7 days.

Major bleeding (e.g., pharyngeal, retropharyngeal, retroperitoneal, CNS): Administer appropriate dose to achieve factor IX levels of 50–100% of normal; repeat every 12–24 hours for 7–10 days.

Perioperative hemostasis: For surgery associated with moderate bleeding (e.g., dental extractions), administer appropriate dose to achieve factor IX levels of 25–50% of normal; repeat every 12–24 hours until bleeding resolves and healing begins, about 2–7 days. For surgery associated with major bleeding, administer appropriate dose to achieve factor IX levels of 50–100% of normal; repeat every 12–24 hours for 7–10 days.

Routine prophylaxis: Manufacturer does not provide specific dosage regimen; however, in clinical studies, a mean dose of 40.3 units/kg (given an average of twice a week) was administered in previously treated patients and a mean dose of 73.3 units/kg (given at least once or twice weekly) was administered in previously untreated patients for primary or secondary prophylaxis. Individualize prophylactic regimens; evaluate patients periodically to determine continued need for prophylaxis.

Rixubis

IV

Minor bleeding (e.g., uncomplicated hemarthroses, superficial muscle, soft tissue): Administer appropriate dose to achieve target factor IX levels of 20–30% of normal; repeat every 12–24 hours for at least 1 day until healing is achieved.

Moderate bleeding (e.g., intramuscular, soft tissue with dissection, mucous membranes, hematuria): Administer appropriate dose to achieve a factor IX level of 25–50% of normal; repeat every 12–24 hours for 2–7 days until bleeding resolves and healing occurs.

Major bleeding (e.g., pharyngeal, retropharyngeal, retroperitoneal, CNS): Administer appropriate dose to achieve a factor IX level of 50–100% of normal; repeat every 12–24 hours for 7–10 days until bleeding resolves and healing is achieved.

Patients undergoing minor surgery (e.g., dental extractions): Administer appropriate dose to achieve a factor IX level of 30–60% of normal; repeat every 24 hours for at least 1 day until healing is achieved.

Patients undergoing major surgery (e.g., intracranial, intraabdominal, intrathoracic, joint replacement): Administer appropriate dose to achieve a target factor IX level of 80–100%; repeat every 8–24 hours for 7–10 days until bleeding resolves and healing is achieved.

Routine prophylaxis in previously treated patients: Manufacturer recommends initial dosage of 40–60 units/kg twice weekly. Adjust dosage based on patient's age, bleeding pattern, and physical activity. Individualize prophylactic regimens; evaluate patients periodically to determine continued need for prophylaxis.

Cautions for Factor IX (Recombinant)

Contraindications

• Life-threatening, immediate hypersensitivity (e.g., anaphylaxis) or known hypersensitivity to factor IX (recombinant) or any ingredient in the formulation, including hamster protein.

• Rixubis also contraindicated in patients with disseminated intravascular coagulation (DIC) or signs of fibrinolysis.

Warnings/Precautions

Warnings

Thromboembolic Events

Risk of thromboembolic complications. Peripheral thrombophlebitis, DVT, and life-threatening superior vena cava syndrome (in critically ill neonates) reported with at least one preparation of factor IX (recombinant); in several cases, patients received the drug by continuous infusion^{† [off-label]} sometimes via a central venous catheter. (See Pediatric Use under Cautions.)

Monitor for early manifestations of thromboembolic and consumptive coagulopathy in patients with hepatic disease, signs of fibrinolysis, or other risk factors for thromboembolism or DIC. (See Contraindications under Cautions.) Also monitor during perioperative or postoperative period for such events. Weigh risk of thromboembolism against benefits of therapy in patients with (or at risk of) DIC or thromboembolism.

Nephrotic Syndrome

Nephrotic syndrome reported following immune tolerance induction with factor IX-containing preparations in patients with hemophilia B who have factor IX inhibitors and a history of hypersensitivity to factor IX.

Safety and efficacy of factor IX (recombinant) for immune tolerance induction not established.

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions, including bronchospastic reactions and anaphylaxis, reported. Manifestations have included pruritus, rash, urticaria, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, generalized discomfort, and fatigue.

Increased risk in patients with certain genetic mutations of factor IX and/or those with inhibitors to factor IX. Up to 50% of hemophilia B patients with inhibitors to factor IX may experience a severe hypersensitivity reaction, including anaphylaxis, to factor IX concentrates.

Closely observe for hypersensitivity reactions, especially during initial exposure to the drug. Administer initial (e.g., approximately 10–20) infusions in a hospital or clinic setting where severe allergic reactions can be managed. If manifestations of hypersensitivity or anaphylaxis occur, discontinue drug immediately and initiate appropriate therapy.

Evaluate any patient who experiences a hypersensitivity reaction to factor IX (recombinant) for presence of inhibitors. (See Development of Inhibitors to Factor IX under Cautions.)

Commercially available preparations of factor IX (recombinant) (BeneFIX, Rixubis) contain trace amounts of hamster proteins; possibility of hypersensitivity reactions to these nonhuman mammalian proteins. (See Contraindications.)

General Precautions

Development of Inhibitors to Factor IX

Risk for development of neutralizing antibodies (inhibitors) to factor IX following treatment with factor IX preparations. Inhibitors reported in about 1–5% of patients with hemophilia B, usually within the first 10–20 days of treatment. Patients with certain genetic mutations of the factor IX gene may be at higher risk of inhibitor development and of experiencing a hypersensitivity reaction. (See Hypersensitivity Reactions under Cautions.)

High-titer inhibitors observed in a few previously untreated pediatric patients receiving BeneFIX; may require use of an alternative treatment to factor IX replacement therapy.

Neutralizing antibodies to factor IX not reported to date with Rixubis; however, inhibitor formation is a concern with any clotting factor therapy.

Monitor regularly for development of inhibitors with appropriate clinical observation and laboratory tests. Suspect presence of inhibitors if expected factor IX levels not achieved or bleeding is not controlled with a recommended dose.

Patients who develop inhibitors may be at increased risk of anaphylaxis following re-exposure to factor IX (recombinant). (See Hypersensitivity Reactions under Cautions.)

Consultation with a hemophilia treatment center strongly recommended for patients with inhibitors.

Laboratory Monitoring

Monitor factor IX levels to guide dosing and assess therapeutic response. Use of one-stage clotting assay recommended.

Monitor for development of inhibitors (with clinical observation and appropriate laboratory tests). (See Development of Inhibitors to Factor IX under Cautions.) If expected plasma factor IX levels are not attained or bleeding is not controlled with the recommended dose, perform appropriate laboratory test (Bethesda assay) to detect presence of factor IX inhibitors.

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether distributed into human milk; use with caution.

Pediatric Use

Safety, efficacy, and pharmacokinetics of BeneFIX evaluated in previously treated and previously untreated pediatric patients <15 years of age; on average, in vivo recovery of factor IX is lower in such pediatric patients than in older individuals and dosage adjustments may be necessary.

Safety, efficacy, and pharmacokinetics of Rixubis evaluated in previously treated pediatric patients <12 years of age; on average, in vivo recovery of factor IX is lower in such pediatric patients than in older individuals and dosage adjustments may be necessary.

High-titer inhibitors detected in several pediatric patients receiving BeneFIX who had no prior exposure to factor IX preparations; these patients were withdrawn from study.

Rare postmarketing reports of critically ill neonates who experienced thrombotic events, including life-threatening superior vena cava syndrome, while receiving continuous infusions of BeneFIX through a central venous catheter. (See Thromboembolic Events under Cautions.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients. Individualize dosage.

Common Adverse Effects

BeneFIX: Headache, dizziness, nausea, injection site reactions/pain, skin-related hypersensitivity reactions (e.g., rash, hives).

Rixubis: Dysgeusia, pain in extremity, positive furin antibody test.

Drug Interactions

No formal drug interaction studies to date.

Factor IX (Recombinant) Pharmacokinetics

Absorption

Plasma Concentrations

In vivo recovery of factor IX following IV administration of 50 units/kg factor IX (recombinant) as the BeneFIX preparation was approximately 28% lower than that achieved following administration of equivalent dose of plasma-derived factor IX; difference presumably due to structural modifications of factor IX (recombinant).

Decreased in vivo recovery in pediatric patients ≤15 years of age compared with patients >15 years of age. Incremental recovery of Rixubis in pediatric patients <12 years of age approximately 22% lower than in older individuals; mean incremental recovery lower in younger (<6 years of age) versus older (6–12 years of age) pediatric patients.

Pharmacokinetic profiles of the 2 currently available preparations of factor IX (recombinant) (BeneFIX and Rixubis) appear to be comparable.

Distribution

Extent

Readily diffuses through interstitial fluid; distributes through both intravascular and extravascular compartments.

Circulates in plasma as unbound drug.

Binds rapidly and reversibly to vascular endothelium.

Not known whether factor IX (recombinant) crosses the placenta or is distributed into milk.

Elimination

Elimination Route

Clearance correlates with body weight; generally increases through adolescence, then stabilizes during adulthood. Clearance of Rixubis is higher in younger (<6 years of age) versus older (6–12 years of age) pediatric patients.

Half-life

Half-life of BeneFIX is approximately 18–24 hours in adults and approximately 20–21 hours in pediatric patients.

Half-life of Rixubis is approximately 26.7 hours in adults and adolescents ≥12 years of age; in pediatric patients, half-life is approximately 23 hours for those 6–11 years of age and approximately 28 hours for those < 6 years of age.

Stability

Storage

Parenteral

Powder for Infusion

BeneFIX: Store at room temperature (≤30°C) or under refrigeration (2–8°C); avoid freezing to prevent damage to diluent syringe.

Rixubis: Store at 2–8°C for up to 24 months; do not freeze. May store at room temperature (≤30°C) for a period of up to 12 months; once stored at room temperature, do not return to refrigerator.

May store reconstituted solution of BeneFIX or Rixubis at room temperature prior to administration; use solution within 3 hours of reconstitution.

Actions

• Biosynthetic (recombinant DNA origin) preparation of blood coagulation factor IX.

• Factor IX is essential for blood clotting and maintenance of hemostasis.

• Patients with hemophilia B (Christmas disease) have decreased levels of endogenous factor IX, 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 in patients with hemophilia B correlate with the degree of deficiency of factor IX activity. Patients with mild hemophilia B 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 factor IX (recombinant) to patients with hemophilia B results in increased plasma levels of factor IX and temporarily corrects coagulation defect. Treatment also may normalize aPTT, which is typically prolonged in patients with hemophilia B.

• Similar in structure and function to plasma-derived factor IX, but associated with substantially reduced risk of transmission of bloodborne human viruses (e.g., HIV, HAV, HBV, HCV).

• Produced by recombinant DNA technology in a mammalian cell expression system using several purification and virus-inactivating/removal processes (e.g., chromatography, nanofiltration, solvent/detergent). Manufactured without animal or human components.

Advice to Patients

• Importance of patients reporting to their clinician any adverse effects or problems following administration of factor IX (recombinant).

• Importance of discontinuing therapy and immediately informing a clinician if hives, generalized urticaria, chest tightness, difficulty in breathing, wheezing, faintness, rapid heart rate, low BP, swelling of the face, or other manifestations of a hypersensitivity reaction or anaphylaxis occur or, alternatively, seeking immediate emergency care depending on the severity of such a reaction.

• Possible development of inhibitors; importance of patients informing a clinician if they experience a lack of response to factor IX (recombinant) therapy.

• Advise patients to always follow the specific instructions (e.g., for storage, reconstitution, and administration) given by their clinician.

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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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