Introduction

Biosynthetic (recombinant DNA origin) preparation of blood coagulation factor IX (rIX-FP) genetically fused to recombinant albumin via a short, cleavable peptide derived from the activation peptide of native factor IX.

Uses for Factor IX (Recombinant), albumin fusion protein

Hemophilia B

On-demand control and prevention of bleeding episodes in patients with hemophilia B (congenital factor IX deficiency; Christmas Disease).

Maintenance of hemostasis in patients with hemophilia B undergoing surgery (i.e., perioperative management).

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

Routine prophylaxis (i.e., administration at regular intervals) to prevent or reduce frequency of hemorrhagic events. Such prophylactic therapy considered the current standard of care for patients with hemophilia B. Decreases frequency of spontaneous musculoskeletal hemorrhage, preserves joint function, and improves quality of life.

Circulating half-life of factor IX (recombinant), albumin fusion protein longer than that of unmodified recombinant or plasma-derived factor IX preparations; may allow for less frequent dosing and improved patient compliance with prophylactic regimens.

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 product, consider characteristics of each clotting factor concentrate, individual patient variables, patient/provider preference, and emerging data.

Manufacturer states that factor IX (recombinant), Fc fusion protein not indicated for induction of immune tolerance in patients with hemophilia B.

Factor IX (Recombinant), albumin fusion protein Dosage and Administration

General

• Individualize dosage and duration of therapy based on severity of factor IX deficiency, location and extent of bleeding, and patient’s clinical condition, age, and recovery of factor IX.

• Monitor factor IX activity (with one-stage clotting assay) to individualize dosage and assess response to therapy. Ensure that adequate levels are attained and maintained. (See Laboratory Monitoring under Cautions.)

Administration

IV Administration

Administer by slow IV injection. (See Rate of Administration under Dosage and Administration.)

Reconstitution and Administration

Reconstitute with sterile water for injection (provided by manufacturer).

Allow drug vial and diluent to warm to room temperature prior to reconstitution. After addition of diluent, gently swirl vial until powder is completely dissolved; do not shake. Resultant solution should be clear or yellow to colorless; do not use if cloudy, discolored or if particulate matter observed.

If more than 1 vial is required to prepare dose, may pool reconstituted contents of multiple vials into a single syringe.

Administer using sterile infusion set and syringe.

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

Administer immediately or within 4 hours after reconstitution.

Consult manufacturer’s labeling for specific instructions on reconstitution and preparation of factor IX (recombinant), albumin fusion protein.

Rate of Administration

Determine rate of administration by patient’s comfort level (not to exceed 10 mL/minute).

Dosage

Dosage (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. Administration of 1 unit/kg factor IX (recombinant), albumin fusion protein increases circulating levels of factor IX by 1.3 units/dL in patients ≥12 years of age and by 1 unit/dL in patients <12 years of age.

Estimate dose required to achieve a particular percentage increase in plasma factor IX using the following formula:

Dose (units) = body weight (in kg) x desired factor IX increase (in % of normal or units/dL) × reciprocal of recovery (in units/kg per 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 for various 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 factor IX activity after a dose is given to verify calculated dose.

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

Pediatric Patients

Hemophilia B

Higher doses or more frequent dosing may be required in pediatric patients because of increased clearance, shorter half-life, and lower recovery of factor IX.

On-Demand Control and Prevention of Bleeding

Minor or moderate bleeding (e.g., uncomplicated hemarthroses, muscle bleeding [except iliopsoas], oral bleeding): Administer appropriate dose to achieve factor IX levels of 30–60% of normal. Repeat every 48–72 hours until bleeding resolves and healing achieved; single injection usually sufficient.

Major bleeding (e.g., limb- or life-threatening hemorrhage; deep muscle bleeding, including iliopsoas; intracranial; retropharyngeal): Administer appropriate dose to achieve factor IX levels of 60–100% of normal; repeat every 48–72 hours for 7–14 days until bleeding resolves and healing achieved. Administer maintenance dose weekly.

Perioperative Hemostasis

Minor surgery (e.g., uncomplicated dental extraction): Administer appropriate dose to achieve a factor IX level of 50–80% of normal. Repeat every 48–72 hours until healing achieved; single injection usually sufficient.

Major surgery (e.g., intracranial, pharyngeal, retropharyngeal, retroperitoneal): Administer appropriate dose to achieve initial factor IX level of 60–100% of normal. Repeat every 48–72 hours for 7–14 days, or until bleeding resolves and healing achieved. Administer maintenance dose 1 or 2 times weekly.

Routine Prophylaxis

Pediatric patients <12 years of age: 40–55 units/kg every 7 days. Adjust dosage based on patient response.

Pediatric patients ≥12 years of age: Initially, 25–40 units/kg every 7 days. Patients well controlled on this regimen may be switched to 50–75 units/kg every 14 days. Adjust dosage based on patient response.

According to MASAC, institute prophylactic therapy at an early age (e.g., 1–2 years), prior to the onset of frequent bleeding; however, optimum duration of prophylaxis not known.

Individualize prophylactic dosage regimens; evaluate patients periodically to determine continued need for prophylaxis.

Adults

Hemophilia B

On-Demand Control and Prevention of Bleeding

Minor or moderate bleeding (e.g., uncomplicated hemarthroses, muscle bleeding [except iliopsoas], oral bleeding): Administer appropriate dose to achieve factor IX levels of 30–60% of normal. Repeat every 48–72 hours until bleeding resolves and healing achieved; single injection usually sufficient.

Major bleeding (e.g., limb- or life-threatening hemorrhage; deep muscle bleeding, including iliopsoas; intracranial; retropharyngeal): Administer appropriate dose to achieve factor IX levels of 60–100% of normal; repeat every 48–72 hours for 7–14 days until bleeding resolves and healing achieved. Administer maintenance dose weekly.

Perioperative Hemostasis

Minor surgery (e.g., uncomplicated dental extraction): Administer appropriate dose to achieve a factor IX level of 50–80% of normal. Repeat dose every 48–72 hours until healing achieved; single injection usually sufficient.

Major surgery (e.g., intracranial, pharyngeal, retropharyngeal, retroperitoneal): Administer appropriate dose to achieve initial factor IX level of 60–100% of normal. Repeat every 48–72 hours for 7–14 days, or until bleeding resolves and healing achieved. Administer maintenance dose 1 or 2 times weekly.

Routine Prophylaxis

Initially, 25–40 units/kg every 7 days. Patients well controlled on this regimen may be switched to 50–75 units/kg every 14 days. Adjust dosage based on patient response.

Individualize prophylactic dosage regimens; evaluate patients periodically to determine continued need for prophylaxis. Optimum duration of prophylaxis not known.

Contraindications

• Known history of life-threatening hypersensitivity to factor IX (recombinant), albumin fusion protein or any ingredient in the formulation (including hamster proteins).

Warnings/Precautions

Development of Inhibitors to Factor IX

Risk for development of inhibitors to factor IX following treatment with any factor IX preparation. Reported in <5% of patients with hemophilia B receiving factor IX concentrates.

Monitor patients regularly for development of inhibitors with appropriate clinical observation and laboratory tests. (See Laboratory Monitoring under Cautions.) Suspect presence of inhibitors if expected factor IX levels not achieved or bleeding not controlled with recommended dose, particularly in those who previously achieved a response.

Because of an association between inhibitor development and allergic reactions, evaluate for presence of inhibitors in any patient experiencing hypersensitivity. (See Hypersensitivity under Cautions.) In patients with inhibitors, increased risk of anaphylaxis following re-exposure to factor IX (recombinant), albumin fusion protein.

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

Thromboembolic Events

Risk of thromboembolic complications (e.g., pulmonary embolism, venous thromboembolism, arterial thrombosis).

Monitor for early manifestations of thromboembolism and consumptive coagulopathy in patients with hepatic disease, signs of fibrinolysis, or other risk factors for thromboembolism or disseminated intravascular coagulation (DIC).

Nephrotic Syndrome

Nephrotic syndrome reported following attempted immune tolerance induction in hemophilia B patients with factor IX inhibitors and history of allergic reactions. Safety and efficacy of factor IX (recombinant), albumin fusion protein for immune tolerance induction not established.

Laboratory Monitoring

Monitor factor IX levels (using aPTT-based one-stage clotting assay) to guide dosing and assess therapeutic response. Results can vary based on type of aPTT reagent; a kaolin-based reagent is likely to result in an underestimation of factor IX activity.

Monitor for development of inhibitors. Perform appropriate laboratory test (i.e., Bethesda assay) to confirm presence of an inhibitor. (See Development of Inhibitors to Factor IX under Cautions.)

Sensitivity Reactions

Hypersensitivity

Risk of hypersensitivity reactions, including anaphylaxis.

Closely observe patient for signs and symptoms of hypersensitivity (e.g., angioedema, chest tightness, hypotension, generalized urticaria, wheezing, dyspnea). If a hypersensitivity reaction occurs, immediately discontinue drug and initiate appropriate therapy.

Specific Populations

Pregnancy

No adequate and well-controlled studies of factor IX (recombinant), albumin fusion protein in pregnant women. Animal reproductive and development studies lacking. Use during pregnancy only when clearly needed.

Lactation

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

Pediatric Use

Safety, efficacy, and pharmacokinetics of factor IX (recombinant), albumin fusion protein evaluated in 32 pediatric patients. Prophylactic administration of factor IX (recombinant), albumin fusion protein successful in preventing spontaneous bleeding episodes; no differences in safety profile in pediatric patients compared with adults.

Compared with adults, pediatric patients may have higher body weight-adjusted clearance, shorter half-life, and lower factor IX recovery; higher doses or more frequent dosing may be required. (See Dosage under Dosage and Administration.)

Geriatric Use

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

Common Adverse Effects

Headache.

General

• Individualize dosage and duration of therapy based on severity of factor IX deficiency, location and extent of bleeding, and patient’s clinical condition, age, and recovery of factor IX.

• Monitor factor IX activity (with one-stage clotting assay) to individualize dosage and assess response to therapy. Ensure that adequate levels are attained and maintained. (See Laboratory Monitoring under Cautions.)

Administration

IV Administration

Administer by slow IV injection. (See Rate of Administration under Dosage and Administration.)

Reconstitution and Administration

Reconstitute with sterile water for injection (provided by manufacturer).

Allow drug vial and diluent to warm to room temperature prior to reconstitution. After addition of diluent, gently swirl vial until powder is completely dissolved; do not shake. Resultant solution should be clear or yellow to colorless; do not use if cloudy, discolored or if particulate matter observed.

If more than 1 vial is required to prepare dose, may pool reconstituted contents of multiple vials into a single syringe.

Administer using sterile infusion set and syringe.

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

Administer immediately or within 4 hours after reconstitution.

Consult manufacturer’s labeling for specific instructions on reconstitution and preparation of factor IX (recombinant), albumin fusion protein.

Rate of Administration

Determine rate of administration by patient’s comfort level (not to exceed 10 mL/minute).

Dosage

Dosage (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. Administration of 1 unit/kg factor IX (recombinant), albumin fusion protein increases circulating levels of factor IX by 1.3 units/dL in patients ≥12 years of age and by 1 unit/dL in patients <12 years of age.

Estimate dose required to achieve a particular percentage increase in plasma factor IX using the following formula:

Dose (units) = body weight (in kg) x desired factor IX increase (in % of normal or units/dL) × reciprocal of recovery (in units/kg per 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 for various 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 factor IX activity after a dose is given to verify calculated dose.

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

Pediatric Patients

Hemophilia B

Higher doses or more frequent dosing may be required in pediatric patients because of increased clearance, shorter half-life, and lower recovery of factor IX.

On-Demand Control and Prevention of Bleeding

Minor or moderate bleeding (e.g., uncomplicated hemarthroses, muscle bleeding [except iliopsoas], oral bleeding): Administer appropriate dose to achieve factor IX levels of 30–60% of normal. Repeat every 48–72 hours until bleeding resolves and healing achieved; single injection usually sufficient.

Major bleeding (e.g., limb- or life-threatening hemorrhage; deep muscle bleeding, including iliopsoas; intracranial; retropharyngeal): Administer appropriate dose to achieve factor IX levels of 60–100% of normal; repeat every 48–72 hours for 7–14 days until bleeding resolves and healing achieved. Administer maintenance dose weekly.

Perioperative Hemostasis

Minor surgery (e.g., uncomplicated dental extraction): Administer appropriate dose to achieve a factor IX level of 50–80% of normal. Repeat every 48–72 hours until healing achieved; single injection usually sufficient.

Major surgery (e.g., intracranial, pharyngeal, retropharyngeal, retroperitoneal): Administer appropriate dose to achieve initial factor IX level of 60–100% of normal. Repeat every 48–72 hours for 7–14 days, or until bleeding resolves and healing achieved. Administer maintenance dose 1 or 2 times weekly.

Routine Prophylaxis

Pediatric patients <12 years of age: 40–55 units/kg every 7 days. Adjust dosage based on patient response.

Pediatric patients ≥12 years of age: Initially, 25–40 units/kg every 7 days. Patients well controlled on this regimen may be switched to 50–75 units/kg every 14 days. Adjust dosage based on patient response.

According to MASAC, institute prophylactic therapy at an early age (e.g., 1–2 years), prior to the onset of frequent bleeding; however, optimum duration of prophylaxis not known.

Individualize prophylactic dosage regimens; evaluate patients periodically to determine continued need for prophylaxis.

Adults

Hemophilia B

On-Demand Control and Prevention of Bleeding

Minor or moderate bleeding (e.g., uncomplicated hemarthroses, muscle bleeding [except iliopsoas], oral bleeding): Administer appropriate dose to achieve factor IX levels of 30–60% of normal. Repeat every 48–72 hours until bleeding resolves and healing achieved; single injection usually sufficient.

Major bleeding (e.g., limb- or life-threatening hemorrhage; deep muscle bleeding, including iliopsoas; intracranial; retropharyngeal): Administer appropriate dose to achieve factor IX levels of 60–100% of normal; repeat every 48–72 hours for 7–14 days until bleeding resolves and healing achieved. Administer maintenance dose weekly.

Perioperative Hemostasis

Minor surgery (e.g., uncomplicated dental extraction): Administer appropriate dose to achieve a factor IX level of 50–80% of normal. Repeat dose every 48–72 hours until healing achieved; single injection usually sufficient.

Major surgery (e.g., intracranial, pharyngeal, retropharyngeal, retroperitoneal): Administer appropriate dose to achieve initial factor IX level of 60–100% of normal. Repeat every 48–72 hours for 7–14 days, or until bleeding resolves and healing achieved. Administer maintenance dose 1 or 2 times weekly.

Routine Prophylaxis

Initially, 25–40 units/kg every 7 days. Patients well controlled on this regimen may be switched to 50–75 units/kg every 14 days. Adjust dosage based on patient response.

Individualize prophylactic dosage regimens; evaluate patients periodically to determine continued need for prophylaxis. Optimum duration of prophylaxis not known.