Introduction

Biosynthetic (recombinant DNA origin) preparation of blood coagulation factor IX covalently linked to the Fc domain of human immunoglobulin G₁ (IgG₁).

Uses for Factor IX (Recombinant), Fc fusion protein

Hemophilia B

On-demand treatment and control of hemorrhagic episodes in patients with hemophilia B (congenital factor IX deficiency, or Christmas disease). Designated an orphan drug by FDA for such use.

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

Routine prophylaxis (i.e., administration at regular intervals on an ongoing basis) to reduce frequency of hemorrhagic events. Such prophylactic therapy with factor IX concentrates 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.

Half-life of factor IX (recombinant), Fc fusion protein longer than that of conventional preparations of recombinant factor IX; may allow for less frequent dosing and possibly improve 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 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.

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

General

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

• 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.)

Safety and efficacy of continuous IV infusions of the drug not established. Thromboembolic complications reported with use of other factor IX preparations administered as a continuous IV infusion. (See Thromboembolic Complications under Cautions.)

Reconstitution

Reconstitute with manufacturer-supplied prefilled diluent syringe. May require reconstitution of more than one vial depending on dose.

Allow drug vial and diluent syringe 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 to slightly opalescent and colorless; do not use if cloudy, discolored, or particulate matter observed.

Administer immediately or within 3 hours after reconstitution; do not refrigerate reconstituted solution.

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

Consult manufacturer's labeling for specific instructions on reconstitution and administration of factor IX (recombinant), Fc fusion protein.

Rate of Administration

Inject over a period of several minutes; determine administration rate by patient's comfort level (not to exceed 10 mL/minute).

Dosage

Dose (potency) expressed in terms of international units (IU, units) of factor IX activity. Potency determined by an aPTT-based one-stage clotting assay calibrated against a WHO standard. Administration of 1 unit/kg of factor IX (recombinant), Fc fusion protein increases factor IX levels by approximately 1%.

Individualize dosage and duration of therapy based on severity of factor IX deficiency, location and extent of bleeding, and patient's clinical and pharmacokinetic (e.g., in-vivo recovery, half-life) response.

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

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

Determine desired factor IX level by the clinical situation and severity of hemorrhage. For recommendations on target factor IX levels for a given clinical situation, see the specific dosage sections 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 of inhibitor development. (See Development of Inhibitors to Factor IX under Cautions.)

Pediatric Patients

Hemophilia B

Higher doses or more frequent dosing may be required in patients <12 years of age because of increased clearance, shorter half-life, and lower recovery of factor IX.

On-Demand Treatment and Control of Bleeding

Minor or moderate hemorrhage (e.g., uncomplicated hemarthroses, superficial muscle [except iliopsoas] without neurovascular compromise, superficial soft tissue, mucous membranes): Administer appropriate dose to achieve factor IX levels of 30–60% of normal; repeat dose every 48 hours until bleeding resolves.

Major hemorrhage (e.g., iliopsoas and deep muscle with neurovascular injury or substantial blood loss, pharyngeal, retropharyngeal, retroperitoneal, CNS): Administer appropriate dose to achieve factor IX levels of 80–100% of normal; consider repeat dose after 6–10 hours, and then every 24 hours for the first 3 days. After third day, may reduce dose and extend dosing frequency to every 48 hours or longer until bleeding resolves and healing is achieved.

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 24–48 hours as needed until bleeding resolves or healing is achieved; a single injection usually is sufficient.

Major surgery: Administer appropriate dose to achieve an initial factor IX level of 60–100% of normal. Consider repeat dose after 6–10 hours, and then every 24 hours for the first 3 days. After third day, may reduce dose and extend dosing frequency to every 48 hours or longer until bleeding resolves and healing is achieved.

Routine Prophylaxis

Initially, 50 units/kg once a week or 100 units/kg once every 10 days. Adjust dosage based on patient response.

MASAC states that prophylactic therapy should be instituted 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 Treatment and Control of Bleeding

Minor or moderate hemorrhage (e.g., uncomplicated hemarthroses, superficial muscle [except iliopsoas] without neurovascular compromise, superficial soft tissue, mucous membranes): Administer appropriate dose to achieve factor IX levels of 30–60% of normal; repeat every 48 hours until bleeding resolves.

Major hemorrhage (e.g., iliopsoas and deep muscle with neurovascular injury or substantial blood loss, pharyngeal, retropharyngeal, retroperitoneal, CNS): Administer appropriate dose to achieve factor IX levels of 80–100% of normal; consider repeat dose after 6–10 hours, and then every 24 hours for the first 3 days. After third day, may reduce dose and extend dosing frequency to every 48 hours or longer until bleeding resolves and healing is achieved.

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 24–48 hours as needed until bleeding resolves or healing is achieved; a single injection usually is sufficient.

Major surgery: Administer appropriate dose to achieve an initial factor IX level of 60–100% of normal. Consider repeat dose after 6–10 hours, and then every 24 hours for the first 3 days. After third day, may reduce dose and extend dosing frequency to every 48 hours or longer until bleeding resolves and healing is achieved.

Routine Prophylaxis

Initially, 50 units/kg once a week or 100 units/kg once every 10 days. Adjust dosage based on patient response.

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

Contraindications

• Known history of hypersensitivity (e.g., anaphylaxis) to factor IX (recombinant), Fc fusion protein or other components of the preparation.

Warnings/Precautions

Warnings

Development of Inhibitors to Factor IX

Risk for development of inhibitors (neutralizing antibodies) to factor IX following treatment with any factor IX preparation. Reported in less than 5% of patients with hemophilia B receiving factor IX concentrates; not reported in principal efficacy study with factor IX (recombinant), Fc fusion protein.

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 a hypersensitivity reaction. (See Hypersensitivity Reactions under Cautions.) Increased risk of anaphylaxis following re-exposure to factor IX (recombinant), Fc fusion protein in patients with inhibitors.

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

Thromboembolic Complications

Thromboembolic complications reported with use of factor IX products, particularly when administered by continuous IV infusion through a central venous catheter.

Administer factor IX (recombinant), Fc fusion protein by direct IV (“bolus”) injection only. (See Rate of Administration under Dosage and Administration.)

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 Reactions

Risk of hypersensitivity reactions, including anaphylaxis.

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

Specific Populations

Pregnancy

Category C.

Lactation

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

Pediatric Use

Safety and efficacy evaluated in patients ≥12 years of age in principal efficacy study; manufacturer states that efficacy in patients <12 years of age is supported by data in older pediatric patients. Additional pharmacokinetic and safety data are available in a limited number of pediatric patients 2–11 years of age.

Efficacy in patients <2 years of age may be extrapolated from pharmacokinetic data.

No specific safety issues identified in patients <12 years of age.

Geriatric Use

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

Common Adverse Effects

Headache, oral paresthesia.

General

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

• 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.)

Safety and efficacy of continuous IV infusions of the drug not established. Thromboembolic complications reported with use of other factor IX preparations administered as a continuous IV infusion. (See Thromboembolic Complications under Cautions.)

Reconstitution

Reconstitute with manufacturer-supplied prefilled diluent syringe. May require reconstitution of more than one vial depending on dose.

Allow drug vial and diluent syringe 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 to slightly opalescent and colorless; do not use if cloudy, discolored, or particulate matter observed.

Administer immediately or within 3 hours after reconstitution; do not refrigerate reconstituted solution.

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

Consult manufacturer's labeling for specific instructions on reconstitution and administration of factor IX (recombinant), Fc fusion protein.

Rate of Administration

Inject over a period of several minutes; determine administration rate by patient's comfort level (not to exceed 10 mL/minute).

Dosage

Dose (potency) expressed in terms of international units (IU, units) of factor IX activity. Potency determined by an aPTT-based one-stage clotting assay calibrated against a WHO standard. Administration of 1 unit/kg of factor IX (recombinant), Fc fusion protein increases factor IX levels by approximately 1%.

Individualize dosage and duration of therapy based on severity of factor IX deficiency, location and extent of bleeding, and patient's clinical and pharmacokinetic (e.g., in-vivo recovery, half-life) response.

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

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

Determine desired factor IX level by the clinical situation and severity of hemorrhage. For recommendations on target factor IX levels for a given clinical situation, see the specific dosage sections 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 of inhibitor development. (See Development of Inhibitors to Factor IX under Cautions.)

Pediatric Patients

Hemophilia B

Higher doses or more frequent dosing may be required in patients <12 years of age because of increased clearance, shorter half-life, and lower recovery of factor IX.

On-Demand Treatment and Control of Bleeding

Minor or moderate hemorrhage (e.g., uncomplicated hemarthroses, superficial muscle [except iliopsoas] without neurovascular compromise, superficial soft tissue, mucous membranes): Administer appropriate dose to achieve factor IX levels of 30–60% of normal; repeat dose every 48 hours until bleeding resolves.

Major hemorrhage (e.g., iliopsoas and deep muscle with neurovascular injury or substantial blood loss, pharyngeal, retropharyngeal, retroperitoneal, CNS): Administer appropriate dose to achieve factor IX levels of 80–100% of normal; consider repeat dose after 6–10 hours, and then every 24 hours for the first 3 days. After third day, may reduce dose and extend dosing frequency to every 48 hours or longer until bleeding resolves and healing is achieved.

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 24–48 hours as needed until bleeding resolves or healing is achieved; a single injection usually is sufficient.

Major surgery: Administer appropriate dose to achieve an initial factor IX level of 60–100% of normal. Consider repeat dose after 6–10 hours, and then every 24 hours for the first 3 days. After third day, may reduce dose and extend dosing frequency to every 48 hours or longer until bleeding resolves and healing is achieved.

Routine Prophylaxis

Initially, 50 units/kg once a week or 100 units/kg once every 10 days. Adjust dosage based on patient response.

MASAC states that prophylactic therapy should be instituted 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 Treatment and Control of Bleeding

Minor or moderate hemorrhage (e.g., uncomplicated hemarthroses, superficial muscle [except iliopsoas] without neurovascular compromise, superficial soft tissue, mucous membranes): Administer appropriate dose to achieve factor IX levels of 30–60% of normal; repeat every 48 hours until bleeding resolves.

Major hemorrhage (e.g., iliopsoas and deep muscle with neurovascular injury or substantial blood loss, pharyngeal, retropharyngeal, retroperitoneal, CNS): Administer appropriate dose to achieve factor IX levels of 80–100% of normal; consider repeat dose after 6–10 hours, and then every 24 hours for the first 3 days. After third day, may reduce dose and extend dosing frequency to every 48 hours or longer until bleeding resolves and healing is achieved.

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 24–48 hours as needed until bleeding resolves or healing is achieved; a single injection usually is sufficient.

Major surgery: Administer appropriate dose to achieve an initial factor IX level of 60–100% of normal. Consider repeat dose after 6–10 hours, and then every 24 hours for the first 3 days. After third day, may reduce dose and extend dosing frequency to every 48 hours or longer until bleeding resolves and healing is achieved.

Routine Prophylaxis

Initially, 50 units/kg once a week or 100 units/kg once every 10 days. Adjust dosage based on patient response.

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