Factor IX (Human), Factor IX Complex (Human) (Monograph)

Brand names: AlphaNine SD, Bebulin, Mononine, Profilnine
Drug class: Hemostatics
VA class: BL500
CAS number: 37224-63-8

Medically reviewed by Drugs.com on Jan 15, 2024. Written by ASHP.

Introduction

Factor IX (human): Preparation of blood coagulation factor IX derived from pooled human plasma.

Factor IX complex (human): Preparation of nonactivated blood coagulation factors II, VII, IX, and X derived from pooled human plasma; also known as a 3-factor prothrombin complex concentrate (PCC).

Uses for Factor IX (Human), Factor IX Complex (Human)

Hemophilia B

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

Maintenance of hemostasis in patients with hemophilia B undergoing surgery.

In patients with preexisting thromboembolic risk factors, some experts state that pure (i.e., single-factor) factor IX preparations are preferred over factor IX complex for treatment of hemophilia B. (See Thromboembolic Events under Cautions.)

Also used for routine prophylaxis (i.e., administration at regular intervals on an ongoing basis) to prevent or reduce frequency of hemorrhagic 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. (See Risk of Transmissible Agents in Plasma-derived Preparations under Cautions.) 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.

Factor IX (human) is not indicated for treatment of coagulation factor II, VII, or X deficiency or for management of hemophilia A in patients with inhibitors to factor VIII.

Factor IX complex (human) is not indicated for treatment of factor VII deficiency or other coagulation factor deficiencies.

Reversal of Warfarin Anticoagulation

Factor IX complex (human) (i.e., 3-factor PCC) has been used for urgent reversal of warfarin anticoagulation^{† [off-label]} in patients experiencing major bleeding or in those who require immediate reversal of anticoagulation for other reasons (e.g., urgent surgery).

Factor IX (human) is not indicated for treatment or reversal of coumarin-induced anticoagulation or for treatment of hemorrhagic states caused by hepatitis-induced lack of production of liver-dependent coagulation factors.

Factor IX (Human), Factor IX Complex (Human) Dosage and Administration

General

• Individualize dosage and duration of therapy based on severity and location of hemorrhage, degree of factor IX deficiency, desired factor IX levels, and clinical response. (See Laboratory Monitoring under Cautions.)

• Monitor factor IX levels frequently to individualize dosage and assess response to therapy. Close monitoring of factor IX levels is particularly important in cases of severe hemorrhage or major surgery. (See Laboratory Monitoring under Cautions.)

Administration

IV Administration

Administer factor IX (human) and factor IX complex (human) by slow IV injection or IV infusion.

Have been given by continuous infusion^{† [off-label]}.

Some manufacturers recommend that factor IX preparations be administered using plastic syringes only since such solutions may adhere to glass.

Filter solution prior to administration.

Instructions on reconstitution, dilution, and administration vary according to preparation; consult manufacturer’s labeling for specific information on each factor IX (human) or factor IX complex (human) preparation.

Reconstitution

Prior to reconstitution, allow factor IX (human) or factor IX complex (human) injection concentrate and diluent to warm to room temperature (≤37°C).

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

Gently swirl solution to dissolve powder completely; do not shake.

Administer immediately or within 3 hours after reconstitution; discard any unused solution after 3 hours. Do not refrigerate reconstituted solutions.

Rate of Administration

Individualize infusion rates based on specific preparation and patient response and comfort. Administer slowly to avoid vasomotor reactions.

AlphaNine SD: Administer at a rate ≤10 mL/minute.

Mononine: Administer solutions containing 100 units/mL at a rate of approximately 2 mL/minute; has been administered at rates up to 225 units/minute without unusual adverse effects.

Bebulin: Administer at a rate ≤2 mL/minute.

Profilnine: Administer at a rate ≤10 mL/minute.

Dosage

Dosage (potency) of factor IX (human) and factor IX complex (human) expressed in terms of international units (IU, units) of factor IX activity. One unit is approximately equivalent to amount of factor IX activity in 1 mL of pooled normal human plasma.

Administration of 1 unit/kg of AlphaNine SD, Mononine, or Profilnine generally increases factor IX activity by 1%. Administration of 1 unit/kg of Bebulin generally increases factor IX activity by 0.8%.

Estimate dosage of AlphaNine SD, Mononine, or Profilnine using the following formula:

Units required = body weight (in kg) × 1 unit/kg × desired factor IX increase (in % of normal)

Estimate dosage of Bebulin using the following formula:

Units required = body weight (in kg) × 1.2 units/kg × desired factor IX increase (in % of normal)

The desired factor IX level is determined by the clinical situation and severity of hemorrhage. For recommendations on target factor IX levels, see the individual product-specific dosage sections below. These calculations and suggested dosage regimens are only approximations and should not preclude appropriate laboratory determinations and individualization of dosage based on the hemostatic requirements of patients.

If calculated dose is ineffective in achieving appropriate factor IX levels, consider the possibility that inhibitors to factor IX may have developed. Manufacturer of Mononine suggests that higher doses may be required in such situations; however, caution is advised when administering higher than recommended doses. (See Thromboembolic Events under Cautions.)

Pediatric Patients

Hemophilia B

Mononine (Factor IX [human])

IV

Minor (spontaneous) hemorrhage or prophylaxis: Initially, up to 20–30 units/kg to achieve a plasma factor IX level of 15–25% of normal; repeat once at 24 hours, if necessary.

Major trauma: Initially, up to 75 units/kg every 18–30 hours to achieve a plasma factor IX level of 25–50% of normal. Up to 10 days of treatment may be necessary, depending on severity of bleeding.

Surgery: Initially, up to 75 units/kg every 18–30 hours to achieve a plasma factor IX level of 25–50% of normal. Up to 10 days of treatment may be necessary.

Routine Prophylaxis

IV

Various dosing regimens have been recommended; optimal dosage remains to be established. Dosages of 25–40 units/kg twice a week commonly recommended. Individualize prophylactic regimens; evaluate patients periodically to determine continued need for prophylaxis.

Adults

Hemophilia B

AlphaNineSD (Factor IX [human])

IV

Minor hemorrhage (e.g., bruises, cuts, scrapes, uncomplicated joint hemorrhage): 20–30 units/kg twice daily to achieve a plasma factor IX level of at least 20–30% of normal until bleeding resolves or healing occurs, usually 1–2 days.

Moderate hemorrhage (e.g., epistaxis, mouth and gum bleeding, tooth extraction, hematuria): 25–50 units/kg twice daily to achieve a plasma factor IX level of 25–50% of normal until healing occurs, average 2–7 days.

Major hemorrhage (e.g., joint or muscle bleeding [especially in large muscles], major trauma, hematuria, intracranial bleeding, intraperitoneal bleeding): Initially, 30–50 units/kg twice daily to achieve a plasma factor IX level of 50% of normal for at least 3–5 days. Administer additional doses of 20 units/kg twice daily to maintain a plasma factor IX level of 20% of normal until healing occurs. Up to 10 days of treatment may be necessary.

Surgery: Initially, 50–100 units/kg twice daily to achieve a plasma factor IX level of 50–100% of normal prior to surgery. Administer additional doses of 50–100 units/kg twice daily for 7–10 days (or until healing achieved) to maintain a factor IX level of 50–100% of normal.

Mononine (Factor IX [human])

IV

Minor (spontaneous) hemorrhage or prophylaxis: Initially, up to 20–30 units/kg to achieve a plasma factor IX level of 15–25% of normal; repeat once at 24 hours, if necessary.

Major trauma: Initially, up to 75 units/kg every 18–30 hours to achieve a plasma factor IX level of 25–50% of normal. Up to 10 days of treatment may be necessary, depending on severity of bleeding.

Surgery: Initially, up to 75 units/kg every 18–30 hours to achieve a plasma factor IX level of 25–50% of normal. Up to 10 days of treatment may be necessary.

Bebulin (Factor IX Complex [human])

IV

Minor hemorrhage (e.g., early hemarthrosis, minor epistaxis, gingival bleeding, mild hematuria): Initially, 25–35 units/kg to achieve a plasma factor IX level of 20% of normal. Single administration usually sufficient; may repeat once after 24 hours, if necessary.

Moderate hemorrhage (e.g., severe joint bleeding, early hematoma, major open bleeding, minor trauma, minor hemoptysis, minor hematemesis, minor melena, major hematuria): Initially, 50–65 units/kg to achieve a plasma factor IX level of approximately 40% of normal; may repeat every 24 hours for 2 days or until adequate healing occurs.

Major hemorrhage (e.g., severe hematoma, major trauma, severe hemoptysis, severe hematemesis, severe melena): Initially, 75–90 units/kg to achieve a plasma factor IX level of ≥60% of normal, unless patient has a high risk for thrombosis. (See Thromboembolic Events under Cautions.) May repeat every 24 hours for 2–3 days or until adequate healing occurs.

Minor surgery (e.g., tooth extraction): Initially 50–75 units/kg to achieve a plasma factor IX level of approximately 40–60% of normal 1 hour prior to surgery. One dose is usually sufficient for single tooth extraction. For extraction of several teeth and other minor surgical procedures, administer additional doses of 25–65 units/kg for 1–2 weeks after surgery to maintain plasma factor IX levels of approximately 20–40% of normal. More frequent (e.g., every 12 hours) dosing may be required for initial treatments, while longer intervals (e.g., every 24 hours) usually sufficient during later postoperative period.

Major surgery: Initially, 75–90 units/kg to achieve a plasma factor IX level of ≥60% of normal 1 hour prior to surgery, unless patient has a high risk for thrombosis. (See Thromboembolic Events under Cautions.) Administer additional doses of 25–75 units/kg for 1–2 weeks postoperatively to maintain a plasma factor IX level of approximately 20–60% of normal, then 25–35 units/kg from week 3 onward to maintain plasma factor IX levels of approximately 20% of normal. More frequent (e.g., every 12 hours) dosing may be required for initial treatments, while longer intervals (e.g., every 24 hours) usually sufficient during later postoperative period.

Profilnine (Factor IX Complex [human])

IV

Mild to moderate hemorrhage: Administer appropriate dosage to achieve a plasma factor IX level of 20–30% of normal; single administration usually sufficient.

Severe hemorrhage: Administer appropriate dosage to achieve a plasma factor IX level of 30–50% of normal; daily infusions usually required.

Surgery: Administer appropriate dosage to achieve a plasma factor IX level of approximately 30–50% of normal for at least 1 week following surgery.

Tooth extractions: Administer appropriate dosage to achieve factor IX levels of 50% of normal prior to procedure; may give additional doses if bleeding recurs.

Routine Prophylaxis

IV

Various dosing regimens have been recommended; optimal dosage remains to be established. Dosages of 25–40 units/kg twice a week commonly recommended. Individualize prophylactic regimens; evaluate patients periodically to determine continued need for prophylaxis.

Prescribing Limits

Adults

Hemophilia B

IV

AlphaNine SD, Profilnine: Maximum rate of infusion 10 mL/minute.

Bebulin: Maximum rate of infusion 2 mL/minute.

Cautions for Factor IX (Human), Factor IX Complex (Human)

Contraindications

• Mononine: Known hypersensitivity to murine protein.

• Bebulin: Known hypersensitivity to factor IX complex (human), hypersensitivity to heparin, or history of heparin-induced thrombocytopenia (HIT).

• The manufacturers state that there are no known contraindications to the use of AlphaNine SD or Profilnine.

Warnings/Precautions

Warnings

Risk of Transmissible Agents in Plasma-derived Preparations

Possibility exists for transmission of human viruses (e.g., HIV, hepatitis A virus [HAV], hepatitis B virus [HBV], hepatitis C virus [HCV]) and other infectious agents (e.g., unknown viruses; causative agents for Creutzfeldt-Jakob disease [CJD] or variant CJD [vCJD]).

Improved donor screening and viral-inactivating/eliminating procedures (e.g., solvent/detergent, heat-treatment, chromatography, nanofiltration) have reduced but not completely eliminated risk of pathogen transmission with plasma-derived factor IX and factor IX complex preparations.

Although transmission of nonenveloped viruses, including HAV and parvovirus B19, has been documented following administration of plasma-derived coagulation factors, risk has been reduced with additional viral attenuation methods such as nanofiltration. Nevertheless, monitor for signs and symptoms of parvovirus B19 and hepatitis A infection during therapy. (See Advice to Patients.)

Carefully weigh risk of pathogen transmission versus benefits of therapy.

Report any infections thought to be associated with factor IX (human) or factor IX complex (human) to the manufacturer, FDA, and CDC.

Risk of Hepatitis

Risk of hepatitis A or hepatitis B infection.

Monitor closely for signs and symptoms of hepatitis A during therapy. (See Advice to Patients.)

Hepatitis B vaccine is recommended in all individuals with a bleeding disorder at birth or at time of diagnosis. Immunization with hepatitis A vaccine is recommended for all individuals ≥1 year of age with hemophilia or other congenital bleeding disorders.

Individuals receiving blood or plasma infusions may develop signs and symptoms of other viral infections, particularly non-A or non-B hepatitis.

Risk of HIV Infection

Potential vehicle for transmission of HIV. HIV seroconversion reported previously in patients who received factor IX complex (human) from donors not screened for HIV and/or prepared using suboptimal viral-inactivating procedures (e.g., heat-treatment only).

No reports to date of HIV transmission with currently available plasma-derived clotting factor preparations.

Risk of Creutzfeldt-Jakob Disease

Theoretic possibility of transmitting causative agent of CJD or vCJD. Several probable cases of vCJD transmission reported from transfusion of human RBCs. However, no reports to date of CJD or vCJD transmission from commercially available factor IX products. For further information on CJD and vCJD precautions related to blood and blood products, consult the FDA’s guidance for industry ().

Risk of West Nile Virus Infection

Evidence of West Nile virus (WNV) transmission through transplanted organs (e.g., heart, liver, kidney) and blood products. However, WNV transmission through commercially available factor IX preparations unlikely due to current viral-inactivating procedures.

For further information on WNV precautions related to blood and blood products, consult the FDA’s guidance for industry ().

Thromboembolic Events

Serious and potentially fatal thromboembolic events (e.g., MI, venous thrombosis, PE, disseminated intravascular coagulation [DIC]) reported with use of factor IX (human) and factor IX complex (human) preparations. Increased risk in patients with preexisting thrombotic risk factors (e.g., liver disease, concomitant use of thrombogenic drugs, history of thrombosis, DIC) and in those receiving prolonged therapy and/or high dosages of factor IX complex concentrates; also increased risk during postoperative period in patients undergoing surgery, and in neonates. Exercise caution when factor IX (human) or factor IX complex (human) is used in such patients.

Weigh potential benefits of the drug against risks of thrombotic complications. Consider using pure (i.e., single-factor) factor IX preparations that may be less thrombogenic than factor IX complex in high-risk patients. Patients undergoing surgery and those with other predisposing risk factors should be monitored closely for manifestations of thromboembolism (e.g., changes in BP or pulse rate, respiratory distress, chest pain, cough) and DIC. Follow recommended dosage guidelines to decrease risk of thromboembolic complications. If evidence of thrombosis or DIC occurs during therapy, discontinue drug immediately and administer appropriate treatment.

Nephrotic Syndrome

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

Safety and efficacy of factor IX products for immune tolerance induction not established.

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (hives, pruritus, edema, chest tightness, angioedema, dyspnea, wheezing, faintness, hypotension, tachycardia, generalized urticaria, shock) reported with use of all factor IX products.

Increased risk in patients with certain genetic mutations of factor IX and those with inhibitors to factor IX. (See Development of Inhibitors to Factor IX under Cautions.) Up to 50% of patients with inhibitors to factor IX may experience severe hypersensitivity reactions, including anaphylaxis.

Closely observe for hypersensitivity reactions, especially during the initial phases of therapy.

If manifestations of hypersensitivity reactions or anaphylaxis occur, discontinue drug immediately and initiate appropriate therapy.

Antibody Formation to Trace Animal Proteins

Mononine contains trace amounts of murine protein, which may stimulate antibody production and cause hypersensitivity reactions. (See Contraindications under Cautions.)

General Precautions

Development of Inhibitors to Factor IX

Risk for development of neutralizing antibodies (inhibitors) to factor IX following treatment with factor IX preparations. 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.)

Because of an association between inhibitor development and allergic reactions, evaluate for presence of inhibitors in any patient experiencing hypersensitivity.

Monitor patients regularly for development of inhibitors. (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.

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

Laboratory Monitoring

Monitor factor IX levels at regular intervals to guide dosing and ensure adequate therapeutic response.

Monitor for development of inhibitors during treatment and prior to surgery. (See Development of Inhibitors to Factor IX under Cautions.)

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether factor IX (human) or factor IX complex (human) is distributed into human milk.

Pediatric Use

Use with caution in neonates because of potential increased risk of thromboembolic complications. (See Thromboembolic Events under Cautions.)

AlphaNine SD: Safety and efficacy not established in patients 16 years of age. In a few studies that included pediatric patients, adverse effects in children were similar to those observed in patients >16 years of age.

Bebulin: Safety and efficacy not established.

Mononine: Safety and efficacy established in pediatric patients between the ages of 1 day and 20 years; excellent hemostasis achieved with no thrombotic complications. Dosing in children generally based on the same guidelines as for adults.

Profilnine: Safety and efficacy not established in patients ≤16 years of age. In a clinical study in patients who previously received factor IX concentrates for hemophilia B, the 2 pediatric patients who received factor IX complex (human) responded similarly to adults and no adverse effects were reported.

Geriatric Use

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

Common Adverse Effects

Fever, chills, nausea, vomiting, headache, somnolence, lethargy, flushing, dyspnea, tingling, stinging or burning at infusion site.

Drug Interactions

Specific Drugs

Factor IX (Human), Factor IX Complex (Human) Pharmacokinetics

Absorption

Plasma Concentrations

Following IV infusion over 5–15 minutes, plasma concentrations of factor IX increase by approximately 0.01–0.014 units/mL per unit/kg administered.

Distribution

Extent

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

Circulates in plasma as a free molecule.

Binds rapidly and reversibly to vascular endothelium.

Not known whether factor IX (human) and factor IX complex (human) are distributed into milk.

Elimination

Half-life

Biphasic.

Half-life subject to interindividual variation; approximately 18–25 hours for factor IX, and 18–36 hours for factor IX complex.

Factor IX complex (human) is rapidly cleared from plasma.

Stability

Storage

Parenteral

Powder for Injection

AlphaNine SD: 2–8°C (avoid freezing to prevent damage to the diluent vial); may store at room temperature ≤30°C for up to 1 month. Use solution within 3 hours of reconstitution.

Bebulin: 2–8°C (avoid freezing to prevent damage to the diluent vial). Do not refrigerate after reconstitution; use solution within 3 hours of reconstitution.

Mononine: 2–8°C (avoid freezing to prevent damage to the diluent vial); may store at room temperature ≤25°C for up to 1 month. Do not refrigerate after reconstitution; use solution within 3 hours of reconstitution.

Profilnine: ≤25°C; do not freeze. Use solution within 3 hours of reconstitution.

Actions

• Factor IX (human) and factor IX complex (human) preparations are purified concentrates of factor IX derived from human plasma. Factor IX complex (human) preparations also contain variable amounts of vitamin K-dependent clotting factors II, VII, and X.

• 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 exogenous factor IX to patients with hemophilia B results in increased plasma levels of factor IX and temporarily corrects coagulation defects.

• Factor IX (human) and factor IX complex (human) are prepared from pooled human plasma; different methods (e.g., murine monoclonal antibody, chromatography, nanofiltration) are used to isolate and purify factor IX. Undergoes viral inactivation processes (e.g., heat, solvent/detergent) to reduce risk of viral transmission.

Advice to Patients

• Importance of discontinuing therapy and immediately informing clinician if fever, rash, urticaria, nausea, vomiting, or other manifestations of hypersensitivity reactions or anaphylaxis occur or, alternatively, seeking immediate emergency care depending on severity of such reactions.

• Risk of transmission of parvovirus B19 and/or hepatitis A from human plasma-derived factor concentrates. Importance of informing clinician promptly if symptoms of potential parvovirus B19 infection (fever, drowsiness, chills and rhinorrhea followed by rash and joint pain 2 weeks later) or hepatitis A infection (low-grade fever, anorexia, nausea, vomiting, fatigue, jaundice, dark urine, abdominal pain) occur. Parvovirus B19 infection is especially serious in pregnant or immunocompromised patients.

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., liver disease).

• 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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