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

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

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

introduction

Factor IX complex (human): production of non-activated coagulation factors II, VII, IX and X derived from pooled human plasma; also known as 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 pre-existing thromboembolic risk factors, some experts indicate that pure (i.e. single factor) factor IX preparations are preferable to factor IX complex for the treatment of hemophilia B. (See “Thromboembolic Events” under “Precautions”).

Also used for routine prophylaxis (i.e. continuous administration at regular intervals) to prevent or reduce the frequency of hemorrhagic events. Such prophylactic therapy is currently considered the standard treatment for patients with hemophilia B. It reduces the frequency of spontaneous musculoskeletal bleeding, preserves joint function and improves quality of life.

Several factor IX concentrates are currently available in the United States, including various recombinant and plasma-derived preparations; The National Hemophilia Foundation's Medical and Scientific Advisory Council (MASAC) recommends the preferred use of recombinant factor IX preparations due to their potentially superior safety profile with respect to pathogen transmission. (See “Risk of transmissible pathogens in plasma-derived preparations” under “Precautions.”) Other experts (e.g., World Federation of Hemophilia) state that the choice of preparation should be based on local criteria. When selecting an appropriate factor IX preparation, consider the characteristics of each coagulation factor concentrate, individual patient variables, patient/provider preferences, and emerging data.

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

Factor IX complex (human) is not indicated for the 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 with severe bleeding or in patients who require immediate reversal of anticoagulation for other reasons (e.g., urgent surgery).

Factor IX (human) is not indicated for the treatment or reversal of coumarin-induced anticoagulation or for the treatment of hemorrhagic conditions caused by deficient production of liver-dependent clotting factors caused by hepatitis.

Dosage and administration of Factor IX (Human), Factor IX Complex (Human).

Generally

• Individualize dosage and duration of therapy based on the severity and location of bleeding, degree of factor IX deficiency, desired factor IX levels, and clinical response. (See Laboratory Monitoring under “Precautions.”)

• Monitor factor IX levels frequently to individualize dosage and assess response to therapy. Close monitoring of factor IX levels is particularly important during severe bleeding or major surgery. (See Laboratory Monitoring under “Precautions.”)

Administration

IV administration

Administer Factor IX (Human) and Factor IX Complex (Human) by slow intravenous injection or intravenous infusion.

Administered as a continuous infusion† [off-label].

Some manufacturers recommend that factor IX preparations be administered only with plastic syringes because such solutions can stick to glass.

Filter the solution before administration.

Instructions for reconstitution, dilution, and administration vary depending on the preparation; Specific information for each factor IX preparation (human) or factor IX complex preparation (human) can be found on the manufacturer's labeling.

Restoration

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

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

Swirl the solution gently to completely dissolve the powder. Don't shake.

Administer immediately or within 3 hours of reconstitution; Discard any unused solution after 3 hours. Do not store reconstituted solutions in the refrigerator.

Board of Directors

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

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

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

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

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

dosage

Dosage (potency) of factor IX (human) and factor IX complex (human), expressed in international units (IU, units) of factor IX activity. One unit is approximately equal to the 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 bebulin generally increases factor IX activity by 0.8%.

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

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

Estimate the bebulin dose using the following formula:

Required units = 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 the severity of the bleeding. Recommendations regarding target levels for Factor IX can be found in the individual product-specific dosage sections below.These calculations and recommended dosing regimens are approximate only and should not preclude appropriate laboratory determinations and individual dosage adjustment based on patient hemostatic requirements.

If the calculated dose is insufficient to achieve adequate factor IX levels, consider the possibility that factor IX inhibitors may have developed. The manufacturer of Mononine advises that higher doses may be necessary in such situations; However, caution should be exercised when administering doses higher than recommended. (See “Thromboembolic Events” under “Precautions.”)

Pediatric patients

Hemophilia B

Mononine (factor IX [human])

IV

Minor (spontaneous) bleeding or prophylaxis: Initially up to 20-30 units/kg to achieve a plasma factor IX level of 15-25% of normal; Repeat once every 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. Depending on the severity of the bleeding, treatment for up to 10 days may be necessary.

Surgery: Initially up to 75 units/kg every 18-30 hours to achieve a plasma factor IX level of 25-50% of normal. A treatment period of up to 10 days may be required.

Routine prophylaxis

IV

Various dosing regimens have been recommended; The optimal dosage still needs to be determined. Generally, dosages of 25-40 units/kg twice per week are recommended. Individualize prophylactic measures; Assess patients regularly to determine whether continued prophylaxis is necessary.

Adult

Hemophilia B

AlphaNineSD (Factor IX [human])

IV

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

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

Severe bleeding (e.g. joint or muscle bleeding). [especially in large muscles], major trauma, hematuria, intracranial hemorrhage, intraperitoneal hemorrhage): 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 plasma factor IX levels at 20% of normal until healing occurs. A treatment period of up to 10 days may be required.

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

Mononine (factor IX [human])

IV

Minor (spontaneous) bleeding or prophylaxis: Initially up to 20-30 units/kg to achieve a plasma factor IX level of 15-25% of normal; Repeat once every 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. Depending on the severity of the bleeding, treatment for up to 10 days may be necessary.

Surgery: Initially up to 75 units/kg every 18-30 hours to achieve a plasma factor IX level of 25-50% of normal. A treatment period of up to 10 days may be required.

Bebulin (factor IX complex [human])

IV

Minor bleeding (e.g., early hemarthrosis, mild epistaxis, gingival bleeding, mild hematuria): Initially, 25-35 units/kg to achieve a plasma factor IX level of 20% of normal. A single administration is usually sufficient; can be repeated once after 24 hours if necessary.

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

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

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

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

Profilnine (Factor IX complex [human])

IV

Mild to moderate bleeding: Administer an appropriate dosage to achieve a plasma factor IX level of 20-30% of normal; A single administration is usually sufficient.

Severe bleeding: Administer an appropriate dosage to achieve a plasma factor IX level of 30-50% of normal; Daily infusions are usually required.

Surgery: Administer an appropriate dosage to achieve a plasma factor IX level of approximately 30-50% of normal at least one week after surgery.

Tooth extractions: Administer an appropriate dosage before the procedure to achieve a factor IX level of 50% of normal; may give additional doses if bleeding recurs.

Routine prophylaxis

IV

Various dosing regimens have been recommended; The optimal dosage still needs to be determined. Generally, dosages of 25-40 units/kg twice per week are recommended. Individualize prophylactic measures; Assess patients regularly to determine whether continued prophylaxis is necessary.

Prescription Limits

Adult

Hemophilia B

IV

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

Bebulin: Maximum infusion rate 2 ml/minute.

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

Contraindications

• Mononin: Known hypersensitivity to mouse 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 pathogens in plasma-derived preparations

There is a possibility of 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; pathogens of Creutzfeldt-Jakob disease). [CJD] or variant CJD [vCJD]).

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

Although transmission of non-enveloped viruses, including HAV and parvovirus B19, has been documented following administration of plasma-derived clotting factors, the risk has been reduced by additional viral attenuation methods such as nanofiltration. However, monitor for signs and symptoms of parvovirus B19 and hepatitis A infection during therapy. (See Notes for Patients.)

Carefully weigh the risk of pathogen transmission and the benefits of therapy.

Report all infections suspected to be related to factor IX (human) or factor IX complex (human) to the manufacturer, FDA, and CDC.

Hepatitis risk

Risk of hepatitis A or hepatitis B infection.

Monitor carefully for signs and symptoms of hepatitis A during therapy. (See Instructions for Patients.)

The hepatitis B vaccination is recommended for anyone who has a blood clotting disorder at birth or at the time of diagnosis. Vaccination against hepatitis A is recommended for anyone age one year and older with hemophilia or other congenital bleeding disorders.

People who receive blood or plasma infusions may develop signs and symptoms of other viral infections, especially non-A or non-B hepatitis.

Risk of HIV infection

Possible vehicle for transmission of HIV. HIV seroconversion has previously been reported in patients receiving factor IX complex (human) from donors who were not screened for HIV and/or prepared with suboptimal virus-inactivating procedures (e.g., heat treatment alone).

To date, there are no reports of HIV transmission using currently available plasma clotting factor preparations.

Risk of Creutzfeldt-Jakob disease

Theoretical possibility of transmission of the pathogen from CJD or vCJD. Several probable cases of vCJD transmission have been reported through transfusion of human red blood cells. However, to date there have been no reports of transmission of CJD or vCJD through commercially available factor IX products. For more information about CJD and vCJD precautions related to blood and blood products, see FDA's Guidance for Industry ().

Risk of West Nile virus infection

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

For more information about WNV precautions related to blood and blood products, see FDA's Guidance for Industry ().

Thromboembolic events

Serious and potentially fatal thromboembolic events (e.g. myocardial infarction, venous thrombosis, PE, disseminated intravascular coagulation). [DIC]) reported using factor IX preparations (human) and factor IX complex preparations (human). Increased risk in patients with pre-existing thrombotic risk factors (e.g. liver disease, concomitant use of thrombogenic drugs, history of thrombosis, DIC) and in patients receiving prolonged therapy and/or high doses of factor IX complex concentrates; The risk during the postoperative period in patients undergoing surgery and in newborns is also increased. Use caution when using factor IX (human) or factor IX complex (human) in such patients.

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

Nephrotic syndrome

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

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

Sensitivity reactions

Hypersensitivity reactions

Hypersensitivity reactions (hives, pruritus, edema, chest tightness, angioedema, shortness of breath, wheezing, fainting, hypotension, tachycardia, generalized urticaria, shock) have been reported with the use of all factor IX products.

Increased risk in patients with certain genetic mutations of factor IX and those with inhibitors of factor IX. (See “Development of Factor IX Inhibitors” under “Precautions.”) Severe hypersensitivity reactions, including anaphylaxis, may occur in up to 50% of patients with factor IX inhibitors.

Pay careful attention to hypersensitivity reactions, particularly in the initial phase of therapy.

If signs of hypersensitivity reactions or anaphylaxis occur, the drug should be discontinued immediately and appropriate therapy instituted.

Antibody generation to track animal proteins

Mononin contains trace amounts of mouse protein, which can stimulate antibody production and cause hypersensitivity reactions. (See “Contraindications” under “Warnings.”)

General precautions

Development of inhibitors for factor IX

Risk of developing neutralizing antibodies (inhibitors) against factor IX after treatment with factor IX preparations. Reported in approximately 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 developing inhibitors and experiencing a hypersensitivity reaction. (See “Hypersensitivity Reactions” under “Precautions.”)

Due to an association between the development of inhibitors and allergic reactions, any patient with hypersensitivity should be evaluated for the presence of inhibitors.

Monitor patients regularly for the development of inhibitors. (See Laboratory Monitoring under Warnings.) If expected factor IX levels are not achieved or bleeding is not controlled at the recommended dose, the presence of inhibitors should be suspected, particularly in patients who have previously achieved a response.

For patients on inhibitors, consultation with a hemophilia treatment center is strongly recommended.

Laboratory monitoring

Monitor factor IX levels periodically to control dosage and ensure appropriate therapeutic response.

Monitor for development of inhibitors during treatment and before surgery. (See “Development of Factor IX Inhibitors” under “Precautions.”)

Specific populations

pregnancy

Category C

lactation

It is not known whether factor IX (human) or factor IX complex (human) is excreted in breast milk.

Pediatric use

Use with caution in newborns as the risk of thromboembolic complications may be increased. (See “Thromboembolic Events” under “Precautions.”)

AlphaNine SD: Safety and efficacy not established in patients 16 years of age. In some studies involving pediatric patients, adverse reactions in children were similar to those seen in patients over 16 years of age.

Bebulin: Safety and effectiveness not established.

Mononin: Safety and efficacy demonstrated in pediatric patients aged 1 day to 20 years; Excellent hemostasis was achieved without thrombotic complications. Dosing in children generally follows the same guidelines as adults.

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

Geriatric use

There is insufficient experience in patients ≥ 65 years of age to determine whether geriatric patients respond differently than younger patients. Choose the dosage with caution.

Common side effects

Fever, chills, nausea, vomiting, headache, drowsiness, lethargy, feeling hot, shortness of breath, tingling, stinging, or burning at the infusion site.

Interactions with other medications

Specific medications

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

absorption

Plasma concentrations

Following an intravenous 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

Diffuses easily through interstitial fluid; distributed across both intravascular and extravascular compartments.

Circulates in plasma as a free molecule.

Binds quickly and reversibly to the vascular endothelium.

It is not known whether factor IX (human) and factor IX complex (human) pass into milk.

Elimination

Half-life

Two-phase.

Half-life is subject to inter-individual fluctuations; 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 avoid damage to the diluent vial); can be stored at room temperature ≤30°C for up to 1 month. Use the solution within 3 hours of reconstitution.

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

Mononin: 2-8°C (avoid freezing to avoid damage to the diluent bottle); can be stored at room temperature ≤25°C for up to 1 month. Do not refrigerate after reconstitution; Use the solution within 3 hours of reconstitution.

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

Actions

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

• Factor IX is essential for blood clotting and maintaining hemostasis.

• Patients with hemophilia B (Christmas disease) have reduced endogenous factor IX levels, leading to a tendency to hemorrhage and clinical manifestations such as bleeding into soft tissues, muscles, joints and internal organs.

• The 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, patients with moderate disease generally have 1-5% of normal activity, and patients 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 disorders.

• Factor IX (human) and Factor IX complex (human) are produced from pooled human plasma; Various methods (e.g. murine monoclonal antibody, chromatography, nanofiltration) are used to isolate and purify factor IX. Subjected to viral inactivation processes (e.g. heat, solvents/detergents) to reduce the risk of viral transmission.

Advice for patients

• It is important to discontinue therapy and inform the doctor immediately if fever, rash, urticaria, nausea, vomiting or other manifestations of hypersensitivity reactions or anaphylaxis occur, or alternatively, depending on the severity of these reactions, seek immediate emergency care.

• Risk of transmission of parvovirus B19 and/or hepatitis A through human plasma-derived factor concentrates. It is important to inform the doctor immediately if symptoms of possible parvovirus B19 infection (fever, dizziness, chills and runny nose, followed by rash and joint pain two weeks later) or hepatitis A infection (mild fever, anorexia, nausea, vomiting, fatigue, jaundice, dark urine, abdominal pain) occur. Parvovirus B19 infection is particularly serious in pregnant or immunocompromised patients.

• It is important to inform the doctor about any existing or planned concomitant therapies, including prescription and over-the-counter medicines, as well as any concomitant diseases (e.g. liver disease).

• It is important for women to tell their doctor if they are pregnant, plan to become pregnant, or want to breastfeed.

• It is important to inform patients of other important precautionary information. (See Precautions.)

Preparations

Excipients in commercial drug preparations may have clinically significant effects in some individuals; Details can be found on the respective product labeling.

For information about shortages of one or more of these drugs, visit the ASHP Drug Shortages Resource Center.

Factor IX (human)

Factor IX complex (human)

AHFS DI Essentials™. © Copyright 2024, Selected changes January 25, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Off-Label: Use is not currently included in U.S. Food and Drug Administration-approved labeling.

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