VA Class:BL500
Factor IX (human) is a preparation of blood coagulation factor IX prepared from pooled human plasma.149, 151, 152 Factor IX complex (human), also known as a 3-factor prothrombin complex concentrate (PCC), is a preparation of nonactivated blood coagulation factors II, VII, IX, and X derived from pooled human plasma.100, 140, 173, 174, 188
Factor IX (human) and factor IX complex (human) (also known as a 3-factor prothrombin complex concentrate; PCC) are used for the prevention and control of bleeding in patients with hemophilia B (congenital factor IX deficiency or Christmas disease).100, 140, 151, 152, 156, 173, 174 Factor IX (human) and factor IX complex (human) also are used for maintenance of hemostasis in such patients undergoing surgery.100, 140, 151, 152, 173, 174
Factor IX preparations also have been used for routine prophylaxis (i.e., administration at regular intervals on an ongoing basis) to prevent or reduce joint hemorrhage in individuals with hemophilia B.171, 173, 176, 178, 180, 185, 186 Such prophylactic therapy is currently considered the standard of care for patients with hemophilia B.171, 176 Routine administration of coagulation factor concentrates has been shown to decrease the frequency of spontaneous musculoskeletal hemorrhage, preserve joint function, and improve quality of life.185, 186 Up to 25 years of experience with prophylactic treatment of patients with hemophilia A or B was documented in a study conducted in Sweden; the study showed that boys with severe hemophilia who were initiated on a prophylactic regimen at a young age (1-2 years) and given large doses of factor concentrates (2000-9000 units/kg annually) experienced virtually no bleeding, maintained normal joint structure, and were able to lead normal lives.185, 186 Because of the observed benefits of prophylactic therapy, the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation recommends that routine prophylactic administration of clotting factor concentrates be considered in all individuals with severe hemophilia B (factor IX activity less than 1%).171, 176 Prophylactic therapy should be instituted at an early age (e.g., 1-2 years) prior to the onset of frequent bleeding; however, there are no clear guidelines as to when prophylaxis should be discontinued.176 Once prophylaxis is initiated, it may need to be continued indefinitely, unless the patient develops inhibitor antibodies to factor IX and/or there is a lack of response to the drug.176 When making treatment decisions regarding initiation of long-term prophylaxis, the risks and benefits of such a strategy should be evaluated and thoroughly discussed with the patient and/or their caregivers.176
Several factor IX concentrates currently are available in the US for the treatment of hemophilia B; these include a variety of plasma-derived and recombinant preparations (e.g., factor IX [recombinant], factor IX [human], factor IX [recombinant] Fc fusion protein).156, 191 Because these preparations vary based on characteristics such as purity, half-life, recovery, method of manufacture, viral removal and inactivation processes, potential immunogenicity, and other attributes, they are not pharmacologically or therapeutically equivalent.187 Among the commercially available factor IX concentrates, MASAC recommends preferential use of recombinant factor IX preparations because of their potentially superior safety profile with respect to pathogen transmission.155, 156, 176 Although improved viral depleting and donor screening practices have greatly reduced the risk of transmission of human immunodeficiency virus (HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV) with currently available plasma-derived factor IX preparations, these products are potentially capable of transmitting other disease agents such as nonenveloped viruses (e.g., parvovirus B19) and prions (e.g., causative agent for Creutzfeldt-Jakob disease [CJD] and variant CJD [vCJD]).155, 156 (See Risk of Transmissible Agents in Plasma-derived Preparations under Cautions: Precautions and Contraindications.) In other hemophilia management guidelines (e.g., World Federation of Hemophilia), no preference is given for recombinant over plasma-derived factor concentrates; rather, these experts state that choice of preparation should be determined based on local criteria.171 When selecting an appropriate factor IX preparation for patients with hemophilia B, clinicians should consider the characteristics of each clotting factor concentrate in addition to individual patient variables, patient/provider preference, and emerging data.155, 156, 171, 187 In all patients, the risk of pathogen transmission must be weighed against the benefits of therapy.155
It has been suggested that factor IX (human) may be less thrombogenic than factor IX complex (human) in patients with hemophilia B since it contains only negligible concentrations of other vitamin K-dependent coagulation factors compared with concentrations contained in factor IX complex (human).148, 151, 152, 171 Because of a decreased risk of thrombotic complications with pure (i.e., single-factor) factor IX preparations, some experts state that such preparations are preferred over factor IX complex preparations in patients with preexisting thromboembolic risk factors.148, 171, 174 (See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.)
Factor IX (human) is a highly purified concentrate of factor IX and contains nontherapeutic concentrations of factors II, VII, and X.148, 151, 152 Therefore, the manufacturers state that factor IX (human) should not be used as replacement therapy for factor II, VII, or X deficiency or for the treatment or reversal of coumarin anticoagulant-induced hemorrhage151, 152 or for the treatment of hemorrhagic states caused by hepatitis-induced lack of production of liver-dependent coagulation factors.152
The manufacturers state that efficacy and safety of factor IX complex (human) for treatment of coagulation deficiencies other than factor IX deficiency have not been established.100 Although factor IX complex (human) contains factor VII, only low (nontherapeutic) concentrations are present; therefore, the preparation should not be used for the treatment of factor VII deficiency.100, 140 MASAC states that factor IX complex (human) can be used to treat patients with deficiencies of factors II and X; however, it should be noted that the amount of these factors contained in different commercial preparations of factor IX complex (human) varies considerably.156
Currently available preparations of factor IX (human) and factor IX complex (human) are not indicated for the management of hemophilia A in patients with inhibitors to factor VIII.100, 151, 152
Reversal of Warfarin Anticoagulation
Factor IX complex (human) (also known as a 3-factor prothrombin complex concentrate, PCC) has been used for the urgent reversal of warfarin anticoagulation† in patients experiencing major bleeding or who require immediate reversal of anticoagulation for other reasons (e.g., urgent surgery).100, 140, 193, 194, 195, 196, 197 The term “PCC” refers to plasma-derived concentrates that contain the vitamin K-dependent coagulation factors II, VII, IX, and X.195, 196, 197 These preparations are classified as 3-factor PCCs or 4-factor PCCs depending on the amount of factor VII they contain; 3-factor PCCs contain lower concentrations of factor VII than 4-factor PCCs.194, 195 Fresh frozen plasma (FFP) traditionally has been used for reversal of anticoagulant effects; however, PCCs may provide certain advantages over FFP (e.g., more rapid reduction of the international normalized ratio [INR]; reduced risk of anaphylaxis, viral transmission, or volume overload) and are therefore recommended by some experts as the treatment of choice for rapid reversal of warfarin anticoagulation.194, 195, 196 Both 3-factor and 4-factor (e.g., Kcentra®) PCCs have been used effectively to reverse the effects of warfarin.192, 194, 196, 197, 199
Pure (i.e., single-factor) factor IX (human) preparations should not be used for the reversal of warfarin-induced anticoagulation.151, 152
Reconstitution and Administration
Factor IX (human) is administered by slow IV injection or infusion.151, 152 Rapid rates of administration may result in vasomotor reactions.151 Factor IX concentrates also have been administered via continuous IV infusion†.171, 173, 174
The rate of administration of factor IX (human) should be individualized according to the specific preparation and the response and comfort of the patient.151, 152 AlphaNine® SD should be administered at a rate not exceeding 10 mL/minute.151 Mononine® solutions containing 100 units/mL should be administered at a rate of approximately 2 mL/minute; the drug has been administered at rates up to 225 units/minute without any unusual adverse effects.152
Prior to reconstitution, the diluent (sterile water for injection) and vial of lyophilized factor IX (human) should be warmed to at least room temperature, but no warmer than 37°C.151, 152 Factor IX (human) should be reconstituted according to the manufacturer's directions.151, 152 After the diluent has been added to the powder for injection as directed by the manufacturer, the solution should be swirled gently until all concentrate is dissolved; complete dissolution generally requires less than 5 minutes.151, 152 Reconstituted solutions of factor IX (human) should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.151, 152 Factor IX (human) must be filtered prior to administration.151, 152 Factor IX (human) should be administered promptly following reconstitution; the manufacturers recommend that solutions of the drug be administered within 3 hours following reconstitution to avoid inadvertent bacterial contamination.151, 152 The reconstituted preparation should not be refrigerated.152 The manufacturer of Mononine® recommends that the drug be administered using plastic syringes only since solutions of this type tend to stick to ground surfaces of glass syringes.152
Factor IX complex (human) is administered by slow IV injection or by IV infusion.100, 140 Rapid rates of administration may result in vasomotor reactions.140 Factor IX concentrates also have been administered via continuous IV infusion†.171, 173, 174
The rate of administration of factor IX complex (human) should be individualized according to the specific preparation used and the patient's response.100, 140 Bebulin® should be administered at a rate that is comfortable for the patient, but the rate should not exceed 2 mL/minute.100 Profilnine® should be administered at a rate not exceeding 10 mL/minute.140
Prior to reconstitution, the diluent (sterile water for injection) and vial of factor IX complex (human) concentrate should be warmed to room temperature (not exceeding 37°C).100, 140 Factor IX complex (human) should be reconstituted according to the manufacturer's directions.100, 140 After the diluent is added to the vial containing the lyophilized powder, the solution should be gently swirled or rotated until the powder is completely dissolved.100, 140 Reconstitution of Profilnine® should take less than 10 minutes.140 Reconstituted solutions of factor IX complex (human) should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.100, 140 Factor IX complex (human) should be filtered before administration.100, 140 It is recommended that administration of the reconstituted preparation begin within 3 hours of reconstitution to avoid inadvertent bacterial contamination.100, 140 The reconstituted preparation should not be refrigerated.100, 140, 151, 152 The manufacturer of Profilnine® recommends that the drug be administered using plastic syringes only.140
Dose (potency) of factor IX (human) and factor IX complex (human) is expressed in terms of international units (IU, units) of factor IX activity.100, 140, 151, 152 One unit is approximately equivalent to the amount of factor IX activity in 1 mL of pooled normal human plasma.100, 140, 151, 152 The dosage of factor IX (human) or factor IX complex (human) required to establish hemostasis in patients with hemophilia B will vary with each patient and circumstance since there is considerable variability among patients and their clinical conditions.100, 140, 151, 152 Therefore, dosage should be carefully individualized and factor IX levels monitored frequently during therapy with the drugs.100, 140, 151, 152 Close monitoring of factor IX levels is particularly important in cases of severe hemorrhage or major surgery.100 The dosing frequency for maintaining sufficiently increased levels of a deficient factor also is variable; although minor bleeding episodes may be controlled with a single dose, more severe bleeding may require administration of additional doses.100
Factor IX (Human) in Patients with Hemophilia B
Administration of 1 unit/kg of factor IX (human) generally increases circulating levels of factor IX by 1%.151, 152
The following formula may be used as a guide in determining the dose of factor IX (human) required to achieve a particular percentage increase in plasma factor IX level:151, 152
Units required = body weight (in kg) × 1 unit/kg × desired factor IX increase (in % of normal)
The desired factor IX level is determined by the clinical situation and severity of hemorrhage.151, 152 (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.151, 152 The manufacturers' dosage recommendations should be consulted for further information on dosage of factor IX (human) in the management of specific types of bleeding in patients with hemophilia B.151, 152
For the treatment of minor hemorrhage (e.g., bruises, cuts, scrapes, uncomplicated joint hemorrhage), the manufacturer of AlphaNine® SD recommends that levels of factor IX be increased to at least 20-30% of normal until bleeding stops or healing occurs (usually 1-2 days).151 This can be achieved by administering a dosage of 20-30 units/kg twice daily.151 For moderate hemorrhage (e.g., epistaxis, mouth and gum bleeding, tooth extraction, hematuria), factor IX levels should be increased to 25-50%, which can be achieved by administering a dosage of 25-50 units/kg twice daily; treatment should continue until healing occurs (usually 2-7 days).151 For major hemorrhage (e.g., joint or muscle bleeding [especially in large muscles], major trauma, hematuria, intracranial bleeding, intraperitoneal bleeding), factor IX levels should be increased initially to 50% for at least 3-5 days; a dosage of 30-50 units/kg twice daily is recommended to achieve such plasma levels.151 Following this treatment period, additional doses of 20 units/kg twice daily should be given to maintain factor IX levels at 20% until healing occurs.151 Up to 10 days of treatment may be necessary for major hemorrhages.151
For patients with factor IX deficiency who are undergoing surgery, the manufacturer of AlphaNine® SD recommends that factor IX levels be increased to 50-100% of normal prior to surgery.151 This can be achieved with doses of 50-100 units/kg twice daily.151 Additional doses of 50-100 units/kg twice daily should be given to maintain factor IX levels at 50-100% of normal for the next 7-10 days or until healing is achieved.151
For treatment or prophylaxis of minor spontaneous hemorrhage, the manufacturer of Mononine® states that patients may receive a single dose of up to 20-30 units/kg to increase plasma factor IX levels to 15-25%; this dose may be repeated in 24 hours if necessary.152 For major trauma or surgery, the manufacturer recommends an initial loading dose of up to 75 units/kg to increase plasma factor IX levels to 25-50%; this dose may be given every 18-30 hours depending on the half-life and measured plasma factor IX levels, for up to 10 days depending on the nature of the insult.152 Although specific information on the use of Mononine® in patients with factor IX inhibitors is not available, the manufacturer states that higher dosages of the drug may be necessary in these patients.152
Factor IX Complex (Human) in Patients with Hemophilia B
The factor IX activity and the activity of factors II, VII, and X contained in currently available preparations of factor IX complex (human) (Bebulin®, Profilnine®) vary.100, 104, 140 The number of units of factor IX activity is indicated on the label of each preparation.100, 104, 140 Administration of 1 unit/kg of Bebulin® generally produces an in vivo increase in plasma factor IX activity of 0.8%,100 and administration of 1 unit/kg of Profilnine® generally produces an increase in plasma factor IX activity of 1%.140
Following administration of an initial loading dose, maintenance dose should be based on response and the factor IX level achieved; according to one manufacturer, usual maintenance doses of two-thirds the initial dose have been given.100
The following formula may be used to calculate the dose of Profilnine® required to achieve a particular percentage increase in plasma factor IX level:140
Units required = body weight (in kg) × 1 unit/kg × desired factor IX increase (in % of normal)
The following formula may be used to calculate the dose of Bebulin® required to achieve a particular percentage increase in plasma factor IX level:100
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.100, 140 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.100, 140 The manufacturers' dosage recommendations should be consulted for further information on dosage of factor IX complex (human) in the management of specific types of bleeding in patients with hemophilia B.100, 140
For the treatment of minor bleeding (e.g., early hemarthrosis, minor epistaxis, gingival bleeding, mild hematuria), the manufacturer of Bebulin® recommends an initial dose of 25-35 units/kg to achieve a plasma factor IX level of approximately 20% of normal.100 A single dose is usually sufficient; if necessary, a second dose may be given after 24 hours.100 For treatment of moderate hemorrhage (e.g., severe joint bleeding, early hematoma, major open bleeding, minor trauma, minor hemoptysis, minor hematemesis, minor melena, major hematuria), an initial dose of 50-65 units/kg is recommended to achieve a plasma factor IX level of approximately 40% of normal; the dose may be repeated every 24 hours for 2 days or until adequate wound healing occurs.100 For treatment of major hemorrhage (e.g., severe hematoma, major trauma, severe hemoptysis, severe hematemesis, severe melena), the manufacturer recommends an initial dose of 75-90 units/kg to achieve a plasma factor IX level of 60% of normal or higher, unless the patient has a high risk of thrombosis.100 (See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.) Doses may be repeated every 24 hours for 2-3 days or until adequate wound healing occurs.100
For patients undergoing minor surgery (e.g., tooth extraction), the manufacturer of Bebulin® recommends an initial dose of 50-75 units/kg administered 1 hour prior to surgery to achieve plasma factor IX levels of approximately 40-60% of normal.100 One dose is usually sufficient for a single tooth extraction.100 For extraction of several teeth and other minor surgical procedures, additional doses of 25-65 units/kg are recommended to maintain plasma factor IX levels of approximately 20-40% of normal during the initial postoperative period (1-2 weeks following surgery).100 More frequent (e.g., every 12 hours) dosing may be required for initial treatment, while longer intervals (e.g., every 24 hours) generally are sufficient during the later postoperative period.100 For major surgery, an initial dose of 70-90 units/kg is recommended 1 hour prior to the procedure to achieve plasma factor IX levels of at least 60% of normal unless the patient has a high risk for thrombosis.100 Additional doses of 25-75 units/kg should be administered during the initial postoperative period (1-2 weeks following surgery) to maintain plasma factor IX levels of approximately 20-60% of normal, followed by doses of 25-35 units/kg from week 3 onward to maintain plasma factor IX levels of approximately 20% of normal.100 More frequent (e.g., every 12 hours) dosing may be required for initial treatment, while longer intervals (e.g., every 24 hours) generally are sufficient during the later postoperative period.100
For treatment of mild to moderate hemorrhage, an appropriate dose of Profilnine® should be administered to achieve plasma factor IX levels of 20-30% of normal.140 A single dose usually is sufficient.140 For more serious hemorrhage, the patient's plasma factor IX levels should be increased to 30-50% of normal; daily infusions usually are required.140
For factor IX deficient patients undergoing surgery, an appropriate dose of Profilnine® should be administered to achieve plasma factor IX levels of 30-50% of normal for at least 1 week following the procedure.140 For dental extractions, levels of factor IX should be increased to 50% immediately prior to the procedure and additional doses given if bleeding recurs.140
Routine Prophylaxis in Patients with Hemophilia B
Various dosing protocols have been recommended for routine prophylaxis with clotting factor concentrates; the optimal regimen remains to be established.100, 171, 176, 185, 186 Dosages of 25-40 units/kg of factor IX concentrates twice a week are commonly recommended for prophylaxis in patients with hemophilia B.171, 173, 185, 186 The Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation states that a factor IX dosage of 40-100 units/kg 2 or 3 times weekly usually is sufficient to maintain trough factor IX concentrations above 1% between infusions.176
MASAC states that prophylactic therapy should be instituted at an early age (e.g., 1-2 years) prior to the onset of frequent bleeding.176 However, the optimum duration of prophylaxis is not known; patients should be evaluated periodically to determine continued need for such therapy.176
Adverse effects that have occurred rarely in patients receiving factor IX complex (human) include fever, chills, headache, urticaria, nausea, vomiting, somnolence, lethargy, flushing, tingling, dyspnea, and stinging or burning at the infusion site.100, 140 Many of these adverse effects may be related to rapid administration of the drug, and may be relieved in most individuals by slowing the rate of administration.140 Hypersensitivity reactions, including anaphylaxis, have been reported with use of all factor IX-containing preparations.100, 140, 151, 152, 172 Patients with certain genetic mutations or inhibitor antibodies to factor IX appear to be at greater risk of hypersensitivity.151, 152, 171, 172, 178, 179, 180, 181 (See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.)
Myocardial infarction (MI), disseminated intravascular coagulation (DIC), venous thrombosis, and pulmonary embolism (PE) have been reported rarely following administration of high doses of factor IX complex (human).140 Development of postoperative thrombosis after treatment with factor IX complex (human) also has been reported.140 (See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.)
Precautions and Contraindications
Risk of Transmissible Agents in Plasma-derived Preparations
Improved viral-depleting processes and improved donor screening practices used during the manufacture of currently available preparations of factor IX (human) and factor IX complex (human) have substantially reduced the viral infectious potential of these plasma-derived preparations.100, 140, 151, 152 However, no method has been shown to be totally effective in removing the risk of viral infectivity from coagulation factor preparations derived from pooled human plasma and there is still a possibility of human viral transmission from these preparations.100, 140, 151, 152
Although transmission of viruses that do not have a lipid envelope, such as parvovirus B19 and hepatitis A virus (HAV), has occurred with commercially available plasma-derived clotting factor concentrates, the risk has been reduced with additional viral attenuation methods such as nanofiltration.100, 140, 151, 152, 155, 156 Nevertheless, patients receiving factor IX (human) or factor IX complex (human) therapy should be informed of the potential risk for such infections and should immediately report any manifestations of parvovirus B19 infection (e.g., fever, drowsiness, chills, runny nose, rash, joint pain) or hepatitis A infection (e.g., low grade fever, anorexia, nausea, vomiting, fatigue, jaundice, dark urine, abdominal pain) to a clinician.100, 152 Parvovirus B19 infection is especially serious in pregnant or immunocompromised patients.100
Although there has been no evidence to date of such transmission, it has been suggested that plasma-derived preparations are potentially capable of transmitting unknown viruses or other disease agents such as prions (e.g., causative agents for Creutzfeldt-Jakob disease [CJD] or variant CJD [vCJD]).155, 156, 161, 162, 145 Parvovirus B19 and prions also may be markers for other blood-borne infectious agents that have not yet been discovered or recognized.155
Clinicians should carefully weigh the risk of pathogen transmission versus benefits of factor IX (human) or factor IX complex (human) therapy.100, 140, 151, 152, 155 Any suspected infections associated with these preparations should be reported to the manufacturer, the FDA, and the Centers for Disease Control and Prevention (CDC).100, 152, 156
Because factor IX (human) and factor IX complex (human) are prepared from pooled human plasma, they are potential vehicles for transmission of viruses, including the causative agents of viral hepatitis.100, 140, 151, 156 Although plasma used in preparation of factor IX (human) and factor IX complex (human) has been tested and shown to be negative for hepatitis B virus (HBV) and hepatitis C virus (HCV) and all currently available factor IX (human) and factor IX complex (human) preparations undergo heat-treatment and/or chemical procedures during manufacturing in an attempt to reduce viral infectious potential, no method has been shown to be totally effective in removing hepatitis infectivity.100, 140, 156 Viral attenuation methods used in the production of currently available factor IX (human) preparations that appear to be effective in reducing the risk for transmission of hepatitis are vapor-heat treatment, chemical (solvent/detergent) treatment, and nanofiltration.100, 140, 151, 152, 156 In addition, purification steps involved in production of factor IX preparations are associated with loss of several additional logs of virus.156
Active immunization against HBV using hepatitis B vaccine is recommended by the American Academy of Pediatrics (AAP) and other experts for all children and for individuals with hemophilia or other congenital bleeding disorders.140, 151, 156, 160 It is recommended that hepatitis B vaccination be initiated at birth or at the time of diagnosis.100, 140, 151, 141, 143, 156 (See Hepatitis B Vaccine 80:12.)
Immunization against HAV with hepatitis A virus vaccine inactivated is recommended for all individuals 1 year of age or older with hemophilia or other congenital bleeding disorders who are HAV seronegative.140, 151, 156, 170 (See Hepatitis A Virus Vaccine Inactivated 80:12.)
Individuals receiving blood or plasma infusions may develop signs and symptoms of other viral infections, particularly non-A, non-B hepatitis.152
Coagulation factor concentrates prepared from pooled human plasma are potential vehicles for transmission of human immunodeficiency virus (HIV).101, 102, 103, 105, 106, 111, 121, 126, 127, 128, 132, 133, 135, 138, 140 Although HIV seroconversion occurred in some hemophilia patients in the past who received blood transfusions and/or previously available plasma-derived coagulation factor concentrates (including factor IX complex [human]) that were obtained from donors who had not been screened for HIV and/or were prepared using a suboptimal viral-inactivating procedure (e.g., heat-treatment only),101, 102, 103, 108, 121, 125, 128, 129, 131, 136, 137, 138 there now is considerable evidence that improved viral-depleting processes and improved donor screening practices used in the manufacture of currently available preparations of factor IX (human) and factor IX complex (human) have resulted in products with greatly reduced risk for transmission of HIV.156
Data obtained during the period prior to the availability of effective viral-inactivating procedures and specific HIV donor screening procedures indicate that the prevalence of HIV seropositivity in patients with coagulation disorders requiring plasma-derived coagulation factor concentrates varied according to type and severity of the disorder, with an overall prevalence of about 70%126 (reported range: 33-92%)131 in hemophilia A patients and about 35%126 (reported range: 14-52%)131 in hemophilia B patients. In factor IX complex (human) recipients, seropositivity was associated with more severe hemophilia and severity of hemophilia was correlated with factor usage.111 The total number of hemophiliacs who developed clinical manifestations of acquired immunodeficiency syndrome (AIDS) during that period was relatively small compared with other high-risk groups,122, 123 but the incidence rates were high (a cumulative incidence estimated at 3% for patients with hemophilia A and 1% for patients with hemophilia B in the US as of September 1987).131 In addition, the cumulative AIDS incidence for seropositive hemophiliacs varied regionally, being calculated to be as high as 18% six years after seroconversion in one US hemophilia treatment center.125, 131 During this period, the incidence rate of AIDS in patients with hemophilia B was approximately 3-6 times lower than the incidence rate in patients with hemophilia A.101, 123, 131
There have been no reports of HIV seroconversion associated with any currently available plasma-derived clotting factor concentrates, including preparations that are heated in aqueous solution (pasteurized), solvent/detergent treated, and/or immunoaffinity purified.156 However, the possibility of transmission of HIV-1 or HIV-2 with use of currently available viral-inactivated plasma-derived products still remains.156
Risk of Creutzfeldt-Jakob Disease or Variant Creutzfeldt-Jakob Disease
Because factor IX (human) and factor IX complex (human) are prepared from human blood, they theoretically may carry a risk of transmitting the causative agent of Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD).140, 145, 151, 155 There have been 3 probable cases of vCJD acquired through transfusion of human red blood cells (RBCs) identified by an ongoing epidemiologic review being conducted in the United Kingdom.155, 167 One of these patients developed symptoms of vCJD 6.5 and 7.8 years, respectively, after receiving non-leukodepleted RBCs from 2 different donors; the donors developed clinical symptoms approximately 40 and 21 months after donating.167 The third probable case of transfusion-associated vCJD had no clinical symptoms of the disease prior to death, but abnormal prion protein was found in postmortem lymphoid tissue (5 years after RBC transfusion); the donor involved in this case had made the RBC donation 18 months before the onset of their clinical symptoms.167 Although attempts to transmit CJD to nonhuman primates via blood transfusion have failed, bovine spongiform encephalopathy (BSE) has been transmitted to at least one sheep through blood transfusion.145, 146
Although there is no evidence to date that CJD or vCJD has been transmitted by plasma-derived preparations such as factor IX (human) or factor IX complex (human), there remains a theoretical risk of such transmission.145, 146, 155 Therefore, the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation states that every effort should be made to make recombinant clotting factors available to all who would benefit from them and that all barriers to conversion from human plasma-derived concentrates to recombinant clotting factors should be removed.155
Tests are being developed to detect CJD and vCJD infection in blood and plasma donors.145 Until such donor screening tests are available for these diseases, the FDA has recommended interim preventive measures that include specific guidelines for deferral of blood and plasma donors with possible exposure to CJD and vCJD that are based on geographic considerations and guidelines for product retrieval, quarantine, and disposition that are based on consideration of risk in the donor and product and the effect that withdrawals and deferrals might have on the supply of blood, blood components, and plasma derivatives.145 For further information on CJD and vCJD precautions related to blood and blood products, the FDA's guidance for industry should be consulted ([Web]).145
There is evidence that West Nile Virus (WNV) can be transmitted in transplanted organs (e.g., heart, liver, kidney) and blood products (e.g., whole blood, packed red blood cells, fresh frozen plasma).143, 153, 154, 163, 164 WNV has been isolated from frozen plasma obtained from a blood donor subsequently found to have WNV, indicating that the virus can survive in frozen blood components.154 It is unlikely that WNV would be transmitted through commercially available plasma-derived preparations of clotting factors since WNV is an enveloped virus, like HCV, which is known to be inactivated by the heat and solvent/detergent viral inactivation procedures used in the manufacture of these preparations.154
Since 2005, several FDA-approved nucleic acid tests have become available to screen donated blood for WNV; when potential donors test positive for WNV infection using one of these licensed donor screening tests, blood donation should be deferred for 120 days.154, 166 The FDA also recommends additional measures to assess donor suitability to help screen out potential blood donors who have past or present symptoms that suggest WNV illness.154 When potential donors have a medical diagnosis of WNV infection or there is suspicion of WNV infection (including diagnosis based on symptoms and/or laboratory results), blood donation should be deferred for 120 days after diagnosis or onset of illness, whichever is later.154 In addition, when donors report an otherwise unexplained febrile illness with headache or other symptoms suggestive of WNV infection within 2 weeks after donation during the typical WNV season (or at other times if there is evidence of local WNV activity), deferment for 120 days following onset of illness is recommended.154 Deferment also is recommended for individuals whose blood or blood components have been potentially associated with a transfusion-related WNV transmission.154 These recommendations apply to donors of whole blood and blood components intended for transfusion and blood components, including recovered plasma, source leukocytes, and source plasma, intended for use in further manufacturing into injectable or noninjectable products.154
Because of the possible transmission of WNV through organ transplants and blood transfusions, any case of WNV that occurs in a patient who received organs, blood, or blood products within the 4 weeks preceding onset of the illness should be reported to CDC through state and local health authorities and serum or tissue samples should be retained for later studies.153, 154 In addition, cases of WNV infection occurring in blood or organ donors within 2 weeks after their donation should be reported to CDC.153, 154 Prompt reporting of such individuals will facilitate withdrawal of potentially infected products.153, 154
For further information on WNV precautions related to blood and blood products, the FDA's guidance for industry should be consulted ([Web]).154
Other Precautions and Contraindications
Serious and potentially fatal thromboembolic events (e.g., MI, venous thrombosis, PE, DIC) have been reported with use of factor IX (human)151, 152 and factor IX complex (human)100, 140 preparations containing high concentrations of factors II, VII, and X.174, 175 Risk appears to be increased in patients with preexisting thrombotic risk factors (e.g., liver disease, concomitant use of thrombogenic drugs, history of thrombosis, DIC) and during a postoperative period.100, 140, 152, 174, 175 Use of high doses of factor IX complex concentrates also is a risk factor and has been associated with MI, DIC, venous thrombosis, and PE.152 Development of postoperative thrombosis after treatment with factor IX complex (human) also has been reported.140 Although the risk of thrombogenicity is markedly lower with pure factor IX preparations than with factor IX complex preparations, there is still a potential risk of thromboembolism in patients receiving such preparations, particularly if they have predisposing risk factors.151, 152, 171
The potential benefits of treatment with factor IX-containing preparations should be weighed against the potential risk of thromboembolic complications.140, 152 Pending further accumulation of clinical data, factor IX complex (human) should be administered only to patients in whom the benefits outweigh the risks.140 Patients who require high dosages of factor IX complex (human) for surgery, those who require prolonged therapy postoperatively, and patients with known liver disease or other risk factors for thrombosis should be closely observed for signs and symptoms of thromboembolic complications, including DIC.100, 140, 151, 152 Caution also should be exercised when administering factor IX complex (human) to neonates.152 If any manifestations of thromboembolic complications occur, the drug should be immediately discontinued and the appropriate treatment administered.100 Recommended dosage guidelines should be followed to decrease the risk of thromboembolic complications.151 Whenever possible, use of pure factor IX preparations should be considered in high-risk patients and during high-risk situations (e.g., surgery) because of their reduced thrombogenic potential compared with factor IX complex preparations.148, 151, 152, 156, 171, 174, 180
Patients with hemophilia B have developed neutralizing antibodies (inhibitors) to factor IX following treatment with factor IX preparations.100, 171, 178, 179, 180, 181 Inhibitors have been reported in about 1-5% of patients with hemophilia B, usually within the first 10-20 days of treatment.171, 173, 178, 181 Patients with certain major deletion mutations of the factor IX gene may be at higher risk of inhibitor development and of experiencing an acute hypersensitivity reaction.151, 152, 171, 178, 179, 180, 181 Patients receiving factor IX (human) or factor IX complex (human), particularly those with known deletion mutations of the factor IX gene, should be carefully monitored for the development of inhibitors with appropriate clinical observation and laboratory tests.151, 152, 171 The presence of inhibitors should be suspected in any patient who fails to respond to adequate factor replacement therapy, particularly in those who had previously achieved a response.171 Patients who receive intensive clotting factor therapy, such as those in whom repeated treatments are administered, also should be monitored for the development of inhibitors.140, 171 Because of an association between inhibitor development and hypersensitivity reactions, patients experiencing any manifestations of an allergic reaction should be evaluated for the presence of inhibitors.100 Consultation with a hemophilia treatment center is strongly recommended for patients with inhibitors.171
Patients should be closely observed for hypersensitivity reactions during treatment with factor IX (human) or factor IX complex (human), especially during the initial phases of therapy.140, 151, 152 The manufacturer of Bebulin® states that the drug is contraindicated in patients with known hypersensitivity to the product; in addition, because this preparation contains small amounts of heparin, Bebulin® also is contraindicated in patients with known allergy to heparin or history of heparin-induced thrombocytopenia (HIT).100 The manufacturer of Alphanine® SD states that anaphylaxis may occur in previously untreated patients after a median exposure of 11 days; therefore, it is recommended that these patients be monitored closely between days 10 and 20 of drug exposure.151 If manifestations of a hypersensitivity reaction (e.g., generalized urticaria, hives, wheezing, chest tightness, hypotension, anaphylaxis) occur, the drug should be discontinued immediately and appropriate therapy initiated.100, 140, 151, 152
Nephrotic syndrome has been reported following immune tolerance induction with factor IX-containing products in patients with hemophilia B who have inhibitors and/or a history of severe hypersensitivity reactions to factor IX.100, 151, 152, 172, 178, 179, 180 The safety and efficacy of factor IX-containing preparations for immune tolerance induction have not been established.151, 152
Mononine® contains trace amounts (less than 50 ng per 100 units of factor IX activity) of murine (mouse) protein.152 Although hypersensitivity reactions have not been reported to date, the possibility exists that patients receiving the drug may develop hypersensitivity to murine protein.152 Mononine® is contraindicated in individuals with known hypersensitivity to murine protein.152
The manufacturer of Mononine® factor IX (human) states that no data are available regarding the use of aminocaproic acid following an initial infusion of Mononine® for the prevention or treatment of oral bleeding following trauma or dental procedures such as extractions.152
Safety and efficacy of AlphaNine® SD have not been established in children 16 years of age or younger.151 In a well-controlled clinical study in patients who previously received factor IX concentrates for hemophilia B and in an ongoing safety and efficacy clinical trial in patients who had not previously received factor IX concentrates, responses observed in pediatric patients were similar to those observed in adults; adverse effects in patients 16 years of age or younger were similar to those observed in older age groups.151 Anecdotal evaluation of the study results indicated no difference in efficacy or safety between the pediatric and adult populations.151
Safety and efficacy of Bebulin® have not been established in pediatric patients; studies evaluating use of the drug in pediatric patients with hemophilia B are not available.100, 177
Safety and efficacy of Mononine® have been established in pediatric patients 1 day to 20 years of age.152 Studies within this age group have demonstrated excellent hemostasis in addition to a lack of viral transmission and thrombotic complications with factor IX (human) therapy.152 The manufacturer states that dosing in children generally is based on the same guidelines as for adults.152
Safety and efficacy of Profilnine® have not been established in patients younger than 16 years of age.140 In a well-controlled clinical study in patients who previously received factor IX concentrates for hemophilia B, responses observed in the 2 pediatric patients receiving Profilnine® were similar to those observed in adults; no adverse effects were reported in the pediatric patients.140 Anecdotal evaluation of the study results indicated no difference in efficacy or safety between the pediatric and adult populations.140
Factor IX (human) should be used with caution in neonates because of a potential increased risk of thromboembolic complications.152
Animal reproduction studies have not been performed with factor IX (human)151, 152 or factor IX complex (human).100, 140 It is not known whether the preparations can cause fetal harm when administered to pregnant women or affect reproduction capacity.100, 140, 151, 152 Factor IX (human) and factor IX complex (human) should be used during pregnancy only when clearly needed.100, 140, 151, 152
Blood coagulation factor IX (Christmas factor or plasma thromboplastin component) is a vitamin K-dependent coagulation factor synthesized in the liver.152 Factor IX, factor VII (proconvertin or serum prothrombin conversion accelerator), and factor X (Stuart-Prower factor) are essential for the conversion of factor II (prothrombin) to thrombin.152, 174, 178 Factor IX is activated by Factor XIa in the intrinsic coagulation pathway.152 Activated factor IX, in combination with activated factor VIII, converts factor X to Xa resulting ultimately in the conversion of factor II (prothrombin) to thrombin and formation of a fibrin clot.152, 174
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.152, 171 Clinical severity and frequency of bleeding in patients with hemophilia B correlate with the degree of deficiency of factor IX activity.171 Patients with mild hemophilia B generally have more than 5% of normal factor IX activity, those with moderate disease generally have 1-5% of normal factor IX activity, and those with severe disease have less than 1% of normal factor IX activity.171, 172, 174, 178, 180 Administration of factor IX to patients with hemophilia B results in increased plasma levels of factor IX and temporarily corrects the coagulation defect.152
The half-life of factor IX (human) has been reported to range from 18-25 hours, but shows considerable interindividual variation.151, 152, 171, 178 Following IV infusion of 40-50 units/kg of factor IX (human) given as AlphaNine® SD in patients with moderate to severe hemophilia B, the plasma half-life of factor IX averages 21 hours.151 In clinical studies, the mean recovery of factor IX following administration of AlphaNine® SD is approximately 48%.151 Following infusion of Mononine® in patients with moderate or severe hemophilia B, plasma half-life averaged 23 hours; for each unit/kg of factor IX (human) administered, the mean recovery of factor IX was approximately 0.67 units/dL.152
Factor IX complex (human) is rapidly cleared from the plasma following IV administration. The half-life of factor IX complex (human) is reported to range between 18-36 hours in factor IX-deficient patients but shows considerable interindividual variation.100, 140, 151 Generally, disappearance curves of factor IX complex (human) are biphasic.173 It has been theorized that the first phase represents an equilibration between intravascular and extravascular compartments and the second phase represents the true rate of utilization.
Endogenous factor IX circulates in plasma as a free molecule and readily diffuses into the interstitial fluid.173 Factor IX appears to be distributed into both intravascular and extravascular compartments.174, 181 Factor IX binds rapidly and reversibly to the vascular endothelium.173
Factor IX (human) is a sterile, lyophilized concentrate of blood coagulation factor IX prepared from pooled human plasma.149, 151, 152 All currently available preparations of factor IX (human) undergo viral inactivation processes during manufacture using chemical and/or heat-treatment procedures to reduce the risk of transmission of viral infection.151, 152, 156 In addition, purification steps used in preparation of factor IX products also help to decrease viral contamination.151, 152, 156 However, no method has been shown to be totally effective in removing the risk of viral infectivity from coagulation factor preparations.152, 156 (See Cautions: Precautions and Contraindications.)
Potency of factor IX (human) is expressed in terms of international units (IU, units) as defined by the World Health Organization Standard.151, 152 One unit of factor IX (human) is defined as the average factor IX activity present in 1 mL of normal fresh pooled plasma.151, 152 Commercially available AlphaNine® SD contains at least 150 units of factor IX activity per mg of protein, 151 and commercially available Mononine® has a specific activity of no less than 190 units of factor IX activity per mg of total protein.152
AlphaNine® SD uses affinity purification steps to isolate factor IX from pooled human plasma and undergoes a chemical (solvent/detergent) process for viral inactivation and a nanofiltration process to remove viruses.151 AlphaNine® SD contains undetectable amounts of factors II, VII, and X and not more than 0.04 units of heparin and not more than 0.2 mg of dextrose per unit of factor IX.151
Mononine® uses murine monoclonal antibody and affinity chromatography to isolate factor IX from pooled human plasma.152 Factor IX is then dissociated from the monoclonal antibody, recovered, and purified further.152 When reconstituted as directed, Mononine® solutions are clear, colorless, isotonic solutions with neutral pH.152 Each mL of the reconstituted solution contains approximately 100 units of factor IX activity, approximately 10 mM histidine, 0.066 M sodium chloride, 0.0075% polysorbate 80, and 3% mannitol; hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.152 Mononine® solutions also contain trace amounts (not more than 50 ng per 100 units of factor IX activity) of murine (mouse) protein.152 (See Cautions: Precautions and Contraindications.)
Factor IX complex (human) is a sterile, lyophilized concentrate of blood coagulation factors II, VII, IX, and X derived from fresh venous plasma obtained from healthy human donors.100, 140, 188 Potency of factor IX complex (human) is expressed in terms of the factor IX component.100, 140 One unit of factor IX is defined as the average factor IX activity present in 1 mL of normal fresh pooled plasma.100, 140 This standard and the potency of each manufactured lot meet standards established by the US Food and Drug Administration (FDA).188
Commercially available preparations of factor IX complex (human) (Bebulin®, Profilnine®) contain different amounts of factor IX activity.100, 104, 140, 173, 174 In addition, the factor II, VII, and X activities contained in these preparations vary.100, 104, 140 For each 100 units of factor IX activity, Profilnine® contains no more than 150 units of factor II activity, no more than 35 units of factor VII activity, and no more than 100 units of factor X.140 Some factor IX complex (human) preparations (e.g., Bebulin®) contain small amounts of heparin as a stabilizing agent.100
All currently available preparations of factor IX complex (human) undergo a viral inactivation process during manufacture using a chemical and/or heat-treatment procedure to reduce the risk of virus transmission; however, no method has been shown to be totally effective in removing the risk of viral infectivity from coagulation factor preparations.100, 140, 141, 156 Treatment procedures currently used include vapor heat (e.g., Bebulin®), or chemical inactivation (solvent/detergent) (e.g., Profilnine®).100, 140, 156 (See Cautions: Precautions and Contraindications.)
Factor IX (human) powder for injection should be stored at 2-8°C; freezing of the diluent should be avoided to prevent damage to the diluent vial.151, 152 AlphaNine® SD may be stored at room temperature (not exceeding 30°C) for up to 1 month.151 Mononine® may be stored for up to 1 month at room temperature (not exceeding 25°C).152 Because of the potential for inadvertent bacterial contamination, factor IX (human) solutions should be administered within 3 hours following reconstitution and any unused portion of reconstituted solution should be discarded.151, 152
Bebulin® should be stored at 2-8°C prior to use;100 freezing should be avoided.100 Profilnine® should be stored at temperatures not exceeding 25°C and should not be frozen.140
Although reconstituted solutions of factor IX complex (human) are stable for up to 3 hours at room temperature, prompt administration is recommended to avoid inadvertent bacterial contamination; these solutions should not be refrigerated after reconstitution.140 Any unused portion of reconstituted factor IX complex (human) should be discarded.140
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV use only | number of units indicated on label | AlphaNine® SD (with sterile water for injection diluent; available with filter transfer set) | |
Mononine® (with sterile water for injection diluent; available with alcohol swabs, transfer needle, filter spike, and an administration set) |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV use only | number of units indicated on label | Bebulin® (with sterile water for injection diluent; available with transfer and filter needles) | |
Profilnine® (with sterile water for injection diluent; available with filter transfer set) | Grifols |
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