VA Class:BL500
Biosynthetic (recombinant DNA origin) preparation of blood coagulation factor IX.1, 7, 21, 25
Factor IX (recombinant) is used for the prevention and control of bleeding episodes in patients with hemophilia B (congenital factor IX deficiency or Christmas disease) and for the maintenance of hemostasis in such patients undergoing surgery;1, 6, 9, 14, 25 factor IX (recombinant) has been designated an orphan drug by FDA for this use.28 Factor IX (recombinant) also is used for routine prophylaxis (i.e., administration at regular intervals on an ongoing basis) to prevent or reduce the frequency of bleeding events in patients with hemophilia B.6, 9, 15, 25, 171, 176
The Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation considers recombinant factor IX preparations the treatment of choice for individuals with hemophilia B because of their potentially superior safety profile with respect to pathogen transmission.155, 156, 176 (See MASAC Recommendations Regarding Treatment of Hemophilia under Uses: Hemophilia B.) In other hemophilia management guidelines, such as those developed by the 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
Prophylactic therapy with factor IX concentrates is considered the current 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.171, 185, 186 In a study documenting up to 25 years of experience with prophylactic treatment of hemophilia A or B in Sweden, boys with severe hemophilia who were started on a prophylactic regimen of factor concentrates at a young age (1-2 years) and given large doses (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, MASAC recommends that routine prophylactic administration of clotting factor concentrates be considered in all individuals with severe hemophilia B (factor IX activity less than 1%). 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
Safety and efficacy of factor IX (recombinant) for the management of patients with hemophilia B have been evaluated in clinical studies in which patients received the drug as prophylactic therapy, on-demand treatment, or for perioperative hemostasis.1, 25 Studies evaluating BeneFIX® have been performed both in patients previously treated with factor IX preparations and in those who have had no prior exposure to factor IX therapy, whereas studies evaluating Rixubis® have been performed only in previously treated patients to date.1, 25 In clinical studies of patients receiving BeneFIX® for on-demand treatment of bleeding episodes, 75-81% of the bleeding events treated were controlled with one dose of the drug, and the hemostatic response was rated “excellent/good” in 90.9-94.1% of cases; bleeding episodes that were successfully treated included hemarthrosis and soft tissue and muscle hemorrhage.1 In studies evaluating prophylactic use of BeneFIX®, the drug was given an average of 2 times per week in previously treated patients for secondary prophylaxis (regular administration of factor IX replacement therapy in patients who may have already demonstrated clinical evidence of arthropathy or joint disease), or once or twice weekly in previously untreated patients for primary or secondary prophylaxis; the hemostatic response to the drug was rated “excellent” or “effective” in about 93-98% of the patients treated.1 The duration of prophylactic treatment was approximately 14-18 months in these studies.1
In the principal efficacy study of Rixubis® in adults and adolescents 12 years of age or older, 84.7% of the 249 bleeding events that occurred were successfully controlled with 1 or 2 injections of the drug at a median dose of 62.3 units/kg per episode; hemostasis was rated “excellent” or “good” in 96% of cases.25, 27 The annualized rate of bleeding was evaluated as a principal measure of efficacy in this study.25 In patients receiving routine prophylaxis with Rixubis® at a dosage of 40-60 units/kg twice weekly, the mean annualized rate of bleeding was 4.3 over a median treatment duration of 6 months.25, 27 In patients receiving on-demand treatment, the mean annualized bleeding rate was 33.9 over a median treatment duration of 3.4 months.25 In another study, 23 pediatric patients 1.8-11.8 years of age received prophylactic treatment with Rixubis® (40-80 units/kg twice weekly) for a minimum of 3 months.25 Of the total 26 bleeding events that occurred, 88.5% were successfully controlled with 1 or 2 injections of the drug.25 The mean annualized bleeding rate was 2.7 in these pediatric patients.25
Factor IX (recombinant) has been used effectively to maintain hemostasis perioperatively and postoperatively in patients undergoing minor surgery (e.g., tooth extraction) and major surgery (e.g., hip prosthesis implant, knee arthroplasty, knee arthroscopic synovectomy, liver transplantation, splenectomy, hernia repair).1, 25 In surgical studies of BeneFIX® in previously treated and previously untreated patients, response to the drug was rated “excellent/good” and hemostasis was effectively maintained during surgery in almost all of the procedures evaluated.1 Efficacy of Rixubis® in the perioperative setting was evaluated in a total of 14 previously treated patients undergoing 14 major or minor surgical, dental, or other invasive procedures; hemostasis was rated “excellent” or “good” in all of the procedures.25 Factor IX (recombinant) has been administered as a continuous infusion† in some patients undergoing surgery; although target factor IX levels were achieved with continuous infusion regimens, the manufacturers state that safety and efficacy of this method of administration have not been established for any factor IX (recombinant) preparation.1, 25 (See IV Administration under Dosage and Administration: Administration.)
The manufacturer of BeneFIX® states that factor IX (recombinant) is not indicated for the treatment of deficiencies of other coagulation factors (e.g., factors II, VII, VIII, X) or for management of hemophilia A patients with inhibitors to factor VIII.1 Factor IX (recombinant) also should not be used for reversal of coumarin-induced anticoagulation or for treatment of hemorrhagic states caused by low concentrations of liver-dependent coagulation factors.1 Safety and efficacy of factor IX (recombinant) for immune tolerance induction in patients with hemophilia B have not been established.1, 25
MASAC Recommendations Regarding Treatment of Hemophilia
Pending further accumulation of data, MASAC makes the following observations and recommendations concerning the treatment of hemophilia B and other bleeding disorders:155, 156, 187
Factor IX (recombinant) therapy should be initiated under the supervision of a clinician experienced in the treatment of hemophilia B.1, 25
Dosage and duration of therapy should be individualized based on the patient's age, severity and location of bleeding, degree of factor IX deficiency, desired factor IX levels, presence of factor IX inhibitors, and clinical and pharmacokinetic (e.g., half-life, incremental recovery) response.1, 25, 27
Factor IX activity should be monitored (by the one-stage clotting assay) to individualize dosage and assess response to therapy.1, 25 (See Laboratory Monitoring under Warnings/Precautions: General Precautions, in Cautions.)
Reconstitution and Administration
Factor IX (recombinant) is administered by IV injection over several minutes.1, 25 Although some preparations of factor IX (recombinant) have been given by continuous infusion†, the manufacturers state that safety and efficacy of continuous infusions of these drugs have not been established.1, 7, 25 Thromboembolic events have been reported in some patients receiving continuous infusions of factor IX (recombinant).1 (See Thromboembolic Events under Warnings/Precautions: Warnings, in Cautions and also see Pediatric Use under Warnings: Specific Populations, in Cautions.)
The manufacturer's labeling should be consulted for specific information on reconstitution and administration of factor IX (recombinant).1
Reconstitution and Administration of BeneFIX®
Factor IX (recombinant) (BeneFIX®) should be reconstituted using the prefilled diluent syringe (containing sodium chloride 0.234%) provided by the manufacturer.1 The drug vial and diluent should be allowed to warm to room temperature prior to reconstitution.1 After addition of the diluent, the vial should be swirled gently until the powder is dissolved completely.1 Reconstituted solutions should be inspected visually for particulate matter and discoloration prior to administration; the solution should be clear and colorless.1 Reconstituted solutions of factor IX (recombinant) should be administered within 3 hours after reconstitution; if not used immediately, the solution may be stored at room temperature.1 Any unused solution should be discarded after 3 hours.1
BeneFIX® should be administered using the infusion set tubing and diluent syringe provided by the manufacturer or using a single sterile disposable plastic syringe.1 Red blood cell (RBC) agglutination has been reported following administration of factor IX (recombinant); in order to minimize this risk, the drug should be administered carefully to prevent blood from entering the tubing and syringe.1 If RBC agglutination occurs, the administration set, syringe, and remaining drug solution should be discarded and administration should be resumed using new materials.1 The manufacturer states that BeneFIX® should not be administered in the same tubing or container with other drugs.1
The surfactant (polysorbate 80) contained in reconstituted solutions of BeneFIX® is known to increase the rate of extraction of diethylhexylphthalate (DEHP) from polyvinyl chloride (PVC); the manufacturer states that this should be considered during preparation and administration of the drug, including consideration of storage time elapsed in a PVC container following reconstitution.1 For additional details on reconstitution and preparation of BeneFIX®, the manufacturer's labeling should be consulted.1
Reconstitution and Administration of Rixubis®
Factor IX (recombinant) (Rixubis®) should be reconstituted with sterile water for injection provided by the manufacturer.25, 26 Prior to reconstitution, the drug vial and diluent should be allowed to warm to room temperature.25 After addition of the diluent, the vial should be swirled gently until the powder is completely dissolved.25 Reconstituted solutions should be inspected visually for particulate matter and discoloration prior to administration; the solution should be clear and colorless.25 Reconstituted solutions of factor IX (recombinant) should be administered within 3 hours after reconstitution.25 If not used immediately, the solution should be kept at room temperature and not refrigerated.25 Any unused solution should be discarded after 3 hours.25 For additional details on reconstitution and preparation of Rixubis®, the manufacturer's labeling should be consulted.25, 26
Factor IX (recombinant) should be administered IV over a period of several minutes.1, 25, 26 The manufacturer of BeneFIX® states that the rate of administration should be individualized based on patient response and comfort; the rate should be decreased or therapy discontinued if any adverse reaction occurs.1 The manufacturer of Rixubis® states that the drug should be administered no faster than 10 mL/minute.25, 26
Dose (potency) of factor IX (recombinant) is expressed in terms of international units (IU, units) of factor IX activity.1, 25 Potency is determined by a one-stage clotting assay based on the activated partial thromboplastin time (aPTT) calibrated against a standard established by the World Health Organization (WHO).1, 25, 29 Results of such potency tests can vary depending on the type of aPTT reagent and reference standard used; one manufacturer states that differences of up to 40% have been observed.25 In clinical trials, administration of 1 unit/kg of BeneFIX® generally increased factor IX levels by approximately 0.8% in adults and 0.7% in pediatric patients younger than 15 years of a administration of 1 unit/kg of Rixubis® generally increased factor IX levels by approximately 0.9% in adults and adolescents 12 years of age or older and by 0.7% in pediatric patients younger than 12 years of age.1, 25
The following formula may be used to estimate the dose of factor IX (recombinant) required to achieve a particular percentage increase in plasma factor IX:1, 20, 25
Dose (units) = body weight (in kg) x reciprocal of observed recovery (in units/kg per units/dL) × desired factor IX increase (in % of normal or units/dL)
The desired factor IX level is determined by the clinical situation and severity of bleeding.1, 25 For recommendations on target factor IX levels, see the specific dosage sections for various types of uses below. Incremental recovery should be based on the patient's individual recovery as determined by serial factor IX activity assays; however, the manufacturer recommends that an initial dose of factor IX (recombinant) may be calculated empirically based on the expected recovery values observed in clinical trials.1, 25 Such values include an average increase of 0.8% in adults and 0.7% in pediatric patients younger than 15 years of age for each unit/kg of BeneFIX® administered, and an average increase of 0.9% in adults and adolescents 12 years of age or older and 0.7% in pediatric patients younger than 12 years of age for each unit/kg of Rixubis® administered.1, 25
For example, based on the empiric finding that 1 unit/kg of factor IX (recombinant) administered as the BeneFIX® preparation increases plasma factor IX levels by 0.8% in adults, the estimated dose is calculated as follows:1
Dose (units) = body weight (in kg) × 1.3 (units/kg per units/dL) × desired factor IX increase (in % of normal or units/dL)
These calculations and suggested dosage regimens are only approximations and should not preclude appropriate clinical monitoring and individualization of dosage based on the hemostatic requirements of patients.1, 25 Serial assays of factor IX activity should be performed (using the one-stage clotting assay) whenever possible to ensure that adequate levels of factor IX have been attained and maintained, and subsequent dosage should be adjusted based on the patient's individual clinical and pharmacokinetic (e.g., half-life, incremental recovery) response.1, 25
If the calculated dose is ineffective in achieving appropriate factor IX levels, consideration should be given to the possibility that inhibitors to factor IX may have developed.1, 25, 171 (See Development of Inhibitors to Factor IX under Warnings/Precautions: General Precautions, in Cautions.)
When switching from plasma-derived preparations of factor IX to factor IX (recombinant), it may be necessary to increase the dose of factor IX (recombinant) to achieve the desired rise in factor IX activity.1, 18, 19 Patients at the low end of the observed factor IX recovery range may require an increase in dose (e.g., to as much as twice the initial empirically calculated dose according to the manufacturer of BeneFIX®) to achieve the intended increase in factor IX activity.1, 25
Prevention and Control of Bleeding
For the management of patients with minor bleeding (e.g., uncomplicated hemarthroses, superficial muscle, soft tissue), the manufacturer of BeneFIX® recommends target factor IX levels of 20-30% of normal; doses should be repeated every 12-24 hours for 1-2 days.1 In patients with moderate bleeding (e.g., intramuscular, soft tissue with dissection, mucous membranes, dental extractions, hematuria), the appropriate dose of factor IX (recombinant) should be administered to achieve a factor IX level of 25-50% of normal; doses should be repeated every 12-24 hours until bleeding resolves and healing begins, about 2-7 days.1 For major bleeding (e.g., pharyngeal, retropharyngeal, retroperitoneal, CNS), the appropriate dose of factor IX (recombinant) should be administered to achieve a factor IX level of 50-100% of normal; doses should be repeated every 12-24 hours for 7-10 days.1 Dosage adjustments may be required in pediatric patients younger than 15 years of age to account for possible lower recovery of factor IX in this age group.1
For the management of patients with minor bleeding (e.g., uncomplicated hemarthroses, superficial muscle, soft tissue), the manufacturer of Rixubis® recommends target factor IX levels of 20-30% of normal; doses should be repeated every 12-24 hours for at least 1 day until healing is achieved.25 In patients with moderate bleeding (e.g., intramuscular, soft tissue with dissection, mucous membranes, hematuria), the appropriate dose of factor IX (recombinant) should be administered to achieve a factor IX level of 25-50% of normal; doses should be repeated every 12-24 hours for 2-7 days until bleeding resolves and healing is achieved.25 For major bleeding (e.g., pharyngeal, retropharyngeal, retroperitoneal, CNS), the appropriate dose of factor IX (recombinant) should be administered to achieve a factor IX level of 50-100% of normal; doses should be repeated every 12-24 hours for 7-10 days until bleeding resolves and healing is achieved.25
In patients undergoing surgery associated with moderate bleeding (e.g., dental extractions), the manufacturer of BeneFIX® recommends that the appropriate dose of factor IX (recombinant) be given to achieve a factor IX level of 25-50% of normal; doses should be repeated every 12-24 hours until bleeding resolves and healing begins, about 2-7 days.1 In patients undergoing surgery associated with major bleeding, the manufacturer of BeneFIX® recommends that the appropriate dose of factor IX (recombinant) be given to achieve a factor IX level of 50-100% of normal; doses should be repeated every 12-24 hours for 7-10 days.1 Dosage adjustments may be required in pediatric patients younger than 15 years of age to account for possible lower recovery of factor IX in this age group.1
In patients undergoing minor surgery (e.g., dental extractions), the manufacturer of Rixubis® recommends that the appropriate dose of factor IX (recombinant) be administered to achieve a factor IX level of 30-60% of normal; doses should be repeated every 24 hours for at least 1 day until healing is achieved.25 For major surgery (e.g., intracranial, intraabdominal, intrathoracic, joint replacement), a target factor IX level of 80-100% is recommended when calculating an appropriate dose of factor IX (recombinant); doses should be repeated every 8-24 hours for 7-10 days until bleeding resolves and healing is achieved.25
Various dosing protocols have been recommended for routine prophylaxis with clotting factor concentrates.6, 18, 171, 185, 186 The Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation states that prophylactic therapy should be instituted at an early age (e.g., 1-2 years), prior to the onset of frequent bleeding.176 The optimum duration of prophylaxis is not known; patients should be evaluated periodically to determine continued need for such therapy.176 MASAC 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% in between infusions.176 Prophylactic dosage regimens should be individualized based on factors such as the patient's age, bleeding pattern, and physical activity level.25, 176
The manufacturer of BeneFIX® does not provide specific dosage recommendations for routine prophylaxis; however, in clinical studies, a mean dose of 40.3 units/kg (given an average of twice a week) was administered in previously treated patients and a mean dose of 73.3 units/kg (given at least once or twice weekly) was administered in previously untreated patients for primary or secondary prophylaxis.1
For routine prophylaxis in previously treated adults and adolescents 12 years of age or older, the manufacturer of Rixubis® recommends an initial factor IX (recombinant) dosage of 40-60 units/kg twice weekly.25 The recommended prophylactic regimen in pediatric patients younger than 12 years of age is 60-80 units/kg twice weekly.25 Dosage should be adjusted based on patient's age, bleeding pattern, and level of physical activity.25
Factor IX (recombinant) is contraindicated in patients with life-threatening, immediate hypersensitivity (e.g., anaphylaxis) or known hypersensitivity reactions to factor IX (recombinant) or any ingredient in the formulation, including hamster protein.1, 25 Treatment with Rixubis® also is contraindicated in patients with disseminated intravascular coagulation (DIC) and in those with signs of fibrinolysis.25
Thromboembolic complications (e.g., deep-vein thrombosis, pulmonary embolism, arterial thrombosis) have been reported following administration of factor IX-containing preparations.1, 25 Cases of peripheral thrombophlebitis and deep-vein thrombosis have been reported during postmarketing experience with at least one preparation of factor IX (recombinant) (i.e., BeneFIX®); several of these patients received factor IX (recombinant) by continuous infusion†.1 In addition, thrombotic events have occurred in patients receiving BeneFIX® by continuous infusion through a central venous catheter, including life-threatening superior vena cava syndrome in critically ill neonates.1 (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.) Although not specifically reported to date with Rixubis®, the risk of thrombosis is considered to be a class effect of all factor IX (recombinant) preparations.25
Patients with hepatic disease, signs of fibrinolysis, or other risk factors for thromboembolism or DIC should be monitored for early manifestations of thromboembolic and consumptive coagulopathy during factor IX (recombinant) therapy.25 (See Cautions: Contraindications.) Patients also should be monitored during perioperative and postoperative periods for such events.25 The risk of thromboembolic complications should be weighed against the benefits of therapy in patients with (or at risk of) DIC or thromboembolism.25
Nephrotic syndrome has been reported following immune tolerance induction with factor IX-containing preparations in patients with hemophilia B who have factor IX inhibitors and a history of hypersensitivity to factor IX.1, 5, 15, 16, 17, 25
Safety and efficacy of factor IX (recombinant) for immune tolerance induction have not been established.1, 25
Hypersensitivity reactions, including bronchospastic reactions and anaphylaxis, have been reported with use of factor IX-containing preparations.1, 5, 11, 12, 25 Manifestations have included pruritus, rash, urticaria, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, generalized discomfort, and fatigue.1, 11, 12
Patients with certain genetic mutations of factor IX and/or those with inhibitor antibodies to factor IX appear to be at increased risk of hypersensitivity.1, 5, 9, 11, 12, 15, 16, 17, 18, 19, 25, 171 Up to 50% of hemophilia B patients with inhibitors to factor IX may experience a severe hypersensitivity reaction, including anaphylaxis, following administration of a factor IX concentrate.
Patients should be observed closely for manifestations of hypersensitivity reactions, especially during initial exposure to factor IX (recombinant).1, 25 The initial infusions (approximately 10-20) should be administered in an appropriate medical setting where severe allergic reactions can be managed.1, 16, 171 If manifestations of hypersensitivity or anaphylaxis occur, factor IX (recombinant) should be discontinued immediately and appropriate therapy initiated.1, 25 Because of an association between inhibitor development and hypersensitivity reactions, patients who experience a hypersensitivity reaction to factor IX (recombinant) should be evaluated for the presence of inhibitors.1, 25 (See Development of Inhibitors to Factor IX under Warnings/Precautions: General Precautions, in Cautions.)
Commercially available preparations of factor IX (recombinant) (BeneFIX®, Rixubis®) contain trace amounts of hamster proteins; there is a possibility that patients who receive these preparations could develop hypersensitivity to these nonhuman mammalian proteins.1, 25 (See Cautions: Contraindications.)
Development of Inhibitors to Factor IX
Patients with hemophilia B have developed neutralizing antibodies (inhibitors) to factor IX following treatment with factor IX preparations.1, 6, 9, 15, 16, 17, 18, 19, 21, 25, 171 Inhibitors have been reported in about 1-5% of patients with hemophilia B receiving factor IX concentrates, usually within the first 10-20 days of treatment.6, 9, 15, 17, 19, 21, 171 Patients with certain genetic mutations of the factor IX gene may be at higher risk of inhibitor development and of experiencing an acute hypersensitivity reaction.1, 5, 9, 14, 15, 16, 17, 18, 19, 21, 171
Low-titer inhibitors were detected in at least one previously treated patient receiving BeneFIX® in clinical studies; in this case, the inhibitor was transient and did not affect factor IX recovery levels upon evaluation 15 months after the inhibitor was initially detected.1 High-titer inhibitors have been observed in a few previously untreated pediatric patients receiving BeneFIX®.1 (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.) Development of high-titer inhibitors may require use of an alternative treatment to factor IX replacement therapy.1, 25 Although neutralizing antibodies to factor IX have not been detected to date in patients receiving Rixubis®,25 inhibitor formation is a concern with any clotting factor therapy.27, 171
Patients receiving factor IX (recombinant) should be monitored regularly for the development of inhibitors.1, 25, 171 (See Laboratory Monitoring under Warnings/Precautions: General Precautions, in Cautions.) If expected factor IX levels are not achieved or bleeding is not controlled with adequate factor replacement therapy, the presence of inhibitors should be suspected.1, 25, 171 Patients who develop inhibitors to factor IX may be at increased risk of anaphylaxis following re-exposure to factor IX (recombinant).25 (See Hypersensitivity Reactions under Warnings/Precautions: Sensitivity Reactions, in Cautions.) Consultation with a hemophilia treatment center is strongly recommended for patients with inhibitors.25
Factor IX levels should be monitored to guide dosing and assess therapeutic response to factor IX (recombinant) therapy.1, 21, 25, 171 Use of the one-stage clotting assay is recommended for monitoring plasma factor IX activity.1, 25
Development of inhibitors should be monitored (with clinical observation and appropriate laboratory tests) during factor IX replacement therapy.1, 25, 171 If expected plasma factor IX levels are not attained or bleeding is not controlled with the recommended dose, the appropriate laboratory test (Bethesda assay) should be performed to detect the presence of factor IX inhibitors.1, 25 (See Development of Inhibitors to Factor IX under Warnings/Precautions: General Precautions, in Cautions.)
Category C.1, 25 (See Users Guide.)
It is not known whether factor IX (recombinant) is distributed into human milk; because many drugs are distributed into milk, the drug should be used with caution in nursing women.1, 25
Safety, efficacy, and pharmacokinetics of BeneFIX® have been evaluated in previously treated and previously untreated pediatric patients younger than 15 years of age.1 On average, in vivo recovery of factor IX is lower in pediatric patients younger than 15 years of age compared with older individuals; therefore, dosage adjustments may be necessary.1
Safety, efficacy, and pharmacokinetics of Rixubis® have been evaluated in previously treated pediatric patients younger than 12 years of age, including a few patients younger than 6 years of age.25 Incremental recovery in this age group is approximately 22% lower than in older individuals; therefore, dosage adjustments may be necessary.25 Younger pediatric patients (under 6 years of age) appear to have lower mean incremental recovery and higher clearance compared with older pediatric patients (6-12 years of age).25
In clinical studies, high-titer inhibitors were detected in several pediatric patients receiving BeneFIX® who had no prior exposure to factor IX preparations; these patients were withdrawn from the study.1
There have been rare postmarketing reports of critically ill neonates who have experienced thrombotic events, including life-threatening superior vena cava syndrome, while receiving continuous infusions of BeneFIX® through a central venous catheter.1 (See Thromboembolic Events under Warnings/Precautions: Warnings, in Cautions.)
There is insufficient experience in patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients.1, 25 Dosage should be individualized in geriatric patients.1, 25
Adverse effects observed in more than 5% of previously treated and previously untreated patients receiving BeneFIX® in clinical trials include headache, dizziness, nausea, injection site reaction, injection site pain, and skin-related hypersensitivity reactions such as rash and hives.1
Adverse effects observed in more than 1% of previously treated patients receiving Rixubis® in clinical trials include dysgeusia, pain in extremity, and positive test for furin antibody.25
Factor IX (recombinant) is a biosynthetic (recombinant DNA origin) preparation of blood coagulation factor IX.1, 7, 21, 25 Coagulation factor IX is essential for blood clotting and maintenance of hemostasis.14, 25 Patients with hemophilia B (Christmas disease) have15 deficient levels of endogenous factor IX, resulting in a hemorrhagic tendency and clinical manifestations such as bleeding into soft tissues, muscles, joints, and internal organs.14, 15, 18, 25, 171 The clinical severity and frequency of bleeding in patients with hemophilia B correlate with the degree of deficiency of factor IX activity.15, 18, 171 Patients with mild hemophilia B generally have more than 5% of normal activity, those with moderate disease generally have 1-5% of normal activity, and those with severe disease have less than 1% of normal activity.5, 14, 15, 18, 171 Administration of factor IX (recombinant) to patients with hemophilia B results in increased plasma levels of factor IX and temporarily corrects the coagulation defect.1, 25 Treatment also may normalize the activated partial thromboplastin time (aPTT), which is typically prolonged in patients with hemophilia B.1, 25
Factor IX (recombinant) is produced by recombinant DNA technology in a mammalian cell expression system and undergoes several purification and virus-inactivating/removal processes (e.g., chromatography, nanofiltration, solvent/detergent).1, 7, 18, 21, 25 Factor IX (recombinant) is manufactured without animal or human components.1, 5, 7, 9, 13, 15, 19, 21, 25 Factor IX (recombinant) is similar in structure and function to plasma-derived factor IX, but is associated with a substantially reduced risk of transmission of bloodborne human viruses (e.g., human immunodeficiency virus [HIV], hepatitis A virus [HAV], hepatitis B virus [HBV], hepatitis C virus [HCV]).1, 6, 7, 9, 13, 15, 25
In a pharmacokinetic study in previously treated patients receiving BeneFIX®, in vivo recovery of factor IX following IV administration of 50 units/kg of the drug was approximately 28% lower than that achieved following administration of an equivalent dose of plasma-derived factor IX; the difference is presumably due to structural modifications of factor IX (recombinant).1, 5, 7, 9, 18, 19, 21 The half-life of BeneFIX® is approximately 18-24 hours in adults and approximately 20-21 hours in pediatric patients.1 Following administration of a single dose of Rixubis® (71.3-79.4 units/kg) in previously treated patients 12 years of age or older, half-life of the drug was approximately 26.7 hours.25 In pediatric patients, half-life of Rixubis® (median dose of 75.3 units/kg) was approximately 23 hours for patients 6-11 years of age and approximately 28 hours for those younger than 6 years of age.25 Results of single- and repeat-dose pharmacokinetic studies indicate that incremental recovery of Rixubis® remains consistent over time in both adult and pediatric populations.25, 27 The pharmacokinetic profiles of the 2 currently available preparations of factor IX (recombinant) (BeneFIX® and Rixubis®) appear to be comparable.27 Decreased in vivo recovery has been observed in pediatric patients 15 years of age or younger compared with older individuals receiving factor IX (recombinant).1, 19, 25 Factor IX (recombinant) readily diffuses through interstitial fluid and distributes in both intravascular and extravascular compartments.6, 14, 17 The drug circulates in plasma as a free molecule.6 Factor IX (recombinant) binds rapidly and reversibly to vascular endothelium.6 Clearance of factor IX correlates with body weight and generally increases through adolescence, then stabilizes during adulthood.6
Importance of patients reporting to their clinician any adverse effects or problems following administration of factor IX (recombinant).25
Importance of discontinuing therapy and immediately informing a clinician if hives, generalized urticaria, chest tightness, difficulty in breathing, wheezing, faintness, rapid heart rate, low blood pressure, swelling of the face, or other manifestations of a hypersensitivity reaction or anaphylaxis occur or, alternatively, seeking immediate emergency care depending on the severity of such a reaction.1, 25
Possible development of inhibitors; importance of patients informing their clinician if they experience a lack of response to factor IX (recombinant) therapy.1, 25
Importance of advising patients to always follow the specific instructions given by their clinician, including those regarding storage, preparation, and administration of the drug.1, 25
Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1, 25
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1, 25
Importance of informing patients of other important precautionary information.1, 25 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
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 | number of units indicated on label (nominally 250, 500, 1000, 2000, or 3000 units) | BeneFIX® (with sodium chloride 0.234% diluent in a prefilled syrin available with infusion set and vial adapter device) | |
number of units indicated on label (nominally 250, 500, 1000, 2000, or 3000 units) | Rixubis® (with sterile water for injection diluent; available with needleless transfer device) |
1. Wyeth. BeneFIX® coagulation factor IX (recombinant) prescribing information. Philadelphia, PA; 2012 Mar.
5. Mannucci PM, Tuddenham EGD. The hemophilias—from royal genes to gene therapy. N Engl J Med . 2001; 344:1773-9. [PubMed 11396445]
6. Björkman S, Berntorp E. Pharmacokinetics of coagulation factor: clinical relevance for patients with haemophilia. Clin Pharmacokinet . 2001; 40: 815-32.
7. White GC II, Beebe A, Nielsen B. Recombinant factor IX. Thromb Haemost . 1997; 78:261-5. [PubMed 9198163]
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