BeneFIX,™ Coagulation Factor IX (Recombinant), is a purified protein produced by recombinant DNA technology for use in therapy of factor IX deficiency, known as hemophilia B or Christmas disease. Coagulation Factor IX (Recombinant) is a glycoprotein with an approximate molecular mass of 55,000 Da consisting of 415 amino acids in a single chain. It has a primary amino acid sequence that is identical to the Ala 148 allelic form of plasma-derived factor IX, and has structural and functional characteristics similar to those of endogenous factor IX.
BeneFIX™ is produced by a genetically engineered Chinese hamster ovary (CHO) cell line that is extensively characterized and shown to be free of infectious agents. The stored cell banks are free of blood or plasma products. The CHO cell line secretes recombinant factor IX into a defined cell culture medium that does not contain any proteins derived from animal or human sources, and the recombinant factor IX is purified by a chromatography purification process that does not require a monoclonal antibody step and yields a high-purity, active product. A membrane filtration step that has the ability to retain molecules with apparent molecular weights >70,000 (such as large proteins and viral particles) is included for additional viral safety. BeneFIX™ is predominantly a single component by SDS-polyacrylamide gel electrophoresis evaluation. The potency (in international units, I.U.) is determined using an in vitro one-stage clotting assay against the World Health Organization (WHO) International Standard for Factor IX concentrate. One international unit is the amount of factor IX activity present in 1 mL of pooled, normal human plasma. The specific activity of BeneFIX™ is greater than or equal to 200 I.U. per milligram of protein. BeneFIX™ is not derived from human blood and contains no preservatives or added animal or human components.
BeneFIX™ is inherently free from the risk of transmission of human blood-borne pathogens such as HIV, hepatitis viruses, and parvovirus.
BeneFIX™ is formulated as a sterile, nonpyrogenic, lyophilized powder preparation. BeneFIX™ is intended for intravenous (IV) injection. It is available in single use vials containing the labeled amount of factor IX activity, expressed in international units (I.U.). Each vial contains nominally 250, 500, or 1000 I.U. of Coagulation Factor IX (Recombinant). After reconstitution of the lyophilized drug product, the concentrations of excipients in the 500 and 1000 I.U. dosage strengths are 10 mM L-histidine, 1% sucrose, 260 mM glycine, 0.005% polysorbate 80. The concentrations after reconstitution in the 250 I.U. dosage strength are half those of the other two dosage strengths. The 500 and 1000 I.U. dosage strengths are isotonic after reconstitution, and the 250 I.U. dosage strength has half the tonicity of the other two dosage strengths after reconstitution. All dosage strengths yield a clear, colorless solution upon reconstitution.
Factor IX is activated by factor VII/tissue factor complex in the extrinsic coagulation pathway as well as by factor XIa in the intrinsic coagulation pathway. Activated factor IX, in combination with activated factor VIII, activates factor X. This results ultimately in the conversion of prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin, and a clot can be formed.
Factor IX is the specific clotting factor deficient in patients with hemophilia B and in patients with acquired factor IX deficiencies. The administration of BeneFIX,™ Coagulation Factor IX (Recombinant), increases plasma levels of factor IX and can temporarily correct the coagulation defect in these patients.
After single intravenous (IV) doses of 50 I.U./kg of BeneFIX™ in 36 patients, each given as a 10-minute infusion, the mean increase in circulating factor IX activity was 0.8 ± 0.2 I.U./dL per I.U./kg infused (ranged from 0.4 to 1.4) and the mean biologic half-life was 19.4 ± 5.4 hours (ranged from 11 to 36). The in vivo recovery using BeneFIX™ was statistically significantly less (28% lower) than the recovery using a highly purified plasma-derived factor IX product. There was no significant difference in biological half-life. In subsequent evaluations at 6 and 12 months, the pharmacokinetic parameters were similar to the initial results.
In clinical studies of BeneFIX™ involving a total of 64 patients (44 previously treated patients [PTPs]. 11 previously untreated patients [PUPs], and the 9 patients participating only in the surgical study), more than 7 million I.U. were administered over a period of up to 18 months. This includes 57 HIV-negative and 7 HIV-positive patients. Forty-five patients were evaluated for efficacy, all of whom were treated successfully for bleeding episodes on an on-demand basis or for the prevention of bleeds. Bleeding episodes that were managed successfully include hemarthroses and bleeding in soft tissue and muscle.
Management of hemostasis was evaluated in the surgical setting. Thirteen surgical procedures have been performed in 12 patients, with a cumulative dose ranging from 10,000 to 348,000 I.U. The 10 major procedures were performed using a pulse replacement regimen (N=7) or a continuous infusion regimen (N=3), and included a liver transplantation, a hernia repair, six orthopedic surgeries, and two dental extractions. Circulatory factor IX levels targeted to restore and maintain hemostasis were achieved with both pulse replacement and continuous infusion regimens. Hemostasis was maintained throughout the surgical period, and there was no clinical evidence of thrombotic complications in any of these patients. In four patients for whom fibrinopeptide A and prothrombin fragment 1 + 2 were measured preinfusion, at 4 to 8 hours, and then daily up to 96 hours, there was no evidence of significant increase in coagulation activation. Data from two additional patients were judged to be not evaluable.
A study of BeneFIX™ has been initiated in patients who had not been treated previously with plasma-derived factor IX concentrate (PUPs). In preliminary data, 11 of the 20 patients enrolled in the study received at least one infusion of BeneFIX.™ These 11 patients received a total of 27,208 I.U. in 42 infusions. Thirty to 50 patients will be enrolled and followed for up to 5 years to complete evaluation of BeneFIX™ in this patient population for safety, efficacy, and immunogenicity.
A low-level inhibitor developed in 1 of 44 BeneFIX™ patients who had previously received plasma-derived products. This patient had an extensive previous history of exposure to plasma-derived factor IX products, including a single subcutaneous exposure, without history of inhibitor development. Antibodies were detected in this patient after 9 months of treatment (39 exposure days) with BeneFIX.™ This patient was able to continue treatment with BeneFIX™ with no anamnestic rise in inhibitor or anaphylaxis.
Twelve days after a dose of BeneFIX™ for a bleeding episode, one hepatitis C antibody positive patient developed a renal infarct. The relationship of the infarct to prior administration of BeneFIX™ is uncertain but was judged to be unlikely by the investigator. The patient continued to be treated with BeneFIX.™
BeneFIX,™ Coagulation Factor IX (Recombinant), is indicated for the control and prevention of hemorrhagic episodes in patients with hemophilia B (congenital factor IX deficiency or Christmas disease), including control and prevention of bleeding in surgical settings.
BeneFIX™ is not indicated for the treatment of other factor deficiencies (e.g., factors II, VII, and X), nor for the treatment of hemophilia A patients with inhibitors to factor VIII, nor for the reversal of coumarin-induced anticoagulation, nor for the treatment of bleeding due to low levels of liver-dependent coagulation factors.
Because BeneFIX,™ Coagulation Factor IX (Recombinant), is produced in a Chinese hamster ovary cell line, it may be contraindicated in patients with a known history of hypersensitivity to hamster protein.
As with any intravenous protein product, allergic type hypersensitivity reactions are possible. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physician if these symptoms occur.
Since the use of factor IX complex concentrates has historically been associated with the development of thromboembolic complications, the use of factor IX-containing products may be potentially hazardous in patients with signs of fibrinolysis and in patients with disseminated intravascular coagulation (DIC).
Historically, the administration of factor IX complex concentrates derived from human plasma, containing factors II, VII, IX and X, has been associated with the development of thromboembolic complications. 1 Although BeneFIX™ contains no coagulation factor other than factor IX, the potential risk of thrombosis and DIC observed with other products containing factor IX should be recognized. Because of the potential risk of thromboembolic complications, caution should be exercised when administering this product to patients with liver disease, to patients postoperatively, to neonates, or to patients at risk of thromboembolic phenomena or DIC. In each of these situations, the benefit of treatment with BeneFIX™ should be weighed against the risk of these complications.
Activity-neutralizing antibodies (inhibitors) have been detected in patients receiving factor IX- containing products. As with all factor IX products, patients using BeneFIX™ should be monitored for the development of factor IX inhibitors (see Clinical Pharmacology ). It has been reported 2 that patients dosed with high-purity plasma-derived factor IX products who develop inhibitors to factor IX are at increased risk of anaphylaxis upon subsequent challenge with factor IX.
Dosing of BeneFIX™ may differ from that of plasma-derived factor IX products (see Clinical Pharmacology and Dosage and Administration ).
BeneFIX,™ Coagulation Factor IX (Recombinant), has been shown to be nonmutagenic in the Ames assay and nonclastogenic in a chromosomal aberrations assay. No investigations on carcinogenesis or impairment of fertility have been conducted.
Animal reproduction and lactation studies have not been conducted with BeneFIX,™ Coagulation Factor IX (Recombinant). It is not known whether BeneFIX™ can affect reproductive capacity or cause fetal harm when given to pregnant women. BeneFIX™ should be administered to pregnant and lactating women only if clearly indicated.
Safety and efficacy studies are ongoing in previously treated children and adolescents and in previously untreated children (see Clinical Pharmacology , , and Precautions ). During clinical studies conducted in PUPs, no adverse reactions related to therapy were reported in 42 infusions.
As with the intravenous administration of any product, the following reactions may be observed after administration: headache, fever, chills, flushing, nausea, vomiting, lethargy, or other manifestations of allergic reactions. During clinical studies with BeneFIX,™ Coagulation Factor IX (Recombinant), conducted in previously treated patients (PTPs), 60 mild adverse reactions definitely, probably, or possibly related to therapy were reported for 2548 infusions. These were nausea (16), discomfort at the IV site (13), altered taste (10), burning sensation in jaw and skull (6), allergic rhinitis (3), lightheadedness (2), headache (2), dizziness (1), chest tightness (1), fever (1), phlebitis/cellulitis at IV site (1), drowsiness (1), dry cough/sneeze (1), rash (1), and a single hive (1). Twelve days after a dose of BeneFIX™ for a bleeding episode, one hepatitis C antibody positive patient developed a renal infarct. The relationship of the infarct to prior administration of BeneFIX™ is uncertain but was judged to be unlikely by the investigator. The patient continued to be treated with BeneFIX.™
If any adverse reaction takes place that is thought to be related to the administration of BeneFIX,™ the rate of infusion should be decreased or the infusion stopped.
Treatment with BeneFIX,™ Coagulation Factor IX (Recombinant), should be initiated under the supervision of a physician experienced in the treatment of hemophilia B.
Dosage and duration of treatment for all factor IX products depend on the severity of the factor IX deficiency, the location and extent of bleeding, and the patient' clinical condition, age and recovery of factor IX. For all these reasons, doses administered should be titrated to the patient' clinical response and, when clinically indicated, factor IX activity recovery levels.
In an eleven patient crossover, randomized PK evaluation of BeneFIX™ and a single lot of high-purity plasma-derived factor IX, the recovery was lower for BeneFIX™ (see Clinical Pharmacology ). On average, on international unit of BeneFIX™ per kilogram of body weight increased the circulating activity of factor IX by 0.8 ± 0.2 (ranged from 0.4 to 1.4) I.U./dL.
Dosing should be based on the reported clinical trial pharmacokinetic results for BeneF IX .™ The following formula provides a guide to empirical dosage calculations:
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In the presence of an inhibitor, higher doses may be required.
The following chart 3 may be used to guide dosing in bleeding episodes and surgery:
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In the clinical efficacy studies, patients were initially administered the same dose previously used for plasma-derived Factor IX. Even in the absence of Factor IX inhibitor, several patients required increased doses in these studies.
To ensure that the desired Factor IX activity level has been achieved, precise monitoring using the Factor IX activity assay is advised, in particular, for surgical interventions.
BeneFIX™ is administered by IV infusion over several minutes after reconstitution of the lyophilized powder with Sterile Water for Injection (USP).
Always wash your hands before performing the following procedures. Aseptic technique should be used during the reconstitution procedure.
BeneFIX,™ Coagulation Factor IX (Recombinant), will be administered by intravenous (IV) infusion after reconstitution with Sterile Water for Injection (diluent).
BeneFIX™ should be administered within 3 hours after reconstitution. The reconstituted solution may be stored at room temperature prior to administration.
BeneFIX,™ Coagulation Factor IX (Recombinant), should be administered using a single sterile disposable plastic syringe. In addition, the solution should be withdrawn from the vial using the sterile filter spike.
After reconstitution, BeneFIX™ should be injected intravenously over several minutes. The rate of administration should be determined by the patient's comfort level (see Adverse Reactions ).
Dispose of all unused solution, empty vials, and used needles and syringes in an appropriate container for throwing away waste that might hurt others if not handled properly.
Product as packaged for sale : BeneFIX™ Coagulation Factor IX (Recombinant), should be stored under refrigeration at a temperature of 2 to 8°C (36 to 46°F). Prior to the expiration date, BeneFIX™ may also be stored at room temperature not to exceed 25°C (77°F) for up to 6 months. The patient should make note of the date the product was placed at room temperature in the space provided on the outer carton. Freezing should be avoided to prevent damage to the diluent vial. Do not use BeneFIX™ after the expiry date on the label.
Product after reconstitution : The product does not contain a preservative and should be used within 3 hours.
BeneFIX,™ Coagulation Factor IX (Recombinant), is supplied in single use vials which contain nominally 250, 500, or 1000 I.U. per vial (NDC # 58394-003-01, 58394-002-01, and 58394-001-01, respectively) with sterile diluent, sterile double-ended needle for reconstitution, sterile filter spike for withdrawal, sterile infusion set, and two (2) alcohol swabs. Actual factor IX activity in I.U. is stated on the label of each vial.
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