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Benefix (Coagulation Factor IX (Recombinant)) - Description and Clinical Pharmacology

 
 



DESCRIPTION

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 Ala148 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 known 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, IU) 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 IU 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 (IU). Each vial contains nominally 250, 500, or 1000 IU of Coagulation Factor IX (Recombinant). After reconstitution of the lyophilized drug product, the concentrations of excipients in the 500 and 1000 IU dosage strengths are 10 mM L-histidine, 1% sucrose, 260 mM glycine, 0.005% polysorbate 80. The concentrations after reconstitution in the 250 IU dosage strength are half those of the other two dosage strengths. The 500 and 1000 IU dosage strengths are isotonic after reconstitution, and the 250 IU dosage strength has half the tonicity of the other two dosage strengths after reconstitution. All dosage strengths yield a clear, colorless solution upon reconstitution.

CLINICAL PHARMACOLOGY

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 IU/kg of BeneFIX® , Coagulation Factor IX (Recombinant), in 37 previously treated adult patients (>15 years), each given as a 10-minute infusion, the mean increase from pre-infusion level in circulating factor IX activity was 0.8 ± 0.2 IU/dL per IU/kg infused (range 0.4 to 1.4 IU/dL per IU/kg) and the mean biologic half-life was 18.8 ± 5.4 hours (range 11 to 36 hours). In the randomized, cross-over pharmacokinetic study in previously treated patients (PTPs), 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. Structural differences of the BeneFIX® molecule compared with pdFIX were shown to contribute to the lower recovery. In subsequent evaluations for up to 24 months, the pharmacokinetic parameters were similar to the initial results.

For specific information regarding pediatric pharmacology, see PRECAUTIONS, Pediatric Use.

CLINICAL STUDIES

There are ongoing safety and efficacy studies of BeneFIX® in previously treated, previously untreated, and minimally treated patients.

In 4 clinical studies of BeneFIX® , a total of 128 subjects 56 previously treated patients [PTPs], 9 subjects participating only in the surgical study, and 63 previously untreated patients (PUPs) received more than 28 million IU administered over a period of up to 64 months. The studies included 121 HIV-negative and 7 HIV-positive subjects.

Fifty-six PTPs received approximately 20.9 million IU of BeneFIX® in two clinical studies. The median number of exposure days was 83.5. These PTPs who were treated for bleeding episodes on an on-demand basis or for the prevention of bleeds were followed over a median interval of 24 months (range 1 to 29 months; mean 23.4 ± 5.34 months). Fifty-five of these PTPs received a median of 42.8 IU/kg (range 6.5 to 224.6 IU/kg; mean 46.6 ± 23.5 IU/kg) per infusion for bleeding episodes. All subjects were evaluable for efficacy. One subject discontinued the study after one month of treatment due to bleeding episodes that were difficult to control; he did not have a detectable inhibitor. The subject's dose had not been adequately titrated. The remaining 55 subjects were treated successfully. Bleeding episodes that were managed successfully included hemarthroses and bleeding in soft tissue and muscle. Data concerning the severity of bleeding episodes were not reported. Eighty-eight percent of the total infusions administered for bleeding episodes were rated as providing an "excellent" or "good" response. Eighty-one percent of all bleeding episodes were managed with a single infusion of BeneFIX® . One subject developed a low titer, transient inhibitor (maximum titer 1.5 BU). This subject had previously received plasma-derived products without a history of inhibitor development. He was able to continue treatment with BeneFIX® with no anamnestic rise in inhibitor or anaphylaxis, however, increased frequency of BeneFIX® administration was required; subsequently the subject's factor IX inhibitor and its effect on the half-life of BeneFIX® resolved.

Forty-one of the subjects had measurements of fibrinopeptide A and prothrombin fragment 1 + 2 prior to infusion, 4 to 8 hours and then 24 hours following the infusion. Twenty-nine of the subjects had elevations in fibrinopeptide A with a maximum value of 35.3 nmol/L (22 of the 29 subjects had elevated baseline values). Ten of the subjects had elevated prothrombin fragment 1 + 2 with a maximum value of 1.82 nmol/L (3 of the 10 subjects had elevated baseline values).

A total of 20 PTPs were treated with BeneFIX® for secondary prophylaxis (the regular administration of FIX replacement therapy to prevent bleeding in patients who may have already demonstrated clinical evidence of hemophilic arthropathy or joint disease) at some regular interval during the study with a mean of 2.0 infusions per week. Nineteen subjects were administered BeneFIX® for routine secondary prophylaxis (at least twice weekly) for a total of 345 patient-months with a median follow-up period of 24 months per subject. The average dose used by these 19 subjects was 40.3 IU/kg, ranging from 13 to 78 IU/kg. One additional subject was treated weekly, using an average dose of 33.3 IU/kg, over a period of 21 months. Ninety-three percent of the responses were rated as "excellent" or "effective". These 20 PTPs received a total of 2985 infusions of BeneFIX® for routine prophylaxis. Seven of these PTPs experienced a total of 26 spontaneous bleeding episodes within 48 hours after an infusion.

Management of hemostasis was evaluated in the surgical setting. Thirty-six surgical procedures have been performed in 28 subjects. Thirteen (13) minor surgical procedures were performed in 12 subjects, including 7 dental procedures, 1 punch biopsy of the skin, 1 cyst removal, 1 male sterilization, 1 nevus ablation, and 2 ingrown toenail removals. Twenty-three (23) major surgical procedures were performed in 19 subjects including a liver transplant, splenectomy, 3 inguinal hernia repairs, 11 orthopedic procedures, a calf-debridement and 6 complicated dental extractions.

Twenty-three (23) subjects underwent 27 surgical procedures with a pulse-replacement regimen. The mean perioperative (preoperative and intraoperative) dose for these procedures was 85 ± 32.8 IU/kg (range 25-154.9 IU/kg). The mean total post-operative (inpatient and outpatient) dose was 63.1 ± 22.0 IU/kg (range 28.6-129.0).

Total BeneFIX® coverage during the surgical period for the major procedures ranged from 4230 to 385,800 IU. The pre-operative dose for the major procedures ranged from 75 to 155 IU/kg. Nine of the major surgical procedures were performed in 8 subjects using a continuous infusion regimen. Following pre-operative bolus doses (94.1 -144.5 IU/kg), continuous infusion of BeneFIX® was administered at a median rate of 6.7 IU/kg/hr (range of average rates: 4.3-8.6 IU/kg/hr; mean 6.4 ± 1.5 IU/kg/hr for a median duration of 5 days (range 1-11 days; mean 4.9 ± 3.1). Six of the 8 subjects who had received continuous infusion of BeneFIX® in conjunction with major surgeries were switched over to intermittent pulse regimens at a median dose of 56.3 IU/kg (range 33.6-89.1 IU/kg; mean 57.8 ± 18.1 IU/kg SD) for a median of 3.5 exposure days (range 1-5 days, mean 3.3 ± 1.4 SD) during the post-operative period. Although circulating factor IX levels targeted to restore and maintain hemostasis were achieved with both pulse replacement and continuous infusion regimens, clinical trial experience with continuous infusion of BeneFIX® for surgical prophylaxis in hemophilia B has been too limited to establish the safety and clinical efficacy of administration of the product by continuous infusion. Subjects administered BeneFIX® by continuous infusion for surgical prophylaxis also received intermittent bolus infusions of the product.

Among the surgery subjects, the median increase in circulating factor IX activity was 0.7 IU/dL per IU/kg infused (range 0.3-1.2 IU/dL; mean 0.8 ± 0.2 IU/dL per IU/kg). The median elimination half-life for the surgery subjects was 19.4 hours (range 10-37 hours; mean 21.3 ± 8.1 hours).

Hemostasis was maintained throughout the surgical period, however, one subject required evacuation of a surgical wound site hematoma and another subject who received BeneFIX® after a tooth extraction required further surgical intervention due to oozing at the extraction site. There was no clinical evidence of thrombotic complications in any of the subjects. In seven subjects for whom fibrinopeptide A and prothrombin fragment 1 + 2 were measured pre-infusion, 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 other subjects were judged to be not evaluable.

Sixty-three PUPs received approximately 6.2 million IU of BeneFIX® in an open-label safety and efficacy study over 89 median exposure days. These PUPs were followed over a median interval of 37 months (range 4 to 64 months; mean 38.1 ± 16.4 months). Fifty-four of these PUPs received a median dose of 62.7 IU/kg (range 8.2 to 292.0 IU/kg; mean 75.6 ± 42.5 IU/kg) per infusion for bleeding episodes. Data concerning the severity of bleeding episodes were not reported. Seventy-five percent of all bleeding episodes were managed with a single infusion of BeneFIX® . Three of these 54 subjects were not successfully treated; including one episode in a subject due to delayed time to infusion and insufficient dosing and in 2 subjects due to inhibitor formation. One subject developed a high titer inhibitor (maximum titer 42 BU) on exposure day 7. A second subject developed a high titer inhibitor (maximum titer 18 BU) after 15 exposure days. Both subjects experienced allergic manifestations in temporal association with their inhibitor development.

Thirty-two PUPs administered BeneFIX® for routine prophylaxis. Twenty-four PUPs administered BeneFIX® at least twice weekly for a total of 2587 infusions. The mean dose per infusion was 72.5 ± 37.1 IU/kg, and the mean duration of prophylaxis was 13.4 ± 8.2 months. Eight PUPs administered BeneFIX® once weekly for a total of 571 infusions. The mean dose per infusion was 75.9 ± 17.9 IU/kg, and the mean duration of prophylaxis was 17.6 ± 7.4 months. Five PUPs experienced a total of 6 spontaneous bleeding episodes within 48 hours after an infusion.

Twenty-three PUPs received BeneFIX® for surgical prophylaxis in 30 surgical procedures. All surgical procedures were minor except 2 hernia repairs. The preoperative bolus dose ranged from 32.3 IU/kg to 247.2 IU/kg. The perioperative total dose ranged from 385 to 23280 IU. Five of the surgical procedures were performed using a continuous infusion regimen over 3 to 5 days. Clinical trial experience with continuous infusion of BeneFIX® for surgical prophylaxis in hemophilia B has been too limited to establish the safety and clinical efficacy of administration of the product by continuous infusion.

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