"The U.S. Food and Drug Administration today approved Alprolix, Coagulation Factor IX (Recombinant), Fc Fusion Protein, for use in adults and children who have Hemophilia B. Alprolix is the first Hemophilia B treatment designed to require less fre"...
Mechanism Of Action
The activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia A. Determination of aPTT is a conventional in vitro assay for the biological activity of FVIII. Treatment with Novoeight normalizes the aPTT over the effective dosing period.
All pharmacokinetic studies with Novoeight were conducted in previously treated patients with severe hemophilia A (factor VIII ≤ 1%). Analysis of plasma samples was conducted using both the one-stage clotting assay and the chromogenic assay.
In a multi-center, multi-national, open-label, single dose pharmacokinetic study, 23 patients with severe hemophilia A received 50 international units/kg of Novoeight intravenously. Two patients were below the age of 18 years (13 and 17 years). The pharmacokinetic parameters for 20 patients who completed the study are summarized in Table 4.
Table 4: Pharmacokinetics of Novoeight in 20 adult and
adolescent patients with hemophilia A
|Parameter||Clotting assay||Chromogenic assay|
|Mean (SD)||Mean (SD)|
|Incremental Recovery (IU/mL)/(IU/kg)||0.020 (0.002)||0.028 (0.006)|
|AUC (IU*h/mL)||14.2 (3.8)||18.7 (5.1)|
|CL (mL/h/kg)||3.74 (0.95)||2.87 (0.80)|
|t½ (h)||10.8 (4.9)||12.0 ( 9.3)|
|Vss (mL/kg)||53.4 (10.9)||44.3 (28.2)|
|Cmax (IU/mL)||1.07 (0.16)||1.54 (0.29)|
|MRT (h)||15.4 (6.4)||16.4 (10.1)|
In a separate pharmacokinetic study, 28 pediatric patients with severe hemophilia A (14 patients were below 6 years of age and 14 patients were between 6 to < 12 years of age) received a single dose of 50 international units/kg Novoeight. The pharmacokinetic parameters of Novoeight are summarized in Table 5 for both age groups.
Table 5: Pharmacokinetics of Novoeight in 28 pediatric
patients with hemophilia A
|Parameters||Clotting Assay||Chromogenic Assay|
|0 to < 6 years||6 to < 12 years||0 to < 6 years||6 to < 12 years|
|Mean (SD)||Mean (SD)|
|Incremental Recovery (IU/mL)/(IU/kg)||0.018 (0.007)||0.020 (0.004)||0.022 (0.006)||0.025 (0.006)|
|AUC (IU*h/mL)||9.9 (4.1)||11.1 (3.7)||12.2 (4.4)||14.4 (3.5)|
|CL (mL/h/kg)||6.26 (3.73)||5.02 (1.67)||4.60 (1.75)||3.70 (1.00)|
|t½ (h)||7.7 (1.8)||8.0 (1.9)||10.0 (1.7)||9.4 (1.5)|
|Vss (mL/kg)||57.3 (26.8)||46.8 (10.6)||55.8 (23.7)||41.2 (6.0)|
|Cmax (IU/mL)||1.00 (0.58)||1.07 (0.35)||1.12 (0.31)||1.25 (0.27)|
|MRT (h)||9.7 (2.5)||9.9 (2.6)||12.1 (1.9)||11.6 (2.3)|
The pharmacokinetic parameters were comparable between younger (0 to < 6 years) and older (6 to < 12 years) children. The mean clearance of Novoeight in younger and older children was 67% and 34% higher (based on per kg body weight) than in adults (3.74 mL/h/kg) when using the clotting assay, and 60% and 29% higher than in adults (2.87 mL/h/kg) when using the chromogenic assay. The mean half-life of Novoeight in younger and older children was 29% and 26% shorter than in adults (10.8 hours) when using the clotting assay, and 16% and 21% shorter than in adults (12 hours) when using the chromogenic assay.
Three multi-center, open-label, non-controlled trials have been conducted to evaluate the safety and efficacy of Novoeight in the control and prevention of breakthrough bleeds, routine prophylaxis and perioperative managenment in previously treated patients with hemophilia A. The analysis included 213 exposed subjects: 150 adolescents or adult subjects from the age of 12 years ( ≥ 150 exposure days) and 63 pediatric subjects below the age of 12 years ( ≥ 50 exposure days). Immunocompetent patients with severe hemophilia A (factor VIII activity ≤ 1%) and no history of FVIII inhibitors were eligible for the trials. A total of 187 out of 213 subjects continued in the safety extension trial. All subjects received preventive treatment every other day or three times weekly at the dose levels described in Table 3. Breakthrough bleeds were treated at the investigator's discretion aiming for a FVIII activity level above 0.5 IU/mL. Treatment during surgery was at the investigator's discretion aiming for a FVIII trough activity level above 0.5 IU/mL.
Control and Prevention of Bleeding Episodes
A total of 991 bleeds in 158 subjects were treated with Novoeight. The majority of the bleeds (89%) were of mild/moderate severity, 62% of the bleeds were spontaneous and 72% of the bleeds were localized in joints.
An overall assessment of efficacy was performed by the subject (for home treatment) or study site investigator (for treatment under medical supervision) using a four-point scale of excellent, good, moderate, or none. If the hemostatic response was rated as “excellent” or “good”, the treatment of the bleed was considered a success. If the hemostatic response was rated as “moderate or none” the treatment was considered a failure. Of these 991 bleeds, 838 (84%) were rated excellent or good in their response to treatment with Novoeight and 17 (1.7%) were rated as having no response. A total of 898 (91%) of the bleeds were resolved with one or two injections of Novoeight.
Clinical trials of Novoeight included 79 previously treated patients between one to 16 years of age. The hemostatic efficacy in treatment of bleeds was rated as either “excellent” or “good” on a pre-specified rating scale for 86% of the 244 bleeds reported in 54 subjects.
All 213 subjects received Novoeight for routine prophylaxis. The prophylactic regimen for the 150 adolescent and adult subjects consisted of 20-40 IU/kg every other day or 20-50 IU/kg three times per week. The prophylactic regimen for the 63 pediatric subjects consisted of 25-50 IU/kg every other day or 25-60 IU/kg three times per week. The majority of the subjects ( > 80%) were treated with the three times per week regimen.
The median annualized bleeding rates are provided in Table 6.
Table 6: Annualized Bleeding Rate in All Patients
|Small children 0 - < 6 years||Older children 6 - < 12 years||Adolescents 12 - < 16 years||Adults ≤ 16 years||Total|
|Annualized bleeding rate (median) (IQR)||2.9 (6.3)||4.1 (8.6)||4.4 (6.9)||3.1 (5.6)||3.1 (7.3)|
A total of 68 subjects were treated with Novoeight for at least 12 months, including seven subjects < 12 years. The ABR was similar for the subjects treated for 12 months when compared to the ABR for the total trial population.
A total of 11 surgeries were performed in 11 previously treated subjects between 14 and 55 years of age, of which 10 were major surgeries (five synovectomies, two total hip arthroplasties, one knee replacement, arthroscopy, and circumcision), and one was minor (tooth extraction).
The investigator's ratings of intra- and post-operative quality of hemostasis for these subjects were “excellent” or “good” for all cases.
Last reviewed on RxList: 3/25/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Novoeight Information
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