"The U.S. Food and Drug Administration today approved Vimizim (elosulfase alfa), the first FDA-approved treatment for Mucopolysaccharidosis Type IVA (Morquio A syndrome). Morquio A syndrome is a rare, autosomal recessive lysosomal storage disease "...
Factor VIII is the specific clotting factor deficient in patients with hemophilia A (classical hemophilia). The administration of ReFacto® (antihemophilic factor) Antihemophilic Factor (Recombinant) increases plasma levels of factor VIII activity and can temporarily correct the in vitro coagulation defect in these patients.
Activated factor VIII acts as a cofactor for activated factor IX accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed. Factor VIII activity is greatly reduced in patients with hemophilia A and therefore replacement therapy is necessary.
In a crossover pharmacokinetic study of eighteen (18) previously treated patients using the chromogenic assay, the circulating mean half-life for ReFacto (antihemophilic factor) was 14.8 ± 5.6 hours (range 7.6-28.5 hours), which was not statistically significantly different from plasma-derived Antihemophilic Factor (Human) (pdAHF), which had a mean half-life of 13.7 ± 3.7 hours (range 8.8-25.1 hours). Mean incremental recovery (K-value) of ReFacto (antihemophilic factor) in plasma was 2.4 ± 0.4 IU/dL per IU/kg (range 1.9-3.3 IU/dL per IU/kg). This was comparable to the mean incremental recovery observed in plasma for pdAHF which was 2.3 ± 0.3 IU/dL per IU/kg (range 1.7-2.9 IU/dL per IU/kg). Results of a comparative study that evaluated the effect of phospholipids on the one-stage clotting and chromogenic assays showed that the one-stage clotting assay gave results that were approximately 50% of the values obtained with the chromogenic assay (see DOSAGE AND ADMINISTRATION).
In 2 additional clinical studies, pharmacokinetic parameters were evaluated for previously treated patients [PTPs] and previously untreated patients [PUPs]. In PTPs (n=101; median age 26 ± 12 years) ReFacto (antihemophilic factor) had a mean incremental recovery at Week 0 of 2.4 ± 0.4 IU/dL per IU/kg (range 1.1-3.8 IU/dL per IU/kg). In measurements over 4 years of use (Month 3 [n=90], Month 6 [n=87], Month 12 [n=88], Month 24 [n=70], Month 36 [n=64], and Month 48 [n=52]), mean incremental recovery was reproducible and ranged from 2.3 to 2.5 IU/dL per IU/kg. A subset of 37 study subjects had evaluable pharmacokinetic profiles at both baseline and Month 12 (Table 1). The 90% confidence intervals for the ratios of the mean values of Month 12-to-baseline AUCT, AUC∞, and K-value were well within the bioequivalence window of 80% to 125%, demonstrating the stability of these pharmacokinetic parameters over 1 year. In PUPs (n=59; median age 10 ± 8.3 months) ReFacto (antihemophilic factor) had a lower mean incremental recovery at Week 0 of 1.5 ± 0.6 IU/dL per IU/kg (range 0.2-2.8 IU/dL per IU/kg) as compared to PTPs. The mean incremental recovery for PUPs was stable over time (5 visits during a 2-year period) and ranged from 1.5 to 1.8 IU/dL per IU/kg of ReFacto (antihemophilic factor) . Population pharmacokinetic modeling using data from 44 PUPs led to a mean estimated half-life of ReFacto (antihemophilic factor) in PUPs of 8.0 ± 2.2 hours.
TABLE 1. MEAN FACTOR VIII PHARMACOKINETIC PARAMETERS FOR
37 PTPS WITH BOTH BASELINE AND MONTH 12 PHARMACOKINETIC PROFILES FOLLOWING A
RAPID INFUSION OF REFACTO (antihemophilic factor) AT A DOSE OF 50 IU/KG
| Half- life
|Mean Residence Time(hr)||Vss (mL/kg)|| K-value
The efficacy of ReFacto (antihemophilic factor) was evaluated in uncontrolled phase 3 studies of 113 PTPs and 101 PUPs who received ReFacto (antihemophilic factor) for on-demand treatment, routine prophylaxis, and/or surgical prophylaxis and were followed for up to 6 years. Hemostatic efficacy was rated on an ordinal scale of excellent, good, fair, and none.
In 112 of 113 PTPs treated on demand, a total of 10,882 bleeding episodes were reported, with a median of 77.5 bleeding episodes per study subject. Of these, the hemostatic efficacy of ReFacto (antihemophilic factor) was assessed following the first infusion for treatment of 10,445 bleeding episodes: 9944 (95%) were rated excellent or good in their response to treatment, 429 (4%) were rated fair, and 72 (0.7%) were rated as having no response; 4% (437/10,882) of the bleeding episodes were not rated. Of the 10,882 bleeding episodes, 7981 (73%) were managed with a single infusion, 1612 (15%) required 2 infusions, 623 (6%) required 3 infusions, and 666 (6%) required 4 or more infusions for satisfactory resolution. The mean dose per infusion was 31 IU/kg.
In 100 of 101 PUPs treated on demand, a total of 2715 bleeding episodes were reported with a median of 19.5 bleeding episodes per study subject. Of these, the hemostatic efficacy of ReFacto (antihemophilic factor) was assessed following the first infusion for treatment of 2604 bleeding episodes: 2459 (94%) were rated excellent or good in their response to treatment, 142 (5%) were rated fair, and 3 (0.1%) were rated as having no response; 4% (111/2,715) of the bleeding episodes were not rated. Of the 2715 bleeding episodes, 1794 (66%) were managed with a single infusion, 502 (19%) required 2 infusions, 229 (8%) required 3 infusions, and 190 (7%) required 4 or more infusions for satisfactory resolution. The mean dose per infusion was 51 IU/kg.
All were treated successfully on an on-demand basis or for the reduction of bleeding episodes except for one PTP and two PUPs who discontinued ReFacto (antihemophilic factor) treatment and switched to another product after the development of inhibitors. Bleeding episodes included hemarthroses, and bleeding in soft tissue, muscle, and other anatomical sites.
One of 113 previously treated patients (PTPs) who were evaluated for efficacy in bleeding episodes developed a high titer inhibitor. The patient was noted initially at a local laboratory to have a treatment-emergent low titer inhibitor (1.2 BU) at 98 exposure days which was confirmed at 2 BU at the central laboratory at 113 exposure days. After 18 months on continued treatment with ReFacto (antihemophilic factor) , the inhibitor level rose to nearly 13 BU and a bleeding episode failed to respond to ReFacto (antihemophilic factor) treatment. In this study the incidence of inhibitor development to factor VIII using ReFacto (antihemophilic factor) is similar to that reported for other factor VIII products1-4.
ReFacto (antihemophilic factor) has been studied in short-term routine prophylaxis. In uncontrolled phase 3 clinical trials, a mean dose of 27 ± 11 IU/kg per infusion in PTPs (n=85) and a mean dose of 49 ± 17 IU/kg per infusion in PUPs (n=45) was given repeatedly at variable intervals (for PTPs: median 94 weeks, range 3-296 weeks; for PUPs: median 61 weeks, range 2-222 weeks). In PTPs and PUPs, the mean rate of spontaneous musculoskeletal bleeding episodes was lower during periods of routine prophylaxis. PTPs (n=85) had a mean of 10 bleeding episodes (spontaneous and injury-related) per year during the prophylactic periods compared to a mean of 25 bleeding episodes per year during on-demand periods. PUPs (n=45) had a mean of 6 bleeding episodes (spontaneous and injury-related) per year during the prophylactic periods compared to a mean of 11 bleeding episodes per year during the on-demand periods. These non-randomized trial results should be interpreted with caution, as the investigators exercised their own discretion in deciding when and in whom prophylaxis was to be initiated and terminated.
Management of hemostasis was evaluated in the surgical setting where 51 surgical procedures were performed in 39 study subjects. Procedures included orthopedic procedures (eg, total knee and hip replacements, removal of a left elbow pseudotumor, and arthroscopic synovectomy of the knee), inguinal hernia repair, epidural hematoma evacuation, ulnar nerve transposition, tonsillectomy, cholecystectomy with extirpation of hepatic abscess, and other minor procedures (eg, venous access catheter placement and explantation, and toenail removal). Of the 51 surgical procedures, 44 procedures were performed in 32 PTPs and 7 procedures were performed in 7 PUPs. In PTPs, the mean total dose for each of the 44 procedures was 104,064 IU administered over a mean of 22.1 exposure days; the mean dose per infusion (peri- and postoperative) was 37.4 IU/kg. In PUPs, the mean total dose for each of the 7 procedures was 21,766 IU administered over a mean of 12.4 exposure days; the mean dose per infusion (peri- and postoperative) was 93.5 IU/kg. Factor VIII activity levels were monitored at the local laboratory using a one-stage assay in 40 procedures and a chromogenic assay in 11 procedures. Circulatory factor VIII levels targeted to restore and maintain hemostasis were achieved regardless of which assay was used. For 50 of 51 rated surgical procedures, hemostatic efficacy was assessed as excellent or good in 99.6% (494/496) of assessments.
The occurrence of neutralizing antibody (inhibitors) is well known in the treatment of patients with hemophilia A5,6,7. Thirty-two out of 101 PUPs (32%) developed an inhibitor: 16 out of 101 (16%) with a high titer ( > 5 BU) (12 of the 16 patients had peak values ≥ 10 BU) and 16 out of 101 (16%) with a low titer ( ≤ 5 BU). In this study the incidence of inhibitor development to factor VIII using ReFacto (antihemophilic factor) is similar to that reported for other factor VIII products5-10.
1. Kessler C, Sachse K. Factor VIII:C inhibitor associated with monoclonal-antibody purified FVIII concentrate. Lancet 1990; 335:1403.
2. Schwartz RS, Abildgaard CF, Aledort LM, et al. Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med 1990;323:1800-1805.
3. White GC II, Courter S, Bray GL, et al. A multicenter study of recombinant factor VIII (recombinate) in previously treated patients with hemophilia A. Thromb Haemost 1997;77(4):660-667.
4. Abshire TC, Brackmann HH, Scharrer I, et al. Sucrose formulated recombinant human antihemophilic Factor VIII is safe and efficacious for treatment of hemophilia A in home therapy: Results of a multicenter, international, clinical investigation. Thromb Haemost 2000;83(6):811-816.
5. Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII and factor IX inhibitors in hemophiliacs. Lancet. 1992;339:594-598.
6. Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factor VIII (Recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood. 1994;83(9):2428-2435.
7. Lusher J, Arkin S, Abildgaard CF, Schwartz RS, Group TKPUPS. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. N Engl J Med. 1993;328:453-459.
8. Scharrer I, Bray G. Incidence of inhibitors in haemophilia A patients - a review of recent studies of recombinant and plasma-derived factor VIII concentrates. Hemophilia 1999; 5:145.
9. Gruppo R, Chen H, Schroth P, et al. Safety and immunogenicity of recombinant factor VIII (Recombinate) in previously untreated patients: A 7.3 year update. Haemophilia 1998;4:228 (abstract no. 291, XXIII Congress of the WFH, The Hague).
10. Lusher J, Abildgaard C, Arkin S, et al. Human recombinant DNA-derived antihemophilic factor in the treatment of previously untreated patients with hemophilia A: Final report on a hallmark clinical investigation. J Thromb Haemost 2004;2:574-583.
Last reviewed on RxList: 2/19/2009
This monograph has been modified to include the generic and brand name in many instances.
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