Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050, Bruxelles, Belgium
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII
ATC code: B02BD02
ReFacto AF contains B-domain deleted recombinant coagulation factor VIII (moroctocog alfa). It is a glycoprotein with an approximate molecular mass of 170,000 Da consisting of 1438 amino acids. ReFacto AF has functional characteristics comparable to those of endogenous factor VIII. Factor VIII activity is greatly reduced in patients with haemophilia A, and, therefore, replacement therapy is necessary.
When infused into a haemophiliac patient, factor VIII binds to the von Willebrand factor present in the patient’s circulation.
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. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy, the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
The data in the table below relates to PUP and PTP data from ReFacto AF studies in patients <12 years.
Consumption and efficacy results in paediatric population:
| PTPs <6 years | PTPs 6 to <12 years | PUPs <6 years | |
|---|---|---|---|
| Dose by weight (IU/kg) per prophylaxis infusiona median (min, max) | N=14 36IU/kg (28, 51) | N=13 32IU/kg (21, 49) | N=22 46IU/kg (17, 161) |
| Total ABR all subjectsb median (min, max) | - | - | N=23 3.17 (0.0, 39.5) |
| Total ABR for subjects who reported following an On Demand regimen at Baselinec median (min, max) | N=5 41.47 (1.6, 50.6) | N=9 25.22 (0.0, 46.6) | - |
| Total ABR for subjects who reported following a Prophylaxis regimen at Baselinec median (min, max) | N=13 1.99 (0.0, 11.2) | N=9 5.55 (0.0, 13.0) | - |
| Dose by weight (IU/kg) per bleeding episode for bleed treatment median (min, max) | N=13 35 IU/kg (28, 86) | N=14 33 IU/kg (17, 229) | N=21 55IU/kg (11, 221) |
| % of bleeds treated successfully with ≤2 infusions | 98.7% | 98.8% | 96.7% |
a The dose and frequency of ReFacto AF prescribed throughout the study were at the investigator’s discretion as per local standard of care.
b Subjects in the PUP study were not required to follow a regular continuous prophylaxis treatment; however, with the exception of one subject (with only on demand (OD) treatment) the majority of subjects took regular prophylaxis infusions. Several began with OD infusions but switched to prophylaxis treatment during their participation, and some had only sporadic prophylaxis infusions.
c Subjects in the PTP study reported their FVIII treatment modality (prophylaxis or on demand) at baseline and were not required to maintain this modality as a condition of study participation. The dose and frequency of ReFacto AF prescribed throughout the study were at the investigator’s discretion as per local standard of care.
Abbreviations: ABR = annualised bleeding rate
Of note, annualised bleeding rate (ABR) is not comparable between different factor concentrates and between different clinical studies.
Data on immune tolerance induction (ITI) have been collected in patients with haemophilia A who had developed inhibitors to factor VIII. As part of the pivotal trial with ReFacto in PUPs, ITI data from 25 patients were reviewed (15 with high titres, 10 with low titres). Of these 25 patients, 20 had a decrease in inhibitor titres to <0.6 BU/mL, of whom initially 11 of 15 had high titres (≥5 BU/mL) and 9 of 10 had low titres. Out of 6 patients who developed low titre inhibitors but did not receive ITI, 5 had similar titre decreases. No long-term outcome is available.
Pharmacokinetic properties of ReFacto, derived from a cross-over study of ReFacto and a plasmaderived FVIII concentrate, using the chromogenic substrate assay (see section 4.2), in 18 previously treated patients are listed in the table below.
Pharmacokinetic parameter estimates for ReFacto in previously treated patients with haemophilia A:
| PK parameter | Mean | SD | Median |
|---|---|---|---|
| AUCt (IU∙h/ml) | 19.9 | 4.9 | 19.9 |
| t1/2 (h) | 14.8 | 5.6 | 12.7 |
| CL (ml/h∙kg) | 2.4 | 0.75 | 2.3 |
| MRT (h) | 20.2 | 7.4 | 18.0 |
| recovery (IU/dl increase in FVIII:C per IU/kg FVIII given) | 2.4 | 0.38 | 2.5 |
Abbreviations: AUCt = area under the plasma concentration-time curve from zero to the last measurable concentration; t½ = half-life; CL = clearance; FVIII:C = FVIII activity; MRT = mean residence time
In a study in which the potency of ReFacto AF, ReFacto and FVIII activity in patient plasma were measured using the chromogenic substrate assay, ReFacto AF was shown to be bioequivalent to ReFacto. The ratios of geometric least-square means of ReFacto AF-to-ReFacto were 100.6%, 99.5% and 98.1% for recovery, AUCt and AUC∞ (area under the plasma concentration curve from time zero to infinity), respectively. The corresponding 90% confidence intervals about the ratios of ReFacto AF to ReFacto geometric means were within the bioequivalence window of 80% to 125%, demonstrating bioequivalence of ReFacto AF to ReFacto.
In a cross-over pharmacokinetic study, the pharmacokinetic parameters for ReFacto AF were determined at baseline and followed up in 25 previously treated patients (≥12 years) after repeated administration of ReFacto AF for six months. The ratios of geometric least-square means of month 6-to-baseline pharmacokinetic were 107%, 100% and 104% for recovery, AUCt and AUC∞, respectively. The corresponding 90% confidence intervals about the ratios of month 6-to-baseline for the above pharmacokinetic parameters were within the equivalence window of 80% to 125%. This indicates no time-dependent changes in the pharmacokinetic properties of ReFacto AF.
In the same study, in which the drug potency of ReFacto AF and a full-length recombinant factor VIII (FLrFVIII) comparator, and the FVIII activity measured in patient plasma samples were all determined using the same one-stage clotting assay at a central laboratory, ReFacto AF was shown to be pharmacokinetically equivalent to FLrFVIII in 30 previously treated patients (≥12 years) using the standard bioequivalence approach.
In PUPs, pharmacokinetic parameters of ReFacto were evaluated using the chromogenic assay. These patients (n=59; median age 10 ± 8.3 months) had a mean recovery at Week 0 of 1.5 ± 0.6 IU/dl per IU/kg (range 0.2 to 2.8 IU/dl per IU/kg) which was lower than that obtained in PTPs treated with ReFacto at Week 0 with a mean recovery of 2.4 ± 0.4 IU/dl per IU/kg (range 1.1 to 3.8 IU/dl per IU/kg). In the PUPs, the mean recovery was stable over time (5 visits during a 2-year period) and ranged from 1.5 to 1.8 IU/dl per IU/kg. Population pharmacokinetic modeling using data from 44 PUPs led to a mean estimated half-life of 8.0 ± 2.2 hours.
In a ReFacto AF study of 19 PUPs, the recovery at the beginning of the study in the 17 children aged 28 days to less than 2 years was 1.32 ± 0.65 IU/dl per IU/kg and in the 2 children aged 2 to <6 years were 1.7 and 1.8 IU/dl per IU/kg. Except in cases where inhibitors were detected, the mean recovery was stable over time (6 visits during a 2-year period) and individual values ranged from 0 (in presence of inhibitor) to 2.7 IU/dl per IU/kg.
In a study of 37 paediatric PTPs, the pharmacokinetic parameters of ReFacto AF observed after a 50 IU/kg dose are shown in the table below.
Mean ± SD FVIII Pharmacokinetic Parameters after Single 50 IU/kg Dose in Paediatric PTPs:
| PK parameter | Number of subjects | Meana ± SD |
|---|---|---|
| Recovery, IU/dl per IU/kg Aged <6 years | 17 | 1.7 ± 0.4 |
| Recovery, IU/dl per IU/kg Aged 6 to <12 years | 19 | 2.1 ± 0.8 |
| Cmax, IU/mLb | 19 | 0.9 (45) |
| AUCinf, IU∙h/mLβ | 14 | 9.9 (41) |
| t1⁄2, hb | 14 | 9.1 ± 1.9 |
| CL, mL/h/kgb | 14 | 4.4 (30) |
| Vss, mL/kgb | 14 | 56.4 (15) |
a Geometric mean (geometric CV%) for all, except for arithmetic mean ±SD for incremental recovery and t½.
b Patients aged 6 to <12 years only.
Abbreviations: Cmax = maximum observed plasma concentration; CV = coefficient of variation; AUCinf = area under the plasma concentration-time profile from time zero extrapolated to infinite time; t½ = terminal half-life; CL = clearance; Vss = steady-state volume of distribution.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity.
No investigations on carcinogenic potential or toxicity to reproduction have been conducted.
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