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 IX
ATC code: B02BD04
BeneFIX contains recombinant coagulation factor IX, (nonacog alfa). Recombinant coagulation factor IX is a single chain glycoprotein with an approximate molecular mass of 55,000 Daltons that is a member of the serine protease family of vitamin K-dependent coagulation factors. Recombinant coagulation factor IX is a recombinant DNA-based protein therapeutic which has structural and functional characteristics comparable to endogenous factor IX. Factor IX is activated by factor VII/tissue factor complex in the extrinsic pathway as well as 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 into fibrin and a clot can be formed. Factor IX activity is absent or greatly reduced in patients with haemophilia B and substitution therapy may be required.
Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor IX 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 IX is increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
Efficacy analysis in study 3090A1-301-WW was based on 22 evaluable paediatric subjects on prophylaxis regimen including 4 on-demand patients who shortly changed to prophylaxis. Two patients underwent surgical procedures (circumcision and port-a-catheter insertion). Safety analysis of 25 evaluable patients reflected a safety profile as expected. The only documented serious adverse event related with BeneFIX was reported from the only included PUP, who experienced hypersensitivity and inhibitor development.
In two open-label studies BeneFIX was found to be safely administered at 100 IU/kg once-weekly. However, the half-life of the product (see section 5.2) and the limited pharmacokinetic study data for the once-weekly regimen do not allow recommending this regimen in general for long-term prophylaxis in severe haemophilia B patients.
In a randomized, cross-over pharmacokinetic study, BeneFIX reconstituted in 0.234% sodium chloride diluent was shown to be pharmacokinetically equivalent to the previously marketed BeneFIX (reconstituted with sterile water) in 24 previously treated patients (≥12 years) at a dose of 75 IU/kg. In addition, pharmacokinetic parameters were followed up in 23 of the same patients after repeated administration of BeneFIX for six months and found to be unchanged compared with those obtained at the initial evaluation. A summary of pharmacokinetic data is presented in Table 1.
Table 1. Pharmacokinetic Parameter Estimates for BeneFIX (75 IU/kg) at Baseline and Month 6 in Previously Treated Patients with Haemophilia B:
| Parameter | Baseline n=24 Mean ± SD | Month 6 n=23 Mean ± SD |
|---|---|---|
| Cmax (IU/dL) | 54.5 ± 15.0 | 57.3 ± 13.2 |
| AUC∞ (IU∙hr/dL) | 940 ± 237 | 923 ± 205 |
| t1/2 (hr) | 22.4 ± 5.3 | 23.8 ± 6.5 |
| CL (mL/hr/kg) | 8.47 ± 2.12 | 8.54 ± 2.04 |
| Recovery (IU/dL per IU/kg) | 0.73 ± 0.20 | 0.76 ± 0.18 |
Abbreviations: AUC∞ = area under the plasma concentration-time curve from time zero to infinity; Cmax = peak concentration; t1/2 = plasma elimination half-life; CL = clearance; SD = standard deviation.
A population pharmacokinetic model was developed using data collected in 73 patients aged 7 months to 60 years. The parameters estimated using the final 2-compartment model are shown in Table 2. Infants and children had higher clearance, larger volume of distribution, shorter half-life and lower recovery than adolescents and adults. The terminal phase has not been covered unambiguously due to lack of data beyond 24 hours in paediatric subjects <6 years of age.
Table 2. Mean ± SD Pharmacokinetic Parameters Based on Individual Bayes Estimates from Population Pharmacokinetic Analysis:
| Age Group (years) | Infants <2 | Children 2 to <6 | Children 6 to <12 | Adolescents 12 to <18 | Adults 18 to 60 |
|---|---|---|---|---|---|
| Number of subjects | 7 | 16 | 1 | 19 | 30 |
| Clearance (mL/h/kg) | 13.1 ± 2.1 | 13.1 ± 2.9 | 15.5 | 9.2 ± 2.3 | 8.0 ± 0.6 |
| Vss (mL/kg) | 252 ± 35 | 257 ± 25 | 303 | 234 ± 49 | 225 ± 59 |
| Elimination half-life (h) | 15.6 ± 1.2 | 16.7 ± 1.9 | 16.3 | 21.5 ± 5.0 | 23.9 ± 4.5 |
| Recovery (IU/dL per IU/kg) | 0.61 ± 0.10 | 0.60 ± 0.08 | 0.47 | 0.69 ± 0.16 | 0.74 ± 0.20 |
Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity.
No investigations on carcinogenicity, fertility impairment and foetal development have been conducted.
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