Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Octapharma Ltd., The Zenith Building, 26 Spring Gardens, Manchester M2 1AB, United Kingdom
Pharmacotherapeutic group: antihaemorrhagics, fibrinogen
ATC code: B02BB01
Human fibrinogen (coagulation factor I), in the presence of thrombin, activated coagulation factor XIII (FXIIIa) and calcium ions, is converted into a stable and elastic three-dimensional fibrin haemostatic clot.
The administration of human fibrinogen provides an increase in plasma fibrinogen level and can temporarily correct the coagulation defect of patients with fibrinogen deficiency.
An open-label, prospective, randomized, controlled, two-arm cross-over single-dose pharmacokinetic phase II study in 22 patients with congenital fibrinogen deficiency (afibrinogenemia) (see section 5.2) also evaluated the maximum clot firmness (MCF) as a surrogate marker for haemostatic efficacy (FORMA-01). MCF was determined by thromboelastometry (ROTEM) testing. For each patient, MCF was determined before (baseline) and one hour after the single-dose administration of FIBRYGA. MCF values were significantly higher after administration of FIBRYGA than at baseline (see the table below).
Table 1. Maximum clot firmness MCF [mm] (ITT population) n=22:
| Time point | Mean ± SD | Median (range) |
|---|---|---|
| Pre-infusion | 0 ± 0 | 0 (0-0) |
| 1 hour post-infusion | 9.7 ± 3.0 | 10.0 (4.0-16.0) |
| Mean change (primary analysis)* | 9.7 ± 3.0 | 10.0 (4.0-16.0) |
MCF = maximum clot firmness; ITT = intention-to-treat.
* p<0.0001 (95% confidence interval 8.37; 10.99)
An interim analysis of an ongoing prospective, open label, uncontrolled, multicentre phase III study (FORMA-02) was conducted in 13 patients with congenital fibrinogen deficiency (afibrinogenemia and hypofibrinogenemia), ranging in age from 13 to 53 years (2 adolescents, 11 adults). This included the treatment of 23 bleeding episodes and 4 surgical procedures. There was significant change from baseline in the MCF as measured by ROTEM and fibrinogen plasma levels. All of the treated bleeding episodes and surgical procedures studied were rated as successful (rating of good or excellent efficacy) by the investigator and by an independent adjudication committee using an objective scoring system.
The prospective, randomised, controlled study FORMA-05 investigated the haemostatic efficacy and safety of FIBRYGA by comparison with cryoprecipitate as fibrinogen supplementation sources in patients developing acquired fibrinogen deficiency during cytoreductive surgery for the extensive abdominal malignancy pseudomyxoma peritonei. The study included 43 adult patients in the Per Protocol (PP) analysis set, 21 patients treated with FIBRYGA and 22 patients treated with cryoprecipitate. Intraoperative fibrinogen supplementation was performed pre-emptively (i.e. after 60-90 minutes in surgery, when excessive blood loss was observed, but before 2 litres of blood had been lost) with doses of 4 g of FIBRYGA or of 2 pools of 5 units of cryoprecipitate, repeated as needed. During the 7.8 ± 1.7 hours of surgery, 6.5 ± 3 g of FIBRYGA (89 ± 39 mg/kg bw) and 4.1 ± 2.2 pools of 5 units of cryoprecipitate were used, respectively. A median of 1 unit and 0.5 units RBC were administered intraoperatively to the patients treated with FIBRYGA and cryoprecipitate, respectively, with a median of 0 units RBC during the first 24 hours post-operatively in both groups (see the table below). No fresh frozen plasma or platelet concentrates were transfused during the study Haemostatic therapy based on fibrinogen supplementation was rated as successful for 100% of the surgeries in both groups by an independent adjudication committee using an objective scoring system.
Table 2. RBC* transfusion [units] intraoperatively and during the first 24 hours postoperatively (PP population):
| Time frame | FIBRYGA group (n=21) Median (range) | Cryoprecipitate group (n=22) Median (range) |
|---|---|---|
| Intraoperatively | 1 (0-4) | 0.5 (0-5) |
| First 24 hours postoperatively | 0 (0-2) | 0 (0-2) |
RBC = red blood cell concentrates; PP = per protocol.
* no transfusion of other allogeneic blood products, such as fresh frozen plasma or platelet concentrates, occurred
FIBRYGA was administered in two clinical studies in 8 patients from 12 to 18 years of age. The European Medicines Agency has deferred the obligation to submit the results of studies with FIBRYGA in the treatment of congenital fibrinogen deficiency in patients less than 12 years of age (see section 4.2 for information on paediatric use).
Human fibrinogen is a normal constituent of human plasma and acts like endogenous fibrinogen. In plasma, the biological half-life of fibrinogen is 3–4 days. FIBRYGA is administered intravenously and is immediately available in a plasma concentration corresponding to the dosage administered.
An open-label, prospective, randomized, controlled, two-arm cross-over phase II study in 22 patients with congenital fibrinogen deficiency (afibrinogenemia), ranging in age from 12 to 53 years (6 adolescents, 16 adults), compared the single-dose pharmacokinetic properties of FIBRYGA with those of another commercially available fibrinogen concentrate in the same patients (FORMA-01). Each patient received a single intravenous 70 mg/kg dose of FIBRYGA and the comparator product. Blood samples were drawn to determine the fibrinogen activity at baseline and up to 14 days after the infusion. The pharmacokinetic parameters of FIBRYGA in the per protocol (PP) analysis (n=21) are summarized in the table below.
Table 3. Pharmacokinetic Parameters (n=21) for Fibrinogen Activity (PP population*):
| Parameter | Mean ± SD | Range |
|---|---|---|
| Half-life [hr] | 75.9 ± 23.8 | 40.0–157.0 |
| Cmax [mg/dL] | 139.0 ± 36.9 | 83.0–216.0 |
| AUCnorm for dose of 70 mg/kg [mg*hr/mL] | 113.7 ± 31.5 | 59.7–175.5 |
| Clearance [mL/hr/kg] | 0.67 ± 0.2 | 0.4–1.2 |
| Mean residence time [hr] | 106.3 ± 30.9 | 58.7–205.5 |
| Volume of distribution at steady state [mL/kg] | 70.2 ± 29.9 | 36.9–149.1 |
* One patient excluded from the PP population because of receiving <90% of the planned dose of FIBRYGA and Comparator product
Cmax = maximum plasma concentration; AUCnorm = area under the curve normalised to the dose administered; SD = standard deviation
The incremental in vivo recovery (IVR) was determined from levels obtained up to 4 hours post-infusion. The median incremental IVR was 1.8 mg/dL (range, 1.08–2.62 mg/dL) increase per mg/kg. The median IVR indicates that a dose of 70 mg/kg will increase the patient’s fibrinogen plasma concentration by approximately 125 mg/dL.
No statistically relevant difference in fibrinogen activity was observed between male and female study participants. In the PP analysis, a small difference was seen in the half-life for patients less than 18 years of age (n=5), being 72.8 ± 16.5 hours as compared to 76.9 ± 26.1 hours for the adult group (n=16). Clearance was almost identical in both age groups, i.e., 0.68 ± 0.18 mL/hr/kg and 0.66 ± 0.21 mL/hr/kg, respectively.
No pharmacokinetic data are available in paediatric patients <12 years of age.
The safety of FIBRYGA has been demonstrated in several non-clinical safety pharmacology (cardiovascular effects, thrombogenic potential) and toxicology studies (acute toxicity, local tolerance). The non-clinical data reveal no special hazard for humans based on these studies. In the venous stasis test (Wessler test) FIBRYGA proved to be non-thrombogenic at doses up to 400 mg/kg body weight.
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