Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: BPL Bioproducts Laboratory GmbH, Dornhofstraße 34, 63263, Neu-Isenburg, Germany
Pharmacotherapeutic group: Anti-haemorrhagics, vitamin K and other haemostatics, coagulation factor X
ATC code: B02BD13
Factor X is an inactive zymogen, which can be activated by factor IXa (via the intrinsic pathway) or by factor VIIa (via the extrinsic pathway). Factor X is converted from its inactive form to the active form (factor Xa) by the cleavage of a 52-residue peptide from the heavy chain. Factor Xa associates with factor Va on a phospholipid surface to form the prothrombinase complex, which activates prothrombin to thrombin in the presence of calcium ions. Thrombin then acts upon soluble fibrinogen and factor XIII to generate a crosslinked fibrin clot.
Coagadex is derived from human plasma and used as a replacement for the naturally existing coagulation factor X in patients with hereditary factor X deficiency.
In a multicentre, open-label, non-randomised clinical trial to evaluate the pharmacokinetics, safety and efficacy of Coagadex, 16 subjects (aged 12 years and above) with moderate to severe hereditary factor X deficiency (FX:C <5 IU/dL) received a dose of 25 IU/kg Coagadex to treat spontaneous, traumatic and menorrhagic bleeding episodes.
The efficacy of Coagadex in treating bleeding episodes was assessed by the subject and/or investigator for each new bleeding episode, using a pre-determined bleed-specific ordinal rating scale of excellent, good, poor and unassessable. Of the 208 bleeding episodes treated with Coagadex, 187 bleeding episodes in 15 subjects were evaluated for efficacy. Ninety eight (53%) were major bleeding episodes, and 88 (47%) were minor bleeds (one bleed was not assessed). Coagadex was considered to be good (7%) or excellent (91%) in treating 98% of bleeding episodes. Of the 187 bleeding episodes in the efficacy analysis, 155 bleeds (83%) were treated with one infusion, 28 bleeds (15%) with two infusions, 3 bleeds (2%) with three infusions and 1 bleed (0.5%) with four infusions. The mean dose per infusion and total dose of Coagadex were 25.4 IU/kg and 30.4 IU/kg, respectively. Four bleeding episodes in two subjects were considered treatment failures. The recommended dose of 25 IU/kg Coagadex to treat a bleed was maintained during the study for 14 of the 16 subjects. The other two subjects used doses up to 30 IU/kg and 33 IU/kg.
A total of 184 infusions of Coagadex were given as a preventative measure. Routine prophylaxis was used by two subjects. One subject, aged 58 years, used 28 IU/kg once weekly for 8 weeks and, later, 25 IU/kg every 2 weeks for more than 5 months. The other subject, aged 22 years, used 24.6 IU/kg once weekly for 8.5 months. Neither subject had any bleeds during these periods.
The third study evaluated the use of Coagadex in routine prophylaxis of bleeding episodes in nine children aged less than 12 years of age. The mean age was 7.3 (range 2.6 to 11.9) years. Eight subjects had severe FX deficiency, the other had moderate deficiency. Four subjects were aged 0 to 5 years and five were aged 6 to 11 years inclusive. Routine prophylaxis was started with unit doses of 40-50 IU/kg and during the first 6 weeks trough levels of Factor X were measured to adjust the dosage regimen to maintain a trough level of at least 5 IU/dL. A total of 537 (mean 59.7 per subject) prophylactic infusions were administered. The median prophylactic dose per infusion per subject was 39.60 IU/kg (mean 38.76 IU/kg), and ranged from 18.0 to 47.3 IU/kg. Median and mean doses per infusion in the four children less than 6 years of age were both 40.1 IU/kg (95% CI 30.70, 49.57) and in the five children 6 to 11 years of age inclusive, median dose was 39.6 IU/kg and mean dose was 37.7 IU/kg (95% CI: 23.42, 51.91). The median dosing interval for all of the nine children was 3 days (range 2 to 8 days). Six children (66.7%) remained free of bleeds during routine prophylaxis. Three children (33.3%), one in the 0-5 years age group and two in the 6-11 years age group had a total of 10 bleeds due to epistaxes, trauma or menorrhagia. All were treated with a single infusion of Coagadex; mean and median doses 31.7 IU/kg (range 24.6 to 38.8 IU/kg) and all recorded efficacy ratings were categorized as excellent. There were no adverse drug reactions in this study in children less than 12 years of age.
The safety and efficacy of Coagadex for perioperative management was evaluated in five subjects aged 14 to 59 years with mild (n=2), moderate (n=1), and severe (n=2) disease, who underwent a total of seven surgical procedures.
For all surgical procedures, Coagadex was assessed as excellent (no post-operative bleeding, no requirement of blood transfusions, and blood loss was no more than ‘as expected’) in controlling blood loss during and after surgery. For major surgery, a median of 13 infusions (range 2 to 15 infusions) and a median cumulative dose of 181 IU/kg (range 45 to 210 IU/kg) were required to maintain haemostasis. For minor surgery, a median of 2.5 infusions (range 1 to 4 infusions) and a median cumulative dose of 89 IU/kg (range 51 to 127 IU/kg) were used to maintain haemostasis.
In a clinical study of Coagadex in subjects with severe or moderate factor X deficiency (basal FX:C <5 IU/dL), the pharmacokinetics of Coagadex were assessed in 16 subjects after administration of a nominal dose of 25 IU/kg. Pharmacokinetic (PK) parameters were calculated from plasma factor X:C (one-stage clotting assay) activity measurements after subtraction of the pre-dose value. Combining IR values for FX:C at the baseline visit (n=16) and the Repeat PK assessment (n=15) gave an overall geometric mean IR of 2.07 IU/dL per IU/kg administered (n=31). Similarly, combining t½ values at the Baseline Visit and the Repeat PK assessment gave an overall geometric mean t½ of 29.36 hours. Systemic exposure to FX:C at the Repeat PK visit (at least 6 months later) was equivalent to that at baseline, since repeat/baseline ratios for all PK parameters were within the range of 90% to 110%.
The mean (CV%) for incremental recovery was 2.08 (18.1). The mean (CV%) maximum plasma concentration (Cmax) was 0.504 (17.2) IU/mL.
The mean (CV%) for area under the curve (AUC0-144h) was 17.1 (21.0) IU.hr/mL.
Human coagulation factor X is largely retained within the vascular compartment: mean apparent volume of distribution (Vss) was 56.3 (24.0) mL/kg.
The mean (CV%) half-life of human coagulation factor X was 30.3 (22.8) hr and clearance was 1.35 (21.7) mL/kg/hr.
No pharmacokinetic studies have been conducted but there is no anticipated effect of gender or renal function on the pharmacokinetic profile of Coagadex.
No pharmacokinetic studies have been conducted but there is no anticipated effect of gender or hepatic function on the pharmacokinetic profile of Coagadex.
No pharmacokinetic studies have been conducted but there is no anticipated effect of age on the pharmacokinetic profile of Coagadex.
Pharmacokinetic studies have not been performed in children under the age of 12 years. The study in young children (see section 5.1) measured incremental recovery at 30 min (IR30min) after the first dose and after the last dose in the study (approximately 6 months later) (see section 5.1). Combining IR30min values for FX:C at the baseline visit (n=9) and the Repeat PK assessment (n=9) gave an overall geometric mean IR of 1.74 (range 1.3-2.2) IU/dL per IU/kg administered (n=9). For the subgroup aged 6-11 years (n=5), the geometric mean IR30min was 1.91 (range 1.6 -2.2) IU/mL per IU/kg and for the youngest subgroup, 0-5 years (n=4) was 1.53range 1.3-1.8) IU/mL per IU/kg.
Trough levels of FX:C were measured during the first 6 weeks of the study to individualise the dosage regimen and to maintain a trough level of at least 5 IU/dL. During the dose-adjustment phase, two trough levels were <5 IU/dL but thereafter none were below this threshold.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeat-dose toxicity, thrombogenicity and local tolerability.
No investigations on genotoxicity, carcinogenicity and reproductive or developmental toxitcity have been conducted since human plasma coagulation factor X (as contained in Coagadex) is an endogenous protein.
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