Continuous intravenous infusion of a plasma‐derived factor IX concentrate (Mononine^®) in haemophilia B

Abstract

This prospective, multicentre, open-label study evaluated the efficacy and safety of a plasma-derived factor IX concentrate [Mononine, Coagulation Factor IX (Human) Monoclonal Antibody Purified] administered by continuous intravenous (CIV) infusion to patients with haemophilia B. Admission criteria included documented diagnosis of haemophilia B (mild, moderate, or severe). Twenty-eight patients (25 surgery, two trauma, one severe spontaneous haemorrhage) were enrolled to receive a therapeutic bolus dose followed by CIV infusion of factor IX (FIX) to maintain FIX:C plasma levels of 0.4-1.0 IU mL(-1) (i.e. 40-100%). A median intravenous bolus dose of 54.2 IU kg(-1) FIX was administered to a subset of 13 non-emergency patients 7-21 days prior to CIV infusion to determine pharmacokinetic parameters in order to guide the dosing for CIV. For treatment, a bolus injection (median FIX dose; 89.6 IU kg(-1)) (range, 12.4-108.3), followed by a median total CIV infusion dose of 396.4 IU kg(-1) (range, 44.9-785.5) was administered at a median rate of 3.84 IU kg(-1) h(-1) (range, 1.74-7.33) for 107.17 h (range, 31.75-144). Twenty-four patients completed 72-120 h of FIX CIV infusion. Overall, 'excellent' (i.e. achievement of normal haemostasis) efficacy was reported in 23 of 24 (96%) evaluable patients, and 'good' (i.e. slight oozing) efficacy was reported in one (4%) patient. Median FIX:C was 72-86% for all patients receiving FIX by CIV on all days. Nine patients reported 13 adverse events that were possibly related to study medication but were not deemed serious by the investigator and were mainly because of local irritation at the infusion site. FIX CIV infusion therapy is safe and effective in the treatment of haemophilia B patients undergoing surgery, exposed to trauma, or experiencing severe spontaneous haemorrhage.

Safety and efficacy of plasma‐derived coagulation factor IX concentrate (AlphaNine® SD) in patients with haemophilia B undergoing surgical intervention: a single institution retrospective analysis

“…The FIX dose decreased as days went on after surgery, with levels closer to other studies [10,11]. The FIX levels in this series were kept constant even after postoperative day five or six, when the dose was changed from continuous infusion to bolus.…”

Continuous infusion of coagulation factors: current opinion

“…These studies comprised a total of 50 patients and 59 continuous infusion treatments (55 for major surgery) and provided evidence of an excellent hemostatic effect [35][36][37][38]46]. The initial factor IX (FIX) bolus of 12.4-155 IU was followed by infusion rates ranging between 1.7 and 8.6 IU/kg/h (median 3.9 IU/ kg/h) and aimed at maintenance FIX levels of more than 0.9 IU/ml in all studies but one that targeted FIX levels of 0.5-1.0 IU/ml.…”

Continuous Infusion of Coagulation Products in Hemophilia

“…Hoots et al [32], in a prospective multicenter study demonstrated CI of pdFIX Mononine to be safe and hemostatically effective in patients with hemophilia B undergoing surgery. Preoperative median clearance was 4.06 mL/kg/h (range 2.45-9.65 mL/kg/h) and hemostasis was achieved by infusion rate of 3.84 IU/kg/h (1.74-7.33 IU/kg/h).…”

“…Fixed-rate continuous infusion Some authors, aiming at FVIII/IX maintenance levels of 1.0 IU/ mL for the first few postoperative days, have shown that this may be achieved with a fixed rate of FVIII and FIX of 4-5 IU/ kg/h and ≥4-6 IU/kg/h, respectively, on average [6,20,[32][33][34]. However, at this regimen often much higher levels are observed than those required to achieve satisfactory postoperative hemostasis [5][6][7]10,20,33]; further, during fixed-rate CI, the levels would be expected to rise gradually over the first 4-6 days owing to the decrease in clearance, which may result in unnecessarily high factor consumption unless appropriate adjustments are made daily, as described above.…”

“…Similarly, Uprichard et al [33] in the setting of CI observed a clearance of rFIX 30% greater than that of pdFIX. Pharmacokinetic evaluation prior to CI of FIX is recommended whenever possible to determine the clearance and to choose the dosing accordingly [32]. However, with FIX it is also important to test the activation peptides to rule out activation that may cause hypercoagulation.…”