OCTAPLAS Solution for infusion Ref.[27452] Active ingredients: Human plasma protein fraction

Coagulation factor activities in the final product are controlled to obtain levels within the range of normal human plasma. Protein S and alpha 2-antiplasmin, which are labile to S/D treatment, are controlled to ensure levels in the final product of ≥0.4 International Units (IU) per mL.

TNBP and Octoxynol used in the manufacturing process for viral inactivation may be present in the final product at levels not exceeding 2.0 µg/mL for TNBP and 5.0 µg/mL for Octoxynol.

Toxicity

No evidence of toxicity was observed for TNBP + Octoxynol in sub-acute toxicity studies.⁵

Mutagenicity

No evidence of mutagenicity was observed in in vitro or in vivo mutagenicity studies performed for TNBP.[6-11

The Octaplas predecessor product was studied in healthy volunteers and in subjects with liver disease, liver transplantation, cardiac surgery and TTP.

A prospective, open-label, parallel group, non-randomized study was performed in surgical patients who were allocated to receive either a single infusion of Octaplas (N=20) or no plasma treatment (N=26) during open heart surgery.¹² A historical control group of patients who received standard single-donor FFP (N=20) was used to compare safety and efficacy. The average dose of Octaplas was 700 mL (range 200 to 3400 mL), compared with 1012 mL (range 500 to 4000 mL) for standard FFP. The choice of plasma product (Octaplas or FFP) did not appear to influence the postoperative course with respect to volume of postoperative bleeding, need for reoperation secondary to bleeding or length of postoperative hospital stay. This study was not powered to detect a difference in efficacy.

A prospective, single-blind, randomized study investigated the safety and efficacy of Octaplas compared with standard FFP in adult patients (N=55) with coagulopathy due to liver disease (LD) or liver transplantation (LTX), and for management of newly diagnosed thrombotic thrombocytopenic purpura (TTP).[13-15] Octaplas was infused in 13 of 24 patients with LD, 12 of 25 patients with LTX and all 3 patients with TTP. Within the LD and the LTX groups, patients were comparable in all clinical aspects and in the dose of plasma given. There were no relevant changes in any coagulation factors, but Protein C and fibrinogen improved in both groups, accompanied by a corresponding improvement in partial thromboplastin time (PTT) levels 24 hours after infusion. Similar degrees of correction of prolonged international normalized ratio (INR) and PTT values were achieved with both Octaplas and FFP. All 3 patients with TTP attained platelet counts of >50 × 10⁹/L by Day 10. This study was not powered to detect a difference in efficacy.

A prospective, open label, non-randomized study was conducted in postoperative open heart surgery patients (N=67) admitted to the surgical intensive care unit who were in need of plasma transfusion for acute bleeding or were at risk of bleeding; 36 patients received Octaplas (600 mL) and 31 received FFP (600 mL).¹⁶ Measured parameters included PT, PTT, free Protein S and alpha 2-antiplasmin measured before treatment and 60 minutes after termination of plasma infusion. The decrease in PT and PTT and the rise in free Protein S were similar between the two study arms. Alpha 2-antiplasmin declined after Octaplas and remained unaffected by FFP. Clinical hemostasis evaluations were similar between the two treatment regimens. This study was not powered to detect a difference in efficacy.

A prospective, open-label, randomized, controlled, cross-over study in two groups (N=30 each) of healthy adult volunteers (mean age: 32.6±9.1 years) was carried out to show the relative recovery of coagulation factors and other hemostatic parameters after infusion of 1200 mL of Octaplas or the predecessor product, following a standard plasmapheresis of 600 mL. Coagulation factors (FI, FII, FV, FVII, FVIII, FIX, FX, and FXI) and hemostatic parameters (aPTT, PT and Protein C) were assessed post-infusion at 15 minutes, 2 hours and 24 hours. The primary objective was to demonstrate equivalence for recovery using a 10% margin. All coagulation and hemostatic parameters met the equivalence criterion. To verify the assumption of improvement in alpha 2-antiplasmin concentrations, a test for superiority was conducted. Statistically significant differences favoring Octaplas were found at 15 minutes (P=0.0012) and 2 hours (P=0.0190) post-transfusion in the per protocol population. Increased plasma levels of alpha 2-antiplasmin after infusion of Octaplas compared with the predecessor product may result from increased concentrations of this plasmin inhibitor found in Octaplas.

A prospective, open-label, multicenter, single arm, postmarketing study was conducted to investigate the safety, tolerability and efficacy of Octaplas in the management of pediatric patients requiring replacement of multiple coagulation factors. A total of 50 patients [37 neonates/infants (0 to 2 years old) and 13 children and adolescents (>2 to 16 years old)] requiring cardiac surgery (N=40), liver transplantation and/or with liver dysfunction (N=5), sepsis-related coagulopathy (N=4) and hypoxic encephalopathy (N=1) were included in the study. There were no hyperfibrinolytic or treatment-related thromboembolic events reported by investigators. The investigators' overall safety assessment was prospectively defined as excellent (treatment was well tolerated by the patient), moderate (adverse reactions were observed, but easily resolved or not clinically significant) or poor (adverse reactions were observed requiring significant medical intervention) to describe the patient’s experience with Octaplas. Overall safety was assessed by investigators as “excellent” for all 50 patients. Hemostatic parameters as measured by INR, PT, aPTT, thromboelastography (TEG) or thromboelastometry (TEM) were within expected ranges following use of Octaplas.

A prospective, open-label, multicenter, single-arm, postmarketing study assessed the safety and tolerability of Octaplas in the management of subjects who underwent therapeutic plasma exchange (TPE). A total of 102 TPE procedures were performed in 41 subjects aged 2 to 20 years [young children: Group 1 (age 2 to <12): N=15; adolescents: Group 2 (12 to <17): N=13; and young adults: Group 3 (≥17): N=13]. Overall, a total of 135,137 mL of Octaplas was administered. The underlying disease category for these subjects included immune system disorders (N=14), nervous system disorders (N=12), renal and urinary disorders (N=8), infections and infestations (N=4), and other disorders (N=3). Each subject underwent between 1 and 6 TPEs (mean: 2.5 TPEs). The actual dose administered per TPE ranged from 4 mL/kg to 72 mL/kg (mean: 28.6 mL/kg), with a mean total volume administered per TPE of 1325 mL (range: 113 mL to 4000 mL). Infusion rates (mean) were similar across age groups (0.32 mL/kg/min to 0.41 mL/kg/min). No thrombotic or thromboembolic events were found in any study subject. In total, 8 adverse reactions were found in 4 subjects (9.8%). These included 5 adverse reactions in three adolescents (4 in TPE #1 and 1 in TPE #4) and 3 adverse reactions in one young adult (2 in TPE #1 and 1 in TPE #2). Adverse reactions in adolescents included citrate toxicity (2 in 2 subjects), and headache, pyrexia, and urticaria (each reported in 1 subject), while adverse reactions found in young adults included inflammatory marker (C-reactive protein, procalcitonin) increased, myalgia, and nausea (each reported in 1 subject). Most (7/8) adverse reactions were mild in intensity and recovered/resolved by end of study. No treatment-related serious adverse events were reported. Overall safety was assessed by investigators as excellent for most subjects (>90%) at 24 hours after each TPE throughout the study using prespecified definitions of excellent, good and poor.