Octaplas is a solvent / detergent (S/D) treated, pooled human plasma indicated for:

• Replacement of multiple coagulation factors in patients with acquired deficiencies
• due to liver disease
• undergoing cardiac surgery and liver transplantation
• Plasma exchange in patients with thrombotic thrombocytopenic purpura (TTP)

For intravenous use only

Administer Octaplas based on ABO-blood group compatibility.

Solution for infusion containing 45 to 70 mg human plasma proteins per mL in a 200 mL volume.

Do not use Octaplas in patients with:

• IgA deficiency
• Severe deficiency of Protein S
• History of hypersensitivity to fresh frozen plasma (FFP) or to plasma-derived products including any plasma protein
• History of hypersensitivity reaction to Octaplas

Serious adverse reactions seen in clinical trials were anaphylactic shock, citrate toxicity and severe hypotension.

The most common adverse reactions observed in ≥ 1% of subjects included pruritis, urticaria, nausea, headache and paresthesia.

Do not inject drugs containing calcium in the same intravenous line with Octaplas because precipitants may block the line.

Passive transmission of analytes (e.g., β-human chorionic gonadotropin) may result in misleading positive results [ 3 ].

Octaplas is a sterile, pyrogen free, frozen solution of solvent/detergent (S/D) treated pooled human plasma.

The active ingredient comprises plasma proteins such as albumin, immunoglobulins, other globulins, coagulation factors, complement proteins and protease inhibitors. The content and distribution of plasma proteins in Octaplas are comparable to reference ranges for healthy blood donors, except for Protein S and alpha 2-antiplasmin. Within a mean total protein content of 57 mg/mL, albumin comprises ~50% and immunoglobulin classes G, A, and M comprise ~12%, ~3% and ~1%, respectively. 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. Plasma lipids and lipoproteins are reduced due to S/D treatment and subsequent oil and solid phase extraction.

Composition of Octaplas

Octaplas is manufactured from human plasma collected in US licensed plasma donation centers. All plasma donations are tested for viral markers in compliance with US regulation. In addition, the manufacturing plasma pool may not contain a titer of human Parvovirus B19 DNA exceeding 10.0 IU per microliter and must have a negative result in a test for human Hepatitis E Virus (HEV) RNA by NAT PCR with a sensitivity of ≤ 2.5 log 10 IU/mL.

Each lot of Octaplas is manufactured from pooled plasma of a single ABO blood group (A, B, AB, or O). The manufacturing plasma pool is limited to 390 kg comprising 630-1,520 individual donors. Frozen plasma units are thawed and pooled. Sodium dihydrogen phosphate dihydrate is added as a buffer against increase in pH due to loss of CO 2 . After filtration through a 1 µm pore size membrane, the plasma pool is treated with S/D reagents [1% tri(n-butyl) phosphate (TNBP) and 1% Octoxynol for 1-1.5 hours at +30°C (86°F)] to inactivate enveloped viruses. The S/D reagents are removed by sequential oil and solid phase extraction procedures. Glycine is added to adjust the osmolality. Plasma with glycine is applied to a column filled with affinity ligand resin intended for selective binding of prion protein (PrP Sc ). The effectiveness of this step in removal of prion infectivity from the product has not been established. After sterile filtration, the product is filled into sterile polyvinyl chloride blood bags, labeled, deep-frozen and stored at a temperature of ≤ -18°C (-0.4°F). The finished product is tested for coagulation factors II, V, VII, VIII, IX, X and XI, Protein C, Protein S, alpha 2-antiplasmin, fibrinogen and ADAMTS13.

The S/D treatment step has been validated to effectively inactivate relevant pathogenic and model enveloped viruses as summarized in Table 1.

Table 1 Virus Reduction During Octaplas Manufacture

HIV-1: Human Immunodeficiency Virus – 1

PRV: Pseudorabies Virus

SBV: Sindbis Virus

BVDV: Bovine Viral Diarrhea Virus

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 x 10 9 /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.

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2. Scully, M., et al. "Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies." British Journal of Haematology 158.3 (2012): 323-35.
3. Jilma-Stohlawetz P, et al. "False-positive pregnancy test after transfusion of solvent/detergent-treated plasma. " Transfusion 57.12 (2017): 2965–8.
4. FDA Briefing Document Risk Communication Advisory Committee Meeting March 5-6, 2018. Communicating Information about Risks in Pregnancy in Product Labeling for Patients and Providers to Make Informed Decisions about the Use of Drugs during Pregnancy
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Octaplas is supplied in polyvinyl chloride blood bags containing 200 mL frozen solution and has a slightly yellow appearance.

Storage and Handling

• Store at ≤ -18°C (-0.4°F) for 3 years from the date of manufacture.
• Store protected from light.
• Thaw product according to instructions in section 2.2.
• Use thawed product within 24 hr. if stored at 1 - 6°C (33.8°F to 42.8°F) or within 8 hr. if stored at 20 - 25°C (68°F to 77°F).
• Do not refreeze thawed product.
• Do not use product that is cloudy or has deposits.
• Discard product after the expiration date printed on the container label.

Inform patients to report:

• Early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, or anaphylaxis.
• Development of edema or volume overload including shortness of breath or breathing difficulties

Remind patients that Octaplas is made from human blood and may contain infectious agents that can cause disease. Report flu-like or other symptoms or viral infection.

Manufactured by:

Octapharma AB

Lars Forssells gata 23

SE- 112 75, Sweden

U.S. License No. 1646

Distributed by:

Octapharma USA Inc.

117 West Century Road

Paramus, NJ 07652

solvent/detergent (S/D) treated human plasma

Octapharma Pharmazeutika Produktionsges.m.b.H

Blood group 0

NDC 68982-955 – 01