Octaplex; Prothrombin Complex Concentrate; PCC; Factors II, VII, IX and X, with Proteins C, S and Z
Status: marketed in European countries
Organizations involved:
Octapharma AG – Manuf.; R&D; Tech.; Europe mark.
New York Blood Center – Tech.
Cross ref.: See the Factor IX Products entry. See also the entries for Anti-Inhibitor Coagulant/Nabi (Autoplex T); Anti-Inhibitor Coagulant/Baxter (FEIBA VH Immuno); and Protein C, activated, rDNA (Xigris).
Description: Octaplex is a lyophilized (freeze-dried) formulation derived from Plasma containing the four coagulation Factors, II, VII, IX and X in a ratio close to a hemostatically balanced (as in blood) approximate 1:1:1:1 ratio; plus therapeutic levels of Protein C (see the Protein C, activated, rDNA or Xigris entry), its cofactor Protein S, and Protein Z. Added heparin and traces of antithrombin-III (AT-III) contribute further to the safety of Octaplex against thrombosis by preventing factor activation upon reconstitution. manufacture includes solvent detergent viral inactivation using tri-n-butyl phosphate (TNBP) and polysorbate 80 (Tween 80), primarily active against enveloped viruses, and virus removal, including noneveloped viruses, by nanofiltration. Octaplex is used for treatment of blood coagulation factor deficiencies (hemophilia A and B), similar to Factor VII, VIII and IX products.
Octaplex is packaged in vials containing 500 IU Factor IX activity, for reconstitution in 20 ml of Water for Injection. Octaplex contains Factor II, VII, X and Proteins C and S at concentrations of 10-40 IU/mL, Factor IX at 20-31 IU/mL, and heparin at 0.2-05 IU/IU Factor IX. Levels of Factors IIa, IXa, and Xa are low or undetectable. The specific Factor activity of IX in Octaplex is greater than 1 IU/mg protein. The heparin level is 0.45 IU heparin (anticoagulant) per 1 IU Factor IX activity. Octaplex has a shelf life of two years at 2-8 °C (refrigerated).
Nomenclature: Prothrombin Complex [BIO]; Octaplex [TR]; Factors II, VII, IX and X, with Proteins C, S and Z [SY]; prothrombin complex concentrate [SY]; PCC [SY]
Biological.: See the Factor IX and VIII entries for information about blood clotting and coagulation. Factor VII (proconvertin) is part of the extrinsic pathway of blood coagulation/clotting. Factor IX is activated by Factor VII/tissue factor complex in the extrinsic coagulation pathway as well as by Factor XIa in the intrinsic coagulation pathway. Activated Factor IX, in combination with activated Factor VIII, activates Factor X, which reacts with activated Factor VIII, resulting ultimately in the conversion of prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin (the major structural/fibrous component of blood clots), and a clot can be formed.
Most other PCC products (marketed internationally) are manufactured using strong ion exchange chromatography and contain relatively high levels of Factor VII (IIa); disproportionately high levels of Factors II and X; and lack Protein S and antithrombin activities. These factors contribute to potential thromboembolic complications, including disseminated intravascular coagulation (DIC). Octaplex was specifically developed to reduce thromboembolic effects through its balanced levels of Factors, II, VII, IX and X, with Protein S and C activity; very low Factor VII and proteolytic activity.
The clotting factors in PCC are believed to bypass Factor VIII inhibitors (antibodies) and directly activate Factor X, making this product useful for hemophilia A patients with inhibitors (antibodies) to Factor VIII. PCC may be used for treatment of hemophilia B (Factor IX deficiency), with PCC providing an increase in plasma levels of Factor IX and/or Factor VII (with Factor IX complex), temporarily correcting the coagulation defect of patients with deficiencies in these factors. Plasma levels of Factor II (prothrombin) and Factor X (Stuart-Prower factor) may also be increased by administration of PCC products.
Companies.: Octaplex was developed and is manufactured and marketed in Europe by Octapharma AG, CBER/FDA est. no. 1646 (with Octaplex manufactured at facilities in Lingolsheim, Austria.
Manufacture: manufacture of Factor IX and PCC from blood plasma is based on the discovery by Pool, et al., in the 1960s that after cold-ethanol fractionation of plasma and removal of cryoprecipitate (Factor VIII and other precipitated clotting factors) most of the Factor IX remains in the supernatant fluid. The resulting product is prothrombin complex concentrate (PCC) containing Factor IX along with other vitamin K-dependent coagulation factors (Factors II, VII and X) and proteins C and S. PCC is often manufactured from eluate fluid removed after cryoprecipitation (freezing and thawing of plasma) subjected to ion exchange chromatography, e.g., diethylaminoethyl (DEAE) Sepharose.
Manufacture of Octaplex involves solid-phase extraction of vitamin K-dependent clotting factors and inhibitors from Plasma, radial anion exchange chromatograhy, nanofiltration for virus removal, and solvent detergent viral inactivation. Cryoprecipitate supernatant plasma is heparinized to prevent activation, and heparin is also added to the final product before sterile filling and freeze drying to prevent activation of the prothrombin complex factors when reconstituted. The rapid chromatography step significantly reduces the time for manufacture of the product. The prothrombin complex factors, II, VII, IX and X, as well as Proteins C and S, are captured by ion exchange chromatography. The goal is to optimize yield of Factor VII while preventing the activation of zymogens through speeding up manufacture by adapting batch adsorption and rapid chromatographic separation. This particularly prevents the activation of Factor VII to Factor VIIa. No albumin is used as a stabilizer.
Manufacture starts with separation of cyroprecipitate from Plasma at the company facilities in Vienna, Austria, followed by addition of heparin; pH adjustment; and ion exchange chromatography. Eluate is subjected to solvent detergent viral inactivation (involving adding 0.3% TNBP and 1% Tween 80 for six hours at 27˚C); nanofitration through a Pall Utrapore VF DV 50 filter; diafiltration; ultrafiltration; further heparin and pH adjustment; sterile filtration; filling of vials; and lyophilization.
Levels (potencies) of constituents of Octaplex have been reported to vary from batch to batch. Based on an average of 39 batches, Octaplex contains (as IU per IU of Factor IX): Protein S, 0.95; Protein C, 0.98; Factor X, 0.98; Factor IX, 1.00; Factor VII, 0.76; and Factor VII, 1.19. Based on a filling volume of 500 mL (based on four batches reported in “Manufacturing of a Prothrombin Concentrate Aiming at Low Thrombogenicity, Thrombosis Research, 100, p. 433-41, 2000), the ranges for constituents are Factor II:C, 570-800; Factor II:CHR, 471-526; Factor VIII:C, 261-377; Factor VII:CR, 193-345; Factor VIIa, 25-39; Factor IX:C, 437-577; Factor X:C, 518-786; Factor IX:CHR, 228-478; Factor X:CHR, 385-546; antithrombin, 2-8; Protein C, 463-653; Protein S; 400-623; Free Protein C, 352-473; Protein Z, 348-572 µg; Factor Xa-like, 1.2; Factor VII:C/VII:CHR ratio, 1.09-1.35; Factor VIIa/VII:CHR ratio; 0.11-0.14; and NAPTT, 157-162 seconds. The content of activated Factor VII (Factor VIIa) is low, and the ratio of Factor VII/VIIa is >5:1, in most cases 10:1.
See Plasma SD (PLAS+SD; #799) for information about solvent detergent viral inactivation involving sequential use of a solvent, e.g., tri(n-butyl)phosphate (TNBP), and a detergent, e.g., polysorbate 80, for inactivation of lipid-enveloped viruses.
Status: Octaplex received its first approval and has been marketed in Norway since 1998, and since June 2003 in Germany. approvals in seven other European countries were granted in mid-2004. The formal international launch of Octaplex was in March 2005. Octaplex has been approved in Germany, Portugal , Austria, Belgium, France, Ireland, Luxemburg, Spain and Sweden.
Indications: [in European countries]:
Octaplex is indicated for the prophylaxis and treatment of bleeding and hereditary or acquired coagulation defects resulting from isolated prothrombin complex factor deficiency or combined with prothrombin complex deficiency.
Tech. transfer: Solvent detergent viral inactivation was developed by and nonexclusively licensed from the New York Blood Center. For example, see U.S. patent 4,820,805. See the entry for Pooled Plasma, Solvent Detergent Treated (SD Plasma) (#799) for further information about solvent detergent viral inactivation, used primarily for inactivation of enveloped viruses (e.g., HIV, hepatitis B and C viruses).
Trials: The efficacy and safety of Octaplex has been demonstrated in both congenital and acquired coagulation factor deficiencies. In trials, not only the recovery but also the half-life of the measured Factors was within the normal range, and Octaplex effectively stopped bleeding. The mean dosages used in trials for achieving clear efficacy and the number of treatment days necessary for completion of treatment were both in the lower ranges of those normally required for treatment of these patients. Thrombotic events, historically reported in connection with the use of PCC, have not been reported with Octaplex; and seroconversions (development of antibodies) and immunogenic reactions have not occurred.
Medical: Octaplex is injected by intravenous infusion at a rate of up to 3 mL per minute. There have been no reported thromboembolic events in routine clinical use.
Market: Octapharma reports successful launches of the product, but has not reported annual sales.
Index Terms:
Companies involvement:
Full monograph
805 Prothrombin Complex
Nomenclature:
Prothrombin Complex [BIO]
Octaplex [TR]
Factors II, VII, IX and X, with Proteins C, S and Z [SY]
PCC [SY]
prothrombin complex concentrate [SY]
FDA Class: Biologic BLA
antihemophilic factors
biopharmaceutical products
blood products
antithrombin III (AT-III)
DEAE Sepharose
ethanol
exempt from CBER lot release requirements
Factor IIa
Factor IX
Factor IX WHO International Standard
Factor VII
Factor X
Factor Xa
filamentous hemagglutinin (FHA), Bordetella pertussis
heparin
lyophilized (freeze-dried)
Namalva cells
p7E3VkhCk
plasdone
polysorbate 80 (Tween 80)
Protein C
Protein S
Protein S
tri-n-butyl phosphate (TNBP)
viral (nano)filtration
viral inactivation, solvent detergent
North American coral snake
EU200 Currently Approved in EU
UM999 Not Available/Not Marketed in US
US000 never filed/no plans
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