Two-Component Fibrin Sealant, Vapor Heated - Tisseel VH S/D; Sealer Protein Concentrate (Human)- plus Thrombin (Human)
Status: marketed in U.S. and Europe
Organizations involved:
Baxter AG – Manuf.; R&D; Tech.
Baxter Hyland Immuno – World mark.
Baxter Healthcare Corp. – Parent
Immuno AG – Former
Oesterreichisches Institut fur Haemoderivate GmbH (OIH) – R&D; Tech.; Former
Cross ref: See the entries for Fibrin Sealant Products entry (#735); Hemaseel APR (#738), which is equi-valent to this product; and Thrombin, conc.(#807), used in the manufacture of Tisseel VH. See also the entry for Anti-Inhibitor Coagulant Complex, Vapor Heated (FEIBA) (#704), a precursor for a Tisseel kit component; and Artiss (entry above), which is another fibrin sealant manufactured by Baxter.
Description: Fibrin Sealant, Two-Component Fibrin Sealant, Vapor Heated Kit or Tisseel VH Kit is a kit containing fibrinogen and thrombin, both fractionated and purified from pooled human plasma and subjected to vapor heating for and solvent-detergent viral inactivation. The kit has two main reactive components–Sealer Protein (fibrinogen) and Thrombin Solution. When combined in a dual-chamber mixing applicator immediately before application, these components form fibrin, essentially mimicking natural clot formation by the mixing of activated fibrinogen and thrombin at bleeding sites. Tisseel was the first fibrin sealant to receive approval in the U.S. Tisseel had been available in many European countries for well over 10 years, and it has been used in over 5 million procedures. Note, Hemaseel APR from Haemacure is essentially the same as Tisseel.
The fibrin sealant is often applied using the supplied sterile Duploject device. This holds two identical disposable syringes with a common plunger to ensure that equal volumes of the two components are fed through a common joining piece before being mixed in the application needle and ejected. Mixing of the Sealer Protein (fibrinogen) and Thrombin Solution components of the Tisseel kit produces a viscous solution that quickly sets into an elastic coagulum. Fibrin establishes a mesh-like structure that holds platelets, small particles in the blood that contribute to the clotting process, and the fibrin mesh traps additional fibrin that forms at the site of bleeding, resulting in improved blood clotting and stopping of excessive bleeding. After the two components have been applied, the sealed tissues are fixed or held in the desired position for at least three to five minutes to ensure that the setting Fibrin Sealant adheres firmly to the surrounding tissue. Solidified Fibrin Sealant reaches its ultimate strength after about two hours (70% after about ten minutes).
The Tisseel VH S/D Kit contains four separate vials: Sealer Protein Concentrate (Human), lyophilized dried powder (containing Fibrinogen); Fibrinolysis Inhibitor Solution (Bovine) containing aprotinin (switched to synthetic aprotinin in 2007); Thrombin (Human), dried powder; and Calcium Chloride Solution. The fibrinogen and thrombin components are combined in the supplied Duploject dual-chamber applicator immediately before application, forming fibrin that is applied much like glue or other sealants to stop bleeding. The Sealer Protein Concentrate (Human), dried powder is a protein concentrate from human blood containing fibrinogen (also fibronectin, Factor III and plasminogen) that forms insoluble fibrin when combined with Thrombin (Human), dried powder, another blood-derived protein that facilitates blood clotting. Thrombin (Human) is a specific protease that converts the fibrinogen in Sealer Protein Concentrate into fibrin.
Thrombin (Human) is formulated as a sterile, non-pyrogenic, lyophilized (freeze-dried), vapor-heated (for virus inactivation) powder made from pooled human plasma. Upon reaction with fibrinogen, the thrombin is partly adsorbed by the fibrin and excess thrombin, if any, is inactivated by protease inhibitors in the blood. Two concentrations of human thrombin are provided in the kit to allow for either rapid (within 4 seconds) or delayed (up to 60 seconds) setting of the sealant, depending on the type of operative procedure being performed.
The Fibrinolysis Inhibitor Solution (Bovine), now replaced by a synthetic equivalent, contains Aprotinin, a polyvalent inhibitor of proteases including plasmin, which prevents premature degradation of fibrin in proteolytic environments. Fibrinolysis Inhibitor Solution is formulated as a sterile, non-pyrogenic solution containing Aprotinin at 3,000 kallidinogenase inactivator units (KIU)/mL. The kit and components are stored at 2-8˚C (refrigerated), and labeled with an expiration date.
After reconstitution of the lyophilized Sealer Protein Concentrate in the Fibrinolysis Inhibitor Solution, the resulting Sealer Protein Solution (Tisseel VH Solution) contains: total protein, 100 to < 130 mg/mL; Fibrinogen, 75 < 115 mg/mL; Fibrinolysis Inhibitor, 3,000 KIU/mL; and excipients. Calcium Chloride Solution is formulated as a sterile, non-pyrogenic solution containing 40 µmol/mL CaCl2. After reconstitution of the lyophilized Throm-bin in Calcium Chloride Solution, the resulting Thrombin Solution contains: Thrombin (Human), 500 IU/mL; calcium chloride, 40 µmol/mL; and excipients. The Sealer Protein and Throm-bin Solutions are then combined (e.g., by delivery with a double-chambered Duploject syringe) to form the Fibrin Sealant. Fibrinotherm, a combined warming and stirring device that is recommended for reconstitution of freeze-dried Sealer Protein Con-centrate, is marketed by Baxter for use with Fibrin Sealant.
Tisseel VH S/D Kits are supplied in 0.5 mL, 1.0 mL, 2.0 mL and 5.0 mL sizes. Each kit includes one vial of Sealer Protein Concentrate (Human), Vapor Heated powder, either 0.5 mL, 1.0 mL, 2.0 mL or 5.0 mL; one vial containing an equal amount of Thrombin (Human), Vapor Heated powder; one vial of Fibrinolysis Inhibitor Solution (Bovine), sterile, 3000 KIU of Aprotinin/mL; one vial of Calcium Chloride Solution, sterile, 40 µmol/mL; and 1 Kit for Reconstitution and Application.
Nomenclature: Fibrin Sealant/Baxter [BIO]; Tisseel VH Kit [TR]; Fibrin Sealant, Vapor Heated, Solvent/Detergent Treated [FDA]; Fibrin Sealant (Tisseel) [FDA]; Two-Component Fibrin Sealant, Vapor Heated Kit [FDA; former]; fibrin sealant kit [SY]; Thrombin Solution [FDA for a component]; Sealer Protein Concentrate (Human) [FDA for a component]; Fibrinogen [FDA for a component]; Fibri-no-lysis Inhibitor Solution (Bovine) [FDA for a component]; Thrombin (Human) [FDA for a component]; Duploject [TR for application device]; Aprotinin [FDA for a component]
Companies.: Tisseel is manufactured by Baxter Hyland Immuno, FDA CBER est. no. 0140, at Baxter AG facilities in Vienna, Austria [formerly Immuno AG, originally Oester-reichisches Institut fur Haemoderivate GmbH (OIH), est. lic. no. 0258)]. The product is marketed in the U.S. by Baxter Hyland Immuno, and marketed internationally by Baxter affiliates.
Baxter obtained Tisseel as part of its 1997 acquisition of Immuno AG (Vienna, Austria). To comply with U.S. Federal Trade Commission (FTC) requirements related to this acquisition (alleviate monopoly concerns), Baxter licensed Immuno’s fibrin sealant technology in the U.S. to Haema-cure Corp. (Kirkland, Quebec, Canada), which currently markets essentially the same product under the trade name Hemaseel APR (see entry below). Baxter retained exclusive rights for Tisseel fibrin sealant outside the U.S., as well as nonexclusive rights within the U.S.
Manufacture: Plasma obtained from U.S. plasma collection centers is used to produce Sealer Protein Concentrate, the fibrinogen component. Anti-Inhibitor Coagulant Complex, Vapor Heated (FEIBA) bulk powder is the starting material for the thrombin component. See the entry for this product, which is used for treatment of hemophilia A patients with Factor VIII inhibitors (antibodies). FEIBA VH Immuno is a lyophilized (freeze-dried) formulation with Factor eight (VIII) inhibitor bypassing activity (FEIBA) containing primarily inactivated Factor VII obtained from pooled and fractionated Plasma, with manufacture including vapor heat treatment and solvent-detergent viral . This product was originally approved in 1982. Thrombin is prepared by dissolving FEIBA bulk powder and incubating the solution with calcium chloride to activate prothrombin to thrombin. After several filtration steps, the final bulk solution is vapor-heated (viral inactivation) and lyophilized (freeze-dried).
The Sealer Protein Concentrate (fibrinogen) is prepared from Plasma cryoprecipitate supernatant purified by DEAE Sephadex chromatography and subjected to vapor heating for virus inactivation. The cryoprecipitate is washed, dissolved in buffer solution, filtered, and freeze-dried.
Fibrinolysis Inhibitor Solution is produced from Plasma-derived Aprotinin Solution manufactured by Talecris (formerly Bayer Corp.), and is identical to that used by Talecris to manufacture their U.S.-approved Aprotinin (Trasylol) product (#713)
As with other blood-derived products, certain viruses, such as parvovirus B19 or hepatitis A virus, are difficult to inactivate by heat treatment; and, theoretically, may contaminate the product (although elaborate screening of donors and donor plasma largely eliminates this risk).
FDA class: Biologic BLA
CBER class: Blood And Blood Derivatives
Approvals: Date = 19980501; first approval; BLA granted to Oesterreichisches Institut fur Haemoderivate GmbH
Date = 20000207; approval revoked and granted (reissued) to Baxter Healthcare Corp.
Date = 20060727; BLA supplement; Indications: = added solvent/detergent treatment
Date = 20070226; BLA supplement; Indications: = replacement of the bovine aprotinin with synthetically derived aprotinin
Date = 20120125; BLA supplement; Indications: = general hemostasis in surgery when control of bleeding by standard surgical techniques is ineffective or impractical [includes patients who have been treated with heparin who may have unique treatment challenges]
Indications: [full text of "INDICATIONS AND USAGE” section from product insert/labeling, 7/2012]:
Hemostasis: TISSEEL is a fibrin sealant indicated for use as an adjunct to hemostasis in patients undergoing surgery when control of bleeding by conventional surgical techniques (such as suture, ligature, and cautery) is ineffective or impractical. TISSEEL is effective in heparinized patients.
Status: On July 27, 2006, FDA approved a BLA supplement (STN: BL 103980/5121) for Baxter's next generation Fibrin Sealant, "Tisseel VH S/D." Solvent/detergent treatment of both biological components of Tisseel VH S/D, specifically Sealer Protein Concentrate (Human) and Thrombin (Human), provides an increased margin of safety relative to Tisseel VH Fibrin Sealant.
On Feb. 26, 2007, FDA approved the PAS (STN: BL 103980/5224) supporting replacement of the bovine aprotinin with equivalent synthetically derived aprotinin.
Tech. transfer: Exemplary U.S. patents covering aspects of Tisseel include 4,362,567, assigned to Immuno AG. This patent describes, “A tissue adhesive on the basis of human or animal protein contains factor XIII and at least 33% by weight of fibrinogen, has a ratio of factor XIII to fibrinogen, expressed in units of factor XIII per gram of fibrinogen, of at least 80, contains fibrinogen and albumin in the total protein at a ratio of 33 to 90:5 to 40, contains plasminogen-activator-inhibitor or plasmin inhibitor in an amount of 250 to 25,000 KIU per g of fibrinogen and has been lyophilized.”
Based on the time during FDA regulatory review of Tisseel (under 35 USC §156), the expiration date of this patent was extended two years, to Feb. 2, 2004.
Market: The 2007 Average Wholesale Price (AWP) is $132/1 mL kit; $264.00/2 mL kit; and $660.00/5 mL kit (Red Book, 2007). These prices are unchanged from 2004.
In its March 22, 2006 price list, FFF Enterprises, a major biologics distributor, reported its price as $120.50/kit ($92.00/kit in 2005) for the 1 mL kit; $213.31/kit ($184.00/kit in 2005) for the 2 mL kit; and $519.38/kit ($460.00/kit in 2005) for the 5 mL kit. Tisseel Value Pack cost $752.30/kit for the 1 mL kit; $1,180.70/kit for the 2 mL kit; $2,807.00/kit and for the 5 mL kit.
Upon FDA approval, Baxter reported that U.S. sales were expected to reach about $200 million annually; and globally projected to reach $400 million.
R&D: In Nov. 2005, Baxter and Kuros Biosurgery AG signed an agreement under which Kuros has granted Baxter exclusive worldwide rights to develop and commercialize a portfolio of hard and soft tissue-repair products. These products will be based on TISSEEL, combined with Kuros’ proprietary biologics and associated binding technology. The combination enables growth factors and other bioactive agents to be attached to fibrin, thereby enhancing the regeneration of bone and soft tissue.
Companies involvement:
Full monograph
737 Fibrin Sealant/Tisseel
Sealing: TISSEEL is a fibrin sealant indicated as an adjunct to standard surgical techniques (such as suture and ligature) to prevent leakage from colonic anastomoses following the reversal of temporary colostomies.
Nomenclature:
Fibrin Sealant/Tisseel [BIO]
Tisseel VH Kit [TR]
Duploject [TR for application device]
Fibrin Sealant (Tisseel) [FDA]
Fibrin Sealant, Two-Component Fibrin Sealant, Vapor Heated Kit [FDA]
Fibrin Sealant, Vapor Heated, Solvent/Detergent Treated [FDA]
Sealer Protein Concentrate (Human) [FDA for a component]
Thrombin (Human) [FDA for a component]
Aprotinin [FDA for a component]
Fibrinogen [FDA for a component]
Fibrinolysis Inhibitor Solution (Bovine) [FDA for a component]
Fibrin Sealant (Human) [SY]
fibrin sealant kit [SY]
Thrombin Solution [FDA for a component]
FDA Class: Biologic BLA
Year of approval (FDA) = 1998
Date of 1st FDA approval = 19980501
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
blood products
bovine materials used<!-- bovinesource -->
fibrin
human materials used<!-- humansource -->
aprotinin, bovine
bovine aprotinin
bovine source warning, unknown/undocumented country
calcium chloride
Duploject syringe
Feiba bulk powder
fibrinogen
heat treatment (pasteurization)
lyophilized (freeze-dried)
Plasma (Human)
plasmin
prothrombin, human
Sephadex
Source Plasma
thrombin, bovine
viral inactivation, solvent detergent
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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