Fibrin Sealant

TISSEEL VH Fibrin Sealant contains Fibrinogen (Sealer Protein Concentrate) as the main active ingredient. It also contains Thrombin, Calcium Chloride Solution, and Fibrinolysis Inhibitor Solution (Aprotinin) which is a substance of bovine origin. The two reconstituted components, the Sealer Protein Solution and Thrombin Solution, are mixed and applied topically as described in the Dosage and Administration Section. Mixing the Sealer Protein Solution and Thrombin Solution produces a viscous solution that quickly sets into an elastic coagulum.

Thrombin is a highly specific protease that transforms the fibrinogen contained in Sealer Protein Concentrate into fibrin. The thrombin is partly adsorbed by the fibrin so formed. Excess thrombin, if any, is inactivated by protease inhibitors in the blood.

Fibrinolysis Inhibitor Solution (Aprotinin) is a polyvalent protease inhibitor which prevents premature degradation of fibrin. Released aprotinin and its metabolites are eliminated by the kidney. (Its half-life in blood is known to average between 30 to 60 minutes. 2 ) Preclinical studies with different Fibrin Sealant preparations simulating the fibrinolytic activity generated by extracorporeal circulation in patients during cardiovascular surgery have shown that incorporation of Aprotinin in the product formulation increases resistance of the Fibrin Sealant clot to degradation in a fibrinolytic environment. 2,3,4,5

To examine the risk of bovine sensitization, Fibrinolysis Inhibitor Solution was injected intravenously into sensitized guinea pigs. 6 None showed shock symptoms. No case of clinically manifest bovine sensitization was observed in any of the clinical studies conducted and no reports of sensitization have been made with respect to a similar product marketed outside the U.S. Nonetheless the physician should be aware of the possibility of sensitization to bovine-derived protein.

The manufacturing procedure for TISSEEL VH Fibrin Sealant includes processing steps designed to reduce the risk of viral transmission. In particular, a two-step vapor heating process is included in the manufacturing of Sealer Protein Concentrate and Thrombin. Validation studies were conducted using samples drawn from manufacturing intermediates for each of the two human plasma derived components, Sealer Protein Concentrate and Thrombin. These samples were spiked with stock virus suspensions of known titers followed by further processing under conditions analogous to those in the respective manufacturing steps.

The virus reduction factors (expressed as log 10 ) of independent manufacturing steps were as follows for each of the viruses tested: 7,8

Reduction Factors for Virus Removal and/or Inactivation during the Manufacture of Sealer Protein Concentrate (Human)

Reduction Factors for Virus Removal and/or Inactivation during the Manufacture of Thrombin (Human)

In a study of 30 patients treated with an earlier version of TISSEEL VH Fibrin Sealant, TISSEEL Fibrin Sealant (processed by a single-step heating method), there were no transmissions by the product of HIV or hepatitis. 9 In post-marketing surveillance in Europe, no cases of viral hepatitis or HIV infection were reported after administration of a product similar to TISSEEL Fibrin Sealant.

TISSEEL Fibrin Sealant was evaluated in an open-label crossover study against control topical hemostatic agents in 489 patients undergoing cardiovascular reoperation or resternotomy at 11 institutions. 9,10,11 Patients were randomized to TISSEEL Fibrin Sealant or control hemostatic agents when a topical hemostatic was needed at the conclusion of surgery and after all attempts at surgical hemostasis. Patients were crossed to the alternative therapy if bleeding continued after the 5 minute endpoint. At 10 centers, TISSEEL Fibrin Sealant was used after administration of protamine sulfate. At one site, TISSEEL Fibrin Sealant could be used before administration of protamine sulfate. For the primary endpoint, successful hemostasis at 5 minutes, TISSEEL Fibrin Sealant was statistically superior to control topical hemostatic agents:

Similarly, absolute time to cessation of bleeding was statistically significantly shorter for TISSEEL Fibrin Sealant than for control topical hemostatic agents (p<0.0001, Wilcoxon-Gehan test, two sided, Monte Carlo option).

In a single center, prospective open label study of 120 patients randomized to standard of care (59 patients) or standard of care plus Fibrin Sealant (61 patients) or elective colostomy closure after temporary colostomy placement for treatment of traumatic injury to the colon, TISSEEL Fibrin Sealant plus standard of care was shown to be statistically significantly superior to standard of care alone (p = 0.0406, Jonckheere-Terpstra test for ordinal data, two sided) with regard to anastomotic complications (leakage, intra-abdominal abscess formation, re-operation, septic shock, and death). 12

In a single center, open label trial, TISSEEL Fibrin Sealant was compared to historical controls in patients undergoing laparotomy for blunt or penetrating traumatic injury to the spleen and/or liver. 13 Use of TISSEEL Fibrin Sealant resulted in the need for statistically significantly fewer splenectomies than control hemostatic maneuvers:

TISSEEL Fibrin Sealant did not result in statistically significantly reduced mortality in patients with blunt or penetrating trauma to the liver alone or to the liver and spleen (p = 0.067, [khgr ] 2 , one-sided).

TISSEEL VH Fibrin Sealant is contraindicated in individuals who are known to be hypersensitive to bovine protein.

To avoid a risk of allergic-anaphylactoid reaction and/or thromboembolic events, which may be life-threatening, do not inject Tisseel VH Fibrin Sealant into a vessel or tissue.