Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1.   Pharmacodynamic properties

Pharmaco-therapeutic group: Local haemostatics, ATC code: B02BC30

TachoSil contains fibrinogen and thrombin as a dried coating on the surface of a collagen matrix. In contact with physiological fluids, e.g. blood, lymph or physiological saline solution the components of the coating dissolve and partly diffuse into the wound surface. This is followed by the fibrinogen-thrombin reaction which initiates the last phase of physiological blood coagulation. Fibrinogen is converted into fibrin monomers which spontaneously polymerise to a fibrin clot, which holds the collagen matrix tightly to the wound surface. The fibrin is then cross linked by endogenous factor XIII, creating a firm, mechanically stable network with good adhesive properties and provides sealing as well.

Clinical studies demonstrating haemostasis were conducted in a total of 240 patients (119 TachoSil, 121 argon beamer) undergoing partial liver resection surgery and 185 patients (92 TachoSil, 93 standard surgical treatment) undergoing surgical resection of superficial renal tumour. A further controlled study in 119 patients (62 TachoSil, 57 haemostatic fleece) demonstrated sealing, haemostasis and suture support in patients undergoing cardiovascular surgery. Tissue sealing in lung surgery was investigated in two controlled trials in patients undergoing lung surgery.
The first controlled clinical trial investigating tissue sealing in lung surgery failed to document superiority over standard treatment measured by air leakage due to the inclusion of a large group of patients (53%) without air leakage.
However, the second study investigating tissue sealing in 299 patients (149 TachoSil, 150 standard surgical treatment) with demonstrated intraoperative air leakage showed the superiority of TachoSil compared to standard treatment.

The efficacy of TachoSil was tested in a randomised controlled study in 726 patients (362 treated with TachoSil and 364 controls) undergoing skull base surgery as an adjunct to suture for sealing the dura mater, in which the efficacy outcome was measured post-operatively as verified cerebrospinal fluid (CSF) leaks or pseudomeningocoele, or treatment failure during surgery. In this study, superiority over current practice (which included suture, duraplasty and fibrin and polymer sealants or combinations of these) could not be documented. The numbers of subjects experiencing an efficacy outcome event were 25 (6.9%) and 30 (8.2%) for TachoSil and current practice treated patients, respectively, providing an Odds Ratio of 0.82 (95% CI: 0.47, 1.43). However, the 95% confidence intervals for the odds ratio results indicated that TachoSil had similar efficacy to current practice. In this study two application techniques for TachoSil were evaluated: application of TachoSil over the dura and application of TachoSil on both sides of the dura. The results did not support the second method. TachoSil was found to be well tolerated and safe for use as an adjunct to dura mater closure in neurosurgery.

Pharmacokinetic Properties

5.2.   Pharmacokinetic properties

TachoSil is intended for epilesional use only. Intravascular administration is contraindicated.
Therefore, intravascular pharmacokinetic studies were not performed in man.
Fibrin Sealants/haemostatics are metabolized in the same way as endogenous fibrin by fibrinolysis and phagocytosis.

In animal studies, TachoSil biodegrades after administration to a wound surface with few remnants left after 13 weeks. Complete degradation of TachoSil was seen in some animals 12 months after its administration to a liver wound, whereas small remnants were still observed in others. The degradation was associated with infiltration of granulocytes and formation of resorptive granulation tissue encapsulating the degraded remnants of TachoSil. No evidence of local intolerability has been observed in animal studies.

From the experience in humans there have been isolated cases where remnants were observed as coincidental findings with no signs of functional impairment