Thrombin

12.1 Mechanism of Action The mechanism of action of TachoSil is based on the interaction between the active biological substances (human fibrinogen and human thrombin) and the physiology of the fibrin clot formation (Fig. 3A) . Upon contact with a bleeding wound surface, the active substances coated onto the equine collagen patch become dissolved and partly diffuse into the wound surface. The subsequent fibrinogen-thrombin reaction initiates the last step in the cascade of biochemical reactions-conversion of fibrinogen into fibrin monomers that further polymerize to form the fibrin clot. Hemostasis is achieved when the formed fibrin clot adheres the collagen patch to the wound surface, thus providing a physical barrier to bleeding (Fig 3B) . TachoSil exhibits flexibility to accommodate for the physiological movements of tissues and organs and can withstand pressures up to 61.4 hPa (46.1 mmHg). Figure 3: Scanning Electron Microscopy Photos of TachoSil A . The side view of the TachoSil patch shows the coating of the human plasma components anchored to the indentations of the collagen carrier. B . The deposition of a fibrin clot formed from fibrinogen and thrombin of the coating results in hemostasis and conglutination of the TachoSil patch to the wound surface. 12a 12b

1 INDICATIONS AND USAGE TachoSil is a fibrin sealant patch indicated for use with manual compression in adult and pediatric patients as an adjunct to hemostasis in cardiovascular and hepatic surgery when control of bleeding by standard surgical techniques (such as suture, ligature or cautery) is ineffective or impractical. Limitations for Use TachoSil cannot safely or effectively be used in place of sutures or other form of mechanical ligation for the treatment of major arterial or venous bleeding. Not for use in children under one month of age. TachoSil is a fibrin sealant patch indicated for use with manual compression in adult and pediatric patients as an adjunct to hemostasis in cardiovascular and hepatic surgery, when control of bleeding by standard surgical techniques (such as suture, ligature or cautery) is ineffective or impractical. ( 1 ) Limitations for Use Not for use in place of sutures or other forms of mechanical ligation in treatment of major arterial or venous bleeding. ( 1 ) Not for use in children under one month of age. ( 8.4 )

2 DOSAGE AND ADMINISTRATION For topical use on cardiovascular or hepatic tissue only Determine the number of patches to be applied by the size of the bleeding area. Apply the yellow, active side of the patch to the bleeding area. When applying TachoSil, do not exceed the maximum number of patches shown in Table 1 [see Warnings and Precautions (5.6) ] . Table 1. Amount of Fibrinogen and Thrombin per Total Patch Size and Maximum Number of TachoSil Patches to be Applied TachoSil Patch Size Human Fibrinogen (mg) Human Thrombin (Units) Maximum Number of Patches to be Applied 3.7 inch x 1.9 inch (9.5 cm x 4.8 cm) 337.4 123.1 10 1.9 inch x 1.9 inch (4.8 cm x 4.8 cm) 170.5 62.2 14 Apply on the surface of cardiovascular or hepatic tissue only. • Determine the number of TachoSil patches to be applied by the size of the bleeding area. ( 2 ) • Apply the yellow, active side of the patch to the bleeding surface. ( 2 ) 2.1 Preparation for Application TachoSil comes ready to use in sterile packages and must be handled using sterile technique in aseptic conditions. Discard damaged packages as resterilization is not possible. When in the operating room, the outer aluminum foil pouch may be opened in a non-sterile environment (Fig. 1A) . The inner sterile blister must be opened in a sterile environment (Fig. 1B) . Remove the TachoSil patch from the blister (Fig. 1C) , which can be used as a container for pre-moistening of the patch, if needed. Determine the size of patch(es) to be applied to the bleeding surface. Select the appropriate TachoSil patch so that it extends 1 to 2 cm beyond the margins of the wound. The patch can be cut to the correct size and shape if desired (Fig. 1D) . If more than one patch is used, overlap patches by at least 1 cm. Prior to application, cleanse the area to be treated to remove disinfectants and other fluids. The fibrinogen and thrombin proteins can be denatured by alcohol, iodine or heavy metal ions. If any of these substances have been used to clean the wound area, thoroughly irrigate the area before the application of TachoSil. Apply TachoSil directly to the bleeding area either wet or dry. If applied wet, pre-moisten TachoSil in 0.9% saline solution and then apply immediately. In the case of a wet tissue surface (e.g., oozing bleeding) TachoSil may be applied without pre-moistening. Figure 1: Pictures illustrating steps for preparation for application of TachoSil A B C D 21a 21b 21c 21d 2.2 Method of Application To ensure TachoSil adheres effectively, follow the recommended handling, preparation, and application procedures. Incorrect handling may result in non-adherence and reduced efficacy of TachoSil. Cleanse surgical instruments, gloves and adjacent tissues with saline solution to reduce the adherence to the TachoSil patch. The white, inactive side of TachoSil may also adhere to surgical instruments (e.g., forceps), gloves or adjacent tissues covered with blood due to the affinity of collagen to blood. It is important to note that failure to adequately clean adjacent tissues may cause adhesions [see Warnings and Precautions (5.4) ] . Apply the yellow, active side of the patch to the bleeding area (Fig. 2A) and hold in place with gentle pressure applied through moistened gloves or a moist pad for at least three minutes (Fig. 2B) . To avoid pulling the patch loose, first place a clean surgical instrument at one end of the patch before relieving the pressure (Fig. 2C) . Gentle irrigation may also aid in removing the pre-moistened pad or gloved hand without removing TachoSil from the bleeding area. Leave TachoSil in place once it adheres to organ tissue. Only remove unattached TachoSil patches (or part of) and replace with new patches. TachoSil cannot be resterilized once removed from inner pouch. Discard unused, opened packages of TachoSil at the end of the procedure. Figure 2: Pictures illustrating steps for method of application of TachoSil A B C Record patient name and TachoSil batch number every time that TachoSil is administered to a patient. 22a 22b 22c 2.3 Retreatment If not satisfied with the placement of the patch, or if bleeding still occurs during or after the specified duration of compression, repeat application procedure above. Do not remove already applied TachoSil.

6 ADVERSE REACTIONS The adverse reactions reported in more than one percent of patients during clinical trials were anemia, nausea and vomiting, fever, abdominal pain, increased white blood cell count, ascites, itching, atrial fibrillation, pleural effusion, gastrointestinal hemorrhage, wound infection, hypophosphatemia, urinary tract infection, and post-procedural bile leakage in hepatic surgery. The most common adverse reactions reported in >1% of patients during clinical trials were anemia, nausea and vomiting, fever, abdominal pain, increased white blood cell count, ascites, itching, atrial fibrillation, pleural effusion, gastrointestinal hemorrhage, wound infection, hypophosphatemia, urinary tract infection and post-procedural bile leakage in hepatic surgery. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Corza Medical GmbH at 1-800-997-1067 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Cardiovascular Surgery In the cardiovascular trial, the most frequently reported adverse reactions were atrial fibrillation and pleural effusion. Seventy-four percent (74%) of patients treated with TachoSil and 75% of comparator treated patients experienced one or more clinically relevant adverse reactions (see Table 2) . Table 2. Most Frequent Adverse Reactions (Cardiovascular Trial) Adverse Reaction TachoSil Comparator Comparator: Hemostatic fleece material without additional active coagulation stimulating compounds. N = 62 As treated population (safety data set). n (%) N = 57 n (%) Atrial fibrillation 18 (29%) 14 (25%) Pleural effusion 14 (23%) 11 (19%) Pyrexia 4 (6%) 3 (5%) Hepatic Surgery In the hepatic surgery trial, the most frequently reported adverse reactions were nausea and anemia (see Table 3). Ninety-four percent (94%) of patients treated with TachoSil and 94% of comparator treated patients experienced one or more clinically relevant adverse reactions. Table 3. Most Frequent Adverse Reactions (Hepatic Resection Trial) Adverse Reaction TachoSil Comparator Comparator: Hemostatic fleece material without additional active coagulation stimulating compounds. N = 114 As treated population (safety data set). n (%) N = 109 n (%) Nausea 34 (30%) 29 (27%) Anemia 26 (23%) 23 (21%) Post-operative bile leakage was observed in 8 (7%) of patients after treatment with TachoSil and 13 (12%) after treatment with comparator. Immunogenicity Antibodies against components of fibrin sealant/hemostatic products may occur. However in a clinical trial with human fibrinogen/human thrombin sponge (patch) in hepatic surgery, in which patients were investigated for the development of antibodies, 26% of the 96 patients tested and treated with human fibrinogen/human thrombin sponge (patch) developed antibodies to equine collagen. The equine collagen antibodies that developed in some patients after human fibrinogen/human thrombin sponge (patch) use were not reactive with human collagen. One patient developed antibodies to human fibrinogen. There were no adverse events attributable to the development of human fibrinogen or equine collagen antibodies. There is very limited clinical data available regarding re-exposure of the human fibrinogen/human thrombin sponge (patch). Two subjects have been re-exposed in a clinical trial and have not reported any immune-mediated adverse events, however, their antibody status to collagen or fibrinogen is unknown. Pediatric Clinical Trial Experience In pediatric patients, the most frequently reported adverse reactions were diarrhea, hypertension and increased transaminases (see Table 4). Ninety-four percent (94%) of patients treated with TachoSil and 100% of comparator treated patients experienced one or more clinically relevant adverse reactions. Table 4. Most Frequent Adverse Reactions in Pediatric Patients (All Trials) Adverse Reaction TachoSil Comparator Comparator: Hemostatic fleece material compounds without additional active coagulation stimulating compounds. N = 36 As treated population (safety data set). n (%) N = 9 n (%) Diarrhea 6 (17%) 0 Hypertension 6 (17%) 1 (11%) Transaminases Increased 4 (11%) 0 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TachoSil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been reported in postmarketing experience with TachoSil: General disorders and administration site conditions : adhesions, drug ineffective or non-adherence of TachoSil, inflammation, granuloma, catheter-related complication, multi-organ failure I