TachoSil

5 WARNINGS AND PRECAUTIONS • Thrombosis can occur if TachoSil is applied intravascularly. Ensure that TachoSil is applied to the surface of cardiac, vascular or hepatic tissue only. ( 5.1 ) • Can cause hypersensitivity or allergic/anaphylactoid reactions with first time or repetitive application. ( 5.2 ) • Avoid use in contaminated areas of the body or in the presence of an active infection. ( 5.3 ) • TachoSil contains collagen, which may adhere to bleeding surfaces. May carry a risk of gastrointestinal obstruction in abdominal surgery due to tissue adhesions. To prevent the development of tissue adhesions at undesired sites, ensure tissue areas outside the application area are adequately cleansed before administration of TachoSil. ( 5.4 ) • Avoid packing in cavities or closed spaces, because this may cause compression of underlying tissue. ( 5.5 ) • Use the least number of patches required to cover the entire bleeding area. Do not pack. Remove any unattached pieces of TachoSil. ( 5.6 ) • May carry a risk of transmitting infectious agents, such as viruses, and theoretically, the variant Creutzfeldt-Jakob disease (vCJD) agent, and the Creutzfeldt-Jakob disease (CJD) agents, despite manufacturing steps designed to reduce the risk of viral transmission. ( 5.7 ) 5.1 Thrombosis Thrombosis can occur if TachoSil is applied intravascularly. Ensure that TachoSil is applied to the surface of cardiac, vascular, or hepatic tissue only. 5.2 Hypersensitivity Reactions Hypersensitivity or allergic/anaphylactoid reactions may occur with TachoSil. Symptoms associated with allergic anaphylactic reactions include: flush, urticaria, pruritus, nausea, drop in blood pressure, tachycardia or bradycardia, dyspnea, severe hypotension and anaphylactic shock. These reactions may occur in patients receiving TachoSil for the first time or may increase with repetitive applications of TachoSil. 5.3 Infection Avoid application to contaminated or infected areas of the body, or in the presence of active infection. 5.4 Adhesions TachoSil contains collagen, which may adhere to bleeding surfaces. To prevent the development of tissue adhesions at undesired sites, ensure tissue areas outside the desired application area are adequately cleansed before administration of TachoSil [see Dosage and Administration (2.2 )] . Events of adhesions to gastrointestinal tissues leading to gastrointestinal obstruction have been reported with use in abdominal surgery carried out in proximity to the bowel. 5.5 Compression When placing TachoSil into cavities or closed spaces, avoid packing because this may cause compression of underlying tissue. 5.6 Non-Adherence or Dislodged Material Non-adherence has occurred after TachoSil application [see Postmarketing Experience (6.2) ]. Follow proper handling, preparation, and application procedures to reduce the risk of non-adherence of TachoSil [see Dosage and Administration (2.2) ]. Theoretically, excess patch material can become dislodged and migrate to other areas of the body. Use only minimum amount of TachoSil patches necessary to achieve hemostasis. Remove unattached pieces of TachoSil; if medically necessary [see Dosage and Administration (2.2) ] . 5.7 Transmissible Infectious Agents Because the biological components of this product are made from human blood, it may carry a risk of transmitting infectious agents (e.g., viruses), and theoretically, the variant Creutzfeldt-Jakob disease (vCJD) agent and the Creutzfeldt-Jakob disease (CJD) agent. The risk that TachoSil will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain virus infections, and by inactivating and removing, certain viruses [see Description (11) ] . Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Corza Medical GmbH, at telephone number 1-800-997-1067. The physician should discuss the risks and benefits of this product with the patient. Some viruses, such as parvovirus B19, are particularly difficult to remove or inactivate at this time. Parvovirus B19 most seriously affects pregnant women (fetal infection); immune-compromised individuals or individuals with an increased erythropoiesis (e.g., hemolytic anemia) [see Use in Specific Populations (8.1) and Patient Counseling Information (17) ] .

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 Injury, poisoning and procedural complications : foreign body trauma, post-procedural pulmonary embolism Vascular disorders : thrombosis Infections and infestations : hepatitis C Respiratory, thoracic and mediastinal disorders : respiratory distress, laryngeal edema, hemothorax Blood and lymphatic system disorders : splenic hemorrhage, eosinophilia Renal and urinary disorders : renal artery thrombosis, renal failure Endocrine disorders : parathyroid disorder Eye disorders : mydriasis Nervous system disorders : nerve compression Gastrointestinal disorders: intestinal obstruction (in abdominal surgeries), ileus (in abdominal surgeries)

<table width="100%"><colgroup><col width="43%"/><col width="25%"/><col width="32%"/></colgroup><tbody><tr><td styleCode="Botrule Toprule" colspan="3" align="center" valign="top"><paragraph>Table 2. Most Frequent Adverse Reactions (Cardiovascular Trial)</paragraph></td></tr><tr><td rowspan="2" valign="middle"><paragraph>Adverse Reaction</paragraph></td><td align="center" valign="middle"><paragraph>TachoSil</paragraph></td><td align="center" valign="middle"><paragraph>Comparator<footnote ID="_Ref350849426">Comparator: Hemostatic fleece material without additional active coagulation stimulating compounds.</footnote></paragraph></td></tr><tr><td styleCode="Botrule" align="center" valign="middle"><paragraph>N = 62<footnote ID="_Ref425156311">As treated population (safety data set).</footnote> n (%)</paragraph></td><td styleCode="Botrule" align="center" valign="middle"><paragraph>N = 57<footnoteRef IDREF="_Ref425156311"/> n (%)</paragraph></td></tr><tr><td styleCode="Toprule" valign="middle"><paragraph>Atrial fibrillation</paragraph></td><td align="center" valign="middle"><paragraph>18 (29%)</paragraph></td><td align="center" valign="middle"><paragraph>14 (25%)</paragraph></td></tr><tr><td valign="middle"><paragraph>Pleural effusion</paragraph></td><td align="center" valign="middle"><paragraph>14 (23%)</paragraph></td><td align="center" valign="middle"><paragraph>11 (19%)</paragraph></td></tr><tr><td styleCode="Botrule" valign="middle"><paragraph>Pyrexia</paragraph></td><td styleCode="Botrule" align="center" valign="middle"><paragraph>4 (6%)</paragraph></td><td styleCode="Botrule" align="center" valign="middle"><paragraph>3 (5%)</paragraph></td></tr></tbody></table>

<table width="100%"><colgroup><col width="43%"/><col width="25%"/><col width="32%"/></colgroup><tbody><tr><td styleCode="Botrule Toprule" colspan="3" align="center" valign="top"><paragraph>Table 3. Most Frequent Adverse Reactions (Hepatic Resection Trial)</paragraph></td></tr><tr><td styleCode="Botrule" rowspan="2" valign="middle"><paragraph>Adverse Reaction</paragraph></td><td align="center" valign="middle"><paragraph>TachoSil</paragraph></td><td align="center" valign="middle"><paragraph>Comparator<footnote ID="_Ref382482600">Comparator: Hemostatic fleece material without additional active coagulation stimulating compounds.</footnote></paragraph></td></tr><tr><td styleCode="Botrule" align="center" valign="middle"><paragraph>N = 114<footnote ID="_Ref425245746">As treated population (safety data set).</footnote> n (%)</paragraph></td><td styleCode="Botrule" align="center" valign="middle"><paragraph>N = 109<footnoteRef IDREF="_Ref425245746"/> n (%)</paragraph></td></tr><tr><td valign="middle"><paragraph>Nausea</paragraph></td><td align="center" valign="middle"><paragraph>34 (30%)</paragraph></td><td align="center" valign="middle"><paragraph>29 (27%)</paragraph></td></tr><tr><td styleCode="Botrule" valign="middle"><paragraph>Anemia</paragraph></td><td styleCode="Botrule" align="center" valign="middle"><paragraph>26 (23%)</paragraph></td><td styleCode="Botrule" align="center" valign="middle"><paragraph>23 (21%)</paragraph></td></tr></tbody></table>

<table width="100%"><colgroup><col width="51%"/><col width="21%"/><col width="28%"/></colgroup><tbody><tr><td styleCode="Botrule Toprule" colspan="3" align="center" valign="top"><paragraph>Table 4. Most Frequent Adverse Reactions in Pediatric Patients (All Trials)</paragraph></td></tr><tr><td styleCode="Botrule" rowspan="2" valign="top"><paragraph>Adverse Reaction</paragraph></td><td align="center" valign="middle"><paragraph>TachoSil</paragraph></td><td align="center" valign="middle"><paragraph>Comparator<footnote ID="_Ref382483722">Comparator: Hemostatic fleece material compounds without additional active coagulation stimulating compounds.</footnote></paragraph></td></tr><tr><td styleCode="Botrule" align="center" valign="middle"><paragraph>N = 36<footnote ID="_Ref425245808">As treated population (safety data set).</footnote> n (%)</paragraph></td><td styleCode="Botrule" align="center" valign="middle"><paragraph>N = 9<footnoteRef IDREF="_Ref425245808"/> n (%)</paragraph></td></tr><tr><td valign="middle"><paragraph>Diarrhea</paragraph></td><td align="center" valign="middle"><paragraph>6 (17%)</paragraph></td><td align="center" valign="middle"><paragraph>0</paragraph></td></tr><tr><td valign="middle"><paragraph>Hypertension</paragraph></td><td align="center" valign="middle"><paragraph>6 (17%)</paragraph></td><td align="center" valign="middle"><paragraph>1 (11%)</paragraph></td></tr><tr><td styleCode="Botrule" valign="middle"><paragraph>Transaminases Increased</paragraph></td><td styleCode="Botrule" align="center" valign="middle"><paragraph>4 (11%)</paragraph></td><td styleCode="Botrule" align="center" valign="middle"><paragraph>0</paragraph></td></tr></tbody></table>