FIBRINOGEN HUMAN: 408 Adverse Event Reports & Safety Profile

TachoSil Fibrin Sealant Patch is a sterile, bioabsorbable combination product comprised of two active substances (human plasma-derived fibrinogen and human plasma-derived thrombin) coated onto a collagen sponge of equine origin. The collagen sponge serves as a flexible and mechanically stable carrier for the active substances to facilitate application of the human fibrinogen and thrombin to the wound surface. The active side of the patch is yellow in color due to the presence of a colorant riboflavin (E101); and the non-active side is off-white in color. Each square inch of the patch contains approximately 35.5 mg of human fibrinogen and 12.9 units of human thrombin. Other inactive ingredients include equine collagen, human albumin, sodium chloride, sodium citrate, and L‑arginine hydrochloride. TachoSil is sterilized by gamma irradiation after completion of inner and outer packaging, resulting in a sterile product in a sterile inner package.

Viral Clearance

The active biological substances of TachoSil (human fibrinogen and human thrombin) are manufactured from pooled human plasma collected in facilities in the United States. Human plasma is tested by a Nucleic Acid Test (NAT) for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus-1 (HIV-1). NAT testing for hepatitis A virus (HAV) and parvovirus B19 is also performed. Human plasma is also tested for the presence of hepatitis B surface antigen (HBsAg), and antibodies to hepatitis C virus (anti-HCV) and human immunodeficiency viruses types 1 and 2 (anti-HIV 1/2). The manufacturing procedure for each TachoSil component and final product include processing steps designed to reduce the risk of viral transmission. In particular, the virus clearance steps in the manufacture of human fibrinogen and thrombin include pasteurization, precipitation and adsorption. The virus clearance step in the manufacture of the collagen sponge is the pH treatment. The virus clearance capacity of these procedures in the manufacture of fibrinogen, thrombin and collagen sponge has been validated using viruses with a wide range of physicochemical characteristics. These in vitro validation studies were conducted using samples from manufacturing intermediates spiked with virus suspensions of known titers followed by further processing under conditions equivalent to those in the respective manufacturing steps. The cumulative virus reduction factors (expressed as log 10 ) are shown in Table 5 for each virus tested.

Table

5.

Cumulative Virus Reduction

Factors for the Components of TachoSil Cumulative Reduction Factors for Virus Removal/Inactivation of Human Thrombin Virus Reduction Factors [log 10 ] Manufacturing step Enveloped Viruses Non-enveloped Viruses HIV HIV: Human Immunodeficiency Virus, HSV HSV: Herpes Simplex Virus BVDV BVDV: Bovine Viral Diarrhea Virus PRV PRV: Pseudorabies Virus CPV CPV: Canine parvovirus HAV HAV: Hepatitis A Virus Pasteurization, precipitation and adsorption steps 15.0 20.4 13.2 16.3 5.4

8.4 Cumulative Reduction Factors for Virus Removal/Inactivation of Human Fibrinogen Virus Reduction Factors [log 10 ] Manufacturing step Enveloped Viruses Non-enveloped Viruses HIV PRV BVDV WNV WNV: West Nile Virus, only single manufacturing step validated CPV HAV Pasteurization, precipitation and lyophilization steps 9.6 8.8 11.2 8.3 4.9

8.6 Reduction Factors for Virus Removal/Inactivation of the Collagen Sponge (equine)

Virus Reduction

Factors [log 10 ] Manufacturing step Enveloped Viruses Non-enveloped Viruses PRV PI-3 PI-3: Parainfluenza Virus type 3 PPV PPV: Porcine Parvovirus Reo3 Reo 3: ReoVirus type 3 pH treatment 5.7 5.9 --- --- A validation study was also conducted to evaluate the capacity for gamma irradiation to inactivate and/or remove viruses in the final TachoSil product. The virus reduction factors (expressed as log 10 ) are shown in Table 6 for each virus tested.

Table

6.

Virus Reduction

Factors for TachoSil Final Sterilization by Gamma Irradiation Reduction Factor of Gamma Irradiation (Final Sterilization of TachoSil)

Virus Reduction

Factors [log 10 ]

Enveloped Viruses

Non-enveloped Viruses Manufacturing step PRV PRV: Pseudorabies Virus PI-3 PI-3: Parainfluenza Virus type 3 PPV PPV: Porcine Parvovirus Reo3 Reo 3: ReoVirus type 3 Gamma Irradiation 4.7 4.0 3.0

6.2 All infections considered by a physician possibly to have been transmitted by this product should be reported to Corza <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span> .

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 )

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> . 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.

Do not use TachoSil for:

• Intravascular application. Bleeding from large defects in visible arteries or veins where the injured vascular wall requires repair and maintenance of vessel patency or where there would be persistent exposure of TachoSil to blood flow during absorption of the product. This can result in life-threatening thromboembolic events [see Warnings and Precautions (5.1) ] .
• Individuals known to have anaphylactic or severe systemic reaction to human blood products or horse proteins [see Warnings and Precautions (5.2) ] . Do not apply TachoSil intravascularly. Intravascular application of TachoSil may result in life-threatening thromboembolic events. ( 4 ) Do not use TachoSil in individuals with known hypersensitivity to human blood products or horse proteins. ( 4 )

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)

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Postmarketing Experience (6.2) ]</span>. Follow proper handling, preparation, and application procedures to reduce the risk of non-adherence of TachoSil <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span>. 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> .

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 <span class="opacity-50 text-xs">[see Description (11) ]</span> . 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) <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) and Patient Counseling Information (17) ]</span> .