TACHOSIL- thrombin human and fibrinogen patch

United States - English - NLM (National Library of Medicine)

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Active ingredient:
HUMAN THROMBIN (UNII: 6K15ABL77G) (HUMAN THROMBIN - UNII:6K15ABL77G), FIBRINOGEN HUMAN (UNII: N94833051K) (FIBRINOGEN HUMAN - UNII:N94833051K)
Available from:
Baxter Healthcare Corporation
INN (International Name):
HUMAN THROMBIN
Composition:
HUMAN THROMBIN 2.0 [USP'U]
Administration route:
TOPICAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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 Do not use TachoSil for: Risk Summary A review of available data suggests that major birth defects occur in 2-4% of the U.S. general population and that miscarriage occurs in 15-20% of clinically recognized pregnancies, regardless of drug exposure. Animal reproduction studies have not been conducted with TachoSil. There are no adequate and well-controlled studies in pregnant women. It is also not known whether TachoSil can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. TachoSil should be administered to pregnant women only if clearly needed. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, ca
Product summary:
Each TachoSil patch is packaged individually in a tray with lidding. This is placed in an outer pouch with a desiccant bag and packaged into a folding carton. TachoSil is supplied in the following pack sizes: (NDC 0338-8701-01) (NDC 0338-8702-02) Storage
Authorization status:
Biologic Licensing Application
Authorization number:
0338-8701-00, 0338-8701-01, 0338-8702-00, 0338-8702-02

TACHOSIL- thrombin human and fibrinogen patch

Baxter Healthcare Corporation

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use TACHOSIL safely and effectively. See full

prescribing information for TACHOSIL.

TACHOSIL Fibrin Sealant Patch

Absorbable Patch for Topical Use

Initial U.S. Approval: 2010

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. (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)

DOSAGE AND ADMINISTRATION

Apply on the surface of cardiovascular or hepatic tissue only.

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

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

®

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)

TachoSil is a topical fibrin sealant patch consisting of human fibrinogen and human thrombin coated onto an equine

collagen sponge.

Each absorbable patch contains, per square inch (inch ): human fibrinogen 23.2 to 47.7 mg (35.5 mg); human

thrombin 8.4 to 17.4 Units (12.9 U) per cm : human fibrinogen 3.6 to 7.4 mg (5.5 mg); human thrombin 1.3 to 2.7

Units (2.0 U). (3)

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)

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)

hemorrhage, wound infection, hypophosphatemia, urinary tract infection and post-procedural bile leakage in hepatic

surgery. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 or

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 7/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Preparation for Application

2.2 Method of Application

2.3 Retreatment

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Thrombosis

5.2 Hypersensitivity Reactions

5.3 Infection

5.4 Adhesions

5.5 Compression

5.6 Dislodged Material

5.7 Transmissible Infectious Agents

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Cardiovascular

14.2 Hepatic

14.3 Pediatric

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

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

2 DOSAGE AND ADMINISTRATION

For topical use on cardiovascular or hepatic tissue only

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

1.9 inch x 1.9 inch

(4.8 cm x 4.8 cm)

170.5

62.2

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.

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.

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)].

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 for no more than one minute 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

2.2 Method of Application

Figure 2: Pictures illustrating steps for method of application of TachoSil

Record patient name and TachoSil batch number every time that TachoSil is administered to a patient.

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.

3 DOSAGE FORMS AND STRENGTHS

TachoSil is a topical fibrin sealant patch consisting of human fibrinogen and human thrombin coated

onto an equine collagen sponge. 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.

Strength:

Each absorbable TachoSil patch contains:

Per square inch:

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.

Human fibrinogen

23.2 – 47.7 mg (35.5 mg)

Human thrombin

8.4 – 17.4 Units (12.9 U)

Per square centimeter:

Human fibrinogen

3.6 – 7.4 mg (5.5 mg)

Human thrombin

1.3 – 2.7 Units (2.0 U)

4 CONTRAINDICATIONS

Do not use TachoSil for:

5 WARNINGS AND PRECAUTIONS

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 Dislodged Material

Use only minimum amount of TachoSil patches necessary to achieve hemostasis. Do not pack.

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)].

Theoretically, excess patch material can become dislodged and migrate to other areas of the body.

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 Baxter Healthcare Corporation, at telephone

number 1-866-888-2472. 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.

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

N = 62

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

Comparator: Hemostatic fleece material without additional active coagulation stimulating compounds.

As treated population (safety data set).

patients experienced one or more clinically relevant adverse reactions.

Table 3. Most Frequent Adverse Reactions (Hepatic Resection Trial)

Adverse Reaction

TachoSil

Comparator

N = 114

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

N = 36

n (%)

N = 9

n (%)

Diarrhea

6 (17%)

Hypertension

6 (17%)

1 (11%)

Transaminases Increased

4 (11%)

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:

Comparator: Hemostatic fleece material without additional active coagulation stimulating compounds.

As treated population (safety data set).

Comparator: Hemostatic fleece material compounds without additional active coagulation stimulating compounds.

As treated population (safety data set).

General disorders and administration site conditions: adhesions, drug ineffective, 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)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

A review of available data suggests that major birth defects occur in 2-4% of the U.S. general

population and that miscarriage occurs in 15-20% of clinically recognized pregnancies, regardless of

drug exposure. Animal reproduction studies have not been conducted with TachoSil. There are no

adequate and well-controlled studies in pregnant women. It is also not known whether TachoSil can

cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. TachoSil

should be administered to pregnant women only if clearly needed.

8.2 Lactation

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human

milk, caution should be exercised when TachoSil is administered to nursing mothers.

8.4 Pediatric Use

The use of TachoSil has been studied in patients aged one month to 16 years; use in children under the

age of one month may be unsafe or ineffective due to small size and limited ability to apply the patch as

recommended. Use of TachoSil in the one month to 16 years age group is supported by evidence from

adequate and well-controlled studies of TachoSil in adults with additional data from two clinical trials,

which included 36 pediatric patients at the age of 16 years or younger. The data supports the use of

TachoSil for hemostasis in pediatric patients undergoing cardiovascular and hepatic surgery [see

Clinical Studies (14.3)].

8.5 Geriatric Use

Clinical trials to date included 326 patients older than 65 years of age receiving TachoSil. No overall

differences in safety or effectiveness were observed between the elderly and younger patients,

however, greater susceptibility of some older patients to adverse reactions cannot be ruled out.

11 DESCRIPTION

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

) 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

Manufacturing step

Enveloped Viruses

Non-enveloped

Viruses

BVDV

Pasteurization, precipitation and

adsorption steps

≥15.0

≥20.4

≥13.2

16.3

Cumulative Reduction Factors for Virus Removal/Inactivation of Human Fibrinogen

Virus Reduction Factors [log

Manufacturing step

Enveloped Viruses

Non-enveloped

Viruses

BVDV

Pasteurization, precipitation and

lyophilization steps

≥9.6

≥11.2

≥8.3

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

Virus Reduction Factors [log

Manufacturing step

Enveloped Viruses

Non-enveloped

Viruses

PI-3

Reo3

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

) 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

Enveloped Viruses

Non-enveloped Viruses

Manufacturing step

PI-3

Reo3

Gamma Irradiation

≥4.7

≥4.0

≥6.2

All infections considered by a physician possibly to have been transmitted by this product should be

reported to Baxter [see Warnings and Precautions (5.7)].

12 CLINICAL PHARMACOLOGY

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

HIV: Human Immunodeficiency Virus,

HSV: Herpes Simplex Virus

BVDV: Bovine Viral Diarrhea Virus

PRV: Pseudorabies Virus

CPV: Canine parvovirus

HAV: Hepatitis A Virus

WNV: West Nile Virus, only single manufacturing step validated

PI-3: Parainfluenza Virus type 3

PPV: Porcine Parvovirus

Reo 3: ReoVirus type 3

PRV: Pseudorabies Virus

PI-3: Parainfluenza Virus type 3

PPV: Porcine Parvovirus

Reo 3: ReoVirus type 3

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of TachoSil or studies to determine the

genotoxicity or the effect of TachoSil on fertility have not been performed. An assessment of the

carcinogenic potential of TachoSil was completed to demonstrate minimal carcinogenic risk from

product use.

13.2 Animal Toxicology and/or Pharmacology

In a study conducted in swine, TachoSil was applied to liver wounds and showed progressive

degradation. However, remnants of the TachoSil patch may remain present for more than 12 months.

Histologic examination at 26 and 52 weeks revealed that granulation tissue encapsulates TachoSil

remnants and forms a firm capsule around them. Remnants were found in all treated animals after 26

weeks (12/12) and in most animals (6/8) after 52 weeks. No other local reactivity or toxicities were

noted.

14 CLINICAL STUDIES

14.1 Cardiovascular

An open-label, multi-center, randomized, parallel-group study comparing TachoSil with comparator

(hemostatic fleece without additional active coagulation stimulating compounds) treatment was

conducted to evaluate TachoSil for control of bleeding in 119 patients undergoing cardiovascular

surgery requiring cardiopulmonary bypass procedure. Of the 119 subjects, 88 (74%) were male and 31

(26%) female. Mean (range) age was 67 (23 to 86) years; subjects older than 65 years constituted 58%

of the male and 74% of the female population. All subjects were White/Caucasian.

In the Intent-to-Treat (ITT) population, 59 patients were randomized to treatment with TachoSil and 60

patients were randomized to treatment with the comparator. A larger proportion of patients in the

TachoSil treatment group (44/59; 75%) than in the comparator treatment group (20/60; 33%) achieved

hemostasis within three minutes, which was a statistically significant difference (p<0.0001).

Fifty-six out of 59 (95%) patients in the TachoSil treatment group achieved hemostasis at six minutes

compared to 43 out of 60 (72%) in the comparator treatment group, which also was statistically

significant (p=0.0006) (see Table 7).

Table 7. Efficacy Results in Cardiovascular Surgery, by Treatment, Intent-to-Treat Population

Total number

Percentage of

95% CI for

Treatment

of patients who

achieved hemostasis

patients who

achieved hemostasis

95% CI for

proportion

p-value

Hemostasis at 3 min

TachoSil (n=59)

[0.635; 0.857]

<0.0001

Comparator

(n=60)

[0.214; 0.453]

Hemostasis at 6 min

TachoSil (n=59)

[0.893;1.000]

0.0006

Comparator

(n=60)

[0.603; 0.831]

14.2 Hepatic

A randomized, open-label, parallel group, multi-center trial comparing TachoSil with comparator was

conducted to evaluate TachoSil for the secondary treatment of local bleeding in patients undergoing

hepatic surgery.

A total of 114 patients were randomized to treatment with TachoSil and 110 patients were randomized to

treatment with comparator. A similar proportion of male patients and female patients were randomly

assigned in the trial (53% and 47%, respectively). The mean (SD) age of patients was 58.1 (13.95) years

and in both treatment groups approximately 30% of the patients were above 65 years. The majority of

patients were White/Caucasian (80%) and the most common ethnicity was non-Hispanic/non-Latino

(88%).

A larger proportion of patients in the TachoSil treatment group (81%) than in the comparator treatment

group (50%) achieved hemostasis within the first three minutes after treatment application. The primary

analysis of the proportion of patients who achieved hemostasis within three minutes showed a

statistically significant difference between treatment groups in favor of TachoSil (p<0.001) and

obtained a clinical relevant difference between the two groups defined from the estimated odds ratio

(see Table 8).

With respect to one of the two secondary endpoints, 108 (95%) patients in the TachoSil group and 84

(76%) patients in the comparator group achieved hemostasis within five minutes in which the secondary

analysis also showed a statistically significant difference between the group in favor of TachoSil

(p<0.001, multiplicity adjusted) (see Table 8).

Table 8. Efficacy Results in Hepatic Surgery, by Treatment, Intent-To-Treat Population

Treatment

Total number of patients

who achieved hemostasis

Percentage of patients

who achieved hemostasis

Odds ratio

[95% CI]

p-value

Hemostasis at 3 min

TachoSil (n=114)

4.87

[2.55; 9.29]

<0.001

Comparator

(n=110)

Hemostasis at 5 min

TachoSil (n=114)

6.24

[2.39;16.30]

<0.001

Comparator

(n=110)

Time to hemostasis

<0.001

TachoSil (n=114)

Comparator

(n=110)

Normal approximation to the binominal distribution is used to construct the asymptotic confidence intervals

Cochran-Mantel-Haenszel test controlling for center

Hemostatic fleece material without additional active coagulation stimulating compounds

Hochberg's adjustment for multiplicity

Hemostatic fleece material made of oxidized cellulose polymer

Analyzed by a log rank test for equality over treatments. Patients who did not achieve hemostasis after 10 minutes

14.3 Pediatric

In a pediatric subset of a randomized, open-label, parallel group, multi-center trial comparing TachoSil

with comparator the efficacy of TachoSil for the secondary treatment of local bleeding in pediatric

patients undergoing hepatic surgery was evaluated.

In the randomized part of the study, eight patients were treated with TachoSil and nine patients were

treated with the comparator. After the randomization phase, an additional 12 patients were treated with

TachoSil in a single extension arm to reach 20 patients exposed to TachoSil. A similar proportion of

male and female pediatric patients were treated overall in the trial (48% and 52%, respectively). The

majority of patients were White/Caucasian (79%) and the most common ethnicity was non-Hispanic/non-

Latino (69%). The mean age was slightly higher in the TachoSil group (4.58 years; range 0.4, 13.0

years) than in the comparator group (3.77 years; range 0.4, 16.0 years).

A larger proportion of the patients in the TachoSil group (7/8 [88%]) than in the comparator group (4/9

[44%]) achieved hemostasis within three minutes in the randomized part of the study. The results were

similar considering the whole set of pediatric patients exposed to TachoSil (17/20 [85%]) (see Table 9).

No statistical testing was performed of the difference between the two groups due to the small sample

size. Seven patients in the TachoSil group (88%) and seven patients in the comparator group (78%)

achieved hemostasis within five minutes (see Table 9).

Table 9. Achievement of Hemostasis of Pediatric Patients Undergoing Hepatic Surgery, Intent-To-

Treat Population/Safety Population

Treatment

Total number of

achieved hemostasis

Percentage

of patients

Exact

[95% CI]

Hemostasis at 3 min

TachoSil (n=8)

[47.3, 99.7]

Comparator

(n=9)

[13.7, 78.8]

Hemostasis at 5 min

TachoSil (n=8)

[47.3, 99.7]

Comparator

(n=9)

[40.0, 97.2]

All TachoSil Patients

Hemostasis at 3 min

[62.1, 96.8]

TachoSil (n=20)

Hemostasis at 5 min

[75.1, 99.9]

TachoSil (n=20)

In another clinical study, 16 pediatric patients were included in a prospective, multi-center,

uncontrolled, study where TachoSil was used in connection with resection of the liver with or without

segmental liver transplantation.

The analysis of the efficacy parameter, time to hemostasis, showed that 13 of 16 patients achieved

hemostasis within three minutes after application of TachoSil. One patient obtained hemostasis eight

minutes after treatment application and two subjects failed to achieve satisfactory hemostasis within 10

minutes, which necessitated alternative hemostatic measures.

The estimated proportion of patients achieving hemostasis within three minutes was 81%, which is

considered similar to results seen in the randomized controlled study.

were censored in the analysis.

Hemostatic fleece material made of oxidized cellulose polymer

Safety analysis set

16 HOW SUPPLIED/STORAGE AND HANDLING

Each TachoSil patch is packaged individually in a tray with lidding. This is placed in an outer pouch

with a desiccant bag and packaged into a folding carton.

TachoSil is supplied in the following pack sizes:

(NDC 0338-8701-01)

(NDC 0338-8702-02)

Storage

17 PATIENT COUNSELING INFORMATION

Distributed by:

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

Manufactured by:

Takeda Austria GmbH

St. Peter Strasse 25

4020 Linz, Austria

U.S. License No. 1894

TachoSil is a trademark of Takeda AS registered with the U.S. Patent and Trademark Office.

All other trademarks are the property of their respective owners.

TAC272 R5

Package with 1 patch of 3.7 inch x 1.9 inch

(9.5 cm x 4.8 cm)

Package with 2 patches of 1.9 inch x 1.9 inch

(4.8 cm x 4.8 cm)

Use TachoSil before expiration date indicated on the package.

Store unopened packages of TachoSil between 2ºC and 25ºC. TachoSil does not require

refrigeration. Do not freeze.

Do not use if package is opened or damaged.

Because TachoSil may cause the formation of clots in blood vessels if exposed intravascularly,

advise patients to consult their physician if they experience chest pain, shortness of breath or

difficulty speaking or swallowing, or leg tenderness or swelling [see Warnings and Precautions

(5.1)].

Instruct patients to consult their physician if symptoms of B19 virus infection appear (fever,

drowsiness and chills) followed about two weeks later by a rash and joint pain. Parvovirus B19

most seriously affects pregnant women (fetal infection); immune-compromised individuals or

individuals with an increased erythropoiesis (e.g., hemolytic anemia) [see Warnings and

Precautions (5.7)].

Advise patients that, because TachoSil is made from human blood, it may carry a risk of

transmitting infectious agents (e.g., viruses), and theoretically, the Creutzfeldt-Jakob (CJD) agent

[see Warnings and Precautions (5.7)].

PRINCIPAL DISPLAY PANEL - 1 Patch Blister Pack Pouch Carton - NDC 0338-8701-01

NDC 0338-8701-01

Fibrin

Sealant Patch

TachoSil

3.7 inch x 1.9 inch

(9.5 cm x 4.8 cm)

Contents: 1 absorbable fibrin sealant patch

Single use only

Topical use only

Do not use intravascularly

Store at 2°C to 25°C (36°F to 77°F)

Do not freeze

Directions for use: See package insert

Do not use if package is opened or damaged

Use immediately once the foil pouch is opened

Do not resterilize

Dispose of any unused product or waste material

in accordance with local requirements

Rx Only

Product Code 1144922

Baxter

®

PRINCIPAL DISPLAY PANEL - 2 Patch Blister Pack Pouch Carton

NDC 0338-8702-02

Fibrin

Sealant Patch

TachoSil

1.9 inch x 1.9 inch

(4.8 cm x 4.8 cm)

®

Contents: 2 absorbable fibrin sealant patches

Single use only

Topical use only

Do not use intravascularly

Store at 2°C to 25°C (36°F to 77°F)

Do not freeze

Directions for use: See package insert

Do not use if package is opened or damaged

Use immediately once the foil pouch is opened

Do not resterilize

Dispose of any unused product or waste material

in accordance with local requirements

Rx Only

Product Code 1144923

Baxter

TACHOSIL

thrombin human and fibrinogen patch

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 338 -8 70 1

Route of Administration

TOPICAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

HUMAN THRO MBIN (UNII: 6 K15ABL77G) (HUMAN THROMBIN - UNII:6 K15ABL77G)

HUMAN THROMBIN

2.0 [USP'U]

FIBRINO GEN HUMAN (UNII: N9 48 330 51K) (FIBRINOGEN HUMAN - UNII:N9 48 330 51K)

FIBRINOGEN HUMAN

5.5 mg

Inactive Ingredients

Ingredient Name

Stre ng th

EQ UINE CO LLAGEN (UNII: 3221SCV0 LS)

ALBUMIN HUMAN (UNII: ZIF514RVZR)

RIBO FLAVIN (UNII: TLM29 76 OFR)

SO DIUM CHLO RIDE (UNII: 451W47IQ8 X)

SO DIUM CITRATE, UNSPECIFIED FO RM (UNII: 1Q73Q2JULR)

ARGININE HYDRO CHLO RIDE (UNII: F7LTH1E20 Y)

Product Characteristics

Color

YELLOW (active side)

S core

S hap e

S iz e

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:0 338 -8 70 1-0 1

1 in 1 CARTON

0 4/0 5/20 10

1

NDC:0 338 -8 70 1-0 0

1 in 1 POUCH

1

1 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

BLA125351

0 4/0 5/20 10

TACHOSIL

thrombin human and fibrinogen patch

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 338 -8 70 2

Route of Administration

TOPICAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

HUMAN THRO MBIN (UNII: 6 K15ABL77G) (HUMAN THROMBIN - UNII:6 K15ABL77G)

HUMAN THROMBIN

2.0 [USP'U]

FIBRINO GEN HUMAN (UNII: N9 48 330 51K) (FIBRINOGEN HUMAN - UNII:N9 48 330 51K)

FIBRINOGEN HUMAN

5.5 mg

Baxter Healthcare Corporation

Inactive Ingredients

Ingredient Name

Stre ng th

EQ UINE CO LLAGEN (UNII: 3221SCV0 LS)

ALBUMIN HUMAN (UNII: ZIF514RVZR)

RIBO FLAVIN (UNII: TLM29 76 OFR)

SO DIUM CHLO RIDE (UNII: 451W47IQ8 X)

SO DIUM CITRATE, UNSPECIFIED FO RM (UNII: 1Q73Q2JULR)

ARGININE HYDRO CHLO RIDE (UNII: F7LTH1E20 Y)

Product Characteristics

Color

YELLOW (active side)

S core

S hap e

S iz e

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:0 338 -8 70 2-0 2

2 in 1 CARTON

0 4/0 5/20 10

1

NDC:0 338 -8 70 2-0 0

1 in 1 POUCH

1

1 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

BLA125351

0 4/0 5/20 10

Labeler -

Baxter Healthcare Corporation (005083209)

Revised: 2/2020

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