EVARREST® Fibrin Sealant Patch

Product Monograph

Evarrest®
Table of Contents
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Summary of Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Indications and Usage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Topical Hemostats  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Ideal Characteristics of a Hemostatic Agent . . . . . . . . . . . . . . . . . . . . 6
Conventional Methods of Achieving Hemostasis  . . . . . . . . . . . . . . . . . 7
Challenges With Current Topical Hemostats   . . . . . . . . . . . . . . . . . . . 8
Safety Concerns with Current Topical Hemostats . . . . . . . . . . . . . . . . . 8
Benefits of EVARREST® Fibrin Sealant Patch . . . . . . . . . . . . . . . . . . . . . . . 9
Clinical Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Absorption of Human Fibrinogen and Human Thrombin . . . . . . . . . . . 10
Absorption of Patch Components . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12
Composition  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Viral Safety  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Rigorous Screening of Plasma for Viral Markers . . . . . . . . . . . . . . . . . .15
Viral Inactivation/Removal Steps . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Virus Validation Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Clinical Trial: Mild to Moderate Soft Tissue Bleeding . . . . . . . . . . . . . . . . 20
Clinical Trial: Parenchymal Bleeding in Hepatic Surgery (2013) . . . . . . . . 23
Clinical Trial: Parenchymal Bleeding in Hepatic Surgery (2015) . . . . . . . . 25
Preclinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Mutagenicity and Genotoxicity Studies . . . . . . . . . . . . . . . . . . . . . . . 26
Warnings and Precautions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Adverse Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Use in Specific Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Viral Clearance  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31
Clinical Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Nonclinical Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Dosage Forms and Strengths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
How Supplied/Storage and Handling . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Patient Counseling Information  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
References  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Prescribing Information  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
 Overview
Intraoperative bleeding is a major surgical complication and can, in some cases, be life
threatening.1–4 Mortality rates are generally low, ranging from less than 0.1% for most routine
surgeries to 1% to 2% for cardiac surgeries and 5% to 8% for elective vascular surgeries. However,
severe, unexpected, and uncontrolled intraoperative bleeding can increase mortality rates from
less than 1% to 20%.4
Clearly, there is a need for rapid and effective hemostasis.1 Whereas good surgical technique
and anesthetic support remain the key components of hemostasis management, the use of
adjunctive topical hemostatic agents can be crucial to optimal patient outcomes. In addition to
improving conservation of blood, topical hemostatic agents may also avoid the adverse events
potentially associated with systemic hemostatic medications, reduce overall operating time, and
facilitate faster recovery.1
EVARREST® Fibrin Sealant Patch is indicated for use with manual compression as an adjunct
to hemostasis for control of bleeding during adult liver surgery and soft tissue bleeding during
open retroperitoneal, intra-abdominal, pelvic, and non-cardiac thoracic surgery in adults when
control of bleeding by standard surgical methods of hemostasis (e.g., suture, ligature, cautery) is
ineffective or impractical.5
EVARREST enables 1st-attempt hemostatic efficacy, with the added
benefits of convenience and ease of use6,7
This product represents the convergence of 3 proven technologies6:
• Oxidized regenerated cellulose (ORC) underlying layer7,8
• Nonwoven polyglactin 910 (PG910) fibers, the same raw material used in the manufacture of Coated VICRYL®
(polyglactin 910) Suture, needle-punched into underlying ORC layer to provide increased surface area and
mechanical strength7
• A surface layer of lyophilized human fibrinogen and human thrombin, the biological components,
manufactured using proven and patented purification and stabilization techniques. No animal-derived
materials are used9
All components of EVARREST, shown in Figure 1, are FDA approved and well known in clinical use.5,7–9
EVARREST is stored from 2°C to 25°C and requires no preparation.5
Figure 1. Cross-sectional Illustration Depicting the Components of EVARREST 5,7–9

Limitations for Use 5

Cannot be used in place of sutures or other forms of mechanical ligation in the treatment of ORC (oxidized
major arterial or venous bleeding. regenerated
cellulose)

EVARREST offers surgeons excellent hemostatic efficacy, providing rapid, reliable hemostasis on
the first attempt with the added benefits of convenience and ease of use.5,6

EVARREST is a sterile, bio-absorbable combination product, composed of two biological

components (human plasma-derived fibrinogen and thrombin) embedded in a flexible
composite patch component. The active side is white-to-yellow in color and powdery in
appearance; the nonactive side has an embossed wave pattern.5

The mechanism of action of EVARREST relates to the interaction between the biological
components and the physiology of the fibrin clot formation. Upon contact with a bleeding
wound surface, the biological components embedded in the patch component are hydrated,
and the subsequent fibrinogen-thrombin reaction initiates the last step in the cascade of
PG910-Coated VICRYL Suture fibers Biological components layer on active side:
biochemical reactions—conversion of fibrinogen into fibrin monomers that further polymerize
needle-punched into ORC backing human fibrinogen and human thrombin
to form the fibrin clot.5

Hemostasis is achieved when the formed fibrin clot integrates with the patch component and
adheres to the wound surface, thus providing a physical barrier to bleeding.5
EVARREST has the potential to fulfill an unmet need for rapid, reliable, surgical hemostasis by delivering
a powerful combination of hemostatic efficacy, adherence, and mechanical strength, to rapidly stop bleeding
in a variety of problematic bleeding situations with unprecedented convenience and ease of use.5–7

2 3
 Summary of Features
EVARREST® Fibrin Sealant Patch:
• Patch component imparts inherent mechanical integrity to the product and supports
clot formation 5
• On contact with a bleeding wound surface, the biological components embedded in the
patch component are hydrated, and the subsequent fibrinogen-thrombin reaction initiates
the last step in the cascade of biochemical reactions—formation of the fibrin clot5
• Achieves hemostasis when the formed fibrin clot integrates with the patch component
and adheres to the wound surface, providing a physical barrier to bleeding 5
• The flexibility of EVARREST accommodates the physiological movement of organs
and tissues5
• Has excellent handling characteristics: conformable, does not stick to instruments or gloves
covered with blood, no need to moisten with saline 5
Contraindications
• Does not contain animal components 5,7
• Achieves absorption at approximately 8 weeks after application, with <10% of the remaining
material degrading exponentially over time 5,7
• Is available in convenient 2 x 4 inch (5.1 x 10.2 cm) and 4 x 4 inch (10.2 x 10.2 cm) sizes
• Human fibrinogen and human thrombin facilitate strong clot formation and rapid time
to hemostasis5,7
4 5
Indications and Usage
EVARREST is a fibrin sealant patch indicated for use with manual compression
as an adjunct to hemostasis for control of bleeding during adult liver surgery and
soft tissue bleeding during open retroperitoneal, intra-abdominal, pelvic, and non-
cardiac thoracic surgery in adults when control of bleeding by standard surgical
methods of hemostasis (e.g., suture, ligature, cautery) is ineffective or impractical.5
Limitations for Use 5
Cannot be used in place of sutures or other forms of mechanical ligation in the
treatment of major arterial or venous bleeding.
Do not use EVARREST for:
• 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 EVARREST to blood flow and/or pressure during absorption
of the product5
• Intravascular application. This can result in life-threatening thromboembolic events5
• Individuals known to have anaphylactic or severe systemic reaction to human
blood products5
 Topical Hemostats
History of Topical Hemostats
For thousands of years, humans have explored various ways to stop bleeding. To the ancient
Egyptians, a mixture of wax, grease, and barley was state-of-the-art topical hemostasis, while the
ancient Greeks experimented with a mixture of hemostatic herbs.10
Biologic Agents
The first biologic hemostatic agents became available more than 100 years ago. Bone
wax, invented in 1886, was followed by the use of fibrin by Bergel in 1909. Just 6 years later,
Lippencott used the first fibrin patches for hemostatic purposes during cerebral procedures.
More sophisticated products became available in the 1940s, when plasma fractionation allowed
for the production of human fibrinogen and thrombin. This led to the first fibrin sealants in 1944;
these early versions, however, were limited by a lack of purified sources of fibrinogen.11
The mass production of highly concentrated fibrinogen in the 1960s resulted in a proliferation
of sealants. However, their use was eventually restricted due to concerns of viral transmission.
Topical thrombin, purified from various sources, has been used as a hemostatic agent for more
than 60 years. Until recently, the only commercially available stand-alone thrombin was bovine
derived (Thrombin JMI). Because exposure to bovine thrombin was linked to various clinical
events, researchers developed alternate sources. In the past decade, human plasma derived
thrombin and, more recently, recombinant human thrombin have become available.1
Conventional Methods of Achieving Hemostasis
Conventional methods of achieving hemostasis include the use of surgical techniques, sutures,
ligatures, or clips, and energy-based coagulation or cauterization. When these conventional
measures are ineffective or impractical, adjunctive hemostasis techniques and products are
typically utilized, including topical absorbable hemostats such as ORC, gelatin, or collagen, and
active hemostats such as topical thrombin or fibrin sealants.7 Table 1 shows techniques that
surgeons use to maintain hemostasis during surgery.1,12
These products have proven to be efficacious in controlling slowly bleeding foci, diffuse oozing,
bleeding from needle puncture sites, and diffuse parenchymal organ hemorrhage. However,
they are not as effective in situations where the topically applied agents can be washed away
from the bleeding site by actively flowing blood. Some products require a dry field for application
and therefore can be ineffective for active bleeding. In more intense bleeding, many of these
conventional adjunctive methods of hemostasis have only marginal efficacy or are impractical.7
There is a need for more effective products or techniques to rapidly control bleeding when
treatment with conventional surgical techniques or conventional adjunctive hemostatic products
is either ineffective or impractical.7
Table 1. Techniques Currently Used to Maintain Hemostasis During Surgery1,12

CONVENTIONAL METHODS
Absorbable Agents
Gelatin foams derived from animal skin gelatin date back to 1945 (Gelfoam® Absorbable Mechanical techniques Thermal techniques
Sponge). In 1942, oxidized cellulose emerged as a topical hemostat. Twenty years later, the more
• Direct pressure • Electrocautery
rapidly conforming regenerated oxidized cellulose launched, marketed as SURGICEL® Original • Sutures • Hemostatic scalpel
Absorbable Hemostat.10,11 • Staples • Laser
• Ligating clips
Ideal Characteristics of a Hemostatic Agent
• Fabric pads
It’s been suggested that the properties of the ideal topical hemostatic agent would include
• Gauzes
the following 1: • Sponges
• Rapid and effective control of bleeding
• Effective contact with the bleeding surface
CONVENTIONAL ADJUNCTIVE METHODS
• Acceptable adverse-event profile
Chemical techniques
• Reliability
• Topical hemostats • Pharmacotherapy
• Ease of handling — Collagen — Hypotensive anesthesia
• Simple preparation — Cellulose — Epinephrine
— Gelatins — Vitamin K
• Available in a variety of delivery options to accommodate different kinds of bleeding
— Thrombins — Protamine
— Desmopressin
• Topical sealants and adhesives — Aminocaproic acid
— Fibrin sealants — Tranexamic acid
— Synthetic glues
• Blood component/replacement therapy

Adapted from Samudrala S. AORN J. 2008;88:S1–S11.

6 The third-party trademarks used herein are trademarks of their respective owners. 7
 Benefits of EVARREST® Fibrin Sealant Patch
A series of maneuvers are frequently needed to limit blood loss during treatment and
achieve permanent hemostasis at an individual bleeding site. The process of applying these
multiple treatments can be cumbersome and time-consuming, and can prevent the surgeon
from proceeding with the procedure until hemostasis has been secured.
Challenges with Current Topical Hemostats
• Bovine thrombin and recombinant thrombin are provided as lyophilized powders that
require reconstitution, whereas the human pooled thrombin is fully mixed but requires
thawing prior to use 12
EVARREST is a fibrin sealant patch indicated for use with manual compression as an adjunct
to hemostasis for control of bleeding during adult liver surgery and soft tissue bleeding during
open retroperitoneal, intra-abdominal, pelvic, and non-cardiac thoracic surgery in adults when
control of bleeding by standard surgical methods of hemostasis (eg, suture, ligature, cautery) is
ineffective or impractical.5
Limitations for Use 5
Cannot be used in place of sutures or other forms of mechanical ligation in the treatment
of major arterial or venous bleeding.

• Preparation of a flowable product requires reconstitution of the thrombin, which must EVARREST
then be mixed with the absorbable gelatin particles12 • Contains a unique fibrin sealant in which a formed fibrin clot integrates with a patch
component and adheres to the wound surface 5
• Blood-soaked gelatin sticks to surgical instruments, making handling difficult1
• Forms a physical barrier to bleeding 5
• Gelatin sponges are easily dislodged because they do not form a tight bond with • Provides excellent hemostatic efficacy and has been shown to be significantly m
 ore effective
the bleeding source1 than a widely used hemostatic device (SURGICEL® Original Absorbable Hemostat)7
Some topical hemostats have storage requirements. Human plasma–derived thrombin is • Achieves durable first-attempt hemostasis with no rebleeding at treated sites7
supplied as a frozen sterile solution that can be refrigerated for up to 30 days. Bovine a nd • Enables surgeons to obtain rapid and reliable control of soft tissue bleeding and parenchymal
human recombinant thrombins are supplied as sterile powders stored at room temperature; bleeding in adult liver surgery7
reconstituted solutions can be stored for 24 hours.
• Improves visualization sooner and allows more rapid progression of the operative procedure7
Differences in storage requirements may be important when considering strategies to • Has documented surgeon satisfaction for ease of use, convenience, and reliability 6
minimize potential waste from unused thawed or reconstituted drug.13
• Provides documented safety for the adjunctive treatment of soft tissue bleeding and
Safety Concerns with Current Topical Hemostats parenchymal bleeding in adult liver surgery6,7
• Bovine thrombin may carry impurities and associated immunologic risks
—— Antibodies may form against host thrombin, prothrombin, factor V, and cardiolipin,
and lead to severe bleeding and/or clotting disorders13,14
—— The frequency of reported antibody development ranges from 10% to 95%13
• Porcine- and bovine-derived agents also have the potential to cause allergic reactions1
• A fibrin sealant product containing a pooled human plasma product with synthetic aprotinin
can also be a potential source of allergic reactions13
• Gelatins and collagens have the potential to swell and may cause injury to neighboring
structures including nerves11,15
Therefore, it would benefit both surgeon and patient to have a safe product that could
rapidly and reliably control intraoperative bleeding while offering improved convenience
and ease of use.1,8

8 9
 Clinical Pharmacology
Absorption of Human Fibrinogen and Human Thrombin
Pharmacokinetic studies of EVARREST® Fibrin Sealant Patch were not considered
necessary given how thoroughly fibrinogen and thrombin have been studied and how
strictly the body regulates thrombin activity and the coagulation cascade. Two historic
studies of human thrombin pharmacokinetics support this position.7,16,17
The potential systemic absorption of human thrombin from EVARREST in biologically
relevant amounts is highly unlikely for a number of reasons7,18,19:
• The close approximation and binding of human thrombin to human fibrinogen/fibrin
• The simple dilution by blood of absorbed human thrombin
• Thrombin rapidly interacts with anti-thrombin and the thrombin—anti-thrombin complex
is removed from the liver
• The presence of high-affinity endothelial cell anticoagulant-antithrombotic systems
• Thrombin inhibition by anti-thrombin III in plasma
The local delivery of human fibrinogen and human thrombin restricts the activity of
the human thrombin from EVARREST to the target bleeding surface, mimicking normal
thrombin activity and control.7,18,20 Furthermore, the mode of action of EVARREST is local at
the target bleeding surface, with the immediate formation of fibrin on exposure to fluid and
blood. This mode of action depends on local active and passive hemostatic mechanisms
that do not rely on traditional drug dosing routes (oral, parenteral, inhalation, or dermal).
The formation of fibrin from the human fibrinogen and human thrombin of EVARREST
does not require metabolic activation and does not depend on the patient’s coagulation
factors. The body controls activated coagulation factors through redundant mechanisms.7
Human thrombin Human fibrinogen
10
The fibrinogen component of the product is rapidly consumed within minutes in the clotting
reaction with the thrombin component that occurs after hydration of the product. Therefore,
no fibrinogen should be available for systemic exposure. The fibrin network generated following
the clotting reaction has a very high affinity to the extracellular proteins, such as collagen and
fibronectin, and to other surface cell proteins, such as integrins, cadherins, and selectins. This
results in anchoring of the fibrinogen (now fibrin monomer or fibrin) into the close proximity
of the wounded tissue. The concentration of thrombin in this product is sufficient to ensure that
fibrinogen is completely reacted.7,21–23
The fibrin that results from application of EVARREST is removed by fibrinolysis and
phagocytosis.7,18,20,24 As such, tissue distribution, protein binding, and excretion studies on the
biological components of EVARREST are neither necessary nor required by the International
Conference on Harmonisation, Biotechnological Products safety guidelines (ICH S6).7
Systemic absorption of human thrombin was studied using 125I -thrombin-spiked CROSSEAL™
in the rabbit liver lobe resection model.7,16,17 Referred to in the study report by the developmental
name of Octacol, CROSSEAL™ is a first-generation fibrin sealant from Omrix Biopharmaceuticals.
After application of 125I -thrombin-spiked CROSSEAL™ to liver resection surfaces, the amount
of 125I -thrombin-related protein detected was of a level that could easily be generated by
any minor hemorrhage and was deemed to be safe in terms of a risk of thromboembolism.
It was further determined that the early 125I -thrombin detected in the blood was inactivated
(suspected to be bound to anti-thrombin III), and that residual 125I -thrombin detected in the
blood was due to the breakdown of the 125I -thrombin-containing fibrin clot. This means that
the 125I -thrombin was also inactivated.7
11

Absorption of Patch Components
The ORC and PG910 patch components have
been used for medical devices for many years. As
a result, their absorption, distribution, metabolism,
and excretion profiles are well known.7
Fibrinogen-
thrombin reaction
12
Composition
Mechanism of Action
The mechanism of action of EVARREST® Fibrin
Sealant Patch is based on the interaction between
the biological components and the physiology of the
fibrin clot formation. Upon contact with a bleeding
wound surface, the biological components embedded
in the patch component are hydrated, and 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.5
Hemostasis is achieved when the formed fibrin
clot integrates with the patch component and adheres
to the wound surface thus providing a physical barrier
to bleeding.5
The patch component provides a large surface area
for the biological components and imparts inherent
mechanical integrity to the product. The flexibility
of EVARREST accommodates the physiological
movements of tissues and organs.5,7
Natural healing occurs as the product is absorbed
by the body. Absorption is considered to take
approximately 8 weeks, as demonstrated in rodent
and swine animal models.5,7
EVARREST is a sterile, bio-absorbable combination product, composed of 2 biological
components (human plasma-derived fibrinogen and thrombin) embedded in a flexible
composite patch component.5,7
EVARREST is supplied in the form of a white-to-yellow sterile patch approximately 2 x 4 inches
(5.1 x 10.2 cm) or 4 x 4 inches (10.2 x 10.2 cm) in size and approximately 2 mm thick that can be
cut to size to accommodate a broad range of surgical procedures.5,7
The patch component of EVARREST consists of an ORC layer underlying a layer of PG910
nonwoven fibers. The biological components of EVARREST are the lyophilized forms of the
human fibrinogen and human thrombin drug substances.5,7
Each 2 x 4 inch (5.1 x 10.2 cm) or 4 x 4 inch (10.2 x 10.2 cm) absorbable patch contains
55.5 mg per square inch (8.6 mg per square cm) human fibrinogen and 241.9 units per
square inch (37.5 Units per square cm) human thrombin. Additional inactive ingredients are:
arginine hydrochloride, calcium chloride, glycine, human albumin, mannitol, sodium acetate,
sodium chloride, and sodium citrate. EVARREST does not contain any preservative.
EVARREST is sterilized by electron-beam irradiation after completion of inner and outer
packaging resulting in a sterile product in a sterile inner package.
Biologic Components: Fibrin Strands Forming
Thrombinand Fibrinogen in EVARREST
13
 Viral Safety
Table 2. Excipients Present in Biological Components 7 Rigorous Screening of Plasma for Viral Markers
The biological components of the product are manufactured from pooled human plasma,
DRUG SUBSTANCE EXCIPIENT* FUNCTION
and thus bear the potential risk of transmission of infectious agents. To minimize this risk,
Human fibrinogen Sodium chloride Buffer component the plasma is rigorously screened for viral markers, and each component undergoes 2 specific
Sodium citrate Buffer component virus inactivation/removal steps during the manufacturing process.5,7
Calcium chloride Buffer component Testing of individual units
L-Arginine-hydrochloride Stabilizer Individual plasma units used in the manufacture of human fibrinogen and human thrombin
Glycine Buffer component are tested by US Food and Drug Administration (FDA)–licensed serologic tests for hepatitis B
surface antigen (HBsAg), human immunodeficiency virus type 1 and type 2 antibody (HIV-1 Ab
Human thrombin Calcium chloride Required for cross-linking
and HIV-2 Ab), and hepatitis C virus antibody (HCV Ab). They are also tested by FDA-licensed
and stabilizing of fibrin clot
nucleic acid testing (NAT) methods for HCV and HIV-1, and must be found to be negative
Sodium acetate Buffer component (nonreactive) in all tests.5,7
Human albumin Stabilizer
The plasma is also tested by NAT for hepatitis A virus (HAV) and hepatitis B virus (HBV).
Mannitol Stabilizer However, since the effectiveness of these test methods in detecting low levels of viral material
Sodium chloride Buffer component is still under investigation, the significance of a negative result for these viruses is unknown.
NAT for parvovirus B19 is also performed, and the level of contamination is not permitted to
*US Pharmacopeia/European Pharmacopoeia grade. exceed 10,000 copies/mL. This limit is applied to restrict the viral load of parvovirus B19 in
the starting plasma pool.7
The patch component consists of PG910 filaments needle-punched into an underlying layer
of ORC (Figure 1). Testing of manufacturing pools
In addition to the screening of individual units, each manufacturing pool is tested for HBsAg,
HIV-1 Ab, HIV-2 Ab, and HCV Ab, as well as by NAT for HCV. Manufacturing pool testing, however,
is of a lower sensitivity than the individual unit testing.7

Viral Inactivation/Removal Steps

The 2 discrete virus inactivation/removal steps used for each of the biological components are
summarized in Table 3.7

Table 3. Virus Inactivation Steps in Manufacture of Fibrinogen and Thrombin7

COMPONENT
Step Human Fibrinogen Human Thrombin

1 Solvent detergent treatment Solvent detergent treatment

(1% TNBP, 1% Triton X-100) (1% TNBP, 1% Triton X-100)
for 4 h at 30°C for 6 h at 26°C

2 Pasteurization (10 h at 60°C) Nanofiltration

TNBP, tri-n-butyl phosphate.

14 15
 The solvent detergent treatment, used in Step 1, is well established as a very efficient means • HIV-1 may be transmitted by blood products and is therefore considered a relevant virus.
of inactivating lipid-enveloped viruses in blood products without affecting the biological activity It also serves as a model for HIV-27
of the plasma proteins.7,25 • Sindbis virus (SBV) was selected, since it is an RNA positive-strand enveloped virus and is
Pasteurization and nanofiltration, used in Step 2, are both nonspecific virus inactivation/ frequently employed as a general model for lipid-enveloped viruses such as HIV-1 and HCV.
removal techniques, reducing the risk of transmission of non-enveloped viruses and adding It is not possible to use HCV itself, because it cannot be propagated7
an extra margin of safety to the inactivation of enveloped viruses.7 • Bovine viral diarrhea virus (BVDV) is an RNA positive-strand enveloped virus of the Flaviviridæ
family, Pestivirus genus. HCV, a Hepacivirus, is also a member of this family. For this reason,
Virus Validation Studies BVDV is regarded as a good model for HCV7
The efficacy of these procedures in inactivating a range of viruses has been assessed.
The viruses used for these validation studies were selected to give a range of physicochemical • Pseudorabies virus (PRV) is a herpesvirus that can serve as a model for human herpes-
characteristics and are summarized in Table 4.7 viruses that may be found in blood (eg, Epstein-Barr virus, cytomegalovirus, and human
herpesvirus 6), since all herpesviruses have a similar structure and are morphologically
indistinguishable. Pseudorabies can also serve as a model for other DNA enveloped viruses.
Pseudorabies is particularly suitable for viral spiking studies, because it can be obtained
in high titers (approximately 9 logs), and an accurate quantitative plaque assay is available7
• Encephalomyocarditis virus (EMCV) is a small, nonenveloped RNA virus that is relatively
Table 4. Viruses Used in Virus Validation Studies 7 resistant to physicochemical treatments. EMCV is a picornavirus and can be considered a
model for HAV, which is also a picornavirus and is the same size7
VIRUS FAMILY GENUS GENOME ENVELOPE SIZE (nm) RESISTANCE
• HAV is considered a relevant virus since its transmission has been associated with certain
HIV-1 Retro Lentivirus RNA Yes 80–130 Low coagulation factors7

SBV Toga Alphavirus RNA Yes 60–70 Low • Canine parvovirus (CPV) was selected as a small, nonenveloped RNA positive-strand virus that
is resistant to the actions of chemical treatments. It can be considered a model for the human
BVDV Flavi Pestivirus RNA Yes 60–70 Low parvovirus B19 on the basis of its morphology and structure7
PRV Herpes Varicellovirus DNA Yes 150–200 Medium • Minute virus of mouse (MVM), like CPV, belongs to the Parvoviridæ family, Parvovirus genus.
Both MVM and CPV are small, nonenveloped, single-stranded DNA viruses with virions of
EMCV Picorna Cardiovirus RNA No 28–30 Medium 18 to 26 nm in diameter. MVM can be considered a model for the human parvovirus B19 on
HAV Picorna Heptaovirus RNA No 28–30 High the basis of its morphology and structure7
The validated reduction factors are summarized in tables 5 and 6.7
CPV Parvo Parvovirus DNA No 18–26 Very High

MVM Parvo Parvovirus DNA No 18–26 Very High

BVDV, bovine viral diarrhea virus; CPV, canine parvovirus; EMCV, encephalomyocarditis virus; HAV, hepatitis A virus; HIV-1, human
immunodeficiency virus type 1; MVM, minute virus of mouse; PRV, pseudorabies virus; SBV, Sindbis virus.

16 17
 Table 5. Virus Inactivation Summary for Fibrinogen7 Transmissible Infectious Agents
Because the biological components of this product are made from human plasma, it may carry
VIRUS HIV-1 SBV BVDV PRV EMCV HAV CPV MVM
a risk of transmitting infectious agents, eg, viruses, the variant Creutzfeldt-Jakob disease (vCJD)
RF (log10 )* agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk of transmitting viral
Not Not Not Not
agents has been minimized by screening plasma donors for prior exposure to certain viruses,
SD treatment >4.4 >4.4 >4.0 0 by testing for the presence of certain current virus infections, and by inactivating and removing
tested tested tested tested
certain viruses during the manufacturing process. Despite these measures, such products still
Pasteurization >4.4†
Not
>5.5† >6.0† 3.7 >5.8† 1.3
Not potentially can transmit disease. There is also the possibility that unknown infectious agents may
tested tested be present in such products.
Not Not Any infection considered by a physician to possibly have been transmitted by this product
Global RF >8.8 >9.9 >10.0 3.7 >9.0 1.3
tested tested should be reported by the physician or other healthcare provider to ETHICON Customer
*Where the entire initial inoculum was inactivated, the maximum likelihood reduction factor (LRF) in format BAC 21 is quoted.
Support Center at 1-877-384-4266.
Where inactivation was incomplete, the minimum LRF is quoted.
† 10 h at 58.5° + 0.5°C. All other experiments were conducted under standard process conditions.

RF, reduction factor; SD, solvent/detergent.

Table 6. Virus Inactivation Summary for Thrombin7

VIRUS HIV-1 SBV BVDV PRV EMCV HAV CPV MVM
RF (log10 ) *

Not Not Not

SD treatment >5.8† >5.3 >4.7 >4.3 0
tested tested tested

Not
Nanofiltration >4.4 >5.3 >5.5 6.4 7.0 5.9 5.8
tested

Global RF >10.2 >10.6 >4.7 >9.8 6.4 7.0 5.9 5.8

*Where the entire initial inoculum was inactivated, the maximum likelihood reduction factor (LRF) in format BAC 21 is quoted.
Where inactivation was incomplete, the minimum LRF is quoted.
† Taking into account the virucidal effect of the starting material.

RF, reduction factor; SD, solvent/detergent.

18 19
 Clinical Trial: Mild to Moderate Soft Tissue Bleeding6
TITLE A prospective, randomized, controlled trial of the efficacy and safety of EVARREST® as
an adjunct to control soft tissue bleeding during abdominal, retroperitoneal, pelvic, and
thoracic surgery
AUTHOR(S) Fischer CO, Bochicchio G, Shen J, Patel B, Batiller, J, Hart JC
SOURCE J Am Coll Surg. 2013;217:385–393
KEY Fibrin Pad has been shown to be safe and effective as an adjunct for rapidly and reliably
TAKEAWAYS achieving hemostasis and superior to SURGICEL® Original Absorbable Hemostat in controlling
soft-tissue bleeding during abdominal, pelvic, retroperitoneal, and (noncardiac) thoracic surgery
Objective
The objective of this study was to evaluate the safety and hemostatic effectiveness of fibrin pad
(FP), compared to the most widely used topical hemostat (SURGICEL Original Hemostat), when
used as an adjunct to control soft tissue bleeding during abdominal, pelvic, retroperitoneal, and
(noncardiac) thoracic surgery, The primary outcome was successful hemostasis within 4 minutes
of randomization and no rebleeding requiring retreatment within a subsequent 6-minute
observation period.
Methods
• Multicenter (11 US centers), randomized controlled trial. March 26, 2008 to April 24, 2009
• Patients 18 years and older, undergoing open, nonemergent abdominal, retroperitoneal, pelvic
or thoracic (noncardiac) surgery with an appropriate soft-tissue target bleeding site (TBS) were
randomized in a 2:1 ratio to receive FP or absorbable hemostat (SURGICEL Original Hemostat,
oxidized regenerated cellulose; [ORC])
—— Other fibrin sealants or topical thrombin were not permitted
• The TBS was identified during soft tissue dissection related to the primary operative procedure
and defined as the first actively bleeding soft tissue site with challenging mild to moderate
bleeding, where conventional methods of control (ie, suture, ligature, cautery) were ineffective
or impractical, and an adjunctive product was required for hemostasis
—— The bleeding was classified as: Mild bleeding was defined as a small area of capillary,
arteriole, or venule oozing; Moderate bleeding as a larger area of capillary, arteriole, or
venule oozing (presenting a challenge due to the larger area involved, increasing blood
volume being lost) or as bleeding more pronounced than oozing which could come from a
small artery or vein, but not massive, pulsatile and flowing
• The appropriate treatment was applied with manual compression until 4 minutes
postrandomization; if hemostasis was achieved at 4 minutes, a subsequent 6-minute
observation followed
• However, after a 10–minute observation period, the use of any other topical hemostat at
the TBS was permitted if hemostasis was not achieved. Surgeons could revert to their own
standard of care at any point if clinically appropriate
• A non-randomized phase of this trial enrolled an additional 51 patients to expand the safety
population for evaluation
20
Outcomes Measured
• Assessments included percentage of patients achieving hemostasis at 4 minutes
after randomization with no bleeding requiring treatment during the subsequent 6 minutes
(primary endpoint), proportion of patients achieving hemostasis at 10 minutes, and
incidence of treatment failure
• Safety evaluations included adverse event (AE) monitoring throughout the study for
up to 30 days from surgery, including AEs potentially related to bleeding at the TBS and
the incidence of AEs potentially related to thrombotic events and transfusion exposure
Results
• No significant differences were identified in preoperative demographics or comorbidities
between treatment groups
• The TBS anatomic compartment locations among the 90 randomized patients (FP: 60 and
ORC: 30) were retroperitoneal (36.7%, n=33) , thoracic (35.6%, n=32), pelvic (21.1%, n=19), and
abdominal (6.7%, n=6)
• Superiority was established for the primary outcome with fibrin pad over absorbable
hemostat at the first interim analysis (FP: 98.3%, n=59/60; ORC: 53.3%, n=16/30) (treatment
difference: 45%; P<.0001)
• Efficacy was maintained with fibrin pad but decreased with absorbable hemostat with
increasing bleeding intensity: In patients with mild bleeding, 100% (n=31/31) achieved
hemostasis with FP vs 80% (n=12/15) for ORC (P=.03). In patients with moderate bleeding,
96.6% (n=28/29) achieved hemostasis with FP vs 26.7% (n=4/15) for ORC (P<.0001)
• Percentages of patients who achieved hemostasis at 10 minutes were: fibrin pad, 98.3% and
absorbable hemostat, 73.3% (P<.0001)
• Consistent hemostatic efficacy at 4 minutes was observed when patients who received fibrin
pad in the non-randomized phase of the study were included in the analysis
• No patient who received fibrin pad experienced rebleeding at the TBS between the final
observation and wound closure compared with 10% (3 of 30) of patients who received ORC.
The overall incidence of treatment failure was 1.7% (1 of 60) in the fibrin pad group and 46.7%
(14 of 40) in the ORC group. The treatment failure in the fibrin pad group was observed during
a chest wall resection operation and upon further examination was identified as originating
from a defect in the wall of the internal thoracic artery, deep to the muscle onto which the
fibrin pad had been originally applied. This TBS was then identified as a protocol deviation.
No treatment failures occurred when FP was applied appropriately
• All 141 patients randomized and nonrandomized (FP, n=111; ORC, n=30) were included in the
safety assessment
21
 Clinical Trial: Parenchymal Bleeding in Hepatic Surgery (2013)26
Results (continued) TITLE A phase III, randomized, controlled, superiority trial evaluating the fibrin pad versus standard of
• Thrombosis-related AEs were reported in 7.2% of FP patients (8/111): venous thromboembolism care in controlling parenchymal bleeding during elective hepatic surgery
accounted for 5.4% (6/111) and arterial thrombosis for 1.8% (2/111) compared with 6.7% of ORC AUTHOR(S) Koea JB, Batiller J, Patel B, Shen J, Hammond J, Hart J, Fischer C, Garden JO
patients (2/30; both venous thromboemboli). Two events in the fibrin pad group that were
SOURCE HBP 2013;15:61–70
potentially related to arterial thrombosis were cerebrovascular accident (stroke) and intestinal
infarction, but neither were considered by the investigators to be related to the use of the KEY • First clinical trial to evaluate the hemostat’s safety and effectiveness in controlling bleeding
TAKEAWAYS during elective hepatic resection
fibrin pad
• Confirmed that the Fibrin Pad is safe and effective at treating parenchymal bleeding after an
• Of the deaths in the fibrin pad group, 1 (massive intraluminal gastrointestinal bleed, although elective hepatectomy in a variety of parenchymal types (ie, cirrhotic, steatotic)
bleeding did not occur at the target TBS) was considered possibly related to study treatment • Due to the highly statistically significant results achieved, the trial was stopped at the first
interim analysis
Study Limitations
• It was not possible to blind surgeons to treatment allocation Objective
• Relatively small sample size of the ITT population • Assess the effectiveness of fibrin pad (FP) at controlling parenchymal bleeding after an
elective hepatectomy.
• Additional clinical trials are needed to further characterize the capability of FP as a surgical • Define the safety and the ability of the FP to achieve hemostasis in both normal and cirrhotic
hemostat in areas with higher bleeding severity or steatotic livers after hepatectomy

Methods
• Phase III, randomized, controlled, multicenter (10 centers: Europe, United Kingdom, Australia,
and New Zealand), superiority study
• Patients >18 years of age, undergoing urgent or elective hepatic resection
• 104 patients were randomized (1:1) to receive FP (n=39) or standard of care (SoC, n=45) which
comprised manual compression with the use of an approved topical absorbable hemostat,
and “run in”/nonrandomized (n=20) group of patients who were included in the safety data set
—— Hemostasis was assessed at 4 minutes from randomization, at 10 minutes from
randomization and at the completion of surgery immediately prior to fascial closure
—— After randomization, the tissue type in the area of the target bleeding site (TBS) was noted
(normal, cirrhotic or steatotic), type of bleeding (arterial, venous or mixed and pulsatile
or nonpulsatile)

Outcomes Measured
The primary endpoint was hemostasis (no detectable bleeding) at 4 minutes from identification
of the TBS with no rebleeding requiring retreatment prior to abdominal closure.

Results
• Intent-to-treat results demonstrated at 4 min after randomization with the release of manual
compression; 34/40 subjects (85%) in the FP group achieved and maintained hemostasis
throughout the duration of the surgery compared with 17/44 patients (38.6%) in the SoC group
• Excluding major protocol violations, results an overall treatment difference of 65.7%
(P<.001), with 33/35 successes (94.3%) in the FP group and 12/42 in the SoC group (28.6%)

22 23
 Clinical Trial: Parenchymal Bleeding in Hepatic Surgery (2015)27
Results (continued)
• The number of subjects achieving hemostasis at 4 min and requiring no treatment for
rebleeding was 33/40 (82.5%) in the FP group and 13/44 (29.5%) in the SoC group (P<.0001)
• The efficacy of the FP was comparable in both normal and abnormal parenchymal groups
although SoC was less effective in patients with abnormal parenchyma
—— The stratification results showed treatment differences between the normal parenchyma
group, 63.6% (95.8% FP vs 32.3% SoC, P<.001) and a larger difference of 72.7% in the
abnormal parenchyma group (90.9% FP vs 18.2% SoC, P=.0003)
• One subject developed further bleeding from the TBS after the FP was dislodged at 9 min
having achieved hemostasis at 4 min, and this was the only patient treated with FP classified
as rebleeding. One patient had an arterial bleeding point, an exclusion criterion, inappropriately
treated with FP
• In the ITT analysis, the absolute time to hemostasis was 4 min (range 4 to 13.2 min) compared
with 9.7 min (range 4 to 31.3 min) in the SoC group (P<.001)
—— Similar results were obtained in the safety group analysis
• The volume of blood lost during surgery and red cell transfusions required were not statistically
significant between groups at the commencement of surgery and the day-30 assessment
• No difference was noted in the postoperative intensive care unit stay or in total hospital stay
between groups and there were no deaths in either treatment group during the study
• Adverse events:
—— Bile leaks occurred in 5/59 (8.5%) of patients treated with FP and 5/45 (11.1%) of patients
treated with SoC in the safety set (P<.059). Post-operative fluid collections at the liver bed
were present in 2/59 (3.4%) of the FP patients and 6/45 (13.3%) of patients in the SoC group
(P<.059). The occurrence of all adverse events was similar between groups
—— Only 3 patients treated with FP were considered to have had an adverse event potentially
related to the FP. One of these was an intra-abdominal collection managed with drainage,
and 2 patients had postoperative drain losses managed conservatively
TITLE Multicenter, phase III, randomized, controlled study evaluating the superiority of EVARREST
versus standard of care treatment in controlling bleeding during elective hepatic surgery
AUTHOR(S) Koea J; Batiller J; Shen J; Kocharian R; Garden JO
KEY • EVARREST is safe and effective when used as an adjunct to hemostasis during hepatic surgery
TAKEAWAYS regardless of the type of resection, or the condition of the parenchymal tissue
• There was no difference in safety profile between EVARREST or SoC groups
Objectives
• Hemostasis following liver resection may be problematic due to anatomic, physiologic
or surgical factors that contribute to the bleeding challenge
• EVARREST is a fibrin pad hemostat designed to be effective in a variety of tissues and across
multiple bleeding challenges and intensities
• This is a clinical evaluation of the hemostat’s safety and effectiveness involving institutions
in the USA, UK, Australia, and New Zealand
Methods
• This randomized trial enrolled 102 subjects of 211 subjects screened in 16 institutions
• Subjects were stratified according to the type of hepatic resection (anatomic/non-anatomic),
and randomized 1:1 after identification of an appropriate bleeding site, EVARREST versus
SoC, which included manual compression with or without the use of an approved topical
absorbable hemostat
• The primary endpoint was hemostasis at 4 minutes from identification of the bleeding site
with no rebleeding requiring retreatment prior to abdominal closure
• All subjects were followed for 60 days post-operatively
Results
• The intent-to-treat analysis showed a significant treatment advantage for EVARREST
and this was most marked when used in non-anatomic resections (Table 7)

—— Only 2 patients in the SoC group and one patient in the FP group developed • Adverse events related to the study procedure were observed in 40/50 subjects (80%)
thromboembolic complications. All patients had a high-risk score pre-operatively for in the EVARREST group and 43/52 subjects (82.7%) in the SoC group
thromboembolic disease indicating that the patient population overall was a high-risk one
Table 7. Type of Hepatic Resection
Study Limitations
TYPE OF HEPATIC EVARREST SoC P VALUE* TREATMENT
• While the patients treated with FP clearly achieved hemostasis before those treated with SoC, RESECTION (N=50) (N=52) DIFFERENCE
operative time, intensive care stay and overall hospital stay were similar
All 96.0% (48/50) 46.2% (24/52) <.0001 49.8%
• While the measured blood loss and transfusion requirements were lower in the FP-treated
cases these did not reach statistical significance Anatomic 96.0% (24/25) 56.5% (13/23) .0012 39.5%

• However, transfusion requirement and hospital stays were secondary endpoints and the Non-anatomic 96.0% (24/25) 37.9% (11/29) <.0001 58.1%
strong trends were shown in the data, suggesting that an adequately powered study may Normal Tissue 97.4% (38/39) 44.4% (16/36) <.0001 53.0%
show significant difference between the study arms for those outcomes Abnormal Tissue 90.9% (10/11) 50.0% (8/16) .0134 40.9%
*Chi-squared test.

24 25
 Preclinical Studies
Preclinical pharmacology evaluations of EVARREST® Fibrin Sealant Patch have been
performed and established the efficacy of the product in models of incisional injury
hemorrhage (either with heparin or without) that are characterized and well documented
in the literature. Toxicologic and safety evaluations have uncovered no significant safety
concerns relevant to the proposed clinical study.7
Mutagenicity and Genotoxicity Studies
Evaluation of the human fibrinogen and human thrombin components of EVARREST for
genotoxicity was not necessary given the nature of the normal human proteins and the
degradation and absorption rates of less than 28 days for the resulting exogenous fibrin
clot. Historical Ames assays on these 2 components are available.7,28,29
Mutagenicity and genotoxicity studies were conducted on extracts of the patch
component following International Organization for Standardization/US Food and
Drug Administration/International Conference on Harmonisation guidelines for genetic
toxicology testing. Mutagenicity studies in the Ames assay (Salmonella typhimurium and
Escherichia coli reverse mutation assay) and the mouse lymphoma assay were performed
with dimethylsulfoxide (DMSO) and saline extracts of the patch component.30–32 Two sets
of tests were conducted at different dosages, and all tests at both dosages passed.7
An in vivo mouse micronucleus assay (chromosomal damage) was conducted using
DMSO and saline extracts of the patch component.33,34 No evidence of genotoxicity or
mutagenicity was observed.7
26
Warnings and Precautions5
Thrombosis
Thrombosis can occur if absorbed systemically. Apply EVARREST topically to the bleeding
site only.
Hypersensitivity Reactions
EVARREST can cause hypersensitivity reactions, including anaphylactic reactions.
Symptoms associated with allergic anaphylactic reactions include flush, urticaria, pruritus,
nausea, drop in blood pressure, tachycardia or bradycardia, dyspnea, severe hypotension,
and anaphylactic shock.
Infection
Avoid application to contaminated or infected areas of the body, or in the presence of
active infection. Infection can occur from application to an infected site.
Adhesions
EVARREST contains oxidized regenerated cellulose which adheres to bleeding surfaces.
Inadvertent adhesions may occur. Meticulous hemostasis should be achieved, particularly
in gynecological procedures, to reduce the potential for postoperative adhesions.
Compression
Avoid using EVARREST in closed spaces (eg, in, around, or in proximity to,
foramina in bone or areas of bony confine) where swelling may cause nerve
or blood vessel compression.
Dislodged Patch Material
Use the least number of patches possible during surgical procedures because portions
of excess patch material can become dislodged and migrate to other areas of the body.
For example, during urological procedures dislodged patch material can plug the urethra,
ureter, or a catheter.
Transmissible Infectious Agents
Because the biological components (human fibrinogen and human thrombin) of this
product are made from human plasma, it may carry a risk of transmitting infectious
agents, such as viruses, and theoretically, the Creutzfeldt-Jakob (CJD) agent. The risk of
transmitting an infectious agent has been minimized by screening plasma donors for prior
exposure to certain viruses, by testing for the presence of certain current virus infections,
and by inactivating and removing certain viruses during the manufacturing process.
Despite these measures, such products still potentially can transmit disease. There is also
the possibility that unknown infectious agents may be present in such products.
Any infection considered by a physician to possibly have been transmitted by this product
should be reported by the physician or other healthcare provider to Ethicon Customer
Support Center at 1-877-384-4266.
27
 Adverse Reactions5
The adverse reactions reported during clinical trials were blood fibrinogen increased, post- Immunogenicity
procedural and intra-abdominal hemorrhage, abdominal distension, anemia, gastrointestinal Immunogenicity was evaluated by testing blood samples collected at baseline, 4 to 6 weeks,
hemorrhage, thoracic cavity drainage, pleural effusion, post-procedural bile leak, abdominal abscess, and 8 to 10 weeks post-surgery for antibodies to human thrombin and fibrinogen by enzyme-
ascites, deep vein thrombosis, localized intra-abdominal fluid collection, and pulmonary embolism. linked immunosorbent assays. Three subjects out of 145 (~2%) in the group treated with
EVARREST showed an increase in the titer of anti-thrombin antibodies after treatment. This
Clinical Trials Experience rate is similar to that reported in the literature for patients treated with other human thrombin
Because clinical trials are conducted under widely varying conditions, adverse reaction rates products. Two subjects out of 145 (~1%) in the group treated with EVARREST showed a transient
observed in clinical trials of a drug cannot be directly compared to rates of adverse reactions increase in fibrinogen antibody titers, with titer levels back at background levels at the 8 to 10
in clinical trials of another drug and may not reflect the rates observed in clinical practice. week time point. No immune response to fibrinogen was detected in any of the other subjects.
EVARREST® Fibrin Sealant Patch was used to treat soft tissue bleeding during retroperitoneal,
intra-abdominal, pelvic, or thoracic surgery, suture hole bleeding during cardiovascular surgery
and parenchymal bleeding during hepatic or renal surgery across all clinical trials involving
306 subjects treated with EVARREST and 191 control subjects. Of the 306 subjects, 302 subjects
were treated with EVARREST as an adjunct to hemostasis. Twenty-eight percent (28%) of
treated subjects (87 subjects out of 306) and 35% of control subjects (67 subjects out of 191)
experienced one or more serious adverse events.

Table 8. Adverse Reactions Reported in Clinical Trials5

EVARREST EVARREST CONTROL
Use in Specific Populations5
ADVERSE REACTIONS Total* Randomized Pregnancy
(N=306) (N=225) (N=191) Pregnancy Category C
n (%) n (%) n (%) Animal reproduction studies have not been conducted with EVARREST. There are no adequate
Blood fibrinogen increased 3 (1%) 3 (1%) 1 (1%) and well-controlled studies in pregnant women. It is also not known whether EVARREST can
cause fetal harm when administered to pregnant women or can affect reproductive capacity.
Post-procedural hemorrhage 2 (1%) 2 (1%) 2 (1%)
EVARREST should be given to a pregnant woman only if clearly needed.
Abdominal distension 1 (0%) 1 (0%) 0 (0%)
Intra-abdominal hemorrhage 1 (0%) 1 (0%) 0 (0%) Nursing Mothers
It is not known whether any component of EVARREST is excreted in human milk. Because many
Anemia 1 (0%) 1 (0%) 0 (0%)
drugs are excreted in human milk, caution should be exercised when EVARREST is administered
Gastrointestinal hemorrhage 1 (0%) 1 (0%) 0 (0%) to a nursing woman.
Thoracic cavity drainage 1 (0%) 1 (0%) 0 (0%)
Pediatric Use
Abdominal abscess 1 (0%) 0 (0%) 0 (0%) Safety and effectiveness in pediatric patients have not been established. Use of EVARREST in
Pleural effusion 1 (0%) 1 (0%) 0 (0%) children under the age of 1 month may be unsafe or ineffective due to small size and limited
ability to apply the patch as recommended. Slow absorption and possibility of adhesions can
Post-procedural bile leak 1 (0%) 1 (0%) 0 (0%)
further complicate use of EVARREST in the neonates.
Ascites 1 (0%) 0 (0%) 0 (0%)
Deep vein thrombosis 1 (0%) 0 (0%) 0 (0%) Geriatric Use
Clinical trials included 141 subjects of 65 years of age or older who were treated with EVARREST.
Localized intra-abdominal fluid collection 1 (0%) 0 (0%) 0 (0%)
No differences in safety or efficacy were observed between the elderly and younger patients.
Pulmonary embolism 1 (0%) 0 (0%) 0 (0%)

*EVARREST Total subjects included 225 randomized subjects and 81 non-randomized subjects.
Demographic characteristics (gender, race, body mass index) were balanced across the treatment groups. No significant
differences were observed in the occurrence of adverse reactions between demographic groups.

28 29
 Description5
EVARREST® Fibrin Sealant Patch is a sterile, bio-absorbable combination product, which is Viral Clearance
comprised of 2 biological components (human plasma-derived fibrinogen and thrombin) The biological components of EVARREST are The manufacturing procedure for human fibrinogen
embedded in a flexible composite patch component. The active side is white-to-yellow in manufactured from pooled human plasma collected and human thrombin includes processing steps
color and powdery in appearance; the non-active side has an embossed wave pattern. in FDA-licensed facilities in the United States. Human designed to reduce the risk of viral transmission.
plasma is tested by FDA-licensed nucleic acid tests In particular, the virus clearance steps in the
The patch component of EVARREST consists of an oxidized regenerated cellulose (ORC) layer (NAT) for hepatitis B virus (HBV), hepatitis C virus manufacture of human fibrinogen include solvent/
underlying a layer of polyglactin 910 (PG910) non-woven fibers. The PG910 layer contains the (HCV), and human immunodeficiency virus-1 (HIV-1). detergent (S/D) treatment and pasteurization. The
embedded biological components. The patch component provides a large surface area for the NAT testing for hepatitis A virus (HAV) and parvovirus virus clearance steps in the manufacture of human
biological components and imparts inherent mechanical integrity to the product. The flexibility B19 is also performed. Human plasma is also tested thrombin include S/D treatment and nanofiltration.
of EVARREST accommodates the physiological movements of tissues and organs. for the presence of hepatitis B surface antigen
(HBsAg), antibodies to hepatitis C virus (anti-HCV), The virus clearance capacity of these procedures
Each 2 x 4 inch (5.1 x 10.2 cm) or 4 x 4 inch (10.2 x 10.2 cm) absorbable patch contains has been validated using viruses with a range of
55.5 mg per square inch (8.6 mg per square cm) human fibrinogen and 241.9 Units per and human immunodeficiency viruses types 1 and 2
(anti-HIV-1/2). physicochemical characteristics. These in vitro
square inch (37.5 Units per square cm) human thrombin. Additional inactive ingredients are: validation studies were conducted using samples
arginine hydrochloride, calcium chloride, glycine, human albumin, mannitol, sodium acetate, from manufacturing intermediates spiked with virus
sodium chloride, and sodium citrate. EVARREST does not contain any preservatives. suspensions of known titers followed by further
EVARREST is sterilized by e-beam irradiation after completion of inner and outer packaging, processing under conditions equivalent to those in
resulting in a sterile product in a sterile inner package. the respective manufacturing steps. The results of
virus clearance validation studies are summarized in
Tables 9 and 10.

Table 9. Virus Reduction Factors of Human Fibrinogen5

REDUCTION FACTOR (log10) OF VIRUS TESTED
ENVELOPED VIRUSES NONENVELOPED VIRUSES
Manufacturing step HIV-1 BVDV PRV EMCV HAV CPV
S/D treatment > 4.42 > 4.39 > 3.96 Not tested Not tested 0.0
Pasteurization > 4.39 > 5.46 6.0 3.69 > 5.78 1.33
Cumulative virus reduction factor > 8.81 > 9.85 > 9.96 3.69 > 5.78 1.33
BVDV, bovine viral diarrhea virus; CPV, canine parvovirus; EMCV, encephalomyocarditis virus; HAV, hepatitis A virus; HIV-1, human immunodeficiency
virus type 1; PRV, pseudorabies virus; S/D, solvent/detergent.

Table 10. Virus Reduction Factors of Human Thrombin5

REDUCTION FACTOR (log10) OF VIRUS TESTED
ENVELOPED VIRUSES NONENVELOPED VIRUSES
Manufacturing step HIV-1 SBV BVDV PRV EMCV HAV CPV
S/D treatment > 5.82 > 5.31 > 4.74 > 4.25 Not tested Not tested 0.0
Nanofiltration > 4.36 > 5.32 Not tested > 5.47 6.37 6.95 5.85
Cumulative virus reduction factor > 10.18 > 10.63 > 4.74 > 9.72 6.37 6.95 5.85
BVDV, bovine viral diarrhea virus; CPV, canine parvovirus; EMCV, encephalomyocarditis virus; HAV, hepatitis A virus; HIV-1, human immunodeficiency
virus type 1; PRV, pseudorabies virus; SBV, Sindbis virus; S/D, solvent/detergent.

30 31
 Clinical Pharmacology5
Mechanism of Action
The mechanism of action of EVARREST® Fibrin Sealant Patch is based on the interaction
between the biological components and the physiology of the fibrin clot formation. Upon
contact with a bleeding wound surface, the biological components embedded in the patch
component are hydrated, and 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 integrates with the patch component and
adheres to the wound surface, thus providing a physical barrier to bleeding.
Nonclinical Toxicology5
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to evaluate the carcinogenic potential of EVARREST or studies
to determine the effects of EVARREST on genotoxicity or fertility have not been performed.
An assessment of the carcinogenic potential of EVARREST was completed to demonstrate
minimal carcinogenic risk from product use.
Animal Toxicology and Pharmacology
In swine and rodent models, topically applied EVARREST was absorbed at approximately
8 weeks after application, with <10% of the remaining material degrading exponentially over
time. The biological components of EVARREST are degraded by fibrinolysis and phagocytosis,
similarly to endogenous fibrin. As absorption progresses, increased fibrinolytic activity is
induced by plasmin, and decomposition of fibrin to fibrin degradation products is initiated.
32
Dosage and Administration5
 For Topical Use Only
• Determine the number of patches to be applied based upon the surface area
and anatomic location of the bleeding to be treated
• Do not use more than eight 2 x 4 inch (5.1 x 10.2 cm) or more than four
4 x 4 inch (10.2 x 10.2 cm) patches
• Use in patients who have been previously exposed to EVARREST has not
been studied
Preparation
• EVARREST 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
• To open the product, remove the foil pouch from the carton, carefully peel open
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33
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12 11 CLINICAL
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absorbed systemically. Ensurethromboembolic
that EVARREST events.
is applied to the
13 12 NONCLINICAL
CLINICAL
4Mechanism
12.1 Mechanism PHARMACOLOGY of Action
TOXICOLOGY 4. Apply a sufficient number of patches to adequately cover the entire bleeding area, with an
cover the entire bleeding area, with an overlap of 5.1 Thrombosis
surface of soft tissue
• Individuals bleeding only.
12.1
13 13.1
NONCLINICAL of Action
TOXICOLOGY Mutagenesis, Impairmentapproximately
4. Apply a sufficient 0.5number
to 1 inch of patches
(1 to 2 tocm). adequately
Use the Thrombosis canknown
occur to have anaphylactic
if EVARREST™ is absorbedor severe systemic reaction
systemically. Ensure that to human
EVARREST bloodis products.
applied to the
13.14Animal
Carcinogenesis, of Fertility
cover the entire bleedingtoarea,
13 13.2
NONCLINICAL TOXICOLOGY
Toxicology and Pharmacolog least number of patches coverwith an overlap
the bleeding of
area 5 WARNINGS
surface of soft tissueAND PRECAUTIONS
bleeding only.
13.1
14 CLINICAL
Carcinogenesis,
13.2 Carcinogenesis,
Animal Toxicology
STUDIES
Mutagenesis,
Mutagenesis,
and Pharmacolog overlap of approximately 0.5 to 1 inch (1 to 2 cm). Use the least number of patches to cover the
Impairment
[see
Impairment of Fertility
of Fertility
approximately
least
Warnings
number of
0.5 Precautions
and to 1 inch (1(5.6)].
patches
4. Apply a sufficient number of patches to adequately to cover
to 2 cm). Use the
the bleeding area
5.1 Thrombosis
13.2 Animal Toxicology and Pharmacolog 1Thrombosis can occur if EVARREST™ is absorbed systemically. Ensure that EVARREST is applied to the
16 14 HOWCLINICAL 4SUPPLIED/STORAGE
14 CLINICAL STUDIES
STUDIES bleeding area.[see Warnings and Precautions (5.6)].
AND HANDLING cover the entire bleeding area, with an overlap of
The Thrombin potency expressed in Units is determined using a clotting assay against an internal reference
surface
standardoffor soft tissuethat
potency bleeding
has been only.
calibrated against the World Health Organization (WHO) Second International
16 HOW SUPPLIED/STORAGE AND HANDLING approximately 0.5 to 1 inch (1 to 2 cm). Use the The Thrombin
Standard potency 01/580.
for Thrombin, expressed in Unitsa isUnit
Therefore, determined
used hereinusing a clottingtoassay
is equivalent
1
against an Unit.
an International internal reference
17 16 PATIENT COUNSELING INFORMATION
HOW SUPPLIED/STORAGE AND HANDLING least number of patches to cover the bleeding area standard for potency that has been calibrated against the World Health Organization (WHO) Second International
17 PATIENT COUNSELING INFORMATION [see Warnings andare Precautions
*Sections
17 PATIENT or subsections
COUNSELING omitted from the full prescribing
INFORMATION information not listed(5.6)]. Standard for Thrombin, 01/580. Therefore, a Unit used herein is equivalent to an International Unit.
5a. Hold dry or moist laparotomy
*Sections or subsections omitted from the full prescribing information are not listed
*Sections or subsections omitted from the full prescribing information are not listed
The Thrombin potency expressed in pads orusingsurgical
Units is determined gauze
a clotting assay against
1
over EVARREST® Fibrin Sealant Patch
an internal reference
standard for potency that has been calibrated against the World Health Organization (WHO) Second International
Evarrest PI 2x4 US_08.08.14.indd 1 5. (a) Hold dry or moist laparotomy pads or surgical 8/8/14 10:18 AM

5aUS_08.08.14.indd 1
4 to achieve full contact with the bleeding surface.
5. gauze
Standard for Thrombin, 01/580. Therefore, a Unit used herein is equivalent to an International Unit.
(a) Holdover dry EVARREST™
or moist laparotomy to achieve padsfullor surgical
contact
5a
4
Evarrest PI 2x4 5. with (a) Hold dry or moist laparotomy padsfull or surgical 8/8/14 10:18 AM
adjunct to gauze theover EVARREST™
bleeding surface. to achieve contact
adjunct to
on-cardiac 5a
4 gauze
with theover EVARREST™
bleeding
with the bleeding surface.
surface.to achieve full contact
adjunct to
on-cardiac
g., suture,
on-cardiac
.g., suture,
.g., suture,
Evarrest PI 2x4 US_08.08.14.indd 1
5b. To ensure hemostasis, immediately apply manual compression over the entire surface of 8/8/14 10:18 AM

the patch (including the area of overlap) sufficient to stem all bleeding. Ensure even pressure
tion in the
tion in the
tion in the
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(b) To ensure hemostasis, immediately apply
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apply
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minutes to control the bleeding.
chnique in
chnique in
chnique in
treated area. If placement of the patch is unsatisfactory, remove the patch and use a new patch.
6. Gently remove laparotomy pads or surgical gauze
oil pouch,
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ble for use Removal of the patch may disrupt the clot and
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ble for use
ments.
ble for use
ments. 8. Discard unused, opened patches at the end of the procedure.
7. EVARREST
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result in re-bleeding.
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ments. 7. EVARREST
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8. Discard
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atch to the
atch to the
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2.3 Retreatment
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procedure.
unused, opened patches at the end of the
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3 DOSAGE
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continued
DOSAGE
bleedingremove
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FORMS AND
the dressing),
FORMS
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is due the
remove
AND
to incomplete
STRENGTHS
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the patch and use a new one.
STRENGTHS
Patch
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consists of human fibrinogen and human thrombin embedded in
not
on use on
visible
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3 flexible
aEVARREST™
EVARREST™
DOSAGE
a flexible composite
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FORMS
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patch Patch
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e bleeding aappearance,
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x 10.2 cm) side
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each an
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contains 55.5 mg per square inch (8.6 mg per square cm) of human fibrinogen and 241.9 Units
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cm)fiabsorbable
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patch
241.9
of EVARREST
of EVARREST
1
per
Units1 per
hth flmanual
uid and contains
square inch 55.5(37.5
mg Units
per square
per squareinch (8.6
cm) ofmghuman
per squarethrombin. cm) of human fibrinogen and 241.9 Units1 per
hthfluid
th manual
and
manual
Do
the dressing), remove the patch and use a new one
4squareCONTRAINDICATIONS
inch (37.5 Units per square cm) of human thrombin.
4 notCONTRAINDICATIONS
use EVARREST™ for
4 Bleeding
•Do notCONTRAINDICATIONS
use EVARREST™
from largefor defects in visible arteries or veins where the injured vascular wall requires
Do not
• repair useand
Bleeding EVARREST™
from largefordefects
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or where or there
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vascular wall requires
of EVARREST
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repair
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ow and/or defects induring
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the product. injured vascular
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ow and/or of
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• Intravascular application. This can result in life-threatening thromboembolic events. the would
product. be persistent exposure of EVARREST
to blood flow application.
and/or pressure during absorption of the product.
•• Individuals
Intravascular known to haveThis can result
anaphylactic orinsevere
life-threatening thromboembolic
systemic reaction to humanevents. blood products.
•• Intravascular
Individuals known application.
to haveThis can result or
anaphylactic in severe
life-threatening thromboembolic
systemic reaction to humanevents. blood products.
5• Individuals
WARNINGS knownANDtoPRECAUTIONS
have anaphylactic or severe systemic reaction to human blood products.
5.15 Thrombosis
WARNINGS AND PRECAUTIONS
dequately 55.1 WARNINGS
Thrombosis Thrombosis
can occur ANDif PRECAUTIONS
EVARREST™ is absorbed systemically. Ensure that EVARREST is applied to the
adequately
overlap of 5.1
surface Thrombosis
Thrombosis of softcantissue
occurbleeding
if EVARREST™ only. is absorbed systemically. Ensure that EVARREST is applied to the
adequately
overlap
m). of
Use the Thrombosis
surface of soft cantissue
occurbleeding
if EVARREST™ only. is absorbed systemically. Ensure that EVARREST is applied to the
overlap
m). of
Usearea
eding the surface of soft tissue bleeding only. *The thrombin potency expressed in Units is determined using a clotting assay against an internal reference standard for
m). Usearea
eding the
eding area potency that has been calibrated against the World Health Organization (WHO) Second International Standard for Thrombin,
The Thrombin potency expressed in Units is determined using a clotting assay against an internal reference
1
34
The Thrombin
standard
1
potency
for potency thatexpressed
has been in Units isagainst
calibrated determined usingHealth
the World a clotting assay against
Organization (WHO)an internal
Second reference
International 01/580. Therefore, a Unit used herein is equivalent to an International Unit. 35
1
standard
The Thrombin
Standard potency that
potency
for Thrombin, has been
expressed
01/580. incalibrated against
Unitsa isUnit
Therefore, used the
determined World
hereinusing Health Organization
a clotting
is equivalent to assay (WHO)anSecond
against
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internal
Unit. reference
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standard Thrombin, 01/580.
that Therefore,
has been a Unit
calibrated usedthe
against herein is equivalent
World to an International
Health Organization Unit. International
(WHO) Second
Standard for Thrombin, 01/580. Therefore, a Unit used herein is equivalent to an International Unit.

8/8/14 10:18 AM
 How Supplied/Storage and Handling5
EVARREST® Fibrin Sealant Patch is packaged in a polyester tray and lid assembly within an outer
pouch composed of polyester laminated aluminum foil with an inner heat seal coating. The tray
and lid assembly maintains product integrity during storage and transport. The aluminum foil
pouch serves as a barrier to moisture and microbial contamination to maintain product sterility.
Each aluminum foil pouch is contained in a labeled cardboard package.
Each individual package contains one 2 x 4 inch (5.1 x 10.2 cm) or 4 x 4 inch (10.2 x 10.2 cm)
EVARREST patch (NDC 63713-050-24, 63713-050-44).
• Use EVARREST before the expiration date indicated on the carton
• Store unopened packages of EVARREST at 2° to 25°C. EVARREST does not require
refrigeration. Do not freeze
• Do not use if package is opened or damaged
• Once opened, keep EVARREST dry to avoid activation of the biological components prior to
use, so that it can remain in the sterile field throughout the surgical procedure
Patient Counseling Information5
Advise patients to consult their physician if they experience chest pain, shortness of
breath, difficulty speaking or swallowing, leg tenderness or swelling, or other symptoms
of thromboembolism.
Inform patients that EVARREST may carry a risk of transmitting infectious agents, eg, viruses
such as hepatitis A and parvovirus B19 and theoretically the CJD agent. Instruct patients to
consult their physician if symptoms of B19 virus infection (fever, drowsiness, and chills, followed
2 weeks later by a rash and joint pain) or hepatitis A (several days to weeks of poor appetite,
fatigue and low-grade fever followed by nausea, vomiting and abdominal pain, dark urine,
yellowed complexion) appear.
36
References
1. Samudrala S. Topical hemostatic agents in surgery: a surgeon’s perspective. AORN J. 2008;88:S1–S11.
2. Boucher BA, Traub O. Achieving hemostasis in the surgical field. Pharmacotherapy. 2009;29(7 pt 2):2S–7S.
3. Stokes ME, Ye X, Shah M, et al. Impact of bleeding-related complications and/or blood product transfusions on
hospital costs in inpatient surgical patients. BMC Health Serv Res. 2011;11:135.
4. Marietta M, Facchini L, Pedrazzi P, Busani S, Torelli G. Pathophysiology of bleeding in surgery. Transplant Proc.
2006;38:812–814.
5. EVARREST® (Fibrin Sealant Patch) [prescribing information]. Somerville, NJ:, Ethicon, Inc.; revised November 2012.
6. Fischer CP, Bochicchio G, Shen J, Patel B, Batiller J, Hart JC. A prospective, randomized, controlled trial of the efficacy
and safety of EVARREST® as an adjunct to control soft tissue bleeding during abdominal, retroperitoneal, pelvic, and
thoracic surgery. J Am Coll Surg. 2013;217(3):385–393.
7. Data on file, Ethicon, Inc. Investigator’s Brochure. Product: EVARREST® Bioactive Matrix (Fibrin Pad). Version 8;
April 27, 2012.
8. GYNECARE INTERCEED® Absorbable Adhesion Barrier [prescribing information]. Somerville, NJ; Ethicon, Inc.; 2007.
9. EVICEL® Fibrin Sealant (Human) [prescribing information]. Somerville, NJ: Ethicon, Inc.; November 2014.
10. Achneck HE, Sileshi B, Jamiolkowski RM, et al. A comprehensive review of topical hemostatic agents: efficacy and
recommendations for use. Ann Surg. 2010;251:217–228.
11. Hong YM, Loughlin KR. The use of hemostatic agents and sealants in urology. J Urol. 2006;176:2367–2374.
12. Spotnitz WD, Burks S. State-of-the-art review: hemostats, sealants, and adhesives II: update as well as how and when
to use the components of the surgical toolbox. Clin Appl Thromb Hemost. 2010;16:497–514.
13. Cheng CM, Meyer-Massetti C, Kayser SR. A review of three stand-alone topical thrombins for surgical hemostasis.
Clin Ther. 2009;31:32–41.
14. Voils S. Pharmacologic interventions for the management of critical bleeding. Pharmacotherapy. 2007;27
(9 pt 2):69S–84S.
15. Spotnitz WD, Burks S. Hemostats, sealants, and adhesives: components of the surgical toolbox. Transfusion.
2008;48:1502–1516.
16. Data on file, Ethicon, Inc. Study 900-005.
17. Data on file, Ethicon, Inc. Study OFI-T004.
18. Lane DA, Philippou H, Huntington JA. Directing thrombin. Blood. 2005;106:2605–2612.
19. Rickenbacher A, Breitenstein S, Lesurtel M, Frilling A. Efficacy of TachoSil a fibrin-based haemostat in different fields
of surgery—a systematic review. Expert Opin Biol Ther. 2009;9:897–907.
20. Tanaka KA, Key NS, Levy JH. Blood coagulation: hemostasis and thrombin regulation. Anesth Analg. 2009;108:
1433–1446.
21. Mosesson MW. Fibrinogen and fibrin structure and functions. J Thromb Haemost. 2005;3:1894–1904.
22. Martinez J, Ferber A, Bach TL, Yaen CH. Interaction of fibrin with VE-cadherin. Ann N Y Acad Sci. 2001;936:386–405.
23. Cambien B, Wagner DD. A new role in hemostasis for the adhesion receptor P-selectin. Trends Mol Med.
2004;10;179–186.
24. Wheat JC, Wolf JS Jr. Advances in bioadhesives, tissue sealants, and hemostatic agents. Urol Clin North Am.
2009;36:265–275.
25. Edwards CA, Piet MP, Chin S, Horowitz B. Tri(n-butyl) phosphate/detergent treatment of licensed therapeutic and
experimental blood derivatives. Vox Sang. 1987;52:53–59.
26. Koea JB, Batiller J, Patel B, et al. A phase III, randomized, controlled, superiority trial evaluating the fibrin pad versus
standard of care in controlling parenchymal bleeding during elective hepatic surgery. HPB (Oxford). 2013;15(1):61–70.
27. Koea JB. Oral Presentation 11th E-AHPBA Congress; April 21–24, 2015; Manchester UK (in press).
28. Data on file, Ethicon, Inc. Study 01-6795.
29. Data on file, Ethicon, Inc. Study 01-6895.
30. Data on file, Ethicon, Inc. Study 05-0471.
31. Data on file, Ethicon, Inc. Study 05-0472.
32. Data on file, Ethicon, Inc. Study 07-0014.
33. Data on file, Ethicon, Inc. Study 05-0473.
34. Data on file, Ethicon, Inc. Study 07-0015.
37
 HIGHLIGHTS OF PRESCRIBING INFORMATION CONTRAINDICATIONS
These highlights do not include all the information needed to use EVARREST® safely and effectively. • Do not use to treat bleeding from large defects in arteries or veins. (4)
See full prescribing information for EVARREST®. • Do not apply intravascularly. (4)
EVARREST® Fibrin Sealant Patch • Do not use in individuals known to have anaphylactic or severe systemic reaction to human blood products. (4)

Important Safety Information Absorbable Patch for Topical Use

Initial US Approval: 2012
WARNINGS AND PRECAUTIONS
• Thrombosis can occur if absorbed systemically. Apply topically to the bleeding site only. (5.1)
Indications and Usage RECENT MAJOR CHANGES • Can cause hypersensitivity reactions including anaphylaxis. (5.2)
• Avoid application to contaminated areas of the body or in the presence of active infection. Infection can
EVARREST is a fibrin sealant patch indicated for use with manual compression as an adjunct Indications and Usage (1) March 2015 occur. (5.3)
Dosage and Administration (2) March 2015
to hemostasis for control of bleeding during adult liver surgery and soft tissue bleeding during Warnings and Precautions (5) March 2015
• EVARREST® contains oxidized regenerated cellulose which adheres to bleeding surfaces. Inadvertent adhesions
can occur. (5.4)
open retroperitoneal, intra-abdominal, pelvic, and non-cardiac thoracic surgery in adults when INDICATIONS AND USAGE • Avoid use in closed spaces (e.g., in, around, or in proximity to, foramina in bone or areas of bony confine) where
control of bleeding by standard surgical methods of hemostasis (e.g., suture, ligature, cautery) EVARREST® is a fibrin sealant patch indicated for use with manual compression as an adjunct to hemostasis swelling may cause compression. (5.5)
for control of bleeding during adult liver surgery and soft tissue bleeding during open retroperitoneal, intra- • Use the least number of patches required to cover the entire bleeding area. (5.6)
is ineffective or impractical. abdominal, pelvic, and non-cardiac thoracic surgery in adults when control of bleeding by standard surgical • May carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD)
methods of hemostasis (e.g., suture, ligature, cautery) is ineffective or impractical. (1) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. (5.7)
Limitations for Use Limitations for Use: • The adverse reactions from repeat use of EVARREST (during a subsequent surgical procedure) have not been
• Cannot be used in place of sutures or other forms of mechanical ligation in the treatment of major arterial or evaluated. A second application of EVARREST at the original site of application (during a subsequent surgical
Cannot be used in place of sutures or other forms of mechanical ligation in the treatment of venous bleeding. procedure) may result in multiple organ adhesions, increased inflammation, fibrosis, encapsulated tissue
and/or necrosis, and hemorrhage (re-bleeding). (5.8)
major arterial or venous bleeding. DOSAGE AND ADMINISTRATION
ADVERSE REACTIONS
For topical use only.
The adverse reactions reported during clinical trials were blood fibrinogen increased, post procedural and
Important Safety Information • Determine the number of patches to be applied based upon the surface area and anatomic location of the
intra-abdominal hemorrhage, abdominal distension, anemia, gastrointestinal hemorrhage, thoracic cavity
bleeding tissue to be treated. (2)
• For topical use only. Do not apply intravascularly. • Keep the patch dry until use. (2.1) drainage, pleural effusion, post-procedural bile leak, abdominal abscess, ascites, deep vein thrombosis, localized
intra-abdominal fluid collection, and pulmonary embolism. (6)
• Place the powdery (active) side of the patch on the surface of tissue. (2.2)
• Do not use to treat bleeding from large defects in arteries or veins. • Apply immediate manual compression over the entire surface of the patch and maintain contact pressure for 3
To report SUSPECTED ADVERSE REACTIONS, contact ETHICON Customer Support Center at 1-877-384-4266
or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
minutes to control the bleeding. (2.2)
• Do not use in individuals known to have anaphylactic or severe systemic reaction to human DOSAGE FORMS AND STRENGTHS
USE IN SPECIFIC POPULATIONS
blood products. EVARREST® Fibrin Sealant Patch consists of human fibrinogen and human thrombin embedded in a flexible
• Pregnancy: No human or animal data. Use only if clearly needed. (8.1)
composite patch component. The active side is powdery, and the non-active side has an embossed wave • Pediatric: Use in children under the age of one month may be unsafe or ineffective due to small size and limited
• Thrombosis can occur if absorbed systemically. Apply topically to the bleeding site only. pattern. (3) ability to apply the patch as recommended. (8.4)
Each 2 x 4 inch (5.1 x 10.2 cm) or each 4 x 4 inch (10.2 x 10.2 cm) absorbable patch contains See 17 for PATIENT COUNSELING INFORMATION.
• Can cause hypersensitivity reactions including anaphylaxis. • 55.5 mg per square inch (8.6 mg per square cm) human fibrinogen Date: March 2015
• 241.9 Units per square inch (37.5 Units per square cm) human thrombin
• Avoid application to contaminated areas of the body or in the presence of active infection.
Infection can occur. FULL PRESCRIBING INFORMATION: CONTENTS* 8 USE IN SPECIFIC POPULATIONS
1 INDICATIONS AND USAGE 8.1 Pregnancy
• EVARREST contains oxidized regenerated cellulose which adheres to bleeding surfaces. 2 DOSAGE AND ADMINISTRATION 8.3 Nursing Mothers
8.4 Pediatric Use
Inadvertent adhesions can occur. 2.1 Preparation
8.5 Geriatric Use
2.2 Application
• Avoid use in closed spaces (e.g., in, around, or in proximity to, foramina in bone or areas 2.3 Retreatment 11 DESCRIPTION
3 DOSAGE FORMS AND STRENGTHS 12 CLINICAL PHARMACOLOGY
of bony confine) where swelling may cause compression. 4 CONTRAINDICATIONS 12.1 Mechanism of Action
5 WARNINGS AND PRECAUTIONS 13 NONCLINICAL TOXICOLOGY
• Use the least number of patches required to cover the entire bleeding area. Portions of 5.1 Thrombosis 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
excess patch material can become dislodged and migrate to other areas of the body. 5.2 Hypersensitivity Reactions 13.2 Animal Toxicology and Pharmacology
5.3 Infection 14 CLINICAL STUDIES
• Do not use more than eight 2x4 inch (5.1 x 10.2 cm) or more than four 4x4 inch 5.4 Adhesions 14.1 Abdominal, pelvic, retroperitoneal, and non-cardiac thoracic surgery
14.2 Liver Surgery
5.5 Compression
(10.2 x 10.2 cm) patches per single surgical procedure. 5.6 Dislodged Patch Material 16 HOW SUPPLIED/STORAGE AND HANDLING
5.7 Transmissible Infectious Agents 17 PATIENT COUNSELING INFORMATION
• May carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob 5.8 Repeat Use During a Subsequent Surgical Procedure
disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. 6 ADVERSE REACTIONS *Sections or subsections omitted from the full prescribing information are not listed
6.1 Clinical Trials Experience
• Adverse reactions from repeat use (during a subsequent surgical procedure) have not been
evaluated. A second application, at the original site of application (during a subsequent FULL PRESCRIBING INFORMATION (b) To ensure hemostasis, immediately apply manual compression
over the entire surface of the patch (including the area of overlap)
surgical procedure) may result in multiple organ adhesions, increased inflammation, fibrosis, 1 INDICATIONS AND USAGE 5b sufficient to stem all bleeding. Ensure even pressure distribution
EVARREST® is a fibrin sealant patch indicated for use with manual compression as an adjunct to hemostasis
encapsulated tissue and/or necrosis and hemorrhage (re-bleeding). for control of bleeding during adult liver surgery and soft tissue bleeding during open retroperitoneal, intra- over EVARREST and avoid movement of the patch. Maintain
abdominal, pelvic, and non-cardiac thoracic surgery in adults when control of bleeding by standard surgical manual compression for 3 minutes to control the bleeding.
• The adverse reactions reported during clinical trials were blood fibrinogen increased, post methods of hemostasis (e.g., suture, ligature, cautery) is ineffective or impractical.
Limitations for Use:
procedural and intra-abdominal hemorrhage, abdominal distension, anemia, gastrointestinal • Cannot safely or effectively be used in place of sutures or other forms of mechanical ligation in the treatment
hemorrhage, thoracic cavity drainage, pleural effusion, post-procedural bile leak, abdominal of major arterial or venous bleeding.
2 DOSAGE AND ADMINISTRATION
abscess, ascites, deep vein thrombosis, localized intra-abdominal fluid collection, and
For topical use only. 6. Gently remove laparotomy pads or surgical gauze from the
pulmonary embolism. • Determine the number of patches to be applied based upon the surface area and anatomic location of the application site without disrupting or dislodging EVARREST or the
bleeding to be treated. 6 clot. Inspect the patch to ensure that it is in full contact with the
Please see package insert for EVARREST Full Prescribing Information. • Do not use more than eight 2 x 4 inch (5.1 x 10.2 cm) or more than four 4 x 4 inch (10.2 x 10.2 cm) patches. treated area. If placement of the patch is unsatisfactory, remove
• Use in patients who have been previously exposed to EVARREST® has not been studied. the patch and use a new patch [see Dosage and Administration
2.1 Preparation (2.3)]. Removal of the patch may disrupt the clot and result in
38 • EVARREST® comes ready to use in sterile packages and must be handled using sterile technique in aseptic re-bleeding. 39
conditions. Discard damaged packages as resterilization is not possible. 7. EVARREST will remain in place, adhere to the tissue, and absorb
• To open the product, remove the foil pouch from the carton, carefully peel open the foil pouch, avoiding over time.
contact with the inside of the foil or the white sterile tray containing EVARREST.
8. Discard unused, opened patches at the end of the procedure.
 excreted in human milk, caution should be exercised when administering to a nursing woman. Table 5. Subje
5.4 Adhesions 14.1 Abdominal, pelvic, retroperitoneal, and non-cardiac thoracic surgery and R
5.5 Compression 14.2 Liver Surgery 8.4 Pediatric Use
5.6 Dislodged Patch Material 16 HOW SUPPLIED/STORAGE AND HANDLING Safety and effectiveness in pediatric patients have not been established. Use of EVARREST® in children under the age
5.7 Transmissible Infectious Agents of one month may be unsafe or ineffective due to small size and limited ability to apply the patch as recommended. EVARREST
17 PATIENT COUNSELING INFORMATION Slow absorption and possibility of adhesions can further complicate use of EVARREST in the neonates.
5.8 Repeat Use During a Subsequent Surgical Procedure 33/40 (82.5%)
8.5 Geriatric Use
6 ADVERSE REACTIONS *Sections or subsections omitted from the full prescribing information are not listed
Clinical trials included 141 subjects of 65 years of age or older who were treated with EVARREST®. No differences in
6.1 Clinical Trials Experience The efficacy da
safety or efficacy were observed between the elderly and younger patients.
efficacy finding
these measures, such products still potentially can transmit disease. There is also the possibility that unknown 1211 CLINICAL
DESCRIPTION PHARMACOLOGY of the target bl
FULL PRESCRIBING INFORMATION (b) To ensure hemostasis, immediately apply manual compression infectious agents may be present in such products. EVARREST®
12.1 Mechanism Fibrin of Sealant
Action Patch is a sterile, bio-absorbable combination product, comprised of two biological initiation of wou
over the entire surface of the patch (including the area of overlap)
1 INDICATIONS AND USAGE 5b sufficient to stem all bleeding. Ensure even pressure distribution
Any infection considered by a physician to possibly have been transmitted by this product should be reported by
the physician or other healthcare provider to ETHICON Customer Support Center at 1-877-384-4266.
components
The mechanism(human
component.
physiology of The
of actionplasma-derived
activeclot
the fibrin
of EVARREST® isfibrinogen
sideformation.
is white-to-yellow
based on the
Upon contact
andinteraction
in color
withand
thrombin)between
embedded
powderywound
a bleeding
in a flexible
the biological
in appearance;
surface, the
composite
components
thebiological
andpatch
non-activecomponents
the
side has an
The second stud
1:1 ratio (50 rand
EVARREST® is a fibrin sealant patch indicated for use with manual compression as an adjunct to hemostasis
for control of bleeding during adult liver surgery and soft tissue bleeding during open retroperitoneal, intra- over EVARREST and avoid movement of the patch. Maintain 5.8 Repeat Use During a Subsequent Surgical Procedure embossed inwave
embedded the pattern.
patch component are hydrated, and the subsequent fibrinogen-thrombin reaction initiates the were white/Cau
abdominal, pelvic, and non-cardiac thoracic surgery in adults when control of bleeding by standard surgical manual compression for 3 minutes to control the bleeding. The adverse reactions from repeat use of EVARREST (during a subsequent surgical procedure) have not been last
Thestep
patchin component
the cascadeofofEVARRESTbiochemical reactions
consists of an -oxidized
conversion of fibrinogen
regenerated into(ORC)
cellulose fibrinlayer
monomers thatafurther
underlying layer of m2 (range: 15 to
methods of hemostasis (e.g., suture, ligature, cautery) is ineffective or impractical. evaluated. A second application of EVARREST at the original site of application (during a subsequent surgical polymerize
polyglactinto910 form the fibrin
(PG910) clot. fibers. The PG910 layer contains the embedded biological components. The patch
non-woven EVARREST was
Limitations for Use: procedure) may result in multiple organ adhesions, increased inflammation, fibrosis, encapsulated tissue and/or componentisprovides
Hemostasis achieved a large
whensurface area forfibrin
the formed the biological components
clot integrates with and
the imparts inherent mechanical
patch component and adheres integrity
to theto 46.2% (p < 0.00
• Cannot safely or effectively be used in place of sutures or other forms of mechanical ligation in the treatment necrosis, and hemorrhage (re-bleeding). the product.
wound surfaceThe thusflexibility
providingof EVARREST
a physicalaccommodates
barrier to bleeding.the physiological movements of tissues and organs. of the target bl
of major arterial or venous bleeding. Each 2 x 4 inch (5.1 x 10.2 cm) or each 4 x 4 inch (10.2 x 10.2 cm) EVARREST patch contains 55.5 mg per square inch initiation of wo
6 ADVERSE REACTIONS 13 NONCLINICAL TOXICOLOGY shown to be gr
(8.6 mg per square cm) of human fibrinogen and 241.9 Units per square inch (37.5 Units per square cm) of human
2 DOSAGE AND ADMINISTRATION The adverse reactions reported during clinical trials were blood fibrinogen increased, post procedural and intra- 13.1 Carcinogenesis,
thrombin. Additional inactive Mutagenesis,
ingredients Impairment
are: arginineofhydrochloride,
Fertility calcium chloride, glycine, human albumin, resection (58.1%
For topical use only. abdominal hemorrhage, abdominal distension, anemia, gastrointestinal hemorrhage, thoracic cavity drainage, Long-term studies acetate,
mannitol, sodium in animals to evaluate
sodium chloride, theand
carcinogenic
sodium citrate. potential of EVARREST®
EVARREST or studies
does not contain anytopreservative.
determine the adjunct to hemo
6. Gently remove laparotomy pads or surgical gauze from the pleural effusion, post-procedural bile leak, abdominal abscess, ascites, deep vein thrombosis, localized intra- effects of EVARREST onbygenotoxicity or fertility haveafter
not completion
been performed.
• Determine the number of patches to be applied based upon the surface area and anatomic location of the application site without disrupting or dislodging EVARREST or the EVARREST is sterilized electron-beam irradiation of innerAnand
assessment of the carcinogenic
outer packaging resulting in a Table 6. Subje
bleeding to be treated. 6 clot. Inspect the patch to ensure that it is in full contact with the
abdominal fluid collection, and pulmonary embolism. potential of EVARREST
sterile product was inner
in a sterile completed
package.to demonstrate minimal carcinogenic risk from product use.
and R
6.1 Clinical Trials Experience 13.2
• Do not use more than eight 2 x 4 inch (5.1 x 10.2 cm) or more than four 4 x 4 inch (10.2 x 10.2 cm) patches. treated area. If placement of the patch is unsatisfactory, remove ViralAnimal
Clearance Toxicology and Pharmacology
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical InTheswine and rodent models,of topically applied EVARREST®
• Use in patients who have been previously exposed to EVARREST® has not been studied. the patch and use a new patch [see Dosage and Administration biological components EVARREST® (human fibrinogenwas andabsorbed at approximately
human thrombin) 8 weeks after
are manufactured from
(2.3)]. Removal of the patch may disrupt the clot and result in trials of a drug cannot be directly compared to rates of adverse reactions in clinical trials of another drug and may application, withplasma
< 10%collected
of the remaining material facilities
degradinginexponentially over time. Theplasma
biological components EVARREST
2.1 Preparation pooled human in FDA-licensed the United States. Human is tested by FDA-
re-bleeding. not reflect the rates observed in clinical practice. oflicensed
EVARREST are degraded by fibrinolysis and phagocytosis, similarly to endogenous fibrin. As absorption
• EVARREST® comes ready to use in sterile packages and must be handled using sterile technique in aseptic Nucleic Acid Tests (NAT) for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency 48/50 (96.0%)
EVARREST® was used to treat soft tissue bleeding during retroperitoneal, intra-abdominal, pelvic, or thoracic progresses, increased
virus-1 (HIV-1). fibrinolytic
NAT testing activityAisvirus
for hepatitis induced
(HAV) byand
plasmin, and decomposition
parvovirus of fibrin to
B19 is also performed. fibrin plasma
Human degradation
is also
conditions. Discard damaged packages as resterilization is not possible. 7. EVARREST will remain in place, adhere to the tissue, and absorb products is initiated.
surgery, suture hole bleeding during cardiovascular surgery, and parenchymal bleeding during hepatic or renal tested for the presence of hepatitis B surface antigen (HBsAg), and antibodies to hepatitis C virus (anti-HCV) and
• To open the product, remove the foil pouch from the carton, carefully peel open the foil pouch, avoiding over time. surgery across all clinical trials involving 306 subjects treated with EVARREST and 191 control subjects. Of the 306 16 HOW SUP
contact with the inside of the foil or the white sterile tray containing EVARREST. 14human immunodeficiency
CLINICAL STUDIES viruses types 1 and 2 (anti-HIV1/2). EVARREST® is p
8. Discard unused, opened patches at the end of the procedure. subjects, 302 subjects were treated with EVARREST as an adjunct to hemostasis. Twenty-eight percent (28%) of
• Remove the white sterile tray from the pouch and place onto the sterile field. The manufacturing
14.1 Abdominal, pelvic, procedure for human fibrinogen
retroperitoneal, and human
and non-cardiac thrombin
thoracic include processing steps designed
surgery laminated alum
treated subjects (87 subjects out of 306) and 35% of control subjects (67 subjects out of 191) experienced one or
• Hold the tray securely in the palm of the hand, ensuring that the side with the holes is facing upwards, and use 2.3 Retreatment more serious adverse events. Atoprospective,
reduce the randomized
risk of viral transmission.
trial includingIn141 particular,
subjectsthe of virus
medianclearance
age 62steps
yearsin(range
the manufacture
26 to 89 years) of human
was during storage a
• Retreatment may be required if there are folds, creases, or crimps in the patch. If not satisfied with the fibrinogen include solvent/detergent (S/D) treatment
performed to compare the safety and hemostatic effectiveness of EVARREST® with and pasteurization. The that
virusofclearance steps in the
oxidized regenerated to maintain pro
the tabs on the side of the tray to remove the top of the tray with the other hand. Table 1. Adverse Reactions Reported in Clinical Trials
placement of the patch, or if bleeding still occurs during or after the specified duration of compression, remove manufacture of human thrombin include S/D treatment and nanofiltration.
cellulose (ORC), an absorbable hemostat, when used as an adjunct to control bleeding after primary methods Each individual
• The lower portion of the tray contains EVARREST with the active side facing downwards. The active side is
powdery in appearance. The non-active side has an embossed wave pattern. the used patch and repeat the application procedure above with a new patch. Adverse Reactions EVARREST EVARREST CONTROL toThe virus hemostasis
achieve clearance capacity of these
(e.g., suture, procedures
cautery, ligature)has beenineffective
proved validated using viruses with
or impractical duringa open
rangeabdominal,
of physico- and NDC 63713-
• If continued bleeding is due to insufficient coverage of the bleeding area, additional patches may be applied. Total* Randomized chemical
pelvic, characteristics.
retroperitoneal, andThese
non-cardiac validation
in vitrothoracic studies were conducted using samples from manufacturing
surgery. • Use EVARRES
• Keep EVARREST dry after opening. The patch can remain in the sterile field to be available for use throughout
the procedure. EVARREST does not stick to gloves, forceps, or surgical instruments. Ensure that the edges overlap (by approximately 0.5 to 1 inch or 1 to 2 cm) with the existing patch. N=306 N=225 N=191 Aintermediates
total of 90 subjectsspikedwere withrandomized
virus suspensions of known
into the trial in a 2:1titers
ratio followed
(60 treatedbywith
further processing
EVARREST, underwith
30 treated conditions
ORC). • Store unope
• If continued bleeding is due to incomplete adherence to the tissue (where bleeding persists from under the n(%) n(%) n(%) Anequivalent
additionalto51those in the
subjects respective
were enrolledmanufacturing
and treated with steps. The results
EVARREST duringofavirus clearance
subsequent validation studies
non-randomized phase.are
2.2 Application • Do not use if
dressing), remove the patch and use a new one. Blood fibrinogen increased 3 (1%) 3 (1%) 1 (1%) Ofsummarized
the total 141in enrolled
Table 2 and Table 3.63.1% were male; 80.1% were white/Caucasian; 18.4% were black; 0.7% were
subjects,
Apply topically to the bleeding site only. Asian; • Once opened
3 DOSAGE FORMS AND STRENGTHS Post procedural hemorrhage 2 (1%) 2 (1%) 2 (1%) Table0.7% wereReduction
2. Virus Hispanic/Latino;
Factors median body mass
for Human index was 27 kg/m2 (range: 17 to 53 kg/m2). Demographic
Fibrinogen remain in th
1. Using sterile scissors, carefully cut the patch to the size and shape characteristics were balanced across the treatment groups.
EVARREST® Fibrin Sealant Patch consists of human fibrinogen and human thrombin embedded in a flexible Abdominal distension 1 (0%) 1 (0%) 0 (0%) Reduction Factor (log10) of
as necessary to fit and maintain contact with the bleeding area EVARREST was shown to have a statistically significant difference compared to virus
ORC, tested
98.3% versus 53.3% 17 PATIENT
1 with an overlap of approximately 0.5 to 1 inch (1 to 2 cm). Keep
composite patch component. The active side is white-to-yellow in color and powdery in appearance, and the Intra-abdominal hemorrhage 1 (0%) 1 (0%) 0 (0%) (p < 0.0001), in the proportion of subjects achieving hemostatic
* Enveloped success at 4 minutes
Viruses † after identification
Non-Enveloped Viruses of the • Advise patie
non-active side has an embossed wave pattern. target bleeding site and randomization, with no re-bleeding requiring treatment during a subsequent 6-minute
the powdery white-to-yellow color active side of the patch facing Anemia 1 (0%) 1 (0%) 0 (0%) or swallowin
down while in the tray. Each 2 x 4 inch (5.1 x 10.2 cm) or each 4 x 4 inch (10.2 x 10.2 cm) absorbable patch of EVARREST contains 55.5 mg Manufacturing
observation period and Stepsustained hemostasis HIV-1
until fascialBVDV
closure at thePRVend of theEMCV
surgery (Table HAV4). CPV
per square inch (8.6 mg per square cm) of human fibrinogen and 241.9 Units1 per square inch (37.5 Units Gastrointestinal hemorrhage 1 (0%) 1 (0%) 0 (0%) • Inform patie
2. Remove excess blood or fluid from the site of application to per square cm) of human thrombin. Thoracic cavity drainage 1 (0%) 1 (0%) 0 (0%) Table 4. Subjects Achieving Hemostasis at 4 Minutes from IdentificationNot Not Bleeding Site
of the Target hepatitis A a
improve visibility. Do not use on non-visualized surfaces. Do not SD Treatment > 4.42
and Randomization, with no Re-bleeding> 4.39 > 3.96
until Fascial Closure Tested
at the End Tested 0.0
of the Surgery if symptoms
4 CONTRAINDICATIONS Pleural effusion 1 (0%) 1 (0%) 0 (0%) pain) or hep
use on visible open large vessels. Pasteurization > 4.39 > 5.46 6.04 3.69 > 5.78 1.33
Do not use EVARREST® for Post-procedural bile leak 1 (0%) 1 (0%) 0 (0%) Treatment 95% Confidence vomiting an
Cumulative Virus Reduction Factor
EVARREST ORC > 8.81 p-value
> 9.85 >Difference
10.00 3.69 > Interval
5.78 1.33
• Bleeding from large defects in visible arteries or veins where the injured vascular wall requires repair and Abdominal abscess 1 (0%) 0 (0%) 0 (0%)
maintenance of vessel patency or where there would be persistent exposure of EVARREST to blood flow and/or * HIV-1: Human Immunodeficiency Virus Type 1
Ascites 1 (0%) 0 (0%) 0 (0%) 59/60 (98.3%) 16/30
pressure during absorption of the product. BVDV: Bovine Viral Diarrhea Virus(53.3%) <0.0001 45.0% 27.9%, 62.5%
3. Apply the active side of the patch to the bleeding area. Allow full Deep vein thrombosis 1 (0%) 0 (0%) 0 (0%) PRV: Pseudorabies Virus
contact with the tissue. The product is activated upon contact • Intravascular application. This can result in life-threatening thromboembolic events. The† EMCV:
efficacyEncephalomyocarditis
data for the 51 non-randomized subjects treated with EVARREST were supportive of the above
3 with fluid and then adheres, conforming to tissue with manual • Individuals known to have anaphylactic or severe systemic reaction to human blood products.
Localized intra-abdominal fluid collection 1 (0%) 0 (0%) 0 (0%)
efficacy
HAV:findings with
Hepatitis
Virus
50/51 subjects (98.0%) achieving hemostatic success at 4 minutes after randomization with
A Virus
compression. Pulmonary embolism 1 (0%) 0 (0%) 0 (0%)
5 WARNINGS AND PRECAUTIONS no re-bleeding
CPV: Caninerequiring
Parvovirustreatment during a subsequent 6-minute observation period.
*EVARREST Total subjects included 225 Randomized subjects and 81 Non-Randomized subjects. 14.2
5.1 Thrombosis TableLiver Surgery
3. Virus Reduction Factors for Human Thrombin
Thrombosis can occur if EVARREST® is absorbed systemically. Apply EVARREST topically to the bleeding site only. Demographic characteristics (gender, race, body mass index) were balanced across the treatment groups. No Two prospective, randomized trials including a total of 206 subjects were performed to compare the safety and
significant differences were observed in the occurrence of adverse reactions between demographic groups. hemostatic effectiveness of EVARREST® with that of Standard Reduction Factor
of Care (log10as
(defined ) ofmanual
virus tested
compression with or
5.2 Hypersensitivity Reactions
Immunogenicity was evaluated in soft tissue clinical studies by testing blood samples collected at baseline, 4 to without a topical absorbable hemostat), when used as an adjunct to control bleeding † after primary methods to
EVARREST® can cause hypersensitivity reactions, including anaphylactic reactions. Symptoms associated with * Enveloped Viruses Non-Enveloped Viruses
allergic anaphylactic reactions include flush, urticaria, pruritus, nausea, drop in blood pressure, tachycardia or 6 weeks, and 8 to 10 weeks post-surgery for antibodies to human thrombin and fibrinogen by enzyme-linked achieve hemostasis (e.g., suture, cautery, ligature) proved ineffective or impractical during liver surgery.
bradycardia, dyspnea, severe hypotension and anaphylactic shock. immunosorbent assays. Three subjects out of 145 (~2%) in the group treated with EVARREST showed an increase TheManufacturing Step104 subjects of median
first study included HIV-1 age 65SBVyears (range
BVDV31 to PRV82 years);EMCV HAVsubjectsCPV
58.7% of the were
in the titer of anti-thrombin antibodies after treatment. Two subjects out of 145 (~1%) in the group treated with male; 95.2% were white/Caucasian; 1.9% were Asian; 1% were black; median bodyNot mass index Distributed by:
Notwas 27 kg/m
2
5.3 Infection EVARREST showed a transient increase in fibrinogen antibody titers, with titer levels back at background levels at (range: 15 to 43 kg/m ). Demographic characteristics Ethicon, Inc.
> 5.82 >were 5.31balanced
> 4.74across>the
4.25treatment
Testedgroups.
2
4. Apply a sufficient number of patches to adequately cover the Avoid application to contaminated or infected areas of the body, or in the presence of active infection. Infection SD Treatment Tested 0.0 Route 22 West,
the 8 to 10 week time point. No immune response to fibrinogen was detected in any of the other subjects. A total of 84 subjects were randomized into the trial in a 1:1 ratio
4 entire bleeding area, with an overlap of approximately 0.5 to can occur from application to an infected site. Not(40 randomized to EVARREST, 44 to Standard Somerville, NJ 0
1 inch (1 to 2 cm). Use the least number of patches to cover the 8 USE IN SPECIFIC POPULATIONS of Nanofiltration
Care). An additional 20 subjects were enrolled> 4.36 and treated Tested
> 5.32 with EVARREST
> 5.47during6.37
a non-randomized
6.95 phase.
5.85 USA
5.4 Adhesions One subject should have been randomized to EVARREST but was treated with Standard of Care. This subject was
bleeding area [see Warnings and Precautions (5.6)]. 8.1 Pregnancy > 10.18 > 10.63
EVARREST® contains oxidized regenerated cellulose which adheres to bleeding surfaces. Inadvertent adhesions Cumulative
analyzed in theVirus Reduction
EVARREST groupFactor
for the Intent to Treat Set. > 4.74 > 9.72 6.37 6.95 5.85 Manufactured b
can occur. Meticulous hemostasis should be achieved, particularly in gynecological procedures, to reduce the Pregnancy Category C. Omrix Biopharm
EVARREST was shown
* HIV-1: Human to have a statistically
Immunodeficiency Virus Type 1significant difference compared to Standard of Care, 82.5% versus
potential for postoperative adhesions. Animal reproduction studies have not been conducted with EVARREST®. There are no adequate and well- 14 Einstein Stree
29.5%SBV:(p <Sindbis
0.0001),
Virusin the proportion of subjects achieving hemostatic success at 4 minutes after identification
5.5 Compression controlled studies in pregnant women. It is also not known whether EVARREST can cause fetal harm when BVDV: Bovine Viral Diarrhea Virus Weizmann Scien
of the target bleeding site and randomization, with no re-bleeding requiring treatment any time prior to the
Avoid using EVARREST® in closed spaces (e.g., in, around, or in proximity to, foramina in bone or areas of bony administered to pregnant women or can affect reproductive capacity. EVARREST should be given to a pregnant PRV: ofPseudorabies Virus (Table 5). The treatment difference between EVARREST and Standard of Care was Nes-Ziona, Israe
initiation wound closure
confine) where swelling may cause nerve or blood vessel compression. woman only if clearly needed. †
EMCV: Encephalomyocarditis Virus
shown to be greater in subjects with bleeding in abnormal hepatic tissue (e.g., cirrhotic or steatotic) than in US License No. 1
8.3 Nursing Mothers HAV: with
subjects Hepatitis
normalA Virus
tissue bleeding (65.2% versus 48.8%, respectively).
5.6 Dislodged Patch Material CPV: Canine Parvovirus
Use the least number of patches possible during surgical procedures because portions of excess patch material can It is not known whether any component of EVARREST® is excreted in human milk. Because many drugs are © 2015 Ethicon,
5. (a) Hold dry or moist laparotomy pads or surgical gauze over excreted in human milk, caution should be exercised when administering to a nursing woman. Table 5. Subjects Achieving Hemostasis at 4 Minutes from Identification of the Target Bleeding Site
become dislodged and migrate to other areas of the body. For example, during urological procedures dislodged and Randomization, with no Re-bleeding until Fascial Closure at the End of the Surgery
EVARREST® to achieve full contact with the bleeding surface.
5a patch material can plug the urethra, ureter, or a catheter. 8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Use of EVARREST® in children under the age
5.7 Transmissible Infectious Agents Standard Treatment 95% Confidence
Because the biological components of this product are made from human plasma, it may carry a risk of of one month may be unsafe or ineffective due to small size and limited ability to apply the patch as recommended. EVARREST of Care p-value Difference Interval
transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, Slow absorption and possibility of adhesions can further complicate use of EVARREST in the neonates.
33/40 (82.5%) 13/44 (29.5%) <0.0001 53.0% 32.9%, 68.5%
the Creutzfeldt-Jakob disease (CJD) agent. The risk of transmitting viral agents has been minimized by screening 8.5 Geriatric Use
plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, Clinical trials included 141 subjects of 65 years of age or older who were treated with EVARREST®. No differences in
The efficacy data for the 20 non-randomized subjects treated with EVARREST were supportive of the above
and by inactivating and removing certain viruses during the manufacturing process [see Description (11)]. Despite safety or efficacy were observed between the elderly and younger patients.
efficacy findings, with 20/20 subjects (100.0%) achieving hemostatic success at 4 minutes after identification
11 DESCRIPTION of the target bleeding site and randomization with no re-bleeding requiring treatment any time prior to the
1
The Thrombin potency expressed in Units is determined using a clotting assay against an internal reference EVARREST® Fibrin Sealant Patch is a sterile, bio-absorbable combination product, comprised of two biological initiation of wound closure.
standard for potency that has been calibrated against the World Health Organization (WHO) Second International components (human plasma-derived fibrinogen and thrombin) embedded in a flexible composite patch The second study included 102 subjects of median age 63 years (range 23 to 85 years) randomized into the trial in a
Standard for Thrombin, 01/580. Therefore, a Unit used herein is equivalent to an International Unit. component. The active side is white-to-yellow in color and powdery in appearance; the non-active side has an 1:1 ratio (50 randomized to EVARREST, 52 to Standard of Care). Sixty-one percent of the subjects were male; 85.3%
embossed wave pattern. were white/Caucasian; 9.8% were black; 2.9% were Asian; 3% were Hispanic; median body mass index was 27 kg/
The patch component of EVARREST consists of an oxidized regenerated cellulose (ORC) layer underlying a layer of m2 (range: 15 to 43 kg/m2). Demographic characteristics were balanced across the treatment groups.
polyglactin 910 (PG910) non-woven fibers. The PG910 layer contains the embedded biological components. The patch EVARREST was shown to have a statistically significant difference compared to Standard of Care, 96% versus
component provides a large surface area for the biological components and imparts inherent mechanical integrity to 46.2% (p < 0.0001), in the proportion of subjects achieving hemostatic success at 4 minutes after identification
the product. The flexibility of EVARREST accommodates the physiological movements of tissues and organs. of the target bleeding site and randomization with no re-bleeding requiring treatment any time prior to the
Each 2 x 4 inch (5.1 x 10.2 cm) or each 4 x 4 inch (10.2 x 10.2 cm) EVARREST patch contains 55.5 mg per square inch initiation of wound closure (Table 6). The treatment difference between EVARREST and Standard of Care was
(8.6 mg per square cm) of human fibrinogen and 241.9 Units per square inch (37.5 Units per square cm) of human shown to be greater in subjects undergoing non-anatomic resection than in subjects undergoing anatomic
thrombin. Additional inactive ingredients are: arginine hydrochloride, calcium chloride, glycine, human albumin, resection (58.1% versus 39.5%, respectively). Data from this study further support the efficacy of EVARREST as an
mannitol, sodium acetate, sodium chloride, and sodium citrate. EVARREST does not contain any preservative. adjunct to hemostasis in the control of bleeding in liver surgery.
EVARREST is sterilized by electron-beam irradiation after completion of inner and outer packaging resulting in a Table 6. Subjects Achieving Hemostasis at 4 Minutes from Identification of the Target Bleeding Site
40 sterile product in a sterile inner package. and Randomization, with no Re-bleeding until Fascial Closure at the End of the Surgery 41
Viral Clearance
The biological components of EVARREST® (human fibrinogen and human thrombin) are manufactured from Standard Treatment 95% Confidence
pooled human plasma collected in FDA-licensed facilities in the United States. Human plasma is tested by FDA- EVARREST of Care p-value Difference Interval
licensed Nucleic Acid Tests (NAT) for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency 48/50 (96.0%) 24/52 (46.2%) <0.0001 49.8% 34.5%, 63.5%
 The patch component of EVARREST consists of an oxidized regenerated cellulose (ORC) layer underlying a layer of m2 (range: 15 to 43 kg/m2). Demographic characteristics were balanced across the treatment groups.
polyglactin 910 (PG910) non-woven fibers. The PG910 layer contains the embedded biological components. The patch EVARREST was shown to have a statistically significant difference compared to Standard of Care, 96% versus
component provides a large surface area for the biological components and imparts inherent mechanical integrity to 46.2% (p < 0.0001), in the proportion of subjects achieving hemostatic success at 4 minutes after identification
the product. The flexibility of EVARREST accommodates the physiological movements of tissues and organs. of the target bleeding site and randomization with no re-bleeding requiring treatment any time prior to the
Each 2 x 4 inch (5.1 x 10.2 cm) or each 4 x 4 inch (10.2 x 10.2 cm) EVARREST patch contains 55.5 mg per square inch initiation of wound closure (Table 6). The treatment difference between EVARREST and Standard of Care was
(8.6 mg per square cm) of human fibrinogen and 241.9 Units per square inch (37.5 Units per square cm) of human shown to be greater in subjects undergoing non-anatomic resection than in subjects undergoing anatomic
thrombin. Additional inactive ingredients are: arginine hydrochloride, calcium chloride, glycine, human albumin, resection (58.1% versus 39.5%, respectively). Data from this study further support the efficacy of EVARREST as an
mannitol, sodium acetate, sodium chloride, and sodium citrate. EVARREST does not contain any preservative. adjunct to hemostasis in the control of bleeding in liver surgery.
y that unknown 12 EVARREST
CLINICAL isPHARMACOLOGY
sterilized by electron-beam irradiation after completion of inner and outer packaging resulting in a Table 6. Subjects Achieving Hemostasis at 4 Minutes from Identification of the Target Bleeding Site
12.1 sterile
MechanismproductofinAction
a sterile inner package. and Randomization, with no Re-bleeding until Fascial Closure at the End of the Surgery
be reported by Viral Clearance
The mechanism of action of EVARREST® is based on the interaction between the biological components and the
6. The biological
physiology of the fibrincomponents of EVARREST®
clot formation. Upon contact (human
with afibrinogen and human
bleeding wound surface,thrombin) are manufactured
the biological components from Standard Treatment 95% Confidence
pooledin human plasma collected EVARREST of Care p-value Difference Interval
embedded the patch component areinhydrated,
FDA-licensed facilities
and the in thefibrinogen-thrombin
subsequent United States. Humanreaction
plasmainitiates
is testedthe
by FDA-
have not been licensed
last step in theNucleic
cascade AcidofTests (NAT) forreactions
biochemical hepatitis-Bconversion
virus (HBV),ofhepatitis C virus
fibrinogen into(HCV),
fibrinand human immunodeficiency
monomers that further 48/50 (96.0%) 24/52 (46.2%) <0.0001 49.8% 34.5%, 63.5%
equent surgical virus-1to(HIV-1).
polymerize form the NAT testing
fibrin clot.for hepatitis A virus (HAV) and parvovirus B19 is also performed. Human plasma is also
ed tissue and/or testedisforachieved
Hemostasis the presence
whenofthe hepatitis
formedB fibrin
surfaceclot
antigen (HBsAg),
integrates withand
theantibodies to hepatitis
patch component andCadheres
virus (anti-HCV)
to the and 16 HOW SUPPLIED/STORAGE AND HANDLING
human immunodeficiency
wound surface thus providing a physical viruses types
barrier1 to
andbleeding.
2 (anti-HIV1/2). EVARREST® is packaged in a polyester tray and lid assembly within an outer pouch composed of polyester
The manufacturing procedure for human fibrinogen and human thrombin include processing steps designed laminated aluminum foil with an inner heat seal coating. The tray and lid assembly maintains product integrity
13 to NONCLINICAL
reduce the risk TOXICOLOGY
of viral transmission. In particular, the virus clearance steps in the manufacture of human during storage and transport. The aluminum foil pouch serves as a barrier to moisture and microbial contamination
dural and intra- 13.1 fibrinogen
Carcinogenesis,includeMutagenesis,
solvent/detergent Impairment of Fertility
(S/D) treatment and pasteurization. The virus clearance steps in the to maintain product sterility. Each aluminum foil pouch is contained in a labeled cardboard package.
cavity drainage, Long-term studies in
manufacture animalsthrombin
of human to evaluate the carcinogenic
include S/D treatment potential of EVARREST® or studies to determine the
and nanofiltration.
localized intra- Each individual package contains two 2 x 4 inch (5.1 x 10.2 cm) EVARREST patches (NDC 63713-050-25 per patch
effectsThe
of EVARREST on genotoxicity
virus clearance capacity oforthese fertility have nothas
procedures beenbeenperformed.
validatedAnusing
assessment of thea carcinogenic
viruses with range of physico- and NDC 63713-050-24 per package) or one 4 x 4 inch (10.2 x 10.2 cm) EVARREST patch (NDC 63713-050-44).
potential of EVARREST
chemical was completed
characteristics. These toin demonstrate
vitro validationminimal
studiescarcinogenic risk from
were conducted product
using samplesuse.from manufacturing
• Use EVARREST before the expiration date indicated on the carton.
13.2 intermediates
Animal Toxicology spikedandwithPharmacology
virus suspensions of known titers followed by further processing under conditions
• Store unopened packages of EVARREST at 2 to 25°C. EVARREST does not require refrigeration. Do not freeze.
erved in clinical equivalent
In swine to those
and rodent in thetopically
models, respectiveapplied
manufacturing
EVARREST® steps.
wasThe results ofatvirus
absorbed clearance validation
approximately 8 weeks studies
after are
er drug and may summarized in Table 2 and
application, with < 10% of the remaining Table 3. material degrading exponentially over time. The biological components • Do not use if package is opened or damaged.
of EVARREST are degraded by fibrinolysis and phagocytosis, similarly to endogenous fibrin. As absorption • Once opened, keep EVARREST dry to avoid activation of the biological components prior to use, so that it can
Table 2. Virus Reduction Factors for Human Fibrinogen remain in the sterile field throughout the surgical procedure.
lvic, or thoracic progresses, increased fibrinolytic activity is induced by plasmin, and decomposition of fibrin to fibrin degradation
hepatic or renal products is initiated. Reduction Factor (log10) of virus tested 17 PATIENT COUNSELING INFORMATION
ects. Of the 306 • Advise patients to consult their physician if they experience chest pain, shortness of breath, difficulty speaking
ercent (28%) of 14 CLINICAL STUDIES * Enveloped Viruses †
Non-Enveloped Viruses
14.1 Abdominal, pelvic, retroperitoneal, and non-cardiac thoracic surgery or swallowing, leg tenderness or swelling, or other symptoms of thromboembolism.
erienced one or Manufacturing Step HIV-1 BVDV PRV EMCV HAV CPV
A prospective, randomized trial including 141 subjects of median age 62 years (range 26 to 89 years) was • Inform patients that EVARREST® may carry a risk of transmitting infectious agents, e.g., viruses such as
performed to compare the safety and hemostatic effectiveness of EVARREST® with that Notof oxidizedNot
regenerated hepatitis A and parvovirus B19 and theoretically the CJD agent. Instruct patients to consult their physician
celluloseSD(ORC),
Treatment
an absorbable hemostat, when>used 4.42 as an>adjunct
4.39 to control
> 3.96 bleeding
Tested Tested methods
after primary 0.0 if symptoms of B19 virus infection (fever, drowsiness, and chills, followed two weeks later by a rash and joint
CONTROL to achieve hemostasis (e.g., suture, cautery, ligature)
Pasteurization > 4.39 proved ineffective or6.04
> 5.46 impractical during open
3.69 abdominal,
> 5.78 1.33 pain) or hepatitis A (several days to weeks of poor appetite, fatigue and low-grade fever followed by nausea,
pelvic, retroperitoneal, vomiting and abdominal pain, dark urine, yellowed complexion) appear.
Cumulative Virusand non-cardiac
Reduction thoracic>surgery.
Factor 8.81 > 9.85 > 10.00 3.69 > 5.78 1.33
N=191 A total of 90 subjects were randomized into the trial in a 2:1 ratio (60 treated with EVARREST, 30 treated with ORC).
n(%) * HIV-1: Human Immunodeficiency Virus Type 1
An additional 51 subjects were enrolled and treated with EVARREST during a subsequent non-randomized phase.
BVDV: Bovine Viral Diarrhea Virus
1 (1%) Of the total 141 enrolled subjects, 63.1% were male; 80.1% were white/Caucasian; 18.4% were black; 0.7% were
PRV: Pseudorabies Virus
2 (1%) Asian; 0.7%
† were Hispanic/Latino; median body mass index was 27 kg/m2 (range: 17 to 53 kg/m2). Demographic
EMCV: Encephalomyocarditis Virus
characteristics
HAV: were balanced
Hepatitis A Virusacross the treatment groups.
0 (0%)
EVARRESTCPV: was Canine
shownParvovirus
to have a statistically significant difference compared to ORC, 98.3% versus 53.3%
0 (0%) (p < 0.0001), in the proportion of subjects achieving hemostatic success at 4 minutes after identification of the
0 (0%) Table 3. Virus Reduction
target bleeding site and randomization,Factors forno
with Human Thrombin
re-bleeding requiring treatment during a subsequent 6-minute
0 (0%) observation period and sustained hemostasis until fascial closure at the end
Reduction of the(log
Factor surgery
) of(Table
virus 4).
tested
10
0 (0%) Table 4. Subjects Achieving Hemostasis at 4 Minutes from Identification of the†Target Bleeding Site
* Enveloped Viruses Non-Enveloped Viruses
0 (0%) and Randomization, with no Re-bleeding until Fascial Closure at the End of the Surgery
0 (0%) Manufacturing Step HIV-1 SBV BVDV PRV EMCV HAV CPV
Treatment 95% Confidence Distributed by:
0 (0%) EVARREST ORC p-value Difference NotInterval
Not Ethicon, Inc.
SD Treatment > 5.82 > 5.31 > 4.74 > 4.25 Tested Tested 0.0 Route 22 West, PO Box 151
0 (0%) 59/60 (98.3%) 16/30 (53.3%) <0.0001 45.0% 27.9%, 62.5%
Not Somerville, NJ 08876-0151
0 (0%) Nanofiltration > 4.36 > 5.32 Tested > 5.47 6.37 6.95 5.85 USA
0 (0%) The efficacy data for the 51 non-randomized subjects treated with EVARREST were supportive of the above
efficacyCumulative Virus
findings with Reduction
50/51 subjectsFactor > 10.18 hemostatic
(98.0%) achieving > 10.63 success
> 4.74 at 4>minutes
9.72 after
6.37 6.95 with
randomization 5.85 Manufactured by:
0 (0%) Omrix Biopharmaceuticals Ltd.
no re-bleeding
* HIV-1: requiring treatment during
Human Immunodeficiency Virusa Type
subsequent
1 6-minute observation period.
SBV: Sindbis Virus 14 Einstein Street
14.2 Liver Surgery Weizmann Science Park
BVDV: Bovine Viral Diarrhea Virus
ent groups. No Two prospective, randomized trials including a total of 206 subjects were performed to compare the safety and
PRV: Pseudorabies Virus Nes-Ziona, Israel
ic groups. hemostatic
† effectiveness of EVARREST® with that of Standard of Care (defined as manual compression with or
EMCV: Encephalomyocarditis Virus
at baseline, 4 to without aHAV:
topical absorbable
Hepatitis A Virushemostat), when used as an adjunct to control bleeding after primary methods to US License No. 1879
enzyme-linked achieve hemostasis
CPV: Canine(e.g., suture, cautery, ligature) proved ineffective or impractical during liver surgery.
Parvovirus © 2015 Ethicon, Inc.
wed an increase The first study included 104 subjects of median age 65 years (range 31 to 82 years); 58.7% of the subjects were
up treated with male; 95.2% were white/Caucasian; 1.9% were Asian; 1% were black; median body mass index was 27 kg/m2
ground levels at (range: 15 to 43 kg/m2). Demographic characteristics were balanced across the treatment groups.
ubjects. A total of 84 subjects were randomized into the trial in a 1:1 ratio (40 randomized to EVARREST, 44 to Standard
of Care). An additional 20 subjects were enrolled and treated with EVARREST during a non-randomized phase.
One subject should have been randomized to EVARREST but was treated with Standard of Care. This subject was
analyzed in the EVARREST group for the Intent to Treat Set.
EVARREST was shown to have a statistically significant difference compared to Standard of Care, 82.5% versus
uate and well-
29.5% (p < 0.0001), in the proportion of subjects achieving hemostatic success at 4 minutes after identification
tal harm when
of the target bleeding site and randomization, with no re-bleeding requiring treatment any time prior to the
n to a pregnant
initiation of wound closure (Table 5). The treatment difference between EVARREST and Standard of Care was
shown to be greater in subjects with bleeding in abnormal hepatic tissue (e.g., cirrhotic or steatotic) than in
subjects with normal tissue bleeding (65.2% versus 48.8%, respectively).
many drugs are
Table 5. Subjects Achieving Hemostasis at 4 Minutes from Identification of the Target Bleeding Site
and Randomization, with no Re-bleeding until Fascial Closure at the End of the Surgery
en under the age Standard Treatment 95% Confidence
recommended. EVARREST of Care p-value Difference Interval
es.
33/40 (82.5%) 13/44 (29.5%) <0.0001 53.0% 32.9%, 68.5%
No differences in
The efficacy data for the 20 non-randomized subjects treated with EVARREST were supportive of the above
efficacy findings, with 20/20 subjects (100.0%) achieving hemostatic success at 4 minutes after identification
of the target bleeding site and randomization with no re-bleeding requiring treatment any time prior to the
two biological initiation of wound closure.
omposite patch The second study included 102 subjects of median age 63 years (range 23 to 85 years) randomized into the trial in a
tive side has an 1:1 ratio (50 randomized to EVARREST, 52 to Standard of Care). Sixty-one percent of the subjects were male; 85.3%
were white/Caucasian; 9.8% were black; 2.9% were Asian; 3% were Hispanic; median body mass index was 27 kg/
rlying a layer of m2 (range: 15 to 43 kg/m2). Demographic characteristics were balanced across the treatment groups.
nents. The patch EVARREST was shown to have a statistically significant difference compared to Standard of Care, 96% versus
nical integrity to 46.2% (p < 0.0001), in the proportion of subjects achieving hemostatic success at 4 minutes after identification
organs. of the target bleeding site and randomization with no re-bleeding requiring treatment any time prior to the
per square inch initiation of wound closure (Table 6). The treatment difference between EVARREST and Standard of Care was
e cm) of human shown to be greater in subjects undergoing non-anatomic resection than in subjects undergoing anatomic
uman albumin, resection (58.1% versus 39.5%, respectively). Data from this study further support the efficacy of EVARREST as an
reservative. adjunct to hemostasis in the control of bleeding in liver surgery.
ng resulting in a Table 6. Subjects Achieving Hemostasis at 4 Minutes from Identification of the Target Bleeding Site
42 and Randomization, with no Re-bleeding until Fascial Closure at the End of the Surgery 43

ufactured from Standard Treatment 95% Confidence

tested by FDA- EVARREST of Care p-value Difference Interval
munodeficiency 48/50 (96.0%) 24/52 (46.2%) <0.0001 49.8% 34.5%, 63.5%
© 2015 Ethicon US, LLC. All rights reserved. 031973-150326