1 HIGHLIGHTS OF PRESCRIBING INFORMATION

2 These highlights do not include all the information needed to use EVICEL® safely
3 and effectively. See full prescribing information for EVICEL®.
4
5
6 EVICEL® Fibrin Sealant (Human)
7 For Topical Use Only
8 Frozen solutions of BAC2 (Fibrinogen) and Thrombin
9 Initial U.S. approval: 2003
10
11 ------RECENT MAJOR CHANGES------
12 DOSAGE AND ADMINISTRATION, Application Techniques (2.3) 04/2013-------
13 WARNINGS and PRECAUTIONS; Application Precautions (5.1) 04/2013------
14 ADVERSE REACTIONS, Clinical Trials Experience (6.1) 04/2013-------
15 ADVERSE REACTIONS, Post-Marketing Experience (6.2) 04/2013-------
16
17 INDICATIONS AND USAGE------
18 • EVICEL® is a fibrin sealant indicated as an adjunct to hemostasis for use in patients
19 undergoing surgery, when control of bleeding by standard surgical techniques (such as
20 suture, ligature or cautery) is ineffective or impractical. (1).
21
22 ------DOSAGE AND ADMINISTRATION------
23 • For Topical Use Only. Do not inject directly into the circulatory system. (2, 4)
24 • After thawing, use the two components of EVICEL® (BAC2 and Thrombin) within 24
25 hours if stored at room temperature, or within 30 days if stored refrigerated.(2,1,16)
26 • Spray or drip EVICEL® Fibrin Sealant (Human) onto the tissue in short bursts (0.1-0.2
27 ml) to produce a thin, even layer. Spray EVICEL® using only pressurized CO2 gas.
28 Apply a second layer if the hemostatic effect is not [Link] amount of
29 EVICEL® required depends upon the area of tissue to be treated and the method of
30 application (2.2).
31 • Vials are for single use only. Discard unused contents (2.2, 16).
32 -------DOSAGE FORMS AND STRENGTHS------
®
33 EVICEL is supplied as a kit consisting of two separate packages:
34 • A package containing one vial each of BAC2 (55-85 mg/ml fibrinogen) and Thrombin
35 (800-1200 IU/ml human thrombin) frozen solutions.

1
36 • A modular spray application device which includes a 6 cm yellow flexible tip.
37 Optional accessory tips are distributed seperatly.
38 The different EVICEL dosage strengths include the following sizes:
BAC2 Vial Size Thrombin Vial Size Package Size
1.0 ml 1.0 ml 2.0 ml
2.0 ml 2.0 ml 4.0 ml
5.0 ml 5.0 ml 10.0 ml
39
40 ------CONTRAINDICATIONS------
41
42 • Do not inject directly into the circulatory system (4.1).
43 • Do not use in individuals known to have anaphylactic or severe systemic reaction to
44 human blood products (4.2).
45 • Do not use for the treatment of severe or brisk arterial bleeding (4.3).
46 • Do not use EVICEL® for spraying in endoscopic (intraluminal) procedures where the
47 minimum recommended distance from the applicator tip to the target site cannot be
48 assured (2.3, 4.4).
49
50 ------WARNINGS AND PRECAUTIONS------
51 • Life-threatening air or gas embolism has occurred with the use of spray devices
52 employing a pressure regulator to administer EVICEL®. This event appears to be
53 related to the use of the spray device at higher than recommended pressures and/or in
54 close proximity to the surface of the tissue (5.1).
55 • Monitor changes in blood pressure, pulse, oxygen saturation and end tidal CO2 when
56 spraying EVICEL® due to the possibility of occurrence of gas embolism (5.1).
57 • To reduce the risk of potentially life-threatening gas embolism, spray EVICEL® using
58 only pressurized CO2 gas at the recommended pressures and distances (2.3).
59 • Use EVICEL® spray application only if it is possible to accurately judge the spray
60 distance, especially during laparoscopy (2.3, 4.4).
61 • Apply EVICEL® as a thin layer (2.3).
62 • Prior to applying EVICEL®, dry surface areas of the wound by standard techniques
63 (e.g. intermittent application of compresses, swabs, use of suction devices) (2.3).
64 • Prepare and administer EVICEL® according to the instructions and with only devices
65 recommended for this product (2.3).
66 • May carry a risk of transmitting infectious agents (e.g., viruses, the bacteria, parasites,
67 variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the classic CJD
68 agent (5.2).
69
70
71
72

2
73 ------ADVERSE REACTIONS------
74 Most common adverse reactions reported in clinical trials (≥5%) are bradycardia, nausea,
75 hypokalemia, insomnia, hypotension, pyrexia, graft infection, vascular graft occlusion,
76 peripheral edema, constipation (6.1).
77 Most common adverse reactions reported in post-marketing expierence are oedema,
78 pyrexia, seroma, haematoma, tachycardia, dyspnoea, and urticaria (6.2).
79 To report SUSPECTED ADVERSE REACTIONS, contact ETHICON Customer
80 Support Center at (877) 384-4266 or FDA at 1-800-FDA-1088 or
81 [Link]/medwatch.
82
83 ------DRUG INTERACTIONS------
84 No drug interactions are known.
85
86 See 17 for PATIENT COUNSELING INFORMATION
87
88 Revised: /2013

3
FULL PRESCRIBING INFORMATION: CONTENTS 1

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION
2.1 THAWING
2.2 PREPARATION PRIOR TO APPLICATION
2.3 APPLICATION TECHNIQUES
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
4.1 INTRAVASCULAR APPLICATION
4.2 HYPERSENSITIVITY
4.3 ARTERIAL BLEEDING
4.4 SPRAY APPLICATION
5 WARNINGS AND PRECAUTIONS
5.1 APPLICATION PRECAUTIONS
5.2 INFECTION RISK FROM HUMAN PLASMA
6 ADVERSE REACTIONS
6.1 CLINICAL TRIALS EXPERIENCE
6.2 POST-MARKETING EXPERIENCE
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 PREGNANCY
8.2 LABOR AND DELIVERY
8.3 NURSING MOTHERS
8.4 PEDIATRIC USE
8.5 GERIATRIC USE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 MECHANISM OF ACTION
12.2 PHARMACODYNAMICS
12.3 PHARMACOKINETICS
13 NONCLINICAL TOXICOLOGY
13.1 LOCAL TOLERANCE AND ACUTE-REPEAT TOXICOLOGY STUDIES
13.2 NEUROTOXICITY
13.4 CARCINOGENESIS
13.5 MUTAGENESIS
13.6 FERTILITY
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION

1
Sections or subsections omitted from the full prescribing information are not listed

4
 1 FULL PRESCRIBING INFORMATION

2 1 INDICATIONS AND USAGE

3 EVICEL® Fibrin Sealant (Human) is indicated as an adjunct to hemostasis for use in patients
4 undergoing surgery, when control of bleeding by standard surgical techniques (such as
5 suture, ligature, or cautery) is ineffective or impractical.

6 2 DOSAGE AND ADMINISTRATION

7 FOR TOPICAL USE ONLY – DO NOT INJECT
8
9 2.1 Thawing
10 Thaw the two components of EVICEL® (BAC2 and Thrombin) in one of the following
11 ways:
12 • 2°C to 8°C (refrigerator); vials thaw within 1 day; or
13 • 20°C to 25°C (room temperature); vials thaw within 1 hour; or
14 • 37°C; vials thaw within 10 minutes and must not be left at this temperature for longer
15 than 10 minutes. The temperature must not exceed 37°C.
16
17 2.2 Preparation Prior to Application
18 Once thawed, use the components of EVICEL® (BAC2 and Thrombin) within 30 days if
19 refrigerated or within 24 hours if stored at room temperature.
20 Do not use after the expiration date stated on the box, or after 30 days if refrigerated after
21 thawing. Do not re-freeze EVICEL® once it has been thawed. Do not refrigerate EVICEL®
22 after storage at room temperature. Discard unused product after 24 hours at room
23 temperature.
24 Discard if the packaging of EVICEL® is damaged.

25 While maintaining a sterile surgical field, prepare the product assembly as follows:
26 a) Draw the BAC2 and Thrombin into the application device (see diagram enclosed in
27 the application device package).
28 b) Both syringes of the application device should be filled with equal volumes and
29 should not contain air bubbles.
30 c) Carefully remove the vial assembly. Use a gentle rotation to ensure valve
31 engagement.
32 Prior to applying EVICEL®, dry surface areas of the wound by standard techniques (e.g.
33 intermittent application of compresses, swabs, use of suction devices).” (2.3)
34
35 The 35 cm and 45 cm accessory tips should only be used by persons trained in laparoscopic,
36 laparoscopic-assisted, endoscopic or open surgical procedures.
37

5
38 Prepare and administer EVICEL® according to the instructions and with only devices
39 recommended for this product.
40 2.3 Application Techniques
41 For Topical Use Only. Apply EVICEL® to the surface of bleeding tissue only. Do not inject
42 directly into the circulatory system.
43 Spray or drip EVICEL® in short bursts (0.1-0.2 ml) onto the tissue to produce a thin, even
44 layer. If the hemostatic effect is not complete, apply a second layer. The amount of
45 EVICEL® required depends upon the area of tissue to be treated and the method of
46 application. As an approximate guide, if a layer of 1 mm thickness is produced by spraying
47 EVICEL®, the surface areas that can be covered by each of the kit sizes are given in Table 1.
48 Table 1: Area of coverage of each kit size
49
BAC2 Vial Thrombin Vial Package Size Area of Coverage
Size Size with Layer of 1
mm Thickness
1.0 ml 1.0 ml 2.0 ml 20 cm2
2.0 ml 2.0 ml 4.0 ml 40 cm2
5.0 ml 5.0 ml 10.0 ml 100 cm2
50
51 Use standard surgical techniques for hemorrhagic control, including suture, ligature and
52 cautery prior to the application of EVICEL®. Remove excess blood from the site of
53 application to the extent possible using standard techniques (e.g. intermittent application of
54 compresses, swabs, use of suction devices). Apply EVICEL ® with the application device
55 supplied. EVICEL® forms a transparent layer on application through which specific
56 bleeding points may be observed; these bleeding points may be sutured or electrocauterized
57 through the layer of EVICEL®.
58 Vials are for single use only. Discard unused contents (see HOW SUPPLIED/STORAGE and
59 HANDLING (16)).
60
61 Application by Dripping
62 a) Keep the tip of the applicator as close to the tissue surface as possible without
63 touching the tissue during application.
64 b) Apply individual drops to the surface area to be treated.
65 c) Allow the drops to separate from each other and from the tip of the applicator. If the
66 applicator tip becomes blocked, wipe the yellow catheter tip clean or cut it back in
67 0.5 cm increments.
68 Application by Spraying
69 a) To reduce the risk of potentially life-threatening gas embolism, spray EVICEL®
70 using only pressurized CO2 gas at the recommended pressures and distances for each
71 applicator tip. Connect the short gas tube on the application device to the luer-lock
72 end of the long gas tube.

6
73 b) Connect the luer-lock of the gas tube (with the 0.2 µm filter) to a pressure regulator
74 capable of delivering 15-25 psi (1.0-1.7 bar) of CO2 pressure.
75 c) Ensure that gas pressure for open or laparoscopic procedures and specific accessory
76 tips is set as indicated by the device manufacturer. The pressure regulator should be
77 set as specified in Table 2 for each applicator tip (see WARNINGS and
78 PRECAUTIONS, Application Precautions (5.1) and ADVERSE REACTIONS, Post-
79 Marketing (6.2)).
80 d) Carefully monitor insufflation pressure in all laparoscopic procedures.
81 e) Ensure that the distance between the applicator tip head and the application bed is
82 within the ranges recommended by the device manufacturer. Specific distances for
83 open or laparoscopic surgery and for each applicator tip are defined in Table 2 (see
84 WARNINGS and PRECAUTIONS, Application Precautions (5.1) and ADVERSE
85 REACTIONS, Post-Marketing (6.2)).
86
87 Table 2: Application Parameters
88
Surgery Applicator tips to be used Distance from target Spray pressure
tissue
Open surgery 6 cm Yellow Flexible Tip
10-15 cm 20-25 psi
35 cm Black Rigid Tip
(4 – 6 in) (1.4-1.7 bar)
45 cm Yellow Flexible Tip
Laparoscopic 35 cm Black Rigid Tip 4 – 10 cm 15 – 20 psi
procedures (1.6 – 4 in) (1.0-1.4 bar)
45 cm Yellow Flexible Tip 4-10 cm (1.6 – 4 20-25 psi
inches) (1.4-1.7 bar)
89
90 See instructions enclosed in the application device and accessory tip packages.
91

92 3 DOSAGE FORMS AND STRENGTHS

93 EVICEL® is supplied as a kit consisting of two separate packages:
94 • A package containing one vial each of BAC2 (55-85 mg/ml fibrinogen) and Thrombin
95 (800-1200 IU/ml human thrombin) frozen solutions.
96 • A modular spray application device which includes a 6 cm flexible yellow tip. Optional
97 accessory tips are distributed seperately.
98 The different EVICEL® dosage strengths include the following sizes (Table 3):
99
100
101
102
103

7
104 Table 3: EVICEL® package sizes
105
BAC2 Vial Size Thrombin Vial Size Package Size
1.0 ml 1.0 ml 2.0 ml
2.0 ml 2.0 ml 4.0 ml
5.0 ml 5.0 ml 10.0 ml
106

107 4 CONTRAINDICATIONS
108 4.1 Intravascular Application
109 Do not inject EVICEL® directly into the circulatory system. Intravascular application of
110 EVICEL® may result in life-threatening thromboembolic events (see WARNINGS and
111 PRECAUTIONS, Application Precautions (5.1) and ADVERSE REACTIONS, Post-
112 Marketing Experience (6.2)).
113
114 4.2 Hypersensitivity
115 Do not use EVICEL® in individuals known to have anaphylactic or severe systemic reaction
116 to human blood products (see ADVERSE REACTIONS, Post-Marketing Experience (6.2)).
117
118 4.3 Arterial Bleeding
119 Do not use EVICEL® for treatment of severe or brisk arterial bleeding. In these situations,
120 EVICEL® will be washed away in the flow of blood before hemostasis can be attained.
121
122 4.4 Spray Application
123 • Do not use EVICEL® for spraying in endoscopic (intraluminal) procedures where the
124 minimum recommended distance from the applicator tip to the target site cannot be
125 assured (2.3, 4.4).
126

127 5 WARNINGS AND PRECAUTIONS

128 5.1 Application Precautions
129 Apply EVICEL® as a thin layer. Excessive clot thickness may negatively interfere with the
130 product’s efficacy and the wound healing process.
131
132 To reduce the risk of potentially life threatening air embolism, spray EVICEL® using
133 pressurized CO2 gas only. For specific spray instructions on the recommended pressure and
134 distance from tissue per type of surgical procedure and length of application tip, see Section
135 2.2.
136

8
137 Use EVICEL® spray application only if it is possible to accurately judge the distance from
138 the spray tip to the tissue surface, especially during laparoscopy.
139
140 Monitor changes in blood pressure, pulse, oxygen saturation and end tidal CO2 when
141 spraying EVICEL® due to the possibility of occurrence of gas embolism.
142
143 When using accessory tips with this product, follow the the instructions for use of the tips
144 with attention to the spray pressure and distance ranges for each tip.
145
146 Prior to applying EVICEL®, dry surface areas of the wound by standard techniques (e.g.
147 intermittent application of compresses, swabs, use of suction devices).
148
149 .
150 5.2 Infection Risk from Human Plasma
151 Because EVICEL® is made from human plasma, it may carry a risk of transmitting
152 infectious agents (e.g., viruses, the bacteria, parasites, variant Creutzfeldt-Jakob disease
153 (vCJD) agent, and, theoretically, the classic CJD agent.”The risk of transmitting an
154 infectious agent has been reduced by screening plasma donors for prior exposure to
155 certain viruses, by testing for the presence of certain current virus infections, and by
156 inactivating and removing certain viruses. Despite these measures, such products can still
157 potentially transmit disease. There is also the possibility that unknown infectious agents
158 may be present in such products. All infections thought by a physician to have been
159 possibly transmitted by this product should be reported by the physician or other
160 healthcare provider to ETHICON Customer Support Center at (877) 384-4266. The
161 physician should discuss the risks and benefits of this product with the patient.
162

163 6 ADVERSE REACTIONS

164 6.1 Clinical Trials Experience
165
166 Because clinical trials are conducted under widely varying conditions, adverse reaction rates
167 observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
168 trials of another drug and may not reflect the rates observed in practice.
169 The following adverse reactions which occurred during clinical studies were evaluated as
170 having a possible causal relationship to treatment with EVICEL®. The frequency of all of the
171 reactions listed below was common (defined as > 1/100, < 1/10).
172
173 Table 4: Adverse Reactions Clinical Trials Experience
MedDRA System Organ Class Preferred Term
Adverse Reactions in Retroperitoneal or Intra-Abdominal Surgery Study
Infections and infestations Abdominal abscess
Adverse Reactions in Vascular Surgery Study

9
 Infections and infestations Graft infection, Staphylococcal
infection
Vascular disorders Hematoma
General disorders and administration Edema, peripheral
site conditions
Investigations Decreased hemoglobin
Injury, Poisoning and Procedural Incision site hemorrhage
Complications
174
175
176 Adverse Reaction Rates in Retroperitoneal or Intra-Abdominal Surgery Study
177 Among 135 patients undergoing retroperitoneal and intra-abdominal surgery (67 patients
178 treated with EVICEL® and 68 controls), one abdominal abscess in the EVICEL® group and
179 one abdominal and one pelvic abscess in the control group) were considered by the Sponsor
180 to be possibly related to study treatment.
181
182 Adverse Reactions - Vascular Surgery
183 In a controlled study involving 147 patients undergoing vascular grafting procedures (75
184 treated with EVICEL® and 72 controls), nine patients experienced 12 adverse events that
185 were assessed by the Sponsor as being possibly related to treatment. These included graft or
186 staphylococcal infection, hematoma, incision site hemorrhage, peripheral edema, and
187 decreased hemoglobin.
188
189 Adverse Reactions - Liver Surgery
190 In a controlled study involving 121 patients undergoing liver surgery (58 treated with fibrin
191 sealant and 63 controls), no adverse reactions causally related to the study treatment were
192 observed.
193
194
195 6.2 Post-Marketing Experience
196 Because these reactions are reported voluntarily from a population of uncertain size, it is
197 not always possible to reliably estimate the frequency or establish a causal relationship to
198 drug exposure.
199 Post-marketing fatalities due to air embolism have been reported in association with the use
200 of EVICEL® when applied using a spray device. These cases have occurred where
201 EVICEL® was sprayed at a higher than indicated pressure for the device in use and when the
202 spray tip was placed closer than the specified distance from the target site.
203
204 The following adverse reactions have been reported in post-marketing experience with
205 EVICEL® and are categorized by MedDRA System Organ Class and Perferred Terms in
206 order of decreasing frequency:

10
207 Table 5: Adverse Reactions Post-Marketing Experience
MedDRA System Organ Class Preferred Term
General disorders and administration site Oedema, pyrexia
conditions
Injury, poisoning and procedural complications Seroma
Vascular disorders Haematoma
Infections and infestations Abdominal abscess
Cardiac disorders Tachycardia, cardiac arrest
Respiratory, Thoracic and Mediastinal disorders Dyspnoea, pulmonary embolism
Skin and subcutaneous tissue disorders Urticaria
208
209

210 7 DRUG INTERACTIONS

211 No drug interactions are known.
212

213 8 USE IN SPECIFIC POPULATIONS

214 8.1 Pregnancy
215 Pregnancy Category C
216 Animal reproduction studies have not been conducted with EVICEL®. It is not known
217 whether EVICEL® can cause fetal harm when administered to a pregnant woman or can
218 affect reproduction capacity. EVICEL® should be given to a pregnant woman only if clearly
219 needed.
220 8.2 Labor and Delivery
221 The safety of EVICEL® for use during labor and delivery has not been established.
222
223 8.3 Nursing Mothers
224 The safety of EVICEL® for use during breast-feeding has not been established. Use only if
225 clearly needed.

11
226 8.4 Pediatric Use
227 Limited data are available to support the safety and effectiveness of EVICEL® in children.
228 No data are currently available for ages 0 to 6 months.
229 Of 135 patients undergoing retroperitoneal and intra-abdominal surgery who were included
230 in the adequate and well controlled study of EVICEL®, 4 patients treated with EVICEL®
231 were age 16 years or younger. Of these, 2 were children age 2 to 11 years and 2 were
232 adolescents of 12 to 16 years.
233 Pediatric patients for vascular surgery are rare and were therefore not included in the clinical
234 trials involving vascular surgery.
235 Of the 155 patients undergoing liver surgery who were treated in adequate and well-
236 controlled studies, eight were pediatric patients. Of these, five were less than 2 years old and
237 three were between 2 and 12 years old.
238 Use of EVICEL® in pediatric patients above age 6 months is supported by these data and by
239 extrapolation of efficacy in adults. Data can not be extrapolated to ages 0 to 6 months.
240
241 8.5 Geriatric Use
242 Clinical trials included 101 patients of 65 years of age or older (30 undergoing
243 retroperitoneal or intra-abdominal surgery, 24 undergoing liver surgery and 47 undergoing
244 vascular surgery).
245 No differences in safety or effectiveness were observed between the elderly and younger
246 patients.
247

248 11 DESCRIPTION
249 EVICEL® is manufactured from pooled human plasma. EVICEL® is provided as a single use
250 kit consisting of two packages: One package contains one vial of Biological Active
251 Component 2 (BAC2) and one vial of Thrombin. The second package contains a sterile
252 spray application device. The two components (BAC2 and Thrombin) should be mixed and
253 applied topically as described in the Dosage and Administration Section (2).
254 The BAC2 and Thrombin components appear as white to slightly yellowish opaque masses
255 when frozen and as clear to slightly opalescent and colorless to slightly yellowish solutions
256 when thawed. The components contain no preservatives.
257 BAC2
258 BAC2 is a sterile solution, pH 6.7-7.2, which consists mainly of a concentrate of human
259 fibrinogen. Fibrinogen is a protein from human blood that forms a clot when combined with
260 thrombin. The composition of the BAC2 solution is as follows:
261 Active ingredient:
262 Concentrate of human fibrinogen (55-85 mg/ml)
263 Other Ingredients:

12
264 Arginine hydrochloride, glycine, sodium chloride, sodium citrate, calcium chloride, water
265 for injection (WFI)
266
267 Thrombin
268 Thrombin is a sterile solution, pH 6.8-7.2, which contains purified human thrombin that
269 activates clotting of the final combined product. Thrombin is a specific protease that
270 transforms the fibrinogen contained in BAC2 into fibrin.
271
272 The composition of the Thrombin solution is as follows:
273
274 Active Ingredient:
275 Human thrombin (800-1200 IU/ml)
276 Other Ingredients:
277 Calcium chloride, human albumin, mannitol, sodium acetate, water for injection (WFI)
278
279 Cryoprecipitate, which is the starting material for BAC2, and cryo-poor plasma, which is the
280 starting material for the production of Thrombin, are both made from pooled human plasma
281 that is obtained from US licensed plasma collection centers. BAC2 is manufactured from
282 pooled human Source Plasma and Thrombin is manufactured from pooled human source or
283 recovered plasma. All the plasma is obtained from US licensed plasma collection centers.
284 Cryoprecipitate manufacture may be performed by Grifols Therapeutics Inc., 155 Duryea
285 Road, Melville, NY 11747 (License No. 1716).
286
287 Viral Clearance
288 Individual plasma units which are obtained for the production of EVICEL® are tested by
289 FDA-licensed serological tests for HBsAg, HIV 1 & 2 Ab and HCV Ab as well as FDA-
290 licensed Nucleic Acid Testing (NAT) methods for HCV and HIV-1. Recovered plasma units
291 are also tested for HTLV I/II.
292
293 Some viruses such as Hepatitis A Virus and Parvovirus B19 are particularly difficult to
294 remove or inactivate. Parvovirus B19 most seriously affects pregnant women or immune-
295 compromised individuals. The plasma units are tested by NAT for HAV, HBV. All tests for
296 HIV, HCV, HBV and HAV must be negative (non-reactive). However, since the
297 effectiveness of these test methods in detecting low levels of viral material is still under
298 investigation, the significance of a negative result for these viruses is unknown. NAT for
299 Parvovirus B19 is also performed, and the level of contamination is not permitted to exceed
300 10,000 copies/ml. This limit is applied to restrict the viral load of Parvovirus B19 in the
301 starting plasma pool.
302 In addition to the screening of plasma, each manufacturing pool is tested for HBsAg, HIV-1
303 & 2 Ab, HCV by NAT and for Parvovirus B19 by NAT. Manufacturing pool testing,
304 however, has a lower sensitivity than that of individual unit testing.
305

13
306 The manufacturing procedure for EVICEL® includes processing steps which are designed to
307 reduce the risk of viral transmission. In particular, both BAC2 and Thrombin undergo two
308 discrete virus inactivation/removal steps, summarized in Table 5:
309
310 Table 6: Steps for the reduction of viral transmission risk
311
Component
Step
BAC2 Thrombin
Solvent detergent treatment (1% Solvent detergent treatment (1%
1 TnBP, 1% Triton X-100) for 4 hours TnBP, 1% Triton X-100) for 6 hours
at 30°C at 26°C
2 Pasteurization (10 hours at 60°C) Nanofiltration
312
313 BAC2 is manufactured by treatment of cryoprecipitate with aluminum hydroxide gel to
314 adsorb the Vitamin K dependent clotting factors and it is then incubated with a solvent
315 detergent (SD) mixture (1% TnBP, 1% Triton X-100) for 4 hours at 30°C. The SD reagents
316 are removed by castor oil extraction and reverse phase chromatography (C-18 column) and
317 the preparation is subsequently treated by pasteurization.
318 Prior to pasteurization, sucrose and glycine are added as stabilizers. The solution is heated
319 to 60±0.5°C and maintained at that temperature for 10 hours. After pasteurization, the
320 stabilizers used for heat treatment are removed by diafiltration and the product is
321 concentrated by ultrafiltration. An affinity chromatography step is then used to remove
322 plasminogen from the product, after which it is concentrated. After concentration the
323 solution is formulated, sterile filtered and aseptically filled and frozen.
324 Thrombin is manufactured by chromatographic purification of prothrombin from cryo-poor
325 plasma followed by activation with calcium chloride. The manufacturing process includes
326 two separate steps for inactivation or removal of viruses. The first of these is treatment with
327 a SD mixture (1% TnBP, 1% Triton X-100) for 6 hours at 26°C to inactivate lipid
328 enveloped viruses.
329 The SD reagents are removed by cation exchange chromatography. Mannitol and human
330 albumin are used to stabilize the solution, which undergoes nanofiltration for removal of
331 both enveloped and non-enveloped viruses. After nanofiltration, the solution is formulated
332 with calcium chloride, sterile filtered and aseptically filled and frozen.
333 The efficiency of the virus inactivation/removal procedures in reducing the level of a range
334 of viruses has been assessed using viruses with a range of physico-chemical characteristics.
335 The results of virus removal/inactivation validation studies are summarized in Table 6:
336

14
337 Table 7: Results of virus removal/inactivation in validation studies
338
339 a) BAC2
340
Virus HIV-1 BVDV PRV EMCV HAV CPV
Reduction factor (log10)
SD Treatment >4.4 >4.4 >4.0 Not Done Not Done 0.0
Pasteurization >4.4 >5.5 6.0 3.7 >5. 8 1.3
Global Reduction Factor >8.8 >9.9 >10.0 3.7 >5. 8 1.3
341
342
343 b) Thrombin
344
Virus HIV-1 SBV BVDV PRV EMCV HAV CPV
Reduction factor (log10)
SD Treatment >5.8 >5.3 >4.7 >4.3 Not Done Not Done 0.0
Nanofiltration >4.4 >5.3 Not Done >5.5 6.4 7.0 5.9
Global Reduction Factor >10.2 >10.6 >4.7 >9.8 6.4 7.0 5.9
345 HIV-1: Human Immunodeficiency Virus Type 1
346 SBV: Sindbis Virus
347 BVDV: Bovine Viral Diarrhea Virus
348 PRV: Pseudorabies Virus
349 EMCV: Encephalomyocarditis virus
350 HAV: Hepatitis A Virus
351 CPV: Canine Parvovirus
352

353 12 CLINICAL PHARMACOLOGY

354 12.1 Mechanism of Action
355 The fibrin sealant system initiates the last phase of physiological blood coagulation.
356 Thrombin activates the conversion of fibrinogen into fibrin, which occurs by the splitting of
357 fibrinogen into fibrin monomers and fibrinopeptides. The fibrin monomers polymerize and
358 form a fibrin clot. Factor XIIIa, which is activated from Factor XIII by thrombin, crosslinks
359 fibrin. Calcium ions are required for FXIII activation by thrombin.
360
361 12.2 Pharmacodynamics
362 Pharmacodynamic studies were not conducted.
363 Clinical studies demonstrating hemostasis were conducted in a total of 167 patients
364 undergoing vascular surgery and in a total of 135 patients undergoing retroperitoneal and
365 intra-abdominal surgery. Efficacy data is provided in section 14.
366
367 12.3 Pharmacokinetics
368

15
369 Because EVICEL® is for topical use only and intravascular administration is contraindicated
370 (see CONTRAINDICATIONS, Intravascular Application (4.1)), pharmacokinetic studies
371 were not performed.
372 Studies have been conducted in rabbits to evaluate the absorption and elimination of
373 thrombin when applied to the cut surface of the liver resulting from partial hepatectomy.
374 Using 125I-thrombin it was shown that a slow absorption of biologically inactive peptides
375 resulting from the breakdown of thrombin occurred, reaching a Cmax in the plasma after 6-8
376 hours. At the Cmax, the plasma concentration represented only 1-2% of the applied dose.
377 The systemic exposure to thrombin when it is administered directly to a hepatic wound was
378 estimated to be approximately equivalent to that generated by minor bleeding.
379 Fibrin sealants are metabolized in the same way as endogenous fibrin, by fibrinolysis and
380 phagocytosis. As wound healing progresses, increased fibrinolytic activity is induced by
381 plasmin and decomposition of fibrin to fibrin degradation products is initiated.
382
383

384 13 NONCLINICAL TOXICOLOGY

385 13.1 Local Tolerance and Acute-Repeat Toxicology Studies
386 EVICEL® has been classified as non-irritant in the Primary Cutaneous Irritation Test and
387 slightly irritant in the Ocular Irritation test.
388 No toxicological effects due to the solvent detergent reagents (TnBP and Triton X-100) used
389 in the virus inactivation procedure are expected based on acute and repeat toxicity studies
390 and since the residual levels are less than 5µg/ml.
391
392 13.2 Neurotoxicity
393 Neurotoxicity studies performed with EVICEL® confirmed that subdural administration in
394 the rabbit was not associated with any evidence of neurotoxicity.
395
396 13.4 Carcinogenesis
397 Long-term animal studies have not been performed to evaluate the carcinogenic potential of
398 EVICEL® due to the human origin of both thrombin and fibrinogen contents.
399
400 13.5 Mutagenesis
401 Neither BAC2 nor Thrombin solution induces mutagenic effects in the Ames test. Studies
402 performed in bacteria to determine mutagenicity were negative for Thrombin alone, BAC
403 (containing fibrinogen, citrate, glycine, tranexamic acid, and arginine hydrochloride), TnBP
404 alone, and Triton X-100 alone at all concentrations tested. All concentrations of the
405 combination of TnBP and Triton X-100 also tested negative in assays performed to
406 determine mammalian cell mutagenicity, chromosomal aberrations and micronuclei
407 induction.
408

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409 13.6 Fertility
410 The effect of EVICEL® on fertility has not been evaluated.
411 Reproductive studies performed in rats with the combination of TnBP and Triton X-100 at
412 doses up to approximately 600-fold (TnBP, 900 µg/kg/day) and 3000-fold (Triton X-100,
413 4500 µg/kg/day) the human dose resulted in increased post-implantation loss and an
414 increased number of late resorptions. No embryo-fetal adverse effects were observed at
415 doses up to 200-fold (TnBP, 300 µg/kg/day) and 1000-fold (Triton X-100, 1500 µg/kg/day)
416 the human dose. Other studies performed with the combination of TnBP at doses
417 approximately 300-fold (TnBP, 450 µg/kg/day) and 1500-fold (Triton X-100, 2250
418 µg/kg/day) the human dose had increased resorption rates, decreased fetal body weights, and
419 an increased number of runts. No embryo-fetal adverse effects were observed at doses up to
420 100-fold (TnBP, 150 µg/kg/day) and 500-fold (Triton X-100, 750 µg/kg/day) the human
421 dose.
422
423

424 14 CLINICAL STUDIES

425
426 a) Retroperitoneal and Intra-Abdominal Surgery
427 In a prospective, randomized, controlled evaluation of the hemostatic efficacy of EVICEL®
428 as an adjunct to hemostasis for soft tissue bleeding during retroperitoneal or intra-abdominal
429 surgery, EVICEL® was shown to be superior to the control product (Surgicel®, oxidized
430 regenerated cellulose) in achieving hemostasis in less than 10 minutes (see Table 7).
431 Superiority was also established at the secondary efficacy endpoints of 7 and 4 minutes.
432 Table 8: Efficacy results in retroperitoneal and intra-abdominal surgery
433
Variable EVICEL® Control Relative Risk 95% CI for
n = 66 n = 69 (RR) RR
Hemostasis at 10 min 63 (95.5%) 56 (81.2%) 1.18 1.04; 1.36
Hemostasis ≤ 7 min 60 (90.9%) 53 (76.8%) 1.18 1.02; 1.40
Hemostasis ≤ 4 min 50 (75.8%) 37 (53.6%) 1.41 1.10; 1.86
434
435 b) Vascular Surgery
436 A prospective, randomized study was performed to compare the hemostatic efficacy of
437 EVICEL® versus manual compression during vascular surgical procedures utilizing
438 polytetrafluoroethylene graft material on end-to-side femoral artery anastomosis or upper
439 extremity vascular access arterial anastomosis.
440 A difference (p<0.001) in time to hemostasis was observed: 83.3% of the treatment subjects
441 as compared to 39.7% of control subjects achieved hemostasis by 4 minutes (see Table 8).
442 Table 9: Efficacy results in vascular surgery

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443
Number (%) of EVICEL® Manual
patients achieving Compression
hemostasis n=72 n=68
At 4 minutes 60 (83.3%) 27 (39.7%)
≤7 minutes 63 (87.5%) 42 (61.8%)
≤10 minutes 66 (91.7%) 48(70.6%)
444
445 c) Liver Surgery
446 EVICEL® was compared in a pivotal Phase III single-blind, randomized, parallel-group,
447 multi-center study to FDA-approved control topical hemostatic agents in 121 patients
448 undergoing liver resection at 15 centers. Patients were randomized (stratified by surgeon) at
449 the conclusion of the liver resection surgery if general oozing was present that could not be
450 controlled by further surgical methods and a topical hemostatic agent was needed to control
451 the bleeding from the liver surface. For the primary endpoint, time to hemostasis, the fibrin
452 sealant was shown to be statistically superior to the control hemostatic agents (5.3 minutes
453 for EVICEL® versus 7.7 minutes for control; one-sided p=0.011).
454
455 Center effects are to be expected in multicenter studies, particularly in surgical indications.
456 Data from one center, which used a specific control agent, made a major contribution to this
457 result. However, of the sixteen surgeons who treated more than one patient in this study, ten
458 found the time to hemostasis to be equivalent to, or shorter than that achieved with the
459 specific control agent used.
460

461 16 HOW SUPPLIED/STORAGE AND HANDLING

462 EVICEL® is supplied as a kit consisting of two separate packages:
463 • A package containing one vial each of BAC2 (55-85 mg/ml fibrinogen) and Thrombin
464 (800-1200 IU/ml human thrombin) frozen solutions.
465 • A spray application device.
466 The different EVICEL® dosage strengths include the following sizes (Table 9):
467 Table 10: EVICEL® package sizes
468
BAC2 Vial Size Thrombin Vial Size Package Size
1.0 ml 1.0 ml 2.0 ml
2.0 ml 2.0 ml 4.0 ml
5.0 ml 5.0 ml 10.0 ml
469
470 Storage and handling

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471 The vials must be stored in an upright position.
472 Store frozen vials at -18 °C or colder (frozen) for up to 2 years.
473 Unopened vials can be stored at 2°C to 8°C (refrigerated) for up to 30 days.
474 The two EVICEL® components, BAC2 and Thrombin, have been shown to be stable for up
475 to 24 hours at room temperature.
476 Do not use after the expiration date stated on the box, or after 30 days if stored at 2°C to 8°C
477 after thawing.
478 Do not re-freeze EVICEL® once it has been thawed.
479 Do not refrigerate EVICEL® once it has reached room temperature. Discard unused product
480 after 24 hours at room temperature.
481 Discard if the packaging of EVICEL® is damaged.

482 Vials are for single use only. Discard unused contents.

483 17 PATIENT COUNSELING INFORMATION

484 Because EVICEL® is made from human plasma, the physician should discuss the risks and
485 benefits with the patient.
486 Instruct patients to consult their physician if symptoms of B19 virus infection (fever,
487 drowsiness, chills, and runny nose followed about two weeks later by a rash and joint pain)
488 or Hepatitis A (several days to weeks of poor appetite, fatigue and low-grade fever followed
489 by nausea, vomiting and abdominal pain, dark urine, yellowed complexion) appear.
490
491
Distributed by: Manufactured by:
Ethicon, Inc. Omrix Biopharmaceuticals Ltd.
P.O. Box 151, MDA Blood Bank, Sheba Hospital
Somerville, NJ 08876-0151 Ramat-Gan
USA POB 888, Kiryat Ono 55000
ISRAEL
492
493 U.S. License No. 1603 Issued 8/2013
494 ETHICON, Inc. 2013 Article No. 80FZ00M3-4
495  Omrix Biopharmaceuticals, Ltd. 2013
496 R6200

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