VISTASEAL: Package Insert and Label Information (Page 3 of 3)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

VISTASEAL contains human fibrinogen and human thrombin. When applied onto the wound site and mixed, these biological components generate a cross-linked fibrin clot in a process that recreates the last stage of the human blood coagulation system. Fibrinogen is converted into fibrin monomers and fibrinopeptides by thrombin. The fibrin monomers aggregate and form a fibrin clot which stops the bleeding. Factor XIIIa, which is activated from factor XIII by thrombin, crosslinks fibrin. Calcium ions are required for both the conversion of fibrinogen and the crosslinking of fibrin.

12.2 Pharmacodynamics

There are no relevant pharmacodynamic data on VISTASEAL.

12.3 Pharmacokinetics

VISTASEAL is metabolized in the same way as endogenous fibrin by fibrinolysis and phagocytosis. No pharmacokinetic studies were conducted for VISTASEAL.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenicity, Mutagenesis, Impairment of Fertility

No animal studies were conducted to evaluate the carcinogenic or mutagenic effect of VISTASEAL or its effects on fertility.

14 CLINICAL STUDIES

Vascular surgery A prospective, randomized, controlled clinical study was performed to evaluate the safety and efficacy of Fibrin Sealant (Human) as adjunct to hemostasis in vascular surgery. Subjects underwent vascular surgical procedures utilizing polytetrafluoroethylene graft material on proximal end-to-side arterial anastomosis or upper extremity vascular access arterial anastomosis. The clinical trial was conducted with Fibrin Sealant (Human) using a Fibrijet® applicator. Fibrin Sealant (Human) was shown to be superior to the control group (manual compression) when comparing the proportion of subjects in each group who achieved hemostasis by 4 minutes (Table 9). Superiority was also established at 10 minutes. The median time to hemostasis was significantly shorter (p‑value <0.001) in the Fibrin Sealant (Human) treatment group (4.0 minutes) compared to the control group (≥10.0 minutes).

Table 9. Efficacy Results in Vascular Surgery (ITT Population)*
*Intent-to-treat (ITT) population: includes all subjects randomized to Fibrin Sealant (Human) or control.1 The ratio of proportion of subjects meeting the efficacy endpoint in the two treatment groups (Fibrin Sealant (Human) relative to control).CI = confidence interval. Tabulated efficacy results are cumulative results.
Efficacy endpoints Fibrin Sealant (Human) N=109 n (%) Control N=57 n (%) Ratio of -proportions1 (95% CI) P-value
Hemostasis by 4 minutes 83 (76.1) 13 (22.8) 3.3 (2.0, 5.4) <0.001
Hemostasis by 10 minutes 96 (88.1) 26 (45.6) 1.9 (1.4, 2.6) <0.001

Parenchyma surgery A prospective, randomized, controlled clinical study was performed to evaluate the safety and efficacy of Fibrin Sealant (Human) as adjunct to hemostasis in parenchyma surgery. Subjects underwent liver resections. The clinical trial was conducted with Fibrin Sealant (Human) using a Fibrijet® applicator. Fibrin Sealant (Human) was shown to be superior to the control group (oxidized regenerated cellulose) in achieving hemostasis by 4 minutes (Table 10). The median time to hemostasis was significantly shorter (p-value <0.001) in the Fibrin Sealant (Human) treatment group (2.0 minutes) compared to the control group (3.0 minutes).

Table 10. Efficacy Results in Liver Surgery (ITT Population)*
*Intent-to-treat (ITT) population: includes all subjects randomized to Fibrin Sealant (Human) or control.1 The ratio of proportions of subjects meeting the efficacy endpoint in the two treatment groups (Fibrin Sealant (Human) relative to control).CI = confidence interval Tabulated efficacy results are cumulative results.
Efficacy endpoints Fibrin Sealant (Human) N = 111 n (%) Control N = 113 n (%) Ratio of proportions 1 (95% CI) P-value
Hemostasis by 4 minutes 103 (92.8) 91 (80.5) 1.2 (1.0, 1.3) 0.010
Hemostasis by 2 minutes 62 (55.9) 47 (41.6) 1.3 (1.0, 1.8) 0.045

Soft tissue surgery A prospective, randomized, controlled clinical study was performed to evaluate the safety and efficacy of Fibrin Sealant (Human) as adjunct to hemostasis in soft tissue bleeding during retroperitoneal and pelvic surgical procedures, and during mastopexies and abdominoplasties. The clinical trial was conducted with Fibrin Sealant (Human) using a Fibrijet® applicator. Fibrin Sealant (Human) was shown to be non-inferior to the control group (oxidized regenerated cellulose) in achieving hemostasis by 4 minutes (Table 11).

Table 11. Efficacy results in retroperitoneal and pelvic surgery, mastopexies and abdominoplasties (ITT population)*
*Intent-to-treat (ITT) population: includes all subjects randomized to Fibrin Sealant (Human).1 The ratio of proportions of subjects meeting the efficacy endpoint in the two treatment groups (Fibrin Sealant (Human) relative to control). CI = confidence interval.Tabulated efficacy results are cumulative results.
Efficacy endpoints Fibrin Sealant (Human) N = 116 n (%) Control N = 108 n (%) Ratio of proportions1 (95% CI) P-value
Hemostasis by 4 minutes 96 (82.8) 84 (77.8) 1.1 (0.9, 1.2) 0.401

16 HOW SUPPLIED/STORAGE AND HANDLING

VISTASEAL is supplied as a single-dose kit comprised of two pre-filled syringes containing sterile frozen solutions of human fibrinogen (component 1) and human thrombin with calcium chloride (component 2), which are assembled in a single syringe holder. The syringe plungers are connected by a plunger link to ensure simultaneous application of the biological components. One Dual Applicator with two additional Airless Spray Tips is co-packaged with the product for application by spraying or dripping. The Airless Spray Tips are radiopaque. See Figure 9.

Figure 9
(click image for full-size original)

Figure 9

The available package sizes for VISTASEAL are shown in Table 12.

Table 12. VISTASEAL Package Sizes and NDC numbers
VISTASEAL Package Size NDC Numbers
Total Volume Human fibrinogen Human thrombin Carton Blister label
2 mL 1 mL 1 mL 61953-0011-1 61953-0011-2
4 mL 2 mL 2 mL 61953-0012-1 61953-0012-2
6 mL 3 mL 3 mL 61953-0013-1 61953-0013-2
10 mL 5 mL 5 mL 61953-0014-1 61953-0014-2

Storage
Store the frozen kit (VISTASEAL Fibrin Sealant (Human) with VISTASEAL Dual Applicator) in a freezer (at -18 °C [0 ºF] or colder) for up to 2 years. The cold storage condition must not be interrupted until use. Thaw before use. Once thawed, do not refreeze.

After thawing, VISTASEAL can be stored before use for not more than 48 hours at 2 ‑ 8 ºC [36 — 46 ºF] or 24 hours at room temperature (20 — 25 °C [68 — 77 ºF]) if it remains sealed in the original packaging. Once the package is opened, use VISTASEAL immediately during the surgery and discard any unused contents.

Keep the sterilized blister in the outer carton to protect from light.

Do not use after the expiration date printed on the outer carton and container labels. Discard if the package is damaged.

17 PATIENT COUNSELING INFORMATION

Instruct patients to immediately report to their physician symptoms of thrombosis or embolism which may include: pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body [ see Thrombosis (5.1)] .

Inform patients that VISTASEAL is made from human plasma and may carry a risk of transmitting infectious agents (e.g., viruses, the vCJD agent and, theoretically, the CJD agent). Instruct patients to report any symptoms that concern them and might be caused by infections.

Manufactured by:
INSTITUTO GRIFOLS, S.A.
BARCELONA — SPAIN
U.S. License No. 1181
Distributed by:
Ethicon, Inc.
Route 22 West, P.O. Box 151
Somerville, New Jersey 08876-0151
USA • 1-877-ETHICON • +1-513-337-6928
© Ethicon, Inc. 2018

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 61953-0011-1
Fibrin Sealant (Human)
VISTASEAL™
Frozen solutions
2 mL
ETHICON
VistaSeal™
Human Fibrinogen / Human Thrombin — For topical use. Do not inject.
CONTENTS
• 1 single-dose kit containing two pre-filled syringes, each with a sterile frozen solution, assembled in a syringe holder.
• 1 Dual Applicator with 2 additional Airless Spray Tips.
Component 1: 1 mL of human fibrinogen (80 mg/mL). Other ingredients: Sodium citrate, sodium chloride, arginine, L-isoleucine, L-glutamic acid monosodium and water for injections.
Component 2: 1 mL of human thrombin (500 IU/mL). Other ingredients: Calcium chloride, human albumin, sodium chloride, glycine and water for injections.
Contains no preservatives.
Store in a freezer (-18 °C [0 °F] or colder). The cold storage chain must not be interrupted until use.
Keep the sterilized blister in the outer carton in order to protect from light.
Thaw for use. Do not refreeze once thawed. After thawing, the kit can be stored before use for not more than 48 hours at 2 — 8 °C [36 — 46 °F] or 24 hours at room temperature (20 — 25 °C [68 — 77 °F]) if it remains sealed in the original packaging. Once packaging is opened, use product immediately.
For usage instructions and precautions, see enclosed package insert.
Discard any unused contents and administration devices after use.
Distributed by:
Ethicon, Inc.
Route 22 West, P.O. Box 151
Somerville, New Jersey 08876-0151
USA • 1-877-ETHICON • +1-513-337-6928
© Ethicon, Inc. 2018
pat. www.ethicon.com/patentmarking
Manufactured by:
Instituto Grifols, S.A.
2 Can Guasch St. Polígono Levante
08150 Parets del Vallès
Barcelona — SPAIN
U.S. License No. 1181
3057851
GTIN: 00361953001118
SN: XXXXXXXXXXXXXXXX
Lot: XXXXXXXXXX
Exp.: DD-MMM-YY

2 mL carton
(click image for full-size original)

Fibrinogen
80 mg/mL
1 mL
Lot
EXP
GRIFOLS
3055487

fibrinogen

Thrombin
500 IU/mL
1 mL
Lot
EXP
GRIFOLS
3055488

thrombin

VistaSeal™ 2mL
Lot
EXP
Thawed Exp:
3055495

removable seal
(click image for full-size original)

Fibrin Sealant (Human)
VistaSeal™
Frozen solutions
NDC 61953-0011-2
2 mL

Rx only
Human Fibrinogen / Human Thrombin — For topical use. Do not inject.
CONTENTS
1 single-dose kit containing two pre-filled syringes, each with a sterile frozen solution, assembled in a syringe holder.
Component 1: 1 mL of human fibrinogen (80 mg/mL). Other ingredients: Sodium citrate, sodium chloride, arginine, L-isoleucine, L-glutamic acid monosodium and water for injections.
Component 2: 1 mL of human thrombin (500 IU/mL). Other ingredients: Calcium chloride, human albumin, sodium chloride, glycine and water for injections.
Contains no preservatives. Store in a freezer (-18 °C [0 °F] or colder). Thaw for use.
Do not refreeze once thawed. For usage instructions and precautions, see enclosed package insert.
ETHICON
LOT
EXP
Manufactured by: Instituto Grifols, S.A.
Barcelona — SPAIN. U.S. License No. 1181
3055503

tyvek label
(click image for full-size original)
VISTASEAL human fibrinogen, human thrombin kit
Product Information
Product Type Item Code (Source) NDC:61953-0011
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:61953-0011-1 1 KIT in 1 PACKAGE, COMBINATION None
Quantity of Parts
Part # Package Quantity Total Product Quantity
Part 1 1 SYRINGE, GLASS 1 mL
Part 2 1 SYRINGE, GLASS 1 mL
Part 1 of 2
FIBRINOGEN fibrinogen solution
Product Information
Route of Administration TOPICAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Fibrinogen Human (Fibrinogen Human) Fibrinogen Human 80 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
Sodium Citrate, Unspecified Form
Sodium Chloride
Arginine
Isoleucine
Monosodium Glutamate Anhydrous
Water
Packaging
# Item Code Package Description Multilevel Packaging
1 1 mL in 1 SYRINGE, GLASS None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125640 11/01/2019
Part 2 of 2
HUMAN THROMBIN human thrombin solution
Product Information
Route of Administration TOPICAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Thrombin Human (Thrombin Human) Thrombin Human 500 [iU] in 1 mL
Inactive Ingredients
Ingredient Name Strength
Calcium Chloride
Albumin Human
Sodium Chloride
Glycine
Water
Packaging
# Item Code Package Description Multilevel Packaging
1 1 mL in 1 SYRINGE, GLASS None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125640 11/01/2019
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125640 11/01/2019
VISTASEAL human fibrinogen, human thrombin kit
Product Information
Product Type Item Code (Source) NDC:61953-0012
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:61953-0012-1 1 KIT in 1 PACKAGE, COMBINATION None
Quantity of Parts
Part # Package Quantity Total Product Quantity
Part 1 1 SYRINGE, GLASS 2 mL
Part 2 1 SYRINGE, GLASS 2 mL
Part 1 of 2
FIBRINOGEN fibrinogen solution
Product Information
Route of Administration TOPICAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Fibrinogen Human (Fibrinogen Human) Fibrinogen Human 80 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
Sodium Citrate, Unspecified Form
Sodium Chloride
Arginine
Isoleucine
Monosodium Glutamate Anhydrous
Water
Packaging
# Item Code Package Description Multilevel Packaging
1 2 mL in 1 SYRINGE, GLASS None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125640 11/01/2019
Part 2 of 2
HUMAN THROMBIN human thrombin solution
Product Information
Route of Administration TOPICAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Thrombin Human (Thrombin Human) Thrombin Human 500 [iU] in 1 mL
Inactive Ingredients
Ingredient Name Strength
Calcium Chloride
Albumin Human
Sodium Chloride
Glycine
Water
Packaging
# Item Code Package Description Multilevel Packaging
1 2 mL in 1 SYRINGE, GLASS None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125640 11/01/2019
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125640 11/01/2019
VISTASEAL human fibrinogen, human thrombin kit
Product Information
Product Type Item Code (Source) NDC:61953-0013
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:61953-0013-1 1 KIT in 1 PACKAGE, COMBINATION None
Quantity of Parts
Part # Package Quantity Total Product Quantity
Part 1 1 SYRINGE, GLASS 3 mL
Part 2 1 SYRINGE, GLASS 3 mL
Part 1 of 2
FIBRINOGEN fibrinogen solution
Product Information
Route of Administration TOPICAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Fibrinogen Human (Fibrinogen Human) Fibrinogen Human 80 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
Sodium Citrate, Unspecified Form
Sodium Chloride
Arginine
Isoleucine
Monosodium Glutamate Anhydrous
Water
Packaging
# Item Code Package Description Multilevel Packaging
1 3 mL in 1 SYRINGE, GLASS None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125640 11/01/2019
Part 2 of 2
HUMAN THROMBIN human thrombin solution
Product Information
Route of Administration TOPICAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Thrombin Human (Thrombin Human) Thrombin Human 500 [iU] in 1 mL
Inactive Ingredients
Ingredient Name Strength
Calcium Chloride
Albumin Human
Sodium Chloride
Glycine
Water
Packaging
# Item Code Package Description Multilevel Packaging
1 3 mL in 1 SYRINGE, GLASS None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125640 11/01/2019
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125640 11/01/2019
VISTASEAL human fibrinogen, human thrombin kit
Product Information
Product Type Item Code (Source) NDC:61953-0014
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:61953-0014-1 1 KIT in 1 PACKAGE, COMBINATION None
Quantity of Parts
Part # Package Quantity Total Product Quantity
Part 1 1 SYRINGE, GLASS 5 mL
Part 2 1 SYRINGE, GLASS 5 mL
Part 1 of 2
FIBRINOGEN fibrinogen solution
Product Information
Route of Administration TOPICAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Fibrinogen Human (Fibrinogen Human) Fibrinogen Human 80 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
Sodium Citrate, Unspecified Form
Sodium Chloride
Arginine
Isoleucine
Monosodium Glutamate Anhydrous
Water
Packaging
# Item Code Package Description Multilevel Packaging
1 5 mL in 1 SYRINGE, GLASS None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125640 11/01/2019
Part 2 of 2
HUMAN THROMBIN human thrombin solution
Product Information
Route of Administration TOPICAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Thrombin Human (Thrombin Human) Thrombin Human 500 [iU] in 1 mL
Inactive Ingredients
Ingredient Name Strength
Calcium Chloride
Albumin Human
Sodium Chloride
Glycine
Water
Packaging
# Item Code Package Description Multilevel Packaging
1 5 mL in 1 SYRINGE, GLASS None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125640 11/01/2019
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125640 11/01/2019
Labeler — GRIFOLS USA, LLC (048987452)
Establishment
Name Address ID/FEI Operations
Instituto Grifols SA 465562213 manufacture (61953-0011), manufacture (61953-0012), manufacture (61953-0013), manufacture (61953-0014)

Revised: 12/2020 GRIFOLS USA, LLC

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