FDA Label for Tisseel Fibrin Sealant

1 Indications And Usage

Hemostasis: TISSEEL is a fibrin sealant indicated for use as an adjunct to hemostasis in adult and pediatric patients (>1 month of age) undergoing surgery when control of bleeding by conventional surgical techniques (such as suture, ligature, and cautery) is ineffective or impractical. TISSEEL is effective in heparinized patients.

Sealing: TISSEEL is a fibrin sealant indicated as an adjunct to standard surgical techniques (such as suture and ligature) to prevent leakage from colonic anastomoses following the reversal of temporary colostomies.

2 Dosage And Administration

FOR TOPICAL USE ONLY – DO NOT INJECT

2.1 Preparation Of Tisseel Kit (Freeze-Dried)

Do not expose to temperature above 37°C
Do not microwave
Do not refrigerate or freeze after reconstitution
Vials and pre-filled syringes are for single use only. Discard any unused product.

Do not use iodine or heavy metal containing preparations such as betadine for disinfection of vial stoppers. Allow alcohol-based disinfectants to evaporate before puncturing stopper.

Use separate syringes and transfer devices for reconstituting Sealer Protein and Thrombin solutions and for application to prevent clotting.

The product must be used within 4 hours after reconstitution.

Freeze-dried Sealer Protein Concentrate and Thrombin are reconstituted in Fibrinolysis Inhibitor Solution and Calcium Chloride Solution, respectively. The Sealer Protein Solution and Thrombin Solution are then combined using the DUPLOJECT Preparation and Application System, or an equivalent delivery device cleared by FDA for use with TISSEEL, to form the Fibrin Sealant.

Prewarming TISSEEL Kit with FIBRINOTHERM
See FIBRINOTHERM manual for complete operating instructions. If a FIBRINOTHERM device is not available, contact Baxter (1-800-423-2090) for assistance.

• 1.Place all four vials from the TISSEEL Kit into the prewarmed wells of the FIBRINOTHERM, using the appropriately sized adapter ring(s), and allow the vials to warm for up to 5 minutes (room temperature product will take less time).

Preparation of Sealer Protein Solution with FIBRINOTHERM

• 1.Remove the caps from the Sealer Protein Concentrate and the Fibrinolysis Inhibitor Solution vials.
• 2.Transfer the Fibrinolysis Inhibitor Solution into the vial containing the freeze-dried Sealer Protein Concentrate using the sterile reconstitution components (see directions provided with the device system for specific reconstitution instructions). Gently swirl the vial to ensure that the product is completely soaked.
• 3.Place the vial into the largest opening of the FIBRINOTHERM device with the appropriate adaptor. Switch on the stirrer and allow the vial contents to stir until all Sealer Protein Concentrate is dissolved. Reconstitution is complete when no undissolved particles are visible.

Notes:

• -If the Sealer Protein Concentrate has not fully dissolved within 20 minutes discard the vial and prepare a fresh kit.
• -Keep the Sealer Protein Solution at 37°C without stirring. Stir shortly before drawing up the solution to ensure homogeneity.

Preparation of Thrombin Solution with FIBRINOTHERM

To reconstitute the Thrombin (Human) with the Calcium Chloride Solution; follow steps 1-3 under Preparation of Sealer Protein with FIBRINOTHERM utilizing the Thrombin and Calcium Chloride vials.

Transferring to the Sterile Field

For transfer of the Sealer Protein and Thrombin Solutions to the sterile field, the circulating nurse should disinfect the tops of the vials with a germicidal solution and allow to dry. The scrub nurse should withdraw the sterile solutions while the circulating nurse holds the non-sterile vials. Slowly withdraw the solution, by firm constant aspiration, to reduce the risk of large air bubbles.

2.2 Preparation Of Tisseel Pre-Filled Syringe (Frozen)

Do not expose to temperature above 37˚C Do not microwave
Do not refrigerate or re-freeze after thawing
Do not use TISSEEL (frozen) until it is completely thawed and warmed (liquid consistency) to 33-37^oC. Do not remove the protective syringe cap until use.

Sterile Water Bath (Quick Thawing): Transfer inner pouch to the sterile field, remove pre-filled syringe from inner pouch and place directly into sterile water bath ensuring the syringe is completely immersed in the water. Maintain the product at 33-37°C until use. If the package is opened or warmed to 33-37°C, it must be used within 4 hours.

Non-Sterile Water Bath: Maintain the pre-filled syringe in pouches and place into a water bath outside the sterile field ensuring the pouches remain submerged. Remove from the water bath after thawing and warming, dry the external pouch and transfer inner pouch with pre-filled syringe onto the sterile field. Maintain the product at 33-37°C until use. If the package is opened or warmed to 33-37°C, it must be used within 4 hours.

Incubator: Maintain the pre-filled syringe in pouches and place into an incubator. Remove from the incubator after thawing and warming. Transfer inner pouch with pre-filled syringe onto the sterile field. Maintain the product at 33-37°C until use. If the package is opened or warmed to 33-37°C, it must be used within 4 hours.

Room Temperature Thawing: Unopened pouches can be stored for up to 48 hours at room temperature (15-25°C). Before use, warm the product to 33-37°C and apply immediately. The total thawing and warming time cannot exceed 48 hours.

2.3 Method Of Application

TISSEEL must be sprayed only onto application sites that are visible. Dry the site of application as much as possible. The surface area of the wound needs to be dried using standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices). Do not use pressurized air or gas to dry the site.

When applying TISSEEL using a spray device, utilize the recommended gas, pressure and distance from tissue within the ranges recommended by the manufacturer as follows:

Apply TISSEEL as a thin layer by dripping or spraying using a cannula or spray set approved for use with TISSEEL. To reduce the risk of potentially life-threatening gas embolism, spray TISSEEL using only the appropriate pressurized gas within the pressure range and distance recommended in the device Instructions For Use (see Warnings and Precautions (5.2)). The treating physician will determine the amount of TISSEEL to be applied based on the surface to be covered. Ensure that the amount applied is sufficient to entirely cover the intended application area. The approximate surface areas covered by each package size of TISSEEL are listed in Table 5:

Avoid application beyond the intended area. Allow at least 2 minutes after application to achieve sufficient polymerization. If repeat application is needed, dry the site as much as possible before reapplying. Reapply after removing residues from the prior application or before polymerization takes place since TISSEEL may not adhere firmly to a polymerized layer.

In cases where very small volumes (1-2 drops) are required, expel and discard the first several drops from the application cannula immediately before application to ensure administration of adequately mixed TISSEEL.

TISSEEL Kit (Freeze-Dried)

Apply TISSEEL using the DUPLOJECT Fibrin Sealant Preparation and Application System or an equivalent delivery device (including open and minimally invasive spray devices) cleared by FDA for use with TISSEEL. Specific instructions for the use of TISSEEL in conjunction with each cleared delivery device are provided with the device.

TISSEEL Pre-filled Syringe (Frozen)

Apply pre-filled TISSEEL using the DUO Set accessory devices provided with the product or an equivalent delivery device (including open and minimally invasive spray devices) cleared by FDA for use with TISSEEL.

•  DUO Set Instructions (see below):
• 1.Insert plunger into syringe barrel.
• 2.Firmly connect the two syringe nozzles to the joining piece (Y connector) and secure it by fastening the tether strap to the syringe.
• 3.Fit an application cannula to the joining piece. Apply by depressing plunger.
•  Note: Interruption of TISSEEL application causes clogging in the cannula. Replace the cannula immediately prior to resuming application. If the opening of the joining piece (Y connector) facing the cannula is clogged, use the spare joining piece provided in the package.

Figure 1: DUO SET - image 01

Figure 1 DUO SET

3 Dosage Forms And Strengths

TISSEEL Kit (Freeze-Dried) is supplied as 2 mL, 4 mL and 10 mL (total volume) pack sizes with and without the DUPLOJECT System. TISSEEL Pre-Filled Syringe (Frozen) is supplied as 2 mL, 4 mL and 10 mL (total volume) pack sizes with the DUO Set.

4.1 Intravascular Application

Do not inject TISSEEL directly into the circulatory system or into highly vascularized tissue. Intravascular application of TISSEEL can lead to intravascular coagulation, can result in life-threatening thromboembolic events, and can increase the likelihood and severity of acute hypersensitivity reactions in susceptible patients (see Warnings and Precautions (5.3) and Adverse Reactions (6.2)).

4.2 Aprotinin Hypersensitivity

Do not use TISSEEL in individuals with a known hypersensitivity to aprotinin (see Warnings and Precautions (5.1) and Adverse Reactions (6)).

4.3 Severe Or Brisk Bleeding

Do not use TISSEEL for treatment of severe or brisk arterial or venous bleeding. In these situations, TISSEEL will be washed away in the flow of blood before hemostasis can be attained.

4.4 Application Below Minimum Recommended Distance From Target Site

Do not spray TISSEEL where the minimum recommended distance from the applicator tip to the target site cannot be assured.

5.1 Hypersensitivity Reactions

Hypersensitivity reactions including allergic/and anaphylactoid reactions can occur with the use of TISSEEL. Cases (<1/10,000) have been reported in post marketing experience with Baxter’s fibrin sealant (see Adverse Reactions (6.2)). In specific cases, these reactions have progressed to severe anaphylaxis. Such reactions may especially be seen if TISSEEL is applied repeatedly over time or in the same setting, or if systemic aprotinin has been administered previously. Even if the first treatment was well tolerated, this may not exclude the occurrence of an allergic reaction after a subsequent administration of TISSEEL or systemic aprotinin. Observed symptoms of allergic anaphylactic reactions to TISSEEL have included: bradycardia, tachycardia, hypotension, flushing, bronchospasm, wheezing, dyspnea, nausea, urticaria, angioedema, pruritus, erythema and paresthesia. Such reactions can also occur in patients receiving TISSEEL for the first time.

Aprotinin is included in TISSEEL for its antifibrinolytic properties. Aprotinin, a protein, is known to be associated with anaphylactic reactions. Even in the case of strict local application of aprotinin, there is a risk of anaphylactic reactions to aprotinin, particularly in the case of previous exposure (see Contraindications (4.2)). TISSEEL does not contain any substances of bovine origin.

Discontinue administration of TISSEEL in the event of hypersensitivity reactions. Mild reactions can be managed with antihistamines. Severe hypotensive reactions require immediate intervention using current principles of shock therapy. Remove remaining product from the application site.

5.2 Application Precautions

Any application of pressurized air or gas is associated with a potential risk of air or gas embolism, tissue rupture, or gas entrapment with compression, which may be life a threatening or fatal.

Life threatening/fatal air or gas embolism has occurred when Fibrin Sealants were administered using pressurized gas with open regulator spray devices. This can occur if a spray device is used at higher than recommended pressures and in closer than recommended proximity to the tissue surface. The solubility of compressed CO₂ is greater than either compressed N₂ or Air thereby reducing the potential effect of embolization.

Regardless of the type of gas used, to reduce the incidence of embolization, spray TISSEEL using only the recommended regulator, set within the recommended pressure range, with the appropriate applicator positioned at the recommended distance in .

Monitor changes in blood pressure, pulse, oxygen saturation and entidal CO₂ due to the possibility of air or gas embolism.

Use only spray catheters or applicators approved for use with TISSEEL.

TISSEEL must not be sprayed in enclosed body areas using the EASYSPRAY device and must be sprayed onto only visible application sites.

For Open Surgical procedures, use the EASYSPRAY device connected to a CO₂, Medical Air or Nitrogen compressed gas source along with the EASYSPRAY spray set, (see Method of Application (2.3)).

For Minimally Invasive Surgery procedures in enclosed body areas use of the DUPLOSPRAY MIS device connected only to compressed CO₂, along with DUPLOSPRAY applicator is recommended. The DUPLOSPRAY MIS device is specifically designed to prevent over pressurization of the body cavity through a dedicated ventline to reduce the risk of gas embolization, (see Method of Application (2.3)).

The sealer protein and thrombin solutions are denatured by alcohol, iodine or heavy metal ions. If any of these substances have been used to clean the wound area, the area must be thoroughly rinsed before the application of TISSEEL.

Apply TISSEEL as a thin layer as excess clot thickness can negatively interfere with wound healing.

5.3 Use In Surgery

To minimize the risk of intravascular application, exercise caution when using TISSEEL in surgery (see Contraindications (4.1) and Adverse Reactions (6.2)).

5.4 Use In Neurosurgical Procedures

The safety and effectiveness of TISSEEL used alone or in combination with biocompatible carriers in neurosurgical procedures or other surgeries involving confined spaces have not been evaluated, and its use in this setting is not approved by FDA (see Adverse Reactions (6.2) and Drug Interactions (7)).

5.5 Infection Risk From Human Plasma

TISSEEL is made from human plasma. Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically the Creutzfeldt-Jakob disease (CJD) agent.

All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxter Healthcare Corporation, telephone # 1-888-229-0001.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Increased D-Dimer levels have been observed during a clinical study in cardiovascular surgery (see Clinical Studies (14)), but did not exceed values reported in the literature occurring after this type of surgery. Postoperatively increased D-Dimers can result at least partly from the degradation of Fibrin Sealant.

There were no reports of serious, associated adverse reactions reported above 1% in clinical studies.

6.2 Post-Marketing Experience

Because adverse reactions are reported voluntarily and the population is of uncertain size, it is not always possible to reliably estimate the frequency of these reactions.

The following adverse reactions have been reported in the post-marketing experience.

Immune System Disorders: Hypersensitivity, including anaphylactic reaction and anaphylactic shock. Anaphylactic reactions and anaphylactic shock have included fatal outcomes.
Vascular Disorders: Hypotension, flushing, embolism, including cerebral artery embolism, cerebral infarction*, air embolism**
Skin and subcutaneous Tissue Disorders: Angioedema, erythema, impaired healing, pruritus, urticaria
Cardiac Disorders: Bradycardia, tachycardia
Respiratory Disorders: Bronchospasm, dyspnea, wheezing
Gastrointestinal Disorders: Nausea
Nervous System Disorders: Paresthesia
* as a result of intravascular application into the superior petrosal sinus
** As with other fibrin sealants life-threatening/fatal air or gas embolism when using devices with pressurized air or gas occurred; this event appears to be related to an inappropriate use of the spray device (e.g. at higher than recommended pressure and in close proximity to the tissue surface),

Class effect: Manifestations of hypersensitivity or allergic reactions associated with the class of fibrin sealant/hemostatic products include: application site irritation, chest discomfort, chills, headache, lethargy, restlessness and vomiting.

There have been reports of serious adverse events such as paralysis and other compressive complications possibly related to the use of fibrin sealants in combination with resorbable hemostatic agents. There have also been reports of fatalities following the misadministration of topical thrombin (see Warnings and Precautions (5.4)).

7 Drug Interactions

Oxidized cellulose-containing preparations can reduce the efficacy of TISSEEL and should not be used as carrier materials. No interaction studies have been performed.

Pregnancy Category C

Animal reproduction studies have not been conducted with TISSEEL. It is also not known whether TISSEEL can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Some viruses, such as parvovirus B19, are particularly difficult to remove or inactivate at this time. Parvovirus B19 most seriously affects pregnant women (fetal infection). TISSEEL should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TISSEEL is administered to nursing mothers.

8.4 Pediatric Use

Limited clinical study data are available with regard to the use of TISSEEL in children. Of 365 patients undergoing repeated cardiac surgery or emergency resternotomy in a clinical trial of TISSEEL, 27 pediatric patients aged 16 years or younger were treated with TISSEEL. Of these, 2 patients were less than 6 months, 2 patients were between the ages of 6 months and 2 years, 15 patients were between 3-11 years of age, and 8 patients were between 12-16 years of age. There were no differences in safety observed between these subjects and the overall population. (see Clinical Studies (14)).

8.5 Geriatric Use

Clinical studies included 218 patients aged 65 years of age or older treated with TISSEEL (159 undergoing cardiac surgery and 59 undergoing vascular surgery) (see Clinical Studies (14)). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

11 Description

TISSEEL [Fibrin Sealant] is a two-component fibrin sealant made from pooled human plasma. When combined, the two components, Sealer Protein and Thrombin mimic the final stage of the blood coagulation cascade.

Sealer Protein (Human)
Sealer Protein (Human) is a sterile, non-pyrogenic, vapor heated and solvent/detergent treated preparation made from pooled human plasma. Sealer Protein (Human) is provided either as a freeze-dried powder for reconstitution with Fibrinolysis Inhibitor Solution or as a finished frozen solution pre-filled into one side of a dual-chambered syringe. The active ingredient in Sealer Protein (Human) is fibrinogen. Sealer Protein (Human) solution contains fibrinolysis inhibitor, synthetic Aprotinin, that delays fibrinolysis. Aprotinin (Synthetic) is manufactured by solid phase synthesis from materials completely of non-human/non-animal origin.

Thrombin (Human)
Thrombin (Human) is a sterile, non-pyrogenic, vapor heated and solvent/detergent treated preparation made from pooled human plasma. Thrombin (Human) is also provided either as a freeze-dried powder for reconstitution with Calcium Chloride Solution or as a finished frozen solution pre-filled into one side of a dual-chambered syringe.

The reconstituted solution or pre-filled syringe contains:
Sealer Protein Solution

•  Total protein: 96 – 125 mg/mL
  Fibrinogen: 67 – 106 mg/mL
  Aprotinin (Synthetic): 2250 – 3750 KIU/mL
  Other ingredients include: human albumin, tri-sodium citrate, histidine, niacinamide, polysorbate 80 and water for injection.

Thrombin Solution

•  Thrombin (Human): 400 – 625 units/mL*
  Calcium Chloride: 36 – 44 µmol/mL
  Other ingredients include: human albumin, sodium chloride and water for injection.

* The potency expressed in units is determined with a clotting assay using an in-house internal standard that has been calibrated against the World Health Organization (WHO) Second International Standard for Thrombin, 01/580. Therefore, a unit (U) is equivalent to an International Unit (IU).

Viral Clearance
TISSEEL is made from pooled human plasma collected at US licensed collection centers. The vapor heat and solvent/detergent treatment steps used in the manufacturing process have been shown to be capable of significant viral reduction. No procedure, however, has been shown to be completely effective in removing viral infectivity from derivatives of human plasma (see Warnings and Precautions (5.5)). Validation studies were conducted using samples drawn from manufacturing intermediates for each of the two human plasma derived components. These samples were spiked with stock virus suspensions of known titers followed by further processing under conditions representative of respective manufacturing steps.

The virus reduction factors (expressed as log₁₀) of manufacturing steps for each of the viruses tested are shown in Table 6.

Table 6: Reduction Factors for Virus Removal and/or Inactivation

Sealer Protein Component
Manufacturing Step	Mean Reduction Factors [log10] of Virus Tested
	HIV-1	HAV	BVDV	PRV	MMV
Early Manufacturing Steps	n.d.	n.d.	n.d.	n.d.	2.7
Solvent/Detergent Treatment	>5.3	n.d.	>5.7	>5.9	n.d.
Vapor Heat Treatment	>5.5	>5.6	>5.7	>6.7	1.2
Overall Reduction Factor (ORF)	>10.8	>5.6	>11.4	>12.6	3.9
Thrombin Component
Manufacturing Step	Mean Reduction Factors [log10] of Virus Tested
	HIV-1	HAV	BVDV	PRV	MMV
Thrombin Precursor Mass Capture	3.2	1.5	1.8	2.5	1.2
Vapor Heat Treatment	>5.5	>4.9	>5.3	>6.7	1.0
Solvent/Detergent Treatment	>5.3	n.d.	>5.5	>6.4	n.d.
Ion Exchange Chromatography	n.d.	n.d.	n.d.	n.d.	3.6
Overall Reduction Factor (ORF)	>14.0	>6.4	>12.6	>15.6	5.8

n.d. = not determined

HIV-1: Human Immunodeficiency Virus 1; HAV: Hepatitis A Virus; BVDV: Bovine Viral Diarrhea Virus, a model for Hepatitis C Virus; PRV: Pseudorabies Virus, a model for lipid enveloped DNA viruses, among those is Hepatitis B Virus; MMV: Mouse Minute Virus, a model for B19V.

In addition, Human Parvovirus B19 (B19V) was used to investigate the upstream Thrombin precursor mass capture step, the Sealer Protein early manufacturing steps and the Thrombin and Sealer Protein vapor heating steps. Using quantitative PCR assays, the estimated B19V log reduction factors were: (a) 1.7 for the Thrombin precursor mass capture step, (b) 3.4 for Sealer Protein early manufacturing steps, (c) >4 for Thrombin vapor heat treatment and (d) 1.0 for Sealer Protein vapor heat treatment.

12.1 Mechanism Of Action

Upon mixing Sealer Protein (Human) and Thrombin (Human), soluble fibrinogen is transformed into fibrin, forming a rubber-like mass that adheres to the wound surface and achieves hemostasis and sealing or gluing of tissues. TISSEEL mimics the final coagulation cascade step as it has all relevant components to form a clot. TISSEEL is effective in heparinized patients and in patients medicated with anti-platelet drugs.

12.2 Pharmacodynamics

Thrombin is a highly specific protease that transforms the fibrinogen contained in Sealer Protein (Human) into fibrin. Fibrinolysis inhibitor, Aprotinin (Synthetic), is a polyvalent protease inhibitor that prevents premature degradation of fibrin. Preclinical studies with different fibrin sealant preparations simulating the fibrinolytic activity generated by extracorporeal circulation in patients during cardiovascular surgery have shown that incorporation of aprotinin in the product formulation increases resistance of the fibrin sealant clot to degradation in a fibrinolytic environment.

12.3 Pharmacokinetics

Unincorporated Aprotinin and its metabolites have a half-life of 30 to 60 minutes and are eliminated by the kidney. Pharmacokinetic studies were not conducted. TISSEEL is expected to be completely resorbed in 10 to14 days

Because TISSEEL is applied only topically, systemic exposure or distribution to other organs or tissues is not expected.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term animal studies to evaluate the carcinogenic potential of TISSEEL or studies to determine the effect of TISSEEL on fertility have not been performed.

14.1 Vascular Surgery

TISSEEL was evaluated in a prospective, controlled, randomized, single-blind, multicenter clinical study against manual compression with gauze pads in 140 subjects undergoing vascular surgery with expanded polytetrafluoroethylene (ePFTE) graft placement (arterio-arterial bypasses and AV shunts for dialysis access in the upper and lower extremity). Subjects received standardized dosages of heparin. Protamine was administered after the primary endpoint had been assessed. Long-term antiplatelet treatments were continued perioperatively at the surgeon’s discretion.

Subjects were randomly assigned to TISSEEL or control when persistent bleeding at the study suture line was present after surgical hemostasis, i.e., sutures. Eligible bleedings before clamping and treatment application were defined as a minimum of 25% of the suture line bleeds or at least 5 suture line bleedings or any pulsatile or spurting needle hole bleeding. For the primary endpoint, hemostasis achieved at the study suture line at 4 minutes and maintained until surgical closure, a single application of TISSEEL was statistically significantly superior to control (p<0.0001; likelihood ratio chi-square test; 2.5% one sided) [ITT].

14.2 Cardiac Surgery

TISSEEL was evaluated in a prospective, parallel design, randomized (1:1), double-blind, multicenter clinical study against an earlier formulation of the product, TISSEEL VH, in 317 subjects undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) and median sternotomy. Patients were treated with TISSEEL or the control product only when hemostasis was not achieved by conventional surgical methods. For the endpoint, hemostasis achieved at the primary treatment site within 5 minutes of treatment and maintained until closure of the surgical wound, TISSEEL was non-inferior to the earlier formulation of the product using a one-sided 97.5% confidence interval on the difference in the proportion of subjects successfully treated.

14.3 Cardiac Reoperations

An earlier formulation of TISSEEL was evaluated in an open-label crossover study against control topical hemostatic agents in 489 patients undergoing cardiovascular reoperation or resternotomy at 11 institutions. Patients were randomized to TISSEEL or control hemostatic agents when a topical hemostatic was needed at the conclusion of surgery and after all attempts at surgical hemostasis. Patients were crossed to the alternative therapy if bleeding continued after the 5 minute endpoint. At 10 centers, TISSEEL was used after administration of protamine sulfate. At one site, TISSEEL could be used before administration of protamine sulfate. 365 of the 489 patients developed bleeding episodes requiring treatment. For the endpoint (successful hemostasis at 5 minutes), TISSEEL was statistically significantly superior to control topical hemostatic agents in these patients. Similarly, absolute time to cessation of bleeding was statistically significantly shorter for TISSEEL than for control topical hemostatic agents (p<0.0001, Gehan- Wilcoxon test, two sided).

14.4 Splenectomy

In a single center, open label trial, an earlier formulation of TISSEEL was compared to historical controls in patients undergoing laparotomy for blunt or penetrating traumatic injury to the spleen and/or liver. Use of TISSEEL resulted in the need for statistically significantly fewer splenectomies than control hemostatic maneuvers (Refer to Table 9). TISSEEL did not result in significantly reduced mortality in patients with blunt or penetrating trauma to the liver alone or to the liver and spleen (p=0.067, χ², one sided).

14.5 Colostomy Closure

In a single center, prospective open label study of 118 patients randomized to standard of care (58 patients) or standard of care plus fibrin sealant (60 patients) for elective colostomy closure after temporary colostomy placement for treatment of traumatic injury to the colon, the earlier version of TISSEEL plus standard of care was also shown to be significantly superior to standard of care alone (p=0.0406, Jonckheere-Terpstra test for ordinal data, two sided) with regard to anastomotic complications (leakage, intra-abdominal abscess formation, re-operation, septic shock, and death).

16 How Supplied/Storage And Handling

How Supplied

TISSEEL is supplied in the following pack sizes and presentations:

TISSEEL Kit contains one vial each of:

• 1.Sealer Protein Concentrate (Human), Vapor Heated, Solvent/Detergent Treated, Freeze-Dried, Sterile
• 2.Fibrinolysis Inhibitor Solution, (Synthetic) Liquid, Sterile
• 3.Thrombin (Human), Vapor Heated, Solvent/Detergent Treated, Freeze-Dried, Sterile
• 4.Calcium Chloride Solution, Liquid, Sterile

TISSEEL Pre-Filled Dual-Chambered Syringe contains:

• 1.Sealer Protein Solution, Vapor Heated, Solvent/Detergent Treated, Frozen Solution, Sterile
• 2.Thrombin Solution, Vapor Heated, Solvent/Detergent Treated, Frozen Solution, Sterile
• 3.Sterile accessory devices (DUO Set: 1 plunger, 2 joining pieces and 4 application cannulas)

Storage
TISSEEL Kit (Freeze-Dried)
Store at 2-25°C. Avoid freezing. Do not freeze or refrigerate reconstituted solutions.

TISSEEL Pre-filled Syringe (Frozen)
Store at ≤ -20°C. Do not refrigerate or re-freeze after thawing.

Do not use after the expiration date. Discard if packaging of any components is damaged.

17 Patient Counseling Information

Discuss the risks and benefits of this product with the patient since it is made from human plasma.

Instruct patients to consult their physician if symptoms of B19 virus infection appear (fever, drowsiness, chills and runny nose) followed about two weeks later by a rash and joint pain (see Use in Specific Populations (8.1)).

Manufactured For Baxter Healthcare Corporation
Deerfield, IL 60015 USA
US License No. 140

Baxter, Duo, Duploject, Duplospray, Easyspray, Fibrinotherm and Tisseel are trademarks of Baxter International Inc.

Package/Label Principal Display Panel

Tisseel Frozen 2mL Representative Pouch Label - NDC 0338-8402-01 - image 02

Fibrin Sealant
TISSEEL 2 mL

NDC 0338-8402-01

Vapor Heated, Solvent/Detergent Treated, Frozen

Baxter Logo

Temperature sensitive – Do NOT expose above 37°C (99°F).

TOPICAL USE ONLY DO NOT INJECT

Read directions for thawing and application before use.

Store at –20°C (–4°F) or colder. Unopened pouches may be
stored for up to 48 hours at room temperature (15 – 25°C).

Do not refrigerate or re-freeze.

Rx Only

Contents:

Pre-filled syringe containing:

– Sealer Protein Solution (1): 1 mL, sterile
– Sealer Protein (Human)
– Fibrinolysis Inhibitor (Aprotinin,
Synthetic), 3000 KIU/mL

– Thrombin Solution (2): 1 mL, sterile
– Thrombin (Human), 500 units/mL
– Calcium Chloride, 40 μmol/mL

DMC

Manufactured for
Baxter Healthcare
Corporation
Deerfield, IL 60015 USA

U.S. License No. 140
0736623

Lot No.:

Exp. Date:

P

0736624

Fibrin Sealant
TISSEEL

Vapor Heated, Solvent/Detergent Treated, Frozen

TOPICAL USE ONLY

2 mL

N3 0338-8402-02 3

Fibrin Sealant
TISSEEL

TOPICAL USE ONLY

2 mL

Fibrin Sealant
TISSEEL

Vapor Heated, Solvent/Detergent Treated, Frozen

NDC 0338-8402-02

Prefilled Syringe

2 mL

TOPICAL USE ONLY

Contents:
Pre-filled syringe containing:

Sealer Protein Solution: 1 mL, sterile
– Sealer Protein (Human)
– Fibrinolysis Inhibitor (Aprotinin, Synthetic), 3000 KIU/mL

Thrombin Solution: 1 mL, sterile
– Thrombin (Human), 500 units/mL
– Calcium Chloride, 40 μmol/mL

The risks and benefits of this product should be discussed with the patient.

Rx Only

DO NOT INJECT

Store at –20°C (–4°F) or colder.

Read enclosed directions for thawing and application before use.

Unopened pouches may be stored for up to 48 hours at room
temperature (15 – 25°C).

Do not refrigerate or re-freeze.

Not made with natural rubber latex

For Single Use Only.

Baxter Logo

Fibrin Sealant
TISSEEL

TOPICAL USE ONLY

2 mL

Fibrin Sealant
TISSEEL

TOPICAL USE ONLY

2 mL

Baxter Logo

736624

Fibrin Sealant
TISSEEL

Vapor Heated, Solvent/Detergent Treated, Frozen

Pre-filled Syringe

2 mL

TOPICAL USE ONLY
DO NOT INJECT

U.S. Pat. No.: 5,962,405

Manufactured for Baxter Healthcare Corporation
Deerfield IL, 60015 USA
1-888-229-0001
U.S. License No. 140
Made in Austria

Reorder Number: 1501261

Baxter and Tisseel are trademarks of
Baxter International Inc.

Baxter Logo

NDC 0338-4210-02

Fibrin Sealant
TISSEEL 2 mL

Vapor Heated, Solvent/Detergent Treated, Kit

Baxter Logo

NDC 0338-4210-02

0103033842100284

Fibrin Sealant
TISSEEL 2 mL

Vapor Heated, Solvent/Detergent Treated, Kit

Contents:

Sealer Protein Concentrate (Human), Vapor Heated,
Solvent /Detergent Treated, freeze dried, sterile, for
1 mL of Sealer Protein Solution

Fibrinolysis Inhibitor Solution (Synthetic), sterile,
3000 KIU of Aprotinin /mL

Thrombin (Human), Vapor Heated, Solvent /Detergent
Treated, freeze dried, sterile, for 1 mL of Thrombin
Solution 500 units/mL

Calcium Chloride Solution, sterile, 40 μmol /mL

The risks and benefits of this product should be discussed
with the patient.
Read enclosed directions for reconstitution and application
before use.
Use within four hours of reconstitution.

NOT FOR INJECTION. For single use only.

Not made with natural rubber latex

Rx only

Manufactured for Baxter Healthcare Corporation
Deerfield, IL 60015 USA

U.S. License No. 140

Made in Austria

U.S. Pat. No.: 5,962,405

Baxter and Tisseel are trademarks of Baxter International Inc.

736640

736640

Fibrin Sealant
TISSEEL 2 mL

Vapor Heated, Solvent/
Detergent Treated, Kit

2 mL

Store at 2°C to 25°C (36°F to 77°F).
Avoid freezing.

Baxter Logo

NDC 0338-4301-02

Fibrin Sealant
TISSEEL 2 mL
Vapor Heated, Solvent/Detergent Treated, Kit

Manufactured for Baxter Healthcare Corporation
Deerfield, IL 60015 USA

U.S. License No. 140

Made in Austria

Reorder Number: 1504514

Baxter, Duploject and Tisseel are trademarks of Baxter International Inc.

U.S. Pat. No.: 5,962,405

Baxter Logo

NDC 0338-4301-02

Fibrin Sealant
TISSEEL 2 mL
Vapor Heated, Solvent/Detergent Treated, Kit

TOPICAL USE ONLY

DO NOT INJECT

Baxter Logo

NDC 0338-4301-02

0103033843010230

Fibrin Sealant
TISSEEL 2 mL
Vapor Heated, Solvent/Detergent Treated, Kit

Contents:

Sealer Protein Concentrate (Human), Vapor Heated,
Solvent /Detergent Treated, freeze dried, sterile, for
1 mL of Sealer Protein Solution

Fibrinolysis Inhibitor Solution (Synthetic), sterile,
3000 KIU of Aprotinin /mL

Thrombin (Human), Vapor Heated, Solvent /Detergent
Treated, freeze dried, sterile, for 1 mL of Thrombin Solution
500 units/mL

Calcium Chloride Solution, sterile, 40 μmol /Ml

The risks and benefits of this product should be discussed
with the patient. Read enclosed directions for
reconstitution and application before use. Use within four
hours of reconstitution.

NOT FOR INJECTION. For single use only.

Not made with natural rubber latex

Rx only

0736642

0736642

N3 0338-4301-02 3

Baxter Label

DUO Set 2 ml / 4ml

Baxter AG, 1221 Vienna, Austria

0297

LOT

USA

Manufactured for:
Baxter Healthcare Corporation,
Westlake Village, CA 91362 USA

Rx only, single use only, non-pyrogenic

Not made with natural rubber latex

AF082407A04

Baxter Logo

DUPLOJET 2 mL / 4 mL

Fibrin Sealant Preparation and
Application System

Baxter Logo

DUPLOJET 2 mL / 4 mL

Fibrin Sealant Preparation and
Application System

BAXTER, DUPLOJET and TISSEEL are trademarks of
Baxter International Inc., registered in the U.S. Patent and
Trademark office.

Manufactured for:
Baxter Healthcare Corporation
Westlake Village, CA 91362 USA

DUPLOJET 2 mL / 4 mL
Fibrin Sealant Preparation and
Application System

For Fibrin Sealant
2 mL or 4 mL Kit

2 mL
4 mL

For the preparation and application of TISSEEL
[Fibrin Sealant] 2 mL / 4 mL Kit.

STERILE – SINGLE PATIENT USE ONLY – DO NOT RESTERILIZE

Use separate devices for reconstruction of Sealer Protein Concentrate
and Thrombin.

Rx only

Made in Austria

000077

M000077

DUPLOJET 2 mL / 4 mL
Fibrin Sealant Preparation and
Application System

For Fibrin Sealant
2 mL or 4 mL Kit

2 mL
4 mL

Baxter Logo
M000239

000239

DUPLOJECT
Fibrin Sealant Preparation and Application System

For the preparation and application of TISSEEL [Fibrin Sealant] kit.

Note: See TISSEEL [Fibrin Sealant] package insert for additional preparation and
application instructions.

1.0 Reconstitution Instructions for the Circulating Nurse (Using the FIBRINO-
THERM Heating and Stirring Device)

1.1 Turn on the warming unit of the FIBRINOTHERM device (amber switch).

1.2 Open TISSEEL [Fibrin Sealant] kit and place all vials into the appropriately sized
heating wells of the FIBRINOTHERM device.

1.3 Place the Sealer Protein vial into the large magnetic stirring well fitted with
the appropriately sized adapter ring (if necessary). Do not activate the stirring
mechanism at this time. The indicator light will remain lit until a temperature of
37°C (98.6°F) is reached. Allow several minutes for proper warming.

1.4 Open Pack A of the DUPLOJECT Preparation and Application System and
assemble the blue-scaled and black-scaled syringes with the needles provided.

1.5 Remove the flip-off caps from the blue-capped Sealer Protein Concentrate
and Fibrinolysis Inhibitor Solution vials and wipe with a non-iodine based dis-
infectant.

1.6 Using the blue-scaled syringe, withdraw the Fibrinolysis Inhibitor Solution from
the vial, tilting the vial slightly to facilitate removal of all solution. Inject the
Fibrinolysis Inhibitor Solution into the Sealer Protein Concentrate vial. Gently
swirl the vial to ensure that the freeze-dried material is fully soaked. Note: Do not
invert or inject air into vials.

1.7 Place the Sealer Protein Concentrate vial in the stirring well and activate the
stirring mechanism of the FIBRINOTHERM device (green switch). Reconstitution
is complete when no undissolved particles are visible. If Sealer Protein is not fully
dissolved after 20 minutes, discard and prepare a fresh kit. Continue with steps 8
through 11.

1.8 Remove the flip-off caps from the black-capped Thrombin and Calcium Chloride
Solution vials and wipe with a non-iodine based disinfectant.

1.9 Using the black-scaled syringe, withdraw the Calcium Chloride Solution from the
vial, tilting the vial slightly to facilitate removal of all solution. Inject the Calcium
Chloride Solution into the Thrombin vial. Note: Do not invert or inject air into vials.

1.10 Swirl contents of the Thrombin vial briefly and return it to an appropriately sized
heating well in the FIBRINOTHERM device.

1.11 Leave the Sealer Protein and Thrombin vials in the FIBRINOTHERM device until
the solutions are ready to be passed into the sterile field.

2.0 Preparation Instructions for the Scrub Nurse

2.1 Open Pack B of the DUPLOJECT Preparation and Application System into the
sterile field.

2.2 Open Packs 1, 2, and 3.

2.3 Assemble the blue-scaled and black-scaled syringes with the needles provided.
Note: For 5 mL DUPLOJECT systems, attach the larger needle to the blue-scaled
syringe.

2.4 While the Circulating Nurse holds the vial slightly tilted, insert needle into
vial (bevel side down) and withdraw all of the Sealer Protein Solution into the
blue-scaled syringe using slow, constant aspiration. Discard needle in sharps
container.

2.5 While the Circulating Nurse holds the vial slightly tilted, insert needle into vial
(bevel side down) and withdraw all of the Thrombin Solution into the black-scaled
syringe using slow, constant aspiration. Discard needle in sharps container.

2.6 Remove any air bubbles from the syringes and ensure both syringes contain the
same volume.

2.7 Snap the filled syringes into the two-syringe clip with the flanges in an up/down
position, as illustrated below.

2.8 Attach the joining piece to the syringe nozzles, ensuring that both are firmly
seated. Secure the joining piece by fastening the retaining strap to the double
syringe clip. Note: Align the syringe nozzles toward the middle for proper
attachment.

2.9 Fit one of the application needles onto the joining piece. A second application
needle is provided in Pack 3 as a spare.

2.10 DUPLOJECT Applicator is ready for use.

2.11 If application of TISSEEL [Fibrin Sealant] is interrupted, replace the needle
immediately before application is resumed. Note: If the apertures of the joining
piece become clogged, Pack 4 contains one spare joining piece and two
additional application needles.

Rx Only
DO NOT REUSE OR RESTERILIZE.
DISPOSE OF CONTAMINATED AND SHARP COMPONENTS PROPERLY.

BAXTER, DUPLOJECT, FIBRINOTHERM and TISSEEL are trademarks of Baxter International Inc.,
registered in the U.S. Patent and Trademark Office.

Baxter Healthcare Corporation
Westlake Village, CA 91362 USA