Tisseel

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 Aprotinin 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). 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 log ) of manufacturing steps for each of the viruses tested are shown in Table 6.

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

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.

Side Effects

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), 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.

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).

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

WarningS

Included as part of the “PRECAUTIONS” Section

Precautions

Hypersensitivity Reactions

Hypersensitivity reactions including allergic/and anaphylactoid reactions can occur with the use of TISSEEL. Cases have been reported in post marketing experience with Baxter’s fibrin sealant (see ADVERSE REACTIONS). 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). 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.

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 Table 4.

Monitor Changes In Blood Pressure, Pulse, Oxygen Saturation And Endtidal 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 Pressure Regulator connected to medical grade CO₂, compressed Air or a Nitrogen compressed gas source along with the TISSEEL/ARTISS spray set, (see Method Of Application).

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).

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.

Use In Surgery

When using TISSEEL in surgery, do not inject intravascularly (see CONTRAINDICATIONS and ADVERSE REACTIONS).

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 and DRUG INTERACTIONS).

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 at 1-888-229-0001.

Nonclinical Toxicology

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.

Use In Specific Populations

Pregnancy

Risk Summary

There are no direct or controlled studies of TISSEEL in pregnant women. No animal reproductive and developmental toxicity studies have 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. Parvovirus B19 most seriously affects pregnant women (fetal infection). In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactation

Risk Summary

There is no information regarding the presence of TISSEEL in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TISSEEL and any potential adverse effects on the breastfed infant from TISSEEL or from underlying maternal condition.

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).

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). 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.

Overdose

No Information Provided

Contraindications

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 and ADVERSE REACTIONS).

Aprotinin Hypersensitivity

Do not use TISSEEL in individuals with a known hypersensitivity to aprotinin (see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS).

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.

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.

Clinical Pharmacology

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.

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.

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.

Clinical Studies

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 chisquare test; 2.5% one sided) [ITT].

Table 7: Vascular Surgery

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.

Table 8: Cardiac Surgery

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).

Table 9: Cardiac Reoperations

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).

Table 10: Splenectomy

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).