2.1 Thawing

Thaw the two components of EVICEL ®(BAC2 and Thrombin) in one of the following ways:

• 2°C to 8°C (refrigerator): vials thaw within 1 day; or
• 20°C to 25°C (room temperature): vials thaw within 1 hour; or
• 37°C (warm water bath): vials thaw within 10 minutes and must not be left at this temperature for longer than 10 minutes. The temperature must not exceed 37°C.

2.2 Preparation Prior to Application

Once thawed, use the components of EVICEL ®(BAC2 and Thrombin) within 30 days if refrigerated or within 24 hours if stored at room temperature.

Do not use after the expiration date stated on the box, or after 30 days if refrigerated after thawing. Do not re-freeze EVICEL ®once it has been thawed. Do not refrigerate EVICEL ®after storage at room temperature. Discard unused product after 24 hours at room temperature.

Discard if the packaging of EVICEL ®is damaged.

While maintaining a sterile surgical field, prepare the product assembly as follows:

• Draw the BAC2 and Thrombin into the application device (see diagram enclosed in the application device package).
• Fill both syringes of the application device with equal volumes. The solutions should not contain air bubbles.
• Carefully remove the vial assembly by rotating it in the direction indicated by the arrows to avoid leakage.

Prior to applying EVICEL ®, dry surface areas of the wound by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices) [see Dosage and Administration (2.3)]. EVICEL®, the application device and accessory tips should only be used by persons trained in laparoscopic, laparoscopic-assisted, endoscopic or open surgical procedures.

Prepare and administer EVICEL ®according to the instructions and with only devices recommended for this product.

2.3 Application Techniques

For topical use only. Apply EVICEL ®to the surface of bleeding tissue only. Do not inject directly into the circulatory system or into tissues.

If the hemostatic effect is not complete, apply a second layer. The amount of EVICEL ®required depends upon the area of tissue to be treated and the method of application. As an approximate guide, if a layer of 1 mm thickness is produced by spraying EVICEL ®, the surface areas that can be covered by each of the kit sizes are given in Table 1.

Use standard surgical techniques for hemorrhagic control, including suture, ligature and cautery prior to the application of EVICEL ®. Remove excess blood from the site of application to the extent possible using standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices). Apply EVICEL ®with the approved application device and accessories supplied. EVICEL ®forms a transparent layer on application through which specific bleeding points may be observed; these bleeding points may be sutured or electrocauterized through the layer of EVICEL ®.

Vials are for single use only. Discard unused contents [see How supplied/ Storage and Handling (16)].

5.1 Application Precautions

Excessive product application thickness may negatively interfere with the product's efficacy and the wound healing process. Apply EVICEL® as a thin layer.

To reduce the risk of potentially life threatening air embolism, follow specific spray instructions for the pressure and distance from tissue recommended for each type of surgical procedure and length of application tip[see Dosage and Administration (2.2)] .

• Spray EVICEL ®using pressurized CO 2gas only.
• When using the Airless Spray Accessory and Laparoscopic Airless Spray Accessory (35 cm Rigid), the need for connection to an external CO 2or other gas source has been eliminated.
• Use EVICEL ®spray application only if it is possible to accurately judge the distance from the spray tip to the tissue surface, especially during laparoscopic or endoscopic procedures.
• Monitor changes in blood pressure, pulse, oxygen saturation and end-tidal CO 2when spraying EVICEL ®because of the possibility of gas embolism.

Prior to applying EVICEL ®, dry surface areas of the wound by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices).

5.2 Infection Risk from Human Plasma

EVICEL ®is made from human plasma and may carry a risk of transmitting infectious agents, e.g. viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob (CJD) agent. There is also the possibility that unknown infectious agents may be present in such products.

All infections thought by a physician to have been possibly transmitted by this product should be reported by the physician or other healthcare provider to ETHICON Customer Support Center at (877) 384-4266. The physician should discuss the risks and benefits of this product with the patient.

6.1 Clinical Trials Experience

Clinical trials are conducted under widely varying conditions; therefore 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.

6.2 Postmarketing Experience

The following adverse reactions are reported voluntarily from a population of uncertain size, therefore, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Postmarketing fatalities attributable to air or gas embolism have been reported with the use of EVICEL ®when applied using a spray device. These cases have occurred where EVICEL ®was sprayed at a pressure higher than indicated for the device in use and when the spray tip was placed closer than the specified distance from the target site.

The following adverse reactions have been reported in postmarketing experience with EVICEL ®in order of decreasing frequency (Table 5):

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Limited data is available to support the safety and effectiveness of EVICEL ®in children. No data is currently available for ages 0 to 6 months.

Of 135 subjects undergoing retroperitoneal and intra-abdominal surgery who were included in a controlled study of EVICEL ®, four subjects treated with EVICEL ®were age 16 years or younger. Of these, two were children age 2 to 11 years and two were adolescents age 12 to 16 years.

Pediatric patients for vascular surgery are rare and were therefore not included in the clinical trials involving vascular surgery.

Of the 155 subjects undergoing liver surgery who were treated in clinical trials, eight were pediatric subjects. Of these, five were less than 2 years old and three were between 2 and 12 years old.

Use of EVICEL ®in pediatric patients above age 6 months is supported by these data and by extrapolation of efficacy in adults. Data can not be extrapolated to ages 0 to 6 months.

8.5 Geriatric Use

Clinical trials included 101 subjects age 65 years or older, of whom 30 underwent retroperitoneal or intra-abdominal surgery, 24 underwent liver surgery and 47 underwent vascular surgery.

No differences in safety or effectiveness were observed between the elderly and younger subjects.

BAC2

BAC2 is a sterile solution, pH 6.7–7.2, which consists of concentrated human fibrinogen plus excipients. Fibrinogen is a protein from human blood that forms a clot when combined with thrombin. The composition of the BAC2 solution is as follows:

Active ingredient: Concentrate of human fibrinogen (55–85 mg/ml)

Other Ingredients: Arginine hydrochloride, glycine, sodium chloride, sodium citrate, calcium chloride, water for injection (WFI)

Thrombin

Thrombin is a sterile solution, pH 6.8–7.2, which contains purified human thrombin that activates clotting of the final combined product. Thrombin is a specific protease that transforms the fibrinogen contained in BAC2 into fibrin. The composition of the Thrombin solution is as follows:

Active Ingredient: Human thrombin (800–1200 IU/ml)

Other Ingredients: Calcium chloride, human albumin, mannitol, sodium acetate, WFI

Cryoprecipitate, which is the starting material for BAC2, and cryo-poor plasma, which is the starting material for the production of Thrombin, are both made from pooled human source plasma that is obtained from US licensed plasma collection centers.

Cryoprecipitate is manufactured in-house or supplied by either Octapharma AG (manufactured by Octapharma Pharmazeutika Produktionsges.m.b.H., Oberlaaer Strasse 235, Vienna, A-1100 Austria, License No. 1646) or Grifols Therapeutics Inc. (manufactured by Kedrion 155 Duryea Road, Melville, NY 11747, License No. 1906).

Viral Clearance

Individual plasma units which are obtained for the production of EVICEL ®are evaluated by FDA-licensed serological tests for hepatitis B surface antigen (HBsAg), human immunodeficiency virus (HIV) 1 & 2 antibody and hepatitis C virus (HCV) antibody as well as with FDA-licensed nucleic acid testing (NAT) methods for HCV and HIV-1.

Some viruses such as hepatitis A virus (HAV) and parvovirus B19 are particularly difficult to remove or inactivate. Parvovirus B19 most seriously affects pregnant women or immune-compromised individuals. The plasma units are tested by NAT for HAV and hepatitis B virus (HBV). All tests for HIV, HCV, HBV and HAV must be negative (non-reactive). However, since the effectiveness of these test methods in detecting low levels of viral material is still under investigation, the significance of a negative result for these viruses is unknown. NAT for parvovirus B19 is also performed, and the level of contamination is not permitted to exceed 10,000 copies/ml. This limit is applied to restrict the viral load of parvovirus B19 in the starting plasma pool.

In addition to the screening of plasma, each manufacturing pool is tested for HBsAg, HIV-1 & 2 antibody, HCV by NAT and for parvovirus B19 by NAT. Manufacturing pool testing, however, has a lower sensitivity than that of individual unit testing.

The manufacturing procedure for EVICEL ®includes processing steps which are designed to reduce the risk of viral transmission. Both BAC2 and Thrombin undergo two discrete virus inactivation/removal steps, summarized in Table 6:

BAC2 is manufactured by treatment of cryoprecipitate with aluminum hydroxide gel to adsorb the Vitamin K dependent clotting factors and it is then incubated with a solvent detergent (SD) mixture (1% TnBP, 1% Triton X-100) for 4 hours at 30°C. The SD reagents are removed by castor oil extraction and reverse phase chromatography (C-18 column) and the preparation is subsequently treated by pasteurization.

Prior to pasteurization, sucrose and glycine are added as stabilizers. The solution is heated to 60±0.5°C and maintained at that temperature for 10 hours. After pasteurization, the stabilizers used for heat treatment are removed by diafiltration and the product is concentrated by ultrafiltration. An affinity chromatography step is then used to remove plasminogen from the product, after which it is concentrated. After concentration the solution is formulated, sterile filtered and aseptically filled and frozen.

Thrombin is manufactured by chromatographic purification of prothrombin from cryo-poor plasma followed by activation with calcium chloride. The manufacturing process includes two separate steps for inactivation or removal of viruses. The first of these is treatment with a SD mixture (1% TnBP, 1% Triton X-100) for 6 hours at 26°C to inactivate lipid enveloped viruses.

The SD reagents are removed by cation exchange chromatography. Mannitol and human albumin are used to stabilize the solution, which undergoes nanofiltration for removal of both enveloped and non-enveloped viruses. After nanofiltration, the solution is formulated with calcium chloride, sterile filtered and aseptically filled and frozen.

The efficiency of the virus inactivation/removal procedures in reducing the level of a range of viruses has been assessed using viruses with a range of physico-chemical characteristics. The results of virus removal/inactivation validation studies are summarized in Table 7:

Tables 7a,b: Results of Virus Removal/Inactivation in Validation Studies

12.1 Mechanism of Action

The fibrin sealant system initiates the last phase of physiological blood coagulation. Thrombin activates the conversion of fibrinogen into fibrin, which occurs by the splitting of fibrinogen into fibrin monomers and fibrinopeptides. The fibrin monomers polymerize and form a fibrin clot. Factor XIIIa, which is activated from Factor XIII (FXIII) by thrombin, crosslinks fibrin. Calcium ions are required for FXIII activation by thrombin.

12.2 Pharmacodynamics

Pharmacodynamic studies were not conducted.

Clinical studies demonstrating hemostasis were conducted in a total of 167 subjects undergoing vascular surgery and in a total of 135 subjects undergoing retroperitoneal and intra-abdominal surgery. Efficacy data is provided in Section 14.

12.3 Pharmacokinetics

EVICEL ®is for topical use only and intravascular administration is contraindicated [see Contraindication (4.1)], therefore pharmacokinetic studies were not performed.

Studies have been conducted in rabbits to evaluate the absorption and elimination of thrombin when applied to the cut surface of the liver resulting from partial hepatectomy. Using 125I-thrombin it was shown that a slow absorption of biologically inactive peptides resulting from the breakdown of thrombin occurred, reaching a C(max) in the plasma after 6–8 hours. At the C(max), the plasma concentration represented only 1–2% of the applied dose. The systemic exposure to thrombin when it is administered directly to a hepatic wound was estimated to be approximately equivalent to that generated by minor bleeding.

Fibrin sealants are metabolized in the same way as endogenous fibrin, by fibrinolysis and phagocytosis. As wound healing progresses, increased fibrinolytic activity is induced by plasmin and decomposition of fibrin to fibrin degradation products is initiated.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

• EVICEL ®has been classified as non-irritant in the Primary Cutaneous Irritation test and slightly irritant in the Ocular Irritation test.
• No toxicological effects secondary to the solvent/detergent reagents (TnBP and Triton X-100) used in the virus inactivation procedure are expected based on acute and repeat toxicity studies and since the residual levels are less than 5 µg/ml.
• Long-term animal studies have not been performed to evaluate the carcinogenic potential of EVICEL ®because of the human origin of both thrombin and fibrinogen contents.
• Neither BAC2 nor Thrombin solution induces mutagenic effects in the Ames test. Studies performed in bacteria to determine mutagenicity were negative for Thrombin alone, BAC (containing fibrinogen, citrate, glycine, tranexamic acid, and arginine hydrochloride), TnBP alone, and Triton X-100 alone at all concentrations tested. All concentrations of the combination of TnBP and Triton X-100 also tested negative in assays performed to determine mammalian cell mutagenicity, chromosomal aberrations and micronuclei induction.
• The effect of EVICEL ®on fertility has not been evaluated in humans.

13.2 Animal Toxicology and/or Pharmacology

• Neurotoxicity studies performed with EVICEL ®confirmed that subdural administration in the rabbit was not associated with any evidence of neurotoxicity.
• Reproductive studies performed in rats with the combination of TnBP and Triton X-100 at doses up to approximately 600-fold (TnBP, 900 µg/kg/day) and 3000-fold (Triton X-100, 4500 µg/kg/day) the human dose resulted in increased post-implantation loss and an increased number of late resorptions. No embryo-fetal adverse effects were observed at doses up to 200-fold (TnBP, 300 µg/kg/day) and 1000-fold (Triton X-100, 1500 µg/kg/day) the human dose. Other studies performed with the combination of TnBP at doses approximately 300-fold (TnBP, 450 µg/kg/day) and 1500-fold (Triton X-100, 2250 µg/kg/day) the human dose had increased resorption rates, decreased fetal body weights, and an increased number of runts. No embryo-fetal adverse effects were observed at doses up to 100-fold (TnBP, 150 µg/kg/day) and 500-fold (Triton X-100, 750 µg/kg/day) the human dose.

Retroperitoneal and Intra-Abdominal Surgery

In a prospective, randomized, controlled evaluation of the hemostatic efficacy of EVICEL ®as an adjunct to hemostasis for soft tissue bleeding during retroperitoneal or intra-abdominal surgery, EVICEL ®was shown to be superior to the control product (oxidized regenerated cellulose) in achieving hemostasis in less than 10 minutes (Table 8). Superiority was also established at 7 and 4 minutes.

Vascular Surgery

A prospective, randomized study was performed to compare the hemostatic efficacy of EVICEL ®versus manual compression during vascular surgical procedures utilizing polytetrafluoroethylene graft material on end-to-side femoral artery anastomosis or upper extremity vascular access arterial anastomosis.

A difference (p<0.001) in time to hemostasis was observed: 83.3% of the treatment subjects as compared to 39.7% of control subjects achieved hemostasis by 4 minutes (Table 9).

Liver Surgery

EVICEL ®was compared in a prospective, randomized, parallel-group, multi-center study to FDA-approved control topical hemostatic agents in 121 subjects undergoing liver resection at 15 centers. Subjects were randomized (stratified by surgeon) at the conclusion of the liver resection surgery if general oozing was present that could not be controlled by further surgical methods and a topical hemostatic agent was needed to control the bleeding from the liver surface. For hemostatic efficacy, the EVICEL ®was shown to be statistically superior to the control hemostatic agents (5.3 minutes for EVICEL ®versus 7.7 minutes for control; one-sided p=0.011).

The vials must be stored in an upright position.

Store frozen vials at -18°C or colder (frozen) for up to 2 years.

Store unopened vials at 2°C to 8°C (refrigerated) for up to 30 days.

The two EVICEL ®components, BAC2 and Thrombin, have been shown to be stable for up to 24 hours at room temperature.

Do not use after the expiration date stated on the box, or after 30 days if stored at 2°C to 8°C after thawing.

Do not re-freeze EVICEL ®once it has been thawed.

Do not refrigerate EVICEL ®once it has reached room temperature. Discard unused product after 24 hours at room temperature.

Discard if the packaging of EVICEL ®is damaged.

Vials are for single use only. Discard unused contents.