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  • CLASSES

    Inhibitors of Fibrinolysis
    Local Hemostatics
    Needles, Syringes and Injection Supplies

    DEA CLASS

    Rx

    DESCRIPTION

    Human plasma-derived, fibrinogen and thrombin sealant
    Used to promote the adherence of autologous skin grafts to burn wounds, for hemostasis of surgical bleeding, and for colonic anastomoses leakage prophylaxis
    For topical use only

    COMMON BRAND NAMES

    ARTISS, Raplixa, TachoSil Absorbable Fibrin Sealant, TISSEEL

    HOW SUPPLIED

    ARTISS/TISSEEL Topical Sol: 1mL, 3000-40-90-500IU, 90-4IU, 90-500IU
    Raplixa Topical Pwd: 1g, 79-699IU
    TachoSil Absorbable Fibrin Sealant Transdermal Film: 35.5-12.9U
    TISSEEL Topical Pwd F/Recon: 1mL, 3000-40-90-500IU

    DOSAGE & INDICATIONS

    For skin graft management by promoting adherence of autologous skin grafts to surgically prepared wound beds from burns.
    Topical dosage (Artiss)
    Adults, Adolescents, and Children

    Apply a thin layer topically to the dry, surgically prepared wound surface. Approximate surface areas covered by each package size are 100 cm2 for the 2 mL package, 200 cm2 for the 4 mL package, and 500 cm2 for the 10 mL package. Immediately position the skin graft after application of the sealant.

    For use as an adjunct to hemostasis in patients undergoing surgery when control of surgical bleeding by standard surgical techniques is ineffective or impractical.
    Topical dosage (Evicel)
    Adults

    Apply a thin layer topically to the surface of the bleeding tissue. If hemostatic effect is not complete, apply a second layer. Approximate surface areas covered by each package size are 20 cm2 for 2 mL package, 40 cm2 for 4 mL package, and 100 cm2 for 10 mL package.

    Infants older than 6 months, Children, and Adolescents

    Apply a thin layer topically to the surface of the bleeding tissue. If hemostatic effect is not complete, apply a second layer. Approximate surface areas covered by each package size are 20 cm2 for 2 mL package, 40 cm2 for 4 mL package, and 100 cm2 for 10 mL package.

    Topical dosage (Raplixa)
    Adults

    Apply a thin layer topically to the surface of the bleeding tissue. Approximate surface areas covered by each package size for vial and spray device, respectively, are 25 cm2 and 50 cm2 for 0.5 g package, 50 cm2 and 100 cm2 for 1 g package, and 100 cm2 and 200 cm2 for 2 g package. In clinical trials, 0.5 to 1 g was used for smaller bleeding sites covering an area of less than 10 cm2, and 1 to 2 g were used for larger bleeding sites covering an area of 10 to 100 cm2. The maximum total dose per surgery is 3 g.

    Topical dosage (TachoSil)
    Adults

    Apply the yellow, active site of the patch to the bleeding area. Determine the number of patches to be applied by the size of the bleeding area. Select the appropriate patch so that it extends 1 to 2 cm beyond the margins of the wound. Use the minimum number of patches necessary to achieve hemostasis. The maximum numbers of patches to be applied by patch size are 10 patches for 3.7 inch by 1.9 inch, 14 patches for 1.9 inch by 1.9 inch, and 42 patches for 1.2 inch by 1 inch. TachoSil is specifically FDA-approved for use with manual compression in cardiovascular or hepatic surgery.

    Infants, Children, and Adolescents

    Apply the yellow, active site of the patch to the bleeding area. Determine the number of patches to be applied by the size of the bleeding area. Select the appropriate patch so that it extends 1 to 2 cm beyond the margins of the wound. Use the minimum number of patches necessary to achieve hemostasis. The maximum numbers of patches to be applied by patch size are 10 patches for 3.7 inch by 1.9 inch, 14 patches for 1.9 inch by 1.9 inch, and 42 patches for 1.2 inch by 1 inch. TachoSil is specifically FDA-approved for use with manual compression in cardiovascular or hepatic surgery.

    Topical dosage (Tisseel)
    Adults

    Apply a thin layer topically to the wound surface. Approximate surface areas covered by each package size for cannula and compressed gas, respectively, are 8 cm2 and 100 cm2 for 2 mL package, 16 cm2 and 200 cm2 for 4 mL package, and 40 cm2 and 500 cm2 for 10 mL package. The application can be repeated, if needed. Tisseel is specifically FDA-approved for cardiopulmonary bypass or blunt or penetrating splenic injuries.

    For use as an adjunct to standard surgical techniques for colonic anastomotic leak prophylaxis after the reversal of temporary colostomies.
    Topical dosage (Tisseel)
    Adults

    Apply a thin layer topically to the surface of the wound surface. Approximate surface areas covered by each package size for cannula and compressed gas, respectively, are 8 cm2 and 100 cm2 for 2 mL, 16 cm2 and 200 cm2 for 4 mL, and 40 cm2 and 500 cm2 for 10 mL. The application can be repeated, if needed.

    MAXIMUM DOSAGE

    Adults

    Artiss, Evicel, and Tisseel: Maximum dosage not specified.
    Raplixa: 3 g.
    TachoSil: 10 patches for 3.7 inch by 1.9 inch, 14 patches for 1.9 inch by 1.9 inch, and 42 patches for 1.2 inch by 1 inch.

    Geriatric

    Artiss, Evicel, and Tisseel: Maximum dosage not specified.
    Raplixa: 3 g.
    TachoSil: 10 patches for 3.7 inch by 1.9 inch, 14 patches for 1.9 inch by 1.9 inch, and 42 patches for 1.2 inch by 1 inch.

    Adolescents

    Artiss, Raplixa, and Tisseel: Safety and efficacy have not been established.
    Evicel: Maximum dosage not specified.
    TachoSil: 10 patches for 3.7 inch by 1.9 inch, 14 patches for 1.9 inch by 1.9 inch, and 42 patches for 1.2 inch by 1 inch.

    Children

    Artiss, Raplixa, and Tisseel: Safety and efficacy have not been established.
    Evicel: Maximum dosage not specified.
    TachoSil: 10 patches for 3.7 inch by 1.9 inch, 14 patches for 1.9 inch by 1.9 inch, and 42 patches for 1.2 inch by 1 inch.

    Infants

    Artiss, Raplixa, and Tisseel: Safety and efficacy have not been established.
    Evicel: Maximum dosage not specified for infants older than 6 months. Safety and efficacy have not been established for infants 6 months and younger.
    TachoSil: 10 patches for 3.7 inch by 1.9 inch, 14 patches for 1.9 inch by 1.9 inch, and 42 patches for 1.2 inch by 1 inch.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Topical Administration
    Other Topical Formulations

    When applying fibrin sealant using a spray device, use pressure within the pressure range and spray from distance specified by the manufacturer. If specific recommendations are not available, avoid using pressure above 20 to 25 psi and spraying closer than 5 to 15 cm from the surface of the tissue. Monitor for changes in blood pressure, pulse, oxygen saturation, and end tidal carbon dioxide when spraying fibrin sealant.
    Artiss :
    Do not expose to temperatures above 37 degrees C during preparation.
    The sealer protein and thrombin solutions of Artiss can be denatured by alcohol, iodine, or heavy metal ions found in antiseptics. If these substances have been used to clean the wound area, thoroughly rinse and dry prior to application of fibrin sealant.
    Preparation (freeze-dried kit)
    Place all 4 vials from the kit into pre-warmed wells of the Fibrinotherm, and allow the vials to warm for up to 5 minutes; room temperature product may take less time.
    To prevent premature clotting, use separate syringes for reconstitution of the sealer protein and thrombin solutions and for application to the wound.
    Remove the flip-off caps from the vials containing sealer protein concentrate and the fibrinolysis inhibitor solution. Disinfect the rubber stoppers with a germicidal solution and allow to dry.
    Using Duploject or an equivalent FDA-approved device, transfer the fibrinolysis inhibitor solution into the vial containing the sealer protein concentrate. Gently swirl the vial to ensure the freeze-dried material is completely soaked.
    Place the vial into the largest opening of the Fibrinotherm, and allow the vial contents to stir until all sealer protein concentrate is dissolved. Reconstitution is complete once no undissolved particles are visible and the solution appears homogeneous. If the particles do not dissolve within 20 minutes, discard the vial and use a new kit. If not used promptly, keep the solution at 37 degrees C without stirring. To ensure homogeneity, switch on the Fibrinotherm stirrer shortly before drawing up the solution.
    Remove the flip-off caps from the vials containing thrombin and calcium chloride solutions. Disinfect the rubber stoppers with a germicidal solution and allow to dry.
    Using Duploject or an equivalent FDA-approved device, transfer the calcium chloride solution into the vial containing thrombin and gently swirl.
    Place the vial into the Fibrinotherm. Reconstitution is complete once all of the concentrate is dissolved. Keep the solution at 37 degrees C until used.
    When transferring the sealer protein solution and the thrombin solution to the sterile field, the circulating nurse should hold the non-sterile vials while the scrub nurse withdraws the solutions slowly by firm constant aspiration to reduce the risk of large air bubbles.
    Storage: After reconstitution, the product must be used within 4 hours. Do not refrigerate or freeze after reconstitution.
    Preparation (pre-filled frozen syringe)
    Do not use unless it is completely thawed and warmed to a liquid consistency. Do not remove the protective syringe cap until thawing is complete and the application tip is ready to be attached.
    Room temperature thawing: Approximate thawing times by package size (pouch) are 60 minutes for 2 mL, 110 minutes for 4 mL, and 160 minutes for 10 mL. Once at room temperature, unopened pouches may be stored for up to 14 days at 15 to 25 degrees C. Prior to use, the product should be warmed to 33 to 37 degrees C in an incubator (15 minutes for 2 mL pouch, 25 minutes for 4 mL pouch, and 35 minutes for 10 mL pouch).
    Quick thawing on the sterile field using a water bath: Transfer the inner pouch to the sterile field. Using a sterile water bath heated to a temperature of 33 to 37 degrees C, remove the prefilled syringe from the inner pouch, and place directly into the sterile bath ensuring that the entire contents of the prefilled syringe are completely under water. Approximate thawing times with pouches removed by pack size are 5 minutes for 2 mL and 4 mL and 12 minutes for 10 mL.
    Quick thawing off the sterile field using a water bath: Using a non-sterile water bath heated to a temperature of 33 to 37 degrees C, immerse the prefilled syringe in both pouches into the water ensuring that the entire contents of the prefilled syringe are completely under water. Approximate thawing times in pouches by pack size are 30 minutes for 2 mL, 40 minutes for 4 mL, and 80 minutes for 10 mL. Once thawed, remove the pouches from the water bath; dry the external pouch, and transfer the inner pouch with the prefilled syringe onto the sterile field.
    Quick thawing off the sterile field using an incubator: Using an incubator heated to a temperature of 33 to 37 degrees C, place the prefilled syringe in both pouches into the incubator. Approximate thawing times in pouches by pack size are 40 minutes for 2 mL, 85 minutes for 4 mL, and 105 minutes for 10 mL. Once thawed, remove from the incubator and transfer the inner pouch containing the prefilled syringe onto the sterile field.
    Storage: Once warmed to 33 to 37 degrees C or if removed from the original pouch, the product must be used within 12 hours. Do not microwave, refrigerate, or refreeze.
    Application
    Apply Artiss using the Easyspray and Spray Set or an equivalent FDA-approved device.
    To prevent adherence, wet gloves with normal saline before product contact.
    Using a painting motion from side to side, apply a thin layer topically to dry wound surface.
    The wound bed will glisten in the area where the fibrin sealant has been applied; any areas not covered by fibrin sealant will be readily visible.
    Attach the skin graft immediately after the fibrin sealant has been sprayed. The surgeon has approximately 60 seconds to manipulate the graft before polymerization.
    Hold the graft in desired position with gentle compression for at least 3 minutes.
    Use cannulas included with the Duploject Preparation and Administration System or Duo Set for small wounds or edges of a skin graft that did not adhere. Immediately before application, expel and discard the first several drops from the cannula.
    For freeze-dried product, refer to Duploject Preparation and Administration System instructions.
    For frozen product, use Duo Set. Insert plunger into syringe barrel. Connect the 2 syringe nozzles to the joining piece and secure by fastening the tether strap to the syringe. Fit an application cannula to the joining piece. If application is interrupted, replace cannula immediately before resuming application.
     
    Evicel :
    Evicel, the application device, and accessory tips should only be used by persons trained in laparoscopic, laparoscopic-assisted, endoscopic, or open surgical procedures.
    Preparation
    Thaw the 2 components (BAC2 and thrombin). Vials thaw within 1 day using temperatures of 2 to 8 degrees C (refrigerator); within 1 hour using temperatures of 20 to 25 degrees C (room temperature); or within 10 minutes using a temperature of 37 degrees C (warm water bath). Do not expose vials to 37 degrees C for more than 10 minutes, and do not exceed 37 degrees C.
    While maintaining a sterile surgical field, draw the BAC2 and thrombin into the application device provided. Fill both syringes with equal volumes. The solutions should not contain air bubbles.
    Carefully remove the vial assembly by rotating in the direction indicated by the arrows.
    Storage: Once thawed, use within 30 days if refrigerated or within 24 hours if stored at room temperature. Do not refreeze after thawing, and do not refrigerate after storage at room temperature.
    Application
    Use standard surgical techniques for hemorrhage control, and dry surface areas of wounds before applying fibrin sealant.
    Apply a thin film topically to the surface of bleeding tissue. If hemostatic effect is not complete, apply a second layer.
    4 cm Control Tip by Drip Method with the Evicel Application Device: Bend tip to desired position. Keep the applicator tip as close as possible to tissue surface without touching the surface during application. Apply product to surface area to be treated, and pull back tip immediately after application. Control the coverage area by varying applied force on the plunger and tip distance from the tissue. If tip becomes clogged, wipe off or remove any visible clot using sterile gauze; do not trim the tip.
    6 cm, 35 cm, and 45 cm Tips by Drip Method with the Evicel Application Device: Keep the applicator tip as close as possible to tissue surface without touching the surface during application. Apply individual drops to the surface area to be treated. Allow the drops to separate from each other and from the applicator tip. If tip becomes clogged, wipe off or remove any visible clot using sterile gauze or may cut it back in 0.5 cm increments for the 6 cm or 45 cm tips; do not trim the 35 cm tip.
    6 cm, 35 cm, and 45 cm Tips by Spray Method with the Evicel Application Device: Use only with carbon dioxide as the gas. Connect the application device short gas tube to the luer-lock end of the long gas hose. Connect the luer-lock of the long gas hose with the 0.2 micron filter to a pressure regulator. For 6 cm, 35 cm, and 45 cm tips for spray use for open surgery, ensure 10 to 15 cm (4 to 6 inch) distance from target tissue and 20 to 25 psi (1.4 to 1.7 bar) spray pressure. For 35 cm and 45 cm tips for spray use for laparoscopic surgery, ensure 4 to 10 cm (1.6 to 4 inch) distance from target tissue and 15 to 20 psi (1 to 1.4 bar) and 20 to 25 psi (1.4 to 1.7 bar) spray pressure, respectively. Carefully monitor insufflation pressure in all laparoscopic/endoscopic procedures. Apply in short bursts (0.1 to 0.2 mL) onto the tissue to produce an even layer.
    Airless Spray Accessory: No connection to external carbon dioxide source is possible. Once the spray accessory is firmly attached, do not depress plungers to prime device until intended use. Position the tip at least 2 cm away from target tissue, and apply firm even pressure to the plunger to spray the fibrin sealant. Increase distance accordingly to achieve desired coverage of target area. After any pause in expression, replace the spray tip. Do not try and clear fibrin clot within the tip by depressing the plunger; the application device may become unusable.
    Specific bleeding points may be visible through the fibrin sealant transparent layer, and these bleeding points may be sutured or electrocauterized through the fibrin sealant layer.
     
    TachoSil :
    Preparation
    When in the operating room, the outer aluminum foil pouch may be opened in a non-sterile environment. The inner sterile blister must be opened in a sterile environment.
    Remove the patch from the blister. If needed, the blister can be used as a container for pre-moistening of the patch.
    Determine the size of patch(es) to be applied to the bleeding surface. Select the appropriate patch so that it extends 1 to 2 cm beyond the margins of the wound. The patch can be cut to the correct size and shape, if desired.
    Cleanse the area to be treated prior to application in order to remove disinfectants and other fluids. The sealer protein and thrombin solutions of TachoSil can be denatured by alcohol, iodine, or heavy metal ions found in antiseptics. If these substances have been used to clean the wound area, thoroughly rinse and dry prior to application of fibrin sealant.
    Cleanse surgical instruments, gloves, and adjacent tissues with saline solution to reduce adherence to the fibrin sealant patch. The white, inactive side of the patch may also adhere to surgical instruments, gloves, and adjacent tissues covered with blood. Failure to adequately clean adjacent tissues may cause adhesions.
    Application
    Apply the yellow, active side of the fibrin sealant patch directly to the bleeding area either wet or dry. If applied wet, pre-moisten the patch in 0.9% Sodium Chloride Injection for no more than 1 minute and then apply immediately. In the case of a wet tissue surface, such as oozing bleeding, the patch may be applied without pre-moistening.
    Hold patch in place with gentle pressure applied through moistened gloves or a moist pad for at least 3 minutes.
    To avoid pulling the patch loose, place a pre-moistened surgical instrument at 1 end of the patch before relieving pressure. Alternatively, gentle irrigation may also be used to remove the pre-moistened pad or gloved hand without removing the patch from the bleeding area.
    Leave the patch in place once it adheres to organ tissue. If not satisfied with patch placement, or if bleeding still occurs after the specified duration of compression, repeat application procedure; do not remove already applied fibrin sealant patch.
    If more than 1 patch is needed, overlap patches by at least 1 cm.
    Remove unattached patches (or part of) and replace with new.
    For record-keeping purposes, the patient name and batch number should be recorded with every administration.
    Storage: Once removed from inner patch, TachoSil cannot be resterilized; discard unused, opened packages.
     
    Tisseel :
    Do not expose to temperatures above 37 degrees C during preparation.
    The safety and effectiveness of the combined use of Tisseel with other biocompatible materials have not been evaluated. Do not use Tisseel with oxycellulose-containing carrier materials as the efficacy of Tisseel may be reduced.
    The sealer protein and thrombin solutions of Tisseel can be denatured by alcohol, iodine, or heavy metal ions found in antiseptics. If these substances have been used to clean the wound area, thoroughly rinse and dry prior to application of fibrin sealant.
    Preparation (freeze-dried kit)
    Place all 4 vials from the kit into pre-warmed wells of the Fibrinotherm, and allow the vials to warm for up to 5 minutes; room temperature product may take less time.
    To prevent premature clotting, use separate syringes for reconstitution of the sealer protein and thrombin solutions and for application to the wound.
    Remove the flip-off caps from the vials containing sealer protein concentrate and the fibrinolysis inhibitor solution. Disinfect the rubber stoppers with a germicidal solution and allow to dry.
    Using Duploject or an equivalent FDA-approved device, transfer the fibrinolysis inhibitor solution into the vial containing the sealer protein concentrate. Gently swirl the vial to ensure the freeze-dried material is completely soaked.
    Place the vial into the largest opening of the Fibrinotherm, and allow the vial contents to stir until all sealer protein concentrate is dissolved. Reconstitution is complete once no undissolved particles are visible and the solution appears homogeneous. If the particles do not dissolve within 20 minutes, discard the vial and use a new kit. If not used promptly, keep the solution at 37 degrees C without stirring. To ensure homogeneity, switch on the Fibrinotherm stirrer shortly before drawing up the solution.
    Remove the flip-off caps from the vials containing thrombin and calcium chloride solutions. Disinfect the rubber stoppers with a germicidal solution and allow to dry.
    Using Duploject or an equivalent FDA-approved device, transfer the calcium chloride solution into the vial containing thrombin and gently swirl.
    Place the vial into the Fibrinotherm. Reconstitution is complete once all of the concentrate is dissolved. Keep the solution at 37 degrees C until used.
    When transferring the sealer protein solution and the thrombin solution to the sterile field, the circulating nurse should hold the non-sterile vials while the scrub nurse withdraws the solutions slowly by firm constant aspiration to reduce the risk of large air bubbles.
    Storage: After reconstitution, the product must be used within 4 hours. Do not microwave, refrigerate, or refreeze.
    Preparation (prefilled-frozen syringes)
    Do not use unless it is completely thawed and warmed to a liquid consistency. Do not remove the protective syringe cap until use.
    Room temperature thawing: Unopened pouches may be stored for up to 48 hours at room temperature (15 to 25 degrees C). When product is thawed, warm to 33 to 37 degrees C prior to use, and use immediately. Total thawing and warming time cannot exceed 48 hours.
    Quick thawing on the sterile field using a water bath: Transfer the inner pouch to the sterile field. Using a sterile water bath heated to a temperature of 33 to 37 degrees C, remove the prefilled syringe from the inner pouch, and place directly into the sterile bath ensuring that the entire contents of the prefilled syringe are completely under water. Approximate thawing times with pouches removed by pack size are 5 minutes for 2 mL and 4 mL and 12 minutes for 10 mL.
    Quick thawing off the sterile field using a water bath: Using a non-sterile water bath heated to a temperature of 33 to 37 degrees C, immerse the prefilled syringe in both pouches into the water ensuring that the entire contents of the prefilled syringe are completely under water. Approximate thawing times in pouches by pack size are 30 minutes for 2 mL, 40 minutes for 4 mL, and 80 minutes for 10 mL. Once thawed, remove the pouches from the water bath; dry the external pouch, and transfer the inner pouch with the prefilled syringe onto the sterile field.
    Quick thawing off the sterile field using an incubator: Using an incubator heated to a temperature of 33 to 37 degrees C, place the prefilled syringe in both pouches into the incubator. Approximate thawing times in pouches by pack size are 40 minutes for 2 mL, 85 minutes for 4 mL, and 105 minutes for 10 mL. Once thawed, remove from the incubator and transfer the inner pouch containing the prefilled syringe onto the sterile field.
    Storage: Once warmed to 33 to 37 degrees C or if removed from the original pouch, the product must be used within 4 hours. Do not microwave, refrigerate, or refreeze.
    Application
    Dry wound surface before application.
    To prevent adherence, wet gloves with normal saline before application.
    Immediately before application, expel and discard the first several drops from the application cannula to ensure adequate mixing of the sealer protein and thrombin solutions in cases where very small volumes (1 to 2 drops) of product are administered.
    Apply a thin layer sufficient to entirely cover the intended application area. The application can be repeated, if necessary; reapply before polymerization takes place since fibrin sealant may not adhere to polymerized layer.
    Fix or hold the sealed parts in the desired position for at least 3 to 5 minutes to ensure the fibrin sealant adheres to the surrounding tissues.
    For freeze-dried product, use the Duploject Preparation and Application System or an equivalent FDA-approved delivery device to apply Tisseel. Refer to delivery device instructions.
    For frozen product, use Duo Set or equivalent FDA-approved delivery device to apply Tisseel. Insert plunger into syringe barrel. Connect the 2 syringe nozzles to the joining piece and secure by fastening the tether strap to the syringe. Fit an application cannula to the joining piece. Apply by depressing plunger. If application is interrupted, replace cannula immediately before resuming application.
     
    Raplixa :
    Do not reconstitute.
    Storage: Use within 1 hour of opening.
    Preparation
    Remove vial from pouch following standard sterile technique to ensure that the vial and surgical field remain sterile.
    Ensure powder is in the bottom of the vial.
    Remove flip-off top, leaving stopper in place until immediately before use.
    Prepare sterile gelatin sponge by trimming to appropriate size for bleeding site.
    Application (direct) with absorbable gelatin sponge
    Remove stopper and sprinkle a uniform coating gently onto bleeding site and apply gentle pressure with gelatin sponge using sterile gauze. Alternately, sprinkle thin layer onto a pre-moistened gelatin sponge and place onto the bleeding site with gentle pressure using the sterile gauze.
    Application using the RaplixaSpray device with absorbable gelatin sponge
    Prepare the pressure regulator according to manufacturer's instructions for use.
    To attach the vial to the RaplixaSpray device, invert the device and place the upright vial into the gray rubber ring on the device. Turn the device upright and return the device to the sterile field for use.
    Activate air or gas flow. Check that the pressure is 22 psi (1.5 bar). Do not push button until ready for use.
    Ensure the vial is kept within 45 degrees of vertical at all times.
    Hold nozzle at a minimum distance of 5 cm from the bleeding site.
    Start application by gently pressing the operating button. Powder should cover the bleeding surface as a uniform thin coating. Apply within 10 to 60 seconds.
    Immediately after application, place a gelatin sponge on top of the powder. The gelatin sponge may be used dry or moistened with sterile saline. A moistened sponge molds more easily to irregularly-shaped and contoured bleeding areas. Hold the gelatin sponge in place with manual pressure using sterile gauze.
    Hold the device upside down and carefully remove the empty vial. If needed, attach the second vial.
    Use no more than 2 vials with the RaplixaSpray device. If a third vial is needed, use a new RaplixaSpray device.

    STORAGE

    Generic:
    - Store between 36 to 77 degrees F
    ARTISS:
    - Do not refreeze
    - Do not refrigerate
    - Protect from light
    - See package insert for detailed storage information
    - Store at or below 68 degrees F
    - Store in original container
    Raplixa:
    - Do not freeze
    - Store between 36 to 77 degrees F
    TachoSil Absorbable Fibrin Sealant:
    - Do not freeze
    - Store between 36 to 77 degrees F
    - Store in original package until time of use
    TISSEEL:
    - Do not freeze reconstituted product
    - Do not refrigerate reconstituted product
    - Protect from freezing
    - See package insert for detailed storage information

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Avoid packing when placing TachoSil patches into cavities or closed spaces; this may cause compression of underlying tissue. Use the minimum number of patches necessary to achieve hemostasis.
     
    TachoSil contains collagen, which may adhere to bleeding surfaces. To prevent development of tissue adhesions at undesired sites, adequately cleanse tissue areas outside the desired application area before TachoSil administration. Adhesions leading to gastrointestinal obstruction have been reported with use in abdominal surgery in proximity to the bowel.
     
    The safety and effectiveness of Tisseel in neurosurgical procedures or other surgeries involving confined spaces have not been evaluated.

    Intraarterial administration, intravenous administration

    The intravascular administration (i.e., intravenous administration or intraarterial administration) of fibrin sealant is contraindicated; life-threatening thromboembolic events may occur and the likelihood and severity of acute hypersensitivity reactions may increase in susceptible patients. Exercise caution with Tisseel use in cardiopulmonary bypass surgery to minimize the risk of inadvertent intravascular application.

    Aprotinin hypersensitivity

    Fibrin sealant, human is contraindicated in patients known to have anaphylactic or severe systemic reaction to human blood products. Artiss and Tisseel are contraindicated in patients with a known aprotinin hypersensitivity. Hypersensitivity or anaphylactoid reactions may occur with the use of fibrin sealant, human. Such reactions may especially be seen if fibrin sealant is applied repeatedly over time or in the same setting, or for those receiving Artiss or Tisseel, if systemic aprotinin has been previously administered. Even if the first treatment was well tolerated, a subsequent administration of fibrin sealant, or for Artiss and Tisseel specifically, systemic aprotinin, may elicit an allergic reaction. Associated symptoms include flushing, urticaria, pruritus, nausea, decrease in blood pressure, tachycardia or bradycardia, dyspnea, severe hypotension, and anaphylactic shock. If a hypersensitivity reaction occurs, discontinue administration of fibrin sealant, and remove the already polymerized product from the surgical field. Mild reactions may be managed with antihistamines; severe hypotensive reactions require immediate intervention using current principles of shock therapy.

    Bleeding

    Fibrin sealant is contraindicated for severe or brisk arterial bleeding, as the sealant will be washed away in the flow of blood before hemostasis can be achieved.

    Infection

    Because fibrin sealant, human is made from human plasma, it may carry a risk of transmitting infectious agents (e.g., viruses), the variant Creutzfeldt-Jakob disease (vCJD), and the Creutzfeldt-Jakob disease (CJD) agent. The risk of infection has been minimized by screening plasma donors, testing for the presence of viruses, and inactivating and removing certain viruses. Some viruses, such as parvovirus B19, are difficult to remove or inactivate. Discuss the risks and benefits of fibrin sealant, human with the patient. Instruct patients to contact their physician if they develop symptoms of B19 virus infection, including fever, drowsiness, and chills followed by a rash and joint pain about 2 weeks later. In addition, avoid application of TachoSil to contaminated or infected areas of the body.

    Pregnancy

    There are no data with fibrin sealant, human in pregnant women to inform a drug-associated risk. It is not known if fibrin sealant, human can cause fetal harm when administered during pregnancy or can affect reproductive capacity. Animal reproduction studies have not been conducted with fibrin sealant, human. Because fibrin sealant, human is made from human plasma, it may carry a risk of transmitting infectious agents (e.g., viruses). Some viruses, such as parvovirus B19, are difficult to remove or inactivate. Parvovirus B19 seriously affects pregnant woman (fetal infection). Fibrin sealant, human should only be used during pregnancy if clearly needed.

    Breast-feeding

    There is no information regarding the presence of fibrin sealant, human in human milk, the effect on the breast-fed infant, or the effects on milk production. Because many drugs are excreted in human milk, use caution when administering fibrin sealant, human to a breast-feeding woman. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for fibrin sealant, human and any potential adverse effects on the breast-fed infant from fibrin sealant, human or the underlying maternal condition.

    ADVERSE REACTIONS

    Severe

    atrial fibrillation / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    cardiac arrest / Early / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    pleural effusion / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    GI obstruction / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    air embolism / Rapid / Incidence not known

    Moderate

    constipation / Delayed / 15.0-24.0
    anemia / Delayed / 0.5-23.0
    elevated hepatic enzymes / Delayed / 11.0-11.0
    hypotension / Rapid / 2.0-8.0
    hypertension / Early / 1.0-5.0
    peripheral edema / Delayed / 0.5-0.5
    ascites / Delayed / 1.0
    hypophosphatemia / Delayed / 1.0
    sinus tachycardia / Rapid / Incidence not known
    erythema / Early / Incidence not known
    edema / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    eosinophilia / Delayed / Incidence not known
    bleeding / Early / Incidence not known

    Mild

    nausea / Early / 25.0-30.0
    diarrhea / Early / 17.0-17.0
    vomiting / Early / 5.0-13.0
    fever / Early / 6.0-8.0
    abdominal pain / Early / 1.0
    infection / Delayed / 1.0
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    flushing / Rapid / Incidence not known
    mydriasis / Early / Incidence not known

    DRUG INTERACTIONS

    Povidone-Iodine: (Moderate) If povidone-iodine has been used to clean the wound area, thoroughly rinse and dry prior to application of fibrin sealant. The sealer protein and thrombin solutions of Artiss, TachoSil, and Tisseel can be denatured by povidone-iodine.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no data with fibrin sealant, human in pregnant women to inform a drug-associated risk. It is not known if fibrin sealant, human can cause fetal harm when administered during pregnancy or can affect reproductive capacity. Animal reproduction studies have not been conducted with fibrin sealant, human. Because fibrin sealant, human is made from human plasma, it may carry a risk of transmitting infectious agents (e.g., viruses). Some viruses, such as parvovirus B19, are difficult to remove or inactivate. Parvovirus B19 seriously affects pregnant woman (fetal infection). Fibrin sealant, human should only be used during pregnancy if clearly needed.

    There is no information regarding the presence of fibrin sealant, human in human milk, the effect on the breast-fed infant, or the effects on milk production. Because many drugs are excreted in human milk, use caution when administering fibrin sealant, human to a breast-feeding woman. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for fibrin sealant, human and any potential adverse effects on the breast-fed infant from fibrin sealant, human or the underlying maternal condition.

    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 splitting fibrinogen into fibrinogen monomers and fibrinopeptides. The fibrinogen monomers polymerize and form a fibrin clot. Factor XIIIa, which is activated from Factor XIII by thrombin, crosslinks fibrin. Hemostasis or sealing of tissues is achieved when the formed fibrin clot adheres to the wound surface. Artiss and Tisseel also contain aprotinin, which has been shown to increase resistance of the fibrin sealant clot to degradation in a fibrinolytic environment.

    PHARMACOKINETICS

    Fibrin sealant, human is applied topically. In general, systemic exposure or distribution to other organs or tissues is not expected. Fibrin sealant is metabolized by fibrinolysis and phagocytosis. With wound healing, increased fibrinolytic activity is induced by plasmin and fibrin decompensation to fibrin degradation products occurs.
     
    Affected cytochrome P450 isoenzymes and drug transporters: none

    Topical Route

    In rabbit studies of thrombin applied to the cut surface of the liver, slow absorption of biologically inactive peptides resulting from the breakdown of thrombin occurred. Cmax was reached in 6 to 8 hours, and at the Cmax, the plasma concentration represented only 1% to 2% of the applied dose. The systemic exposure to thrombin when it is applied directly to a hepatic wound was estimated to be approximately equivalent to that generated by minor bleeding.