Surgiflo Family Comparison wPI

Code 199102S: SURGIFLO® Hemostatic Matrix Kit NOW in a KIT with ThrombinSURGIFLO® Hemostatic Matrix Kit Product Code Configuration 199102S SURGIFLO Hemostatic Matrix and Lyophilized Thrombin packaged together in the same kit box 6 kits = sales unit SURGIFLO® Hemostatic Matrix 1991 SURGIFLO® Hemostatic Matrix with EVITHROM® Thrombin, Topical (Human) 199102 199105 SURGIFLO Hemostatic Matrix and 2mL or 5mL EVITHROM® shipped together but packaged separately 6 eaches of SURGIFLO Hemostatic Matrix Plus 6 eaches of EVITHROM® = one sales unit “Virtual” Kit containing frozen/liquid EVITHROM®. EVITHROM® must be stored in freezer or refrigerator upon receipt of product. Ethicon, Inc. 2009 Ethicon, Inc. SURGIFLO® Hemostatic Matrix Quantity 6 eaches = one sales unit Comments Complete Kit containing 2000 units of lyophilized (freeze dried) EVITHROM®. No need for refrigeration. Does not include thrombin FOR INTERNAL USE ONLY. DO NOT DISTRIBUTE. SFL-0214-09-10/10 1 Inc. Important Safety Information •For topical use only. •Do not use in individuals known to have anaphylactic or severe systemic reaction to human blood products. •There is a potential risk of thrombosis if absorbed systemically. 2009 Ethicon. it may carry a risk of transmitting infectious agents. FOR INTERNAL USE ONLY. such as viruses. •Anaphylactic reactions may occur. SFL-0214-09-10/10 Ethicon. •Do not use for the treatment of severe or brisk arterial bleeding. USP. Inc. •Because this product is made from human plasma. ligature or cautery) is ineffective or impractical. None of the adverse events reported was considered casually related to EVITHROM® administration. the Creutzfeldt-Jakob disease (CJD) agent. and theoretically. The most common adverse event reported was procedural complication and pruritus. •Adverse events were reported in the clinical trial with similar frequency in the two study groups (EVITHROM® or bovine thrombin group). Topical (human) is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture. Do not inject EVITHROM® directly into the circulatory system.EVITHROM® Thrombin. 2 . DO NOT DISTRIBUTE. EVITHROM® may be used in conjunction with an Absorbable Gelatin Sponge. Caution: SURGIFLO Hemostatic Matrix should not be used for the primary treatment of coagulation disorders. concurrent use of topical thrombin or other agents is medically advisable. agitation. INTENDED USE/INDICATIONS SURGIFLO Hemostatic Matrix. have been associated with fever.4%) Dyspepsia 10 ( 7.1%) Diarrhea 9 ( 6.2%) 21 ( 7. paresthesias. dizziness. melena. SURGIFLO Hemostatic Matrix should not be left in the renal pelvis or ureters to eliminate the potential foci for calculus formation. Table 1: Incidence of Treatment Emergent Adverse Events by Treatment Group.3%) 12 ( 8. or in proximity to foramina in bone. ADVERSE EVENTS A total of 142 patients received SURGIFOAM Sponge during a clinical trial comparing SURGIFOAM Sponge to another absorbable gelatin sponge.4%) Anemia 19 (13.7%) Pharyngitis 13 ( 9. Safe and Effective use in neurosurgery has not been proven through randomized. if in the physician’s judgment.2%) 22 ( 7. and impotence. When used in appropriate amounts SURGIFLO Hemostatic Matrix is absorbed completely within 4 to 6 weeks. a luer adapter. confusion. • SURGIFLO Hemostatic Matrix should be removed if possible once hemostasis has been achieved because of the possibility of dislodgment of the device or compression of other nearby anatomic structures. when excessive amounts are not used. SURGIFLO Hemostatic Matrix may swell creating the potential for nerve damage.5%) 10 ( 7. controlled clinical studies in the United States.) plus FlexTip Caution: Federal (U. leukocytosis. This interference is due to mechanical interposition of gelatin and is not secondary to intrinsic interference with wound healing. Mixing is facilitated by using the enclosed accessories. depression.5%) 17 ( 6. thrombocytopenia.1%) 20 (14.3%) Pain 13 ( 9. If signs of infection or abscess develop where SURGIFLO Hemostatic Matrix has been positioned.7%) 22 (15. the product literature for that agent should be consulted for complete prescribing information. and blindness.7%) 34 (24. ecchymosis. an applicator tip is attached to the syringe for product delivery onto a bleeding site.) law restricts this device to sale by or on the order of a physician (or properly licensed practitioner).6%) 17 (12. • SURGIFLO Hemostatic Matrix should be removed from the site of application when used in.2%) 8 ( 5.2%) 22 ( 7. • The use of absorbable gelatin-based hemostatic agents during the repair of dural defects associated with laminectomy and craniotomy operations. PRECAUTIONS Caution: Safe and Effective use of SURGIFOAM Sponge has been reported in a published Neurologic retrospective study involving 1700 cases in Europe. amblyopia. is indicated for surgical procedures (except ophthalmic) for hemostasis. • Excessive fibrosis and prolonged fixation of a tendon have been reported when absorbable gelatin-based sponges were used in severed tendon repair.0%) 18 ( 6. The pre-filled matrix is off-white in appearance. neck and back pain. Caution: Only the minimum amount of SURGIFLO Hemostatic Matrix needed to achieve hemostasis should be used. SURGIFLO Hemostatic Matrix should not be used in this manner unless excess product that is not needed to maintain hemostasis is removed.6%) 5 ( 3.5%) Hypomagnesemia 11 ( 7.2%) 11 ( 7.0%) Hypotension 10 ( 7. • Compression of the brain and spinal cord resulting from the accumulation of sterile fluid have been observed. bradycardia. oliguria. • Fever. Although not necessary.6%) 9 ( 6.3%) 13 ( 9. bladder and bowel dysfunction. eye pain and pneumonia. any excess SURGIFLO Hemostatic Matrix should be carefully removed.4%) 40 (14. • The safety and effectiveness of SURGIFLO Hemostatic Matrix for use in ophthalmic procedures has not been established. the following adverse events have been reported with the use of absorbable porcine gelatin-based hemostatic agents: • Gelatin-based hemostatic agents may serve as a nidus for infection and abscess formation and have been reported to potentiate bacterial growth.3%) 9 ( 6. SURGIFLO Hemostatic Matrix absorbs completely. around.A.1%) Hypokalemia 11 ( 7. saturated with sterile solution.6%) Hematoma 8 ( 5. V dysphagia.S. Table 1 lists those adverse events that occurred in greater than 5% of the SURGIFOAM Sponge patients.2%) Constipation 17 (12.2%) Hypertonia 20 (14. • Foreign body reactions. venous and arteriolar bleeding by pressure.6%) Asthenia 25 (17. Do not use SURGIFLO Hemostatic Matrix in patients with known allergies to porcine gelatin. and asthenia (a general feeling of weakness). and/or the optic nerve and chiasm.7%) 6 ( 4. antibiotic solution or antibiotic powder has not been evaluated in controlled clinical trials.0%) Headache 11 ( 7.7%) 11 ( 7.8%) Pruritus 12 ( 8.P. SURGIFLO Hemostatic Matrix may swell approximately 19 % upon contact with additional fluid. Caution: In urological procedures. and a liquid transfer cup. absorbable porcine gelatin intended for hemostatic use by applying to a bleeding surface.8%) 40 (14.7%) 9 ( 6. Caution: SURGIFLO Hemostatic Matrix is supplied as a sterile product and cannot be re-sterilized. nor will it close off an area of blood collecting behind a tampon. The most common adverse events recorded during and after the application of the device were fever.SURGIFLO® Hemostatic Matrix (Made from SURGIFOAM* Absorbable Gelatin Sponge U.5%) 18 ( 6. neurogenic bladder. and paresis. anxiety.0%) 4 ( 2.9%) 30 (10.0%) Hypocalcemia 9 ( 6. It should not be used where blood or other fluids have pooled or in cases where the point of hemorrhage is submerged.2%) 17 (12.6%) 32 (11.3%) 8 ( 5. somnolence. Do not inject into blood vessels DESCRIPTION The SURGIFLO Hemostatic Matrix is a sterile. chills. • The use of absorbable gelatin-based hemostatic agents have been associated with paralysis. meningitis. hiccups. dehydration.9%) 14 ( 5. hematuria. infection of the urinary tract. including cauda equina syndrome.7%) Nausea 18 (12. Once hemostasis is achieved. Caution: While packing a cavity for hemostasis is sometimes surgically indicated. headaches. leg paresthesias. vertigo. reoperation may be necessary in order to remove the infected material and allow drainage.4%) 11 ( 7.4%) 29 (10. Do not use SURGIFLO Hemostatic Matrix in intravascular compartments because of the risk of embolization.2%) 30 (10. mucous membrane discharge. CONTRAINDICATIONS Do not use SURGIFLO Hemostatic Matrix in closure of skin incisions because it may interfere with the healing of skin edges.0%) Insomnia 16 (11. arachnoiditis.1%) 55 (19. urine retention.8%) 17 ( 6. dyspnea. failure of absorption. and moderate when observed microscopically with SURGIFOAM* Absorbable Gelatin Sponge.0%) Edema General 8 ( 5. ileus.9%) Peripheral Edema 20 (14.7%) 7( 5. In an animal implantation study. GI discomfort.0%) 28 (20.1%) Tachycardia 27 (19.9%) 22 ( 7. Unused open pouches of SURGIFLO Hemostatic Matrix should be discarded.0%) 17 (12. Other adverse events observed in less than 5% of the SURGIFOAM Sponge patients were chest pain.2%) 34 (12. ligature and other conventional procedures is ineffective or impractical. abdominal pain. Microfibrillar collagen has been reported to reduce the strength of methylmethacrylate adhesives used to attach prosthetic devices to bone surfaces. pain.5%) Edema 12 ( 8.8%) 21 ( 7.8%) Infection 11 ( 7. WARNINGS • SURGIFLO Hemostatic Matrix is not intended as a substitute for meticulous surgical technique and the proper application of ligatures or other conventional procedures for hemostasis. cauda equina syndrome. It has been demonstrated that fragments of collagen based hemostatic agents may pass through 40μ transfusion filters of blood scavenging systems. • SURGIFLO Hemostatic Matrix should not be used in instances of pumping arterial hemorrhage. Caution: SURGIFLO Hemostatic Matrix should not be used in conjunction with methylmethacrylate adhesives. • Giant cell granulomas have been observed at implant sites when used in the brain. abnormal healing. tachycardia. TERM SURGIFOAM Control Sponge Total (n=142) (n=139) (n=281) Fever 28 (19. cardiomegaly.9%) 24 ( 8. with little tissue reaction. SURGIFLO Hemostatic Matrix will not act as a tampon or plug in a bleeding site. cellulitis. ACTIONS SURGIFLO Hemostatic Matrix has hemostatic properties.4%) Cough Increased 8 ( 5. anorexia. arrhythmia.6%) 9 ( 6. SURGIFLO Hemostatic Matrix can be used with or without thrombin to achieve hemostasis. infection.5%) 20 ( 7. dry mouth. • The safety and effectiveness of SURGIFLO Hemostatic Matrix has not been established in children and pregnant women. “encapsulation” of fluid.2%) 42 (14. hyperventilation.5%) Vomiting 13 ( 9. during lobectomy. spinal stenosis. flatulence. • SURGIFLO Hemostatic Matrix should not be used for controlling post-partum intrauterine bleeding or menorrhagia. included are a sterile empty syringe. and hematoma have been observed at implant sites.0%) .5%) 10 ( 7.0%) 10 ( 7. due to device migration in the orbit of the eye. abdominal enlargement. hyperglycemia. laminectomy and repair of a frontal skull fracture and lacerated lobe. areas of bony confine. due to device migration into foramina in the bone around the spinal cord.7%) 10 ( 7. tissue reactions were classified as negligible when observed macroscopically. • Multiple neurologic events were reported when absorbable gelatin-based hemostatic agents were used in laminectomy operations. Caution: SURGIFLO Hemostatic Matrix should not be used in conjunction with autologous blood salvage circuits.2%) 20 ( 7. In general. back pain. when control of capillary.7%) 31 (11.1%) Hypertension 16 (11. SURGIFLO Hemostatic Matrix should be used with caution in contaminated areas of the body. When mixed according to the Instructions for Use. the spinal cord. • Toxic shock syndrome was reported in association with the use of absorbable gelatinbased hemostats in nasal surgery. Caution: Although the safety and effectiveness of the combined use of SURGIFLO Hemostatic Matrix with other agents such as topical thrombin.6%) 28 (10. Care should be exercised to avoid overpacking.5%) 62 (22.0%) Paresthesia 11 ( 7. Caution: The safety and effectiveness for use in urological procedures has not been established through a randomized clinical study.1%) 12 ( 8. lung edema.6%) 13 ( 4.8%) Rash 12 ( 8. and hearing loss have been observed when absorbable hemostatic agents were used during tympanoplasty. and is mixed with either sterile saline or thrombin. impotence. • SURGIFLO Hemostatic Matrix should not be used in the presence of infection.3%) 17 ( 6.5%) 19 (13. bladder and bowel incontinence.5%) 17 ( 6. urinary incontinence. Once the hemostatic matrix is mixed with 2-5 ml of additional liquid. The control patients are included for comparison.S. Once hemostasis has been achieved. Use of SURGIFLO* Hemostatic Matrix as a Hemostatic Agent for Nasal/Sinus Bleeding: Surgiflo Hemostatic Matrix has been successfully used with bovine thrombin intraopertively as a hemostatic agent for the control of bleeding post nasal sinus surgery in 30 patients (54 application sites).0 3 (42/64) (39/68) (10/10) Control Sponge 66. Study Results: Two hundred eighty one patients were enrolled into the study and received study treatment. serious adverse events. Caution: Federal (U. Remove the empty syringe and the luer adapter. 4) Begin mixing the two components by injecting the liquid solution into the pre-filled matrix.A. DK-2860 Soeborg Denmark © 2008 ETHICON. 8-11 ml of hemostatic matrix should reside completely in one syringe. The median time to hemostatis for 54 operated sides including manual compression was 61 seconds.4 100. P. Only one of the 206 patients had antibodies at baseline and 6 of the 206 patients had antibodies at the 6 to 8 week time point. excess SURGIFLO Hemostatic Matrix should be removed with gentle irrigation or careful suction.0 6 (63/64) (55/68) (10/10) Control Sponge 95. Sera were collected prior to surgery. Table 2: Summary of Effectiveness Results Comparing SURGIFOAM Sponge absorbable gelatin sponge. indicated by saturation and bleeding through the material. Box 151. INC.9 100. general surgical. One subject failed to achieve hemostasis within 10 minutes of product application. After re-application of SURGIFLO Hemostatic Matrix.S. The study compared the SURGIFOAM Sponge to an absorbable gelatin sponge currently legally marketed in the U.7 100. The sponges were used either soaked with saline or dry. f.1 (125/142) 96. d. b. Open packages of SURGIFLO Hemostatic Matrix should be discarded. Using forceps or an appropriate instrument. 1 flexible applicator tip (blue) with marker lines and numbers. Two hundred six patients were tested at baseline. sterility cannot be assured and the contents should not be used. If the package is damaged or wet. Apply sufficient SURGIFLO Hemostatic Matrix to cover the entire bleeding surface. This patient was treated with local care with immediate resolution. Avoid disrupting the SURGIFLO Hemostatic Matrix clot complex.O. The primary objective of the study was to examine the equivalence of the SURGIFOAM Sponge to the control device as measured by hemostasis within 10 minutes of application. Use of nasal packing is not necessary when satisfactory hemostasis is achieved. These results are also summarized in Table 2.) law restricts this device to sale by or on the order of a physician (or properly licensed practitioner).0 10 (64/64) (61/68) (10/10) Control Sponge 95.0 (62/65) (57/62) (12/12) SURGIFOAM Sponge 100. Three of the patients were in the SURGIFOAM Sponge group and 3 patients were in the control group. Thirty (30) subjects from three (3) US centers undergoing elective endoscopic sinus surgery (ESS) who met the eligibility criteria were treated with SURGIFLO Hemostatic Matrix and bovine thrombin post ESS. and then inspect the site.0 (91/142) 66. c. Patients were followed for two months after surgery to assess the safety of the sponge. Post-operative healing and all complications were recorded during this period. use a moistened cottonoid to approximate the material to the tissue for another minute. For endoscopic sinus surgery and epistaxis: a. The study also collected hemostasis data at 3 and 6 minutes. Cardiovascular. 7) Attach an applicator tip to the filled syringe.9 100. *Trademark Distributed by Manufactured by Ferrosan A/S Sydmarken 5. or serious complication such as synechiae or infections were reported in this study.CLINICAL STUDIES Study Design: An open label. (Percent achieving hemostasis).4 (134/139) STORAGE AND HANDLING SURGIFLO Hemostatic Matrix should be stored dry at controlled room temperature 36° F – 77° F (2°-25° C) It is recommended that SURGIFLO Hemostatic Matrix be used as soon as the package is opened. Study Results: Intraoperative bleeding ceased in 29 out of 30 patients. single-arm study. 6) Once mixed. unmasked study was conducted to evaluate the safety and effectiveness of two hemostatic agents. Caution: The use of SURGIFLO Hemostatic Matrix for mechanical support has not been studied. carefully layer a moistened cottonoid over the SURGIFLO Hemostatic Matrix for 1-2 minutes to ensure the material remains in contact with the bleeding tissue. NJ 08876-0151 USA . 1 syringe luer adapter.4 91. at 2 to 4 weeks post surgery and at 6 to 8 weeks following surgery. If necessary.7 (43/65) (39/62) (11/12) SURGIFOAM Sponge 98. Sterile technique should always be used to remove the SURGIFLO Hemostatic Matrix from its packaging. SURGIFLO Hemostatic Matrix can be applied to the bleeding site saturated with sterile isotonic sodium chloride solution (sterile saline) or sterile topical thrombin solution. SFL-0372-09-12/10 A statistical analysis showed that SURGIFOAM Sponge and the control sponge were equivalent in the ability to achieve hemostasis within 10 minutes. DIRECTIONS FOR USE Before using. 1 applicator tip (white). One patient had mild oozing after surgery.2 (131/139) 95. as it will be bioresorbed. and at 6 to 8 weeks. Use only the minimum amount necessary to achieve hemostasis. 8) The product is now ready for clinical use. Somerville.6 57.4 96. insert the applicator tip through the center of the mass of previously placed SURGIFLO Hemostatic Matrix to deliver fresh material as close as possible to the tissue surface. Subjects were followed at 7 days (± 3 days) and at 30 days (± 7 days) post-operatively. This was a single arm study with no control arm. The study effectiveness results are summarized in Table 2 below. No intraoperative complications. Repeat re-application if necessary.1 (128/142) 94.A. and orthopedic patients were eligible for the study. In cases of persistent bleeding. randomized. Minutes Device General Surgical Cardiovascular Orthopedic % (Ratio) % (Ratio) % (Ratio) SURGIFOAM Sponge 65.S. The analysis of the immunology data indicated that there was no difference in the ability of the SURGIFOAM Sponge to induce antiporcine collagen immunoglobulins when compared to the control sponge. since they are not intended for reuse and/or re-sterilization. inspect the package for signs of damage. controlled. 2 to 4 weeks. The hemostasis data was collected immediately during surgery and the patients were examined at two to four weeks and again at six to eight weeks in order to obtain safety data.4 80. SURGIFLO Hemostatic Matrix should be prepared using the following method: 1) Draw 2-5 ml of sterile saline or thrombin solution into the empty sterile syringe. gentle irrigation and/or careful suction can be used in postoperative period to remove the remaining SURGIFLO Hemostatic Matrix. 3) Attach the luer adapter to the pre-filled syringe and attach the liquid solutioncontaining syringe to the other end of the luer adapter. 2) Remove the cap from the end of the pre-filled syringe. Deliver SURGIFLO Hemostatic Matrix to the source of bleeding using the selected applicator tip attached to the SURGIFLO Hemostatic Matrix syringe. Study Design: This was a multi-center. 1 x 12ml (empty) sterile syringe. The remaining SURGIFLO Hemostatic Matrix does not have to be removed. 5) Continue to mix the components by pushing the combined material back and forth until the consistency is even (this will require approximately 5-6 transfers). Immune Response: Patient sera were tested for the presence of anti-porcine collagen immunoglobulins. Patients were followed for 30 days following surgery.2 62.8 100. HOW SUPPLIED SURGIFLO Hemostatic Matrix is supplied in a kit configuration containing: 1 x 12ml syringe pre-filled with hemostatic matrix. If possible. remove the cottonoid.0 89. prospective.9 91.0 (62/65) (60/62) (12/12) to another Total % (Ratio) 64. e. multi-center.9 (93/139) 90. and 1 liquid transfer cup. 5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12. • Shake gently until the solution is clear. decreased lymphocyte count. add 2 ml of Water for Injection.2 Labor and Delivery 1 INDICATIONS AND USAGE EVITHROM®. CONTRAINDICATIONS • Do not use in individuals known to have anaphylactic or severe systemic reaction to human blood products. USP (2. the final solution contains 1000 (800-1200) units/ml of Thrombin. ligature or cautery) is ineffective or impractical.2 Application Techniques DO NOT INJECT. Vials are for single use only.2 ). increased INR. USP. avoid sponging the clot to assure that it remains securely in place. Impairment of Fertility 13. Therefore. Use aseptic technique when handling vials and syringes. Discard unused contents. • Vials are for single use only.3 Nursing Mothers 8.fda. Reconstituted solution can be stored at room temperature for up to 8 hours and should be used within that time period (16). USP (2. Approval: 2007 --------------------------------------INDICATIONS AND USAGE------------------------------------• EVITHROM is a topical thrombin indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture.2 Post Marketing Experience DRUG INTERACTIONS USE IN SPECIFIC POPULATIONS 8.1 Reconstitution Prior to Application 2. USP (1 ). EVITHROM should only be used in pregnancy if clearly indicated (8. Adverse events were reported in the clinical trial with similar frequency in the two study groups (EVITHROM or bovine thrombin group) (6 ). No data in pregnant women. Therefore. To report SUSPECTED ADVERSE REACTIONS. ----------------------------------------ADVERSE REACTIONS---------------------------------------• The most common adverse reactions during clinical trial (reported in at least 2% of subjects treated with EVITHROM) were prolonged activated partial thromboplastin time. The potency expressed in units is determined using a clotting assay against an internal reference standard for potency that has been calibrated against the World Health Organisation (WHO) Second International Standard for Thrombin. • Immunogenicity was evaluated by testing for the development of antibodies to highly purified antigens: human thrombin. Lyophilized Powder for Reconstitution Initial U.2 Pharmacodynamics 12.2 ). USP.2 Application Techniques DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5. the Creutzfeldt-Jakob disease (CJD) agent. Topical (Human) For Topical Use Only.gov/medwatch. USP to the glass vial.1).1 Clinical Trials Experience 6.1 Pregnancy 8.1 Thrombosis Potential risk of thrombosis if absorbed systemically 4 . DO NOT INJECT. the final solution contains 1000 (800-1200) units/ml of EVITHROM (3 ). EVITHROM® Thrombin. EVITHROM® alone • Sponge target surface (do not wipe) or suction free of blood before application. bovine thrombin and bovine Factor V/Va.2 Transmission of Infectious Agents ADVERSE REACTIONS 6.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13. contact ETHICON Customer Support Center at (877) 384-4266 or FDA at 1-800-FDA-1088 or www. See full prescribing information for EVITHROM. human Factor V/Va. Topical (Human). prolonged prothrombin time and increased neutrophil count. • Remove the flip-off plastic cap from the vial to expose the rubber stopper. --------------------------------DOSAGE FORMS AND STRENGTHS-------------------------------EVITHROM is supplied in vials containing 2000 (1600-2400) units of lyophilized human thrombin powder for reconstitution.2).4 Pediatric Use 8. As an approximate guide. • The amount of EVITHROM required depends upon the area of tissue to be treated and the method of application. • Reconstitute in 2ml Water for Injection. Thrombin. Apply only on the surface of bleeding tissue.1 Carcinogenesis. Thrombin. volumes up to 10ml were used in conjunction with Absorbable Gelatin Sponge. The potency expressed in units is determined using a clotting assay against an internal reference standard for potency that has been calibrated against the World Health Organisation (WHO) Second International Standard for Thrombin. DO NOT INJECT (2. • May carry a risk of transmitting infectious agents such as viruses and theoretically. When reconstituted with 2ml of Water for Injection. USP • Transfer EVITHROM® into a sterile container using aseptic techniques. ligature or cautery) is ineffective or impractical (1 ). ----------------------------------WARNINGS AND PRECAUTIONS---------------------------------• Potential risk of thrombosis if absorbed systemically (5. Mutagenesis. • Do not use for treatment of severe or brisk arterial bleeding (4 ). • Using a sterile needle and syringe. • Immerse gelatin sponge of desired shape in the EVITHROM® solution. The amount of EVITHROM® required depends upon the area of tissue to be treated and the method of application. • Vigorously knead the sponge with moistened gloved fingers until all air is expelled and it can return to its original size and shape. Use EVITHROM® topically. may be used in conjunction with an Absorbable Gelatin Sponge. volumes up to 10 ml were used in clinical studies where EVITHROM® was used in conjunction with Absorbable Gelatin Sponge.1 Mechanism of Action 12. • Anaphylactic reactions may occur (6 ). EVITHROM® in conjunction with Absorbable Gelatin Sponge. is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture. 01/580. None of the patients treated with EVITHROM developed antibodies to human thrombin or to human Factor V/Va. When reconstituted with 2 ml of Water for Injection.2 ). Discard unused contents (2. despite manufacturing steps designed to reduce the risk of viral transmission (5.HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use EVITHROM safely and effectively. EVITHROM. a unit used herein is equivalent to an International Unit.2 Animal toxicology and/or pharmacology 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION: CONTENTS* 1 2 3 4 5 6 7 8 INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION 2.S. See 17 for PATIENT COUNSELING INFORMATION Revised: 9/2009 8.1). The amount of EVITHROM® required depends upon the area of tissue to be treated and the method of application. 01/580. Topical (Human).1 Reconstitution Prior to Application Reconstitute the lyophilized human thrombin powder. • EVITHROM may be used in conjunction with an Absorbable Gelatin Sponge. Topical (Human). USP.1 ). 2 DOSAGE AND ADMINISTRATION FOR TOPICAL USE ONLY. • The surface may be flooded with EVITHROM® using a sterile syringe and small gauge needle. ----------------------------------USE IN SPECIFIC POPULATIONS--------------------------------Pregnancy: Animal data are summarized in the Non Clinical Toxicology section (13 ). ----------------------------------------CONTRAINDICATIONS---------------------------------------• Do not use in individuals known to have anaphylactic or severe systemic reaction to human blood products (4 ). 5 WARNINGS AND PRECAUTIONS 5. • Do not use for the treatment of severe or brisk arterial bleeding.1 Thrombosis 5. 3 DOSAGE FORMS AND STRENGTHS EVITHROM® is supplied in a vial containing 2000 (1600-2400) units of lyophilized human thrombin powder for reconstitution. USP. a unit used herein is equivalent to an International Unit. ----------------------------------DOSAGE AND ADMINISTRATION--------------------------------• Lyophilized powder for reconstitution for topical use only. Reconstituted solution is stable for up to 8 hours at room temperature and should be used within this time period. • After treatment. • Hold the saturated sponge in place with gauze or cotton pledget using moderate pressure until hemostasis is achieved. In clinical studies. 2. 2. 6%) 5 (3. Studies to evaluate the potential reproductive/ developmental toxicity of EVITHROM® have not been performed due to the human origin of thrombin. Anaphylactic reactions may occur in rare cases. HBV and HAV must be negative (non-reactive).37 6. The effectiveness of the S/D treatment and nanofiltration procedures for reducing virus content has been assessed using a series of viruses with a range of physico-chemical characteristics. HCV.3%) 12 (3. The risk of transmitting an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses. in which EVITHROM® is a component.3%) 12 (3. The S/D reagents are removed by cation exchange chromatography. After reviewing all data.2%) 14 (9.3%) 5 (1. 8. None of the patients treated with EVITHROM® developed detectable antibodies to human thrombin or to human Factor V/Va. 7. However. HIV-1 & 2 Ab.74 >4. 8 USE IN SPECIFIC POPULATIONS 8. No differences in safety or effectiveness were observed between the elderly and younger patients. each manufacturing pool is tested for HBsAg. human thrombin.74 >9. EVITHROM® is manufactured by chromatographic purification of prothrombin from cryopoor plasma followed by activation with calcium chloride. Sodium acetate EVITHROM® is made from pooled Human Source and Recovered Plasma obtained from US licensed plasma collection centers. 8. controlled.2 Labor and Delivery The safety of EVITHROM® for use during labor and delivery has not been established. HIV-1 >5.5 Geriatric Use Sixty three (63) subjects over 65 years of age received EVITHROM® in the phase III clinical trial. The composition of the lyophilized powder of EVITHROM® is as follows: Active Ingredients: Human thrombin (1600-2400 units) Other Ingredients: Calcium chloride.0%) 6. Table 1: Incidence of subjects with related adverse events reported in at least 2% of subjects treated with either human or bovine thrombin System Organ Class/Adverse Event Investigations Activated partial thromboplastin time increased International normalized ratio increased Lymphocyte count decreased Prothrombin time prolonged Neutrophil count increased Skin and Subcutaneous Tissue Disorders Pruritis General Disorders and Administration Site Conditions Thrombin Type EVITHROM® Bovine Total (n=153) (n=152) (n=305) 11 (7. Human albumin. prolonged prothrombin time and increased neutrophil count. Overall. decreased lymphocyte count. compared to 12.18 BVDV PRV EMCV HAV CPV Reduction factor (log10) >5.3%) 9 (3. In a phase III multicenter.5. The SAEs reported were associated with post-surgical complications (e.9%) 4 (2. No clinically significant differences were seen in age (<65 years. increased INR. In addition to the screening of plasma units. the Creutzfeldt-Jakob disease (CJD) agent. Additionally. The detection of antibody formation is highly dependent upon the sensitivity and specificity of the assay.36 >10. such as viruses.85 >10.1 Pregnancy Teratogenic effects: Pregnancy category C. 1% Triton X-100) for 6 hours at 26°C to inactivate lipid enveloped viruses. Individual plasma units obtained for production of EVITHROM® are tested by licensed serological tests for HBsAg. Mannitol and human albumin are used to stabilize the solution.63 >4.37 6.95 5. or underlying disease.0%) 4 (2. wound infection 3/153 for EVITHROM® and 2/152 for bovine thrombin) and the medical condition of the subject and were not considered related to study drug. At least one serious adverse event (SAE) was reported for 26/153 (17%) subjects treated with human thrombin and 17/152 (11%) subjects treated with bovine thrombin. EVITHROM® should be used in pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. When reconstituted. The results of the validation studies are summarized in Table 2: Table 2: Reducing factors of S/D treatment and nanofiltration for a series of viruses Virus SD Treatment Nanofiltration Global Reduction Factor HIV-1: SBV: BVDV: PRV: EMCV: HAV: CPV: Immunogenicity In the clinical study. The observed incidence of a positive signal in an assay may be influenced by several factors including timing of sampling. Samples were collected at both time points for 81.0%) 4 (2.0%) 2 (1. and human Factor V/Va. five were less than 2 years old and three were between 2 and 12 years old. The manufacturing process includes two targeted steps for inactivation or removal of viruses. Viral serology was not monitored during the study with EVITHROM®. concomitant medications.2 Transmission of Infectious Agents Because this product is made from human plasma. The protocol did not specify any comparative analysis for immunogenicity data. Severe hypotensive reactions require immediate intervention using current principles of shock therapy.3% of the subjects. and theoretically. such products can still potentially transmit disease. double-blinded study of 305 subjects where EVITHROM® (n=153) was compared with bovine thrombin (n=152). Manufacturing pool testing. The lyophilized powder is white to slightly yellowish in color.3%) 4 (1. The physician should discuss the risks and benefits of this product with the patient.2 Post Marketing Experience No adverse reactions have been identified from spontaneous post-marketing reports.32 Not Done >5.3%) 6 (2. Despite these measures.25 Not Done Not Done 0. The adjudicated results show that 3.g.7% of the subjects developing antibodies in the control group (bovine thrombin). randomized. prospective. No adverse events of this type were reported during the conduct of the clinical trials. Adequate and well-controlled studies in pregnant women have not been performed. HCV. serum samples were collected at baseline and at 5 weeks post-surgery for evaluation of antibodies to bovine thrombin. However. occurrence of adverse events was not statistically different between the two groups. There is also the possibility that unknown infectious agents may be present in such products. Of these. >65 years) or gender subgroup analyses of adverse events. it may carry a risk of transmitting infectious agents.7%) 1 (0. A few control subjects had antibodies that cross-reacted with human thrombin.31 >4. After nanofiltration. 6.0%) 3 (2.3%) 3 (1. 8. since the effectiveness of the HBV and HAV NAT methods in detecting low levels of viral material is still under investigation. Two subjects (1. studies to evaluate the potential reproductive/developmental toxicity of residual levels of Triton X-100 and tri-n-butyl phosphate (solvent/detergent reagents) were conducted in animals and are summarized in the Non Clinical Toxicology section (13). 6 ADVERSE REACTIONS The most common adverse reactions during clinical trials (reported in at least 2% of subjects treated with EVITHROM®) were prolonged activated partial thromboplastin time. however.6%) 8 (5. pyrexia and post-procedural hematoma. All tests for HIV. This limit is applied to restrict the viral load of parvovirus B19 in the starting plasma pool. by testing for the presence of certain current virus infections and by inactivating and removing certain viruses.2%) 4 (2. Greater susceptibility of older patients to adverse reactions cannot be ruled out. 11 DESCRIPTION EVITHROM® is provided as a sterile powder of purified human thrombin. The first of these is treatment with a solvent/detergent (S/D) mixture (1% tri-n-butyl phosphate.6%) 8 (5. human Factor V/Va or bovine Factor V/Va following administration of EVITHROM® with incidence of antibody development following administration of other products may be misleading and the clinical significance of these findings is unknown.8-7.94% of the subjects treated with bovine thrombin (control group) developed antibodies to bovine thrombin and 9. but none had antibodies that cross-reacted with human Factor V/Va.85 SBV Human Immunodeficiency Virus Type 1 Sindbis Virus Bovine Viral Diarrhea Virus Pseudorabies Virus Encephalomyocarditis virus Hepatitis A Virus Canine Parvovirus . 7 DRUG INTERACTIONS No drug interactions are known. adverse reaction rates observed in the clinical trials of a drug product cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. the significance of a negative result for these viruses is unknown. direct comparison of incidence of antibody development to human thrombin. which undergoes nanofiltration for removal of both enveloped and non-enveloped viruses. the solution is formulated with calcium chloride.2. Mild reactions can be managed with antihistamines. 10 OVERDOSAGE No case of overdose has been reported. The level of parvovirus B19 contamination is not permitted to exceed 10. The ELISA data were adjudicated by a panel of experts blinded to treatment assignment. the panel used an algorithm for assigning outcomes for each antigen: seroconversion negative or seroconversion positive. No deaths were reported during the study period. pH 6.6%) 2 (1.0 >5. the plasma units are tested by licensed Nucleic Acid Testing (NAT) for HIV-1. no adverse events indicative of infection with transfusion-transmissible agents were reported.3% of the subjects treated with EVITHROM® (frozen formulation) developed antibodies to any of the four antigens.0%) 4 (1. Three subjects in the bovine thrombin group experienced a treatment emergent severe adverse event: hyperhidrosis.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions.2%) 25 (8.9%) 3 (2. HAV and parvovirus 19. Mannitol. Therefore. is clear to slightly opalescent and colorless to slightly yellowish in color. is of lower sensitivity than individual unit testing. HIV 1 & 2 Ab and HCV Ab and recovered plasma units are also tested for HTLV I/II.47 6.7%) 0 3 (2. and for HCV NAT. only descriptive statistics.4 Pediatric Use Of the 155 patients undergoing liver surgery who were treated in adequate and wellcontrolled studies of EVICEL Fibrin Sealant (Human). EVITHROM® solution. bovine Factor V/Va.0%) 3 (2.52% of these subjects developed antibodies to bovine Factor V/Va.72 6. adverse events occurred in similar proportions of subjects in the two study groups (see Table 1). HBV.3 Nursing Mothers The safety of EVITHROM® for use during breast-feeding has not been established.95 5. However.000 copies/ml.82 >4. eight were pediatric patients.6%) 1 (0.3%) in EVITHROM® group experienced a treatment emergent severe adverse event: respiratory arrest and post-procedural hematoma (in one subject) and extradural hematoma. bovine thrombin. 8. sterile filtered and aseptically filled and frozen. Use only if clearly needed. sample handling. Use of EVITHROM® in pediatric patients is supported by these data and by extrapolation of findings for safety and efficacy in adults. Consult your physician for any new or unusual symptoms. Parvovirus B19 most seriously affects pregnant women or immune-compromised individuals.O. 16 HOW SUPPLIED/STORAGE AND HANDLING EVITHROM® is supplied in a 2 ml vial containing 2000 (1600-2400) units of lyophilized human thrombin powder for reconstitution in 2 ml Water for Injection.02 0. Other studies performed with combinations of TnBP (300-fold human dose. Inc. bovine thrombin: 63.2) (72.8) 1. 200-fold and 1000-fold the human dose.6) (82. both limits of the confidence interval must have been within (0. The effect of EVITHROM® on fertility has not been evaluated.96. 13 NONCLINICAL TOXICOLOGY 13.08 145/153 141/152 Overall (94.0%.6%. 80YZ00Z3D0 U.8) 1. INC.01 0.09 112/153 110/152 3 minutes (73. drowsiness. >90% of subjects from all surgeries in both study groups had achieved hemostasis. vomiting and abdominal pain. These studies were negative for both thrombin and for TnBP or Triton X-100 at all concentrations tested.02 0.12 CLINICAL PHARMACOLOGY EVITHROM® requires no intermediate physiological agent because it clots the fibrinogen of the blood directly.13 0. Symptoms of parvovirus B19 infection include: fever.6) 1.8) (92.2 Animal Toxicology and/or Pharmacology EVICEL Fibrin Sealant (Human). Kiryat Ono 55000 ISRAEL Art.human thrombin: 83.82.00 0. controlled. 1. decreased fetal body weights. The fibrin clot is stabilized by cross-linking occurring as a result of activation of the patient’s endogenous factor XIII.88. Dark urine and a yellowed complexion are also common symptoms. Treatment with EVITHROM® was as successful as treatment with bovine thrombin in achieving the primary efficacy endpoint: hemostasis within 10 minutes of product application and secondary efficacy endpoints: hemostasis within 6 and 3 minutes of product application. respectively. Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of EVITHROM® due to the human origin of thrombin. Evidence of hepatitis A may include several days to weeks of poor appetite.09 1 95% CI is for the ratio of proportions of success 2 For the two treatments to be equivalent. Somerville. was classified as non-irritant in the Primary Cutaneous Irritation Test and slightly irritant in the Ocular Irritation test. Mutagenesis. (2) spinal surgery. chromosomal aberrations and micronuclei induction. 12.93. No toxicological effects due to solvent/detergent reagents [tri-n-butyl phosphate (TnBP) and Triton X-100] used in the virus inactivation procedure are expected since the residual levels are less than 5µg/ml.25) At the 6 minute and 10 minute time points. P. • Vials are for single use only. Consult your physician if such symptoms appear. 1.2 Pharmacodynamics Clinical pharmacodynamic studies with Human Thrombin have not been performed as this would be ethically unacceptable with this type of product.4) 1. which results in clot formation and hemostasis. USP. bovine thrombin: 71. intended for topical application to the surface of tissue at the surgical site. 13. Ramat-Gan POB 888.16 1 95% CI is for the ratio of proportions of success 2 For the two treatments to be equivalent. neurologic (spinal) or general surgical procedures were randomized (stratified by surgical specialty) when there was oozing or bleeding of mild intensity that could not be controlled by other surgical techniques and the surgeon determined that a topical hemostatic agent was necessary. Sheba Hospital. Distributed by: ETHICON. • Keep the vials protected from light.3 Pharmacokinetics Due to the nature of the product.7) 0. • Discard if the packaging of EVITHROM® is damaged. NJ 08876-0151 USA Manufactured by: Omrix Biopharmaceuticals Ltd.3) 1. Bovine thrombin and EVITHROM® were applied with SURGIFOAM* Absorbable Gelatin Sponge. bovine thrombin: 80. The following results were documented for the 3 minute time point as stratified by surgery and study treatment: (1) cardiovascular surgeryhuman thrombin: 61.4) (98. No embryo-fetal adverse effects were observed at doses up to 300 µg/kg/day TnBP and 1500 µg/kg/day Triton X-100. randomized. License No. USP. 1. (3) general surgery.01. All concentrations of the combination of TnBP and Triton X-100 also tested negative in assays performed to determine mammalian cell mutagenicity. • Do not use after the expiration date stated on the vial. 1603 ETHICON. 450 µg/kg/day) and Triton X-100 (1500fold human dose. used in the virus inactivation manufacturing step. Reproductive studies were performed in rats with the combination of solvent detergent impurities. TnBP and Triton X-100 at doses up to approximately 600-fold human dose of TnBP (900 µg/kg/day) and 3000-fold human dose of Triton X-100 (4500 µg/kg/day) resulted in increased postimplantation loss and an increased number of late resorptions.2 N=153 N=152 149/153 148/152 10 minutes (97.4) (97. • Store reconstituted EVITHROM® solution at room temperature for up to 8 hours. in the presence of Factor XIII in the patient’s plasma.0%.4) 1. fatigue and lowgrade fever followed by nausea. 1. Studies were performed in bacteria to determine mutagenicity of human thrombin alone. Failure to clot blood occurs in the rare case where the primary clotting defect is the absence of fibrinogen itself.08 41/45 44/46 General Surgery (91. and an increased number of runts. which includes EVITHROM® as one of the active components.1) (95. thrombin activates fibrinogen in the patient’s plasma to form fibrin. is crosslinked to form a stable clot. Discard unused contents.25) Table 4: Efficacy at 6 minutes (ITT population) Surgical Specialty Treatment Group: # Successes/N (%) Ratio 95% CI for Ratio EVITHROM® Bovine Thrombin Human/Bovine Human/Bovine1. chills and runny nose followed about two weeks later by a rash and joint pain.S.36 Neurosurgical 60/61 59/60 (Spine) (98. which requires the presence of calcium. 1.80. Box 151. • Do not freeze or refrigerate EVITHROM® once it has been reconstituted. 1. No. 2009 © Omrix Biopharmaceuticals Ltd.human thrombin: 71.1 Carcinogenesis. Table 3: Efficacy for Intent to Treat (ITT) population Time Interval Treatment Group: # Successes/N (%) Ratio 95% CI for Ratio EVITHROM® Bovine Thrombin Human/Bovine Human/Bovine1.7%. 12. MDA blood bank.1%..8) (92.1 Mechanism of Action Thrombin (coagulation factor IIa) is a highly specific protease that transforms plasma fibrinogen into fibrin which. prospective.05 145/153 141/152 6 minutes (94. 1. Neurotoxicity studies performed with EVITHROM® or with EVICEL confirmed that intracerebral application of thrombin was not associated with any evidence of neurotoxicity.97.96.7%.2 44/47 38/46 Cardiovascular (93. If absorbed systemically EVITHROM® could potentially cause blood clotting disorders. 12. 2009 . 2250 µg/kg/day) resulted in increased resorption rates. The speed with which thrombin clots blood is dependent upon the concentration of both thrombin and fibrinogen. pharmacokinetic studies were not conducted. double-blinded study of 305 subjects at 22 centers in the US.95 0. 17 PATIENT COUNSELING INFORMATION Some viruses such as hepatitis A virus and parvovirus B19 are particularly difficult to remove or inactivate.00 0. When applied to a surgical wound where bleeding is present.80. Subjects undergoing elective cardiovascular. Storage and handling • Store EVITHROM® powder vials at 2-25ºC (36-77ºF) for up to 2 years. 14 CLINICAL STUDIES EVITHROM® was compared with bovine thrombin in a phase III multicenter.96. for an overall ratio of proportions of 1. 1. both limits of the confidence interval must have been within (0. 1. and solvent/detergent residues [tri-n-butyl phosphate (TnBP) and Triton X-100. 3. NONCLINICAL TOXICOLOGY 13. Using a sterile needle and syringe. The amount of EVITHROM® required depends upon the area of tissue to be treated and the method of application. pyrexia and post-procedural hematoma.2%) Activated partial thromboplastin time 4 (2. • Potential risk of thrombosis if absorbed systemically (5. EVITHROM® should only be used in pregnancy if clearly indicated (8. • Adverse events were reported in the clinical trial with similar frequency in the two study groups (EVITHROM® or bovine thrombin group).1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions. such products can still potentially transmit disease. adverse events occurred in similar proportions of subjects in the two study groups.2). ADVERSE REACTIONS • Anaphylactic reactions may occur (6). However.2).0%) 3 (2. None of the patients treated with EVITHROM® developed antibodies to human thrombin or to human Factor V/Va.2 Pharmacodynamics 12. Thaw EVITHROM® prior to use in one of the following ways (2. Therefore. FULL PRESCRIBING INFORMATION: CONTENTS1 1. USP 1.1 Potential Risks 6. or • 37°C for 2 ml and 5 ml vials only: vials thaw within 10 minutes and must not be left at this temperature for longer than 10 minutes. The physician should discuss the risks and benefits of this product with the patient. a unit used herein is equivalent to an International Unit.2). 2. • The amount of EVITHROM® required depends upon the area of tissue to be treated and the method of application. At least one serious adverse event (SAE) was reported for 26/153 (17%) subjects treated with human thrombin and 17/152 (11%) subjects treated with bovine thrombin.6%) Skin and Subcutaneous Tissue Disorders Pruritis General Disorders and Administration Site Conditions 1 (0. Severe hypotensive reactions require immediate intervention using current principles of shock therapy. WARNINGS AND PRECAUTIONS • May carry a risk of transmitting infectious agents such as viruses and theoretically. DOSAGE AND ADMINISTRATION • Frozen solution for topical use only.HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use EVITHROM® safely and effectively. In a phase III study of 305 subjects where EVITHROM® (n=153) was compared with bovine thrombin (n=152). CONTRAINDICATIONS • Do not inject directly into the circulatory system (4).3%) 5 (1.0%) 3 (2. Each vial contains 800-1200 units/ml of Thrombin. As an approximate guide. such as viruses.3%) in EVITHROM® group experienced a treatment emergent severe adverse event: respiratory arrest and post-procedural hematoma (in one subject) and extradural hematoma.2). Topical (Human) (3). See full prescribing information for EVITHROM®. CONTRAINDICATIONS 5. The risk of transmitting an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses. EVITHROM® Thrombin. USP. Three subjects in the bovine thrombin group experienced a treatment emergent severe adverse event: hyperhidrosis.2 Application Techniques Use EVITHROM® topically. • Immunogenicity was evaluated by testing for the development of antibodies to highly purified antigens: human thrombin. No adverse events of this type were reported during the conduct of the clinical trials. Discard unused contents (2. 5 ml or 20 ml frozen solution containing 800-1200 units/ml of Thrombin. Mutagenesis. volumes up to 10 ml were used in clinical studies where EVITHROM® was used in conjunction with Absorbable Gelatin Sponge. 4. approval: 2007 INDICATIONS AND USAGE • EVITHROM® is a topical thrombin indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture. by testing for the presence of certain current virus infections and by inactivating and removing certain viruses. No deaths were reported during the study period.gov/medwatch.1 Thawing Prior to Application 2.7%) 1 (0. In clinical studies.fda.7%) 0 3 (2. contact ETHICON Customer Support Center at (877) 384-4266 or FDA at 1-800-FDA-1088 or www. you may withdraw the thrombin solution from the glass vial. USE IN SPECIFIC POPULATIONS • Pregnancy: Animal data are summarized in the Non Clinical Toxicology section (13). the Creutzfeldt-Jakob disease (CJD) agent. ligature or cautery) is ineffective or impractical (1). None of the adverse events reported was considered causally related to EVITHROM® administration.gov/medwatch. • Do not use in individuals known to have anaphylactic or severe systemic reaction to human blood products (4). 4.6%) 5 (3.2%) 25 (8. • Do not use in individuals known to have anaphylactic or severe systemic reaction to human blood products. No clinically significant differences were seen in age (<65 years. The time limitations between thawing and application are described in the HOW SUPPLIED/STORAGE AND HANDLING (16). Topical (Human) may be used in conjunction with an Absorbable Gelatin Sponge.0%) 4 (1. or • 20°C to 25°C (room temperature): vials thaw within 1 hour. The surface may be flooded with EVITHROM® using a sterile syringe and small gauge needle. • EVITHROM® may be used in conjunction with an Absorbable Gelatin Sponge. Vials are for single use only. The most common adverse event reported was procedural complications and pruritus (6).2 Application Techniques 3. Immerse gelatin sponge of desired shape in the EVITHROM® solution. DOSAGE AND ADMINISTRATION 2. • Do not use for the treatment of severe or brisk arterial bleeding. human Factor V/Va. despite manufacturing steps designed to reduce the risk of viral transmission (5.0%) Lymphocyte count decreased 4 (2.3%) 3 (1. ligature or cautery) is ineffective or impractical.1 Carcinogenesis.3%) 9 (3. DO NOT INJECT (2. Topical (Human). Vigorously knead the sponge with moistened gloved fingers until all air is expelled and it can return to its original size and shape. EVITHROM® alone 1.1 Pregnancy 8. a unit used herein is equivalent to an International Unit.2 Labor and Delivery 1. USP (1). The time between thawing and application is restricted to 24 hours at room temperature (16).3%) 4 (1. or • 20°C to 25°C (room temperature): vials thaw within 1 hour. DO NOT INJECT. There is also the possibility that unknown infectious agents may be present in such products. OVERDOSAGE 11. EVITHROM® Thrombin. the Creutzfeldt-Jakob disease (CJD) agent. and theoretically. bovine thrombin and bovine Factor V/Va.3%) 12 (3. The temperature must not exceed 37°C. you can remove the rubber stopper (by removing the metal pull tab) to transfer EVITHROM® into a sterile container using aseptic techniques. The most common adverse event reported was procedural complications and pruritus (6).0%) 2 (1. Transfer EVITHROM® into a sterile container using aseptic techniques. Two subjects (1. 01/580. INDICATIONS AND USAGE 2.3%) 6 (2. Overall. The potency expressed in units is determined using a clotting assay against an internal reference standard for potency that has been calibrated against the World Health Organisation (WHO) Second International Standard for Thrombin. wound infection 3/153 for EVITHROM® and 2/152 for bovine thrombin) and the medical condition of the subject and were not considered related to study drug. Remove the flip-off plastic cap from the vial to expose the rubber stopper. EVITHROM® in conjunction with Absorbable Gelatin Sponge. Anaphylactic reactions may occur in rare cases. adverse reaction rates observed in the clinical trials of a drug product cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. CLINICAL STUDIES 16. USP (2.0%) 5. DOSAGE FORMS AND STRENGTHS • EVITHROM® is supplied in vials of 2 ml. volumes up to 10 ml were used in conjunction with Absorbable Gelatin Sponge.1).2%) 14 (9. None of the adverse events reported was considered causally related to EVITHROM® administration. Viral serology was not monitored during the study with EVITHROM®. 3. The temperature must not exceed 37°C. Topical (Human) Frozen solution for Topical Use Only Initial U. Despite these measures.5 Geriatric Use 10.1 Potential Risks Because this product is made from human plasma.1 Mechanism of Action 12. 01/580. 3. Alternatively. After treatment.9%) Neutrophil count increased 3 (2.6%) 8 (5. 5 ml or 20 ml.1 Clinical Trials Experience 6.2 Animal toxicology and/or pharmacology 14. USE IN SPECIFIC POPULATIONS 8. Apply only on the surface of bleeding tissue. 2.1 Thawing Prior to Application Thaw EVITHROM® in one of the following ways: • 2°C to 8°C (refrigerator): vials thaw within 1 day. occurrence of adverse events was not statistically different between the two groups. Topical (Human) is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture. The SAEs reported were associated with post-surgical complications (e. • Do not use for treatment of severe or brisk arterial bleeding (4).fda.1): • 2°C to 8°C (refrigerator): vials thaw within 1 day. avoid sponging the clot to assure that it remains securely in place. • Vials are for single use only.6%) 2 (1. DOSAGE AND ADMINISTRATION 2.3%) 12 (3. or • 37°C for 2 ml and 5 ml vials only: vials thaw within 10 minutes and must not be left at this temperature for longer than 10 minutes. To report SUSPECTED ADVERSE REACTIONS. Sponge target surface (do not wipe) or suction free of blood before application. it may carry a risk of transmitting .4 Pediatric Use 8.g. USP. 2. ADVERSE REACTIONS 6. WARNINGS AND PRECAUTIONS 5. Table 1: Incidence of Subjects with related adverse events reported in at least 2% of subjects treated with either human or bovine thrombin Thrombin Type EVITHROM® Bovine Total System Organ Class/Adverse Event (n=153) (n=152) (n=305) Investigations 11 (7. PATIENT COUNSELING INFORMATION 1 Sections or subsections omitted from the full prescribing information are not listed infectious agents. Discard unused contents.1). Mild reactions can be managed with anti-histamines. ADVERSE REACTIONS 6. DESCRIPTION 12. 2.2 Post Marketing Experience 7. No data in pregnant women.3 Nursing Mothers 8. DOSAGE FORMS AND STRENGTHS 4. DRUG INTERACTIONS 8. HOW SUPPLIED/STORAGE AND HANDLING 17. >65 years) or gender subgroup analyses of adverse events.9%) increased International normalized ratio increased 4 (2.6%) 8 (5. Potential risk of thrombosis if absorbed systemically 6.S. CLINICAL PHARMACOLOGY 12. DOSAGE FORMS AND STRENGTHS EVITHROM® is supplied as a frozen solution in the following packages: • Vial containing 2 ml. Therefore. CONTRAINDICATIONS • Do not inject directly into the circulatory system.3 Pharmacokinetics 13.0%) Prothrombin time prolonged 4 (2. Hold the saturated sponge in place with gauze or cotton pledget using moderate pressure until hemostasis is achieved. WARNINGS AND PRECAUTIONS 5. no adverse events indicative of infection with transfusion-transmissible agents were reported. To report suspected adverse reactions. INDICATIONS AND USAGE EVITHROM® Thrombin. The potency expressed in units is determined using a clotting assay against an internal reference standard for potency that has been calibrated against the World Health Organisation (WHO) Second International Standard for Thrombin. Impairment of Fertility 13. See 17 for PATIENT COUNSELING INFORMATION Revised: 01/2009 8. contact ETHICON Customer Support Center at (877) 384-4266 or FDA at 1-800-FDA-1088 or www. No embryo-fetal adverse effects were observed at doses up to 300 µg/kg/day TnBP and 1500 mg/kg/day Triton X-100. MDA blood bank. five were less than 2 years old and three were between 2 and 12 years old. 8.7%. Discard if the packaging of EVITHROM® is damaged.0%. pharmacokinetic studies were not conducted.6%. Reproductive studies were performed in rats with the combination of solvent detergent impurities. Therefore. A few control subjects had antibodies that cross-reacted with human thrombin. 200-fold and 1000-fold the human dose.02 0. 8. HIV-1 & 2 Ab.32 Not Done >5. When applied to a surgical wound where bleeding is present. fatigue and low-grade fever followed by nausea. NONCLINICAL TOXICOLOGY Reproductive studies performed in rats with the combination of TnBP and Triton X100 at doses up to approximately 600-fold human dose of TnBP (900 µg/kg/day) and 3000-fold human dose of Triton X-100 (4500 µg/kg/day) resulted in increased postimplantation loss and an increased number of late resorptions.08 0.1%. 2250 µg/kg/day) resulted in increased resorption rates. The speed with which thrombin clots blood is dependent upon the concentration of both thrombin and fibrinogen. 1. the plasma units are tested by licensed Nucleic Acid Testing (NAT) for HIV-1. controlled. The observed incidence of a positive signal in an assay may be influenced by several factors including timing of sampling.3 Nursing Mothers The safety of EVITHROM® for use during breast-feeding has not been established. drowsiness. Sodium acetate. however. used in the virus inactivation manufacturing step.2 0. However.37 6. 1. Dark urine and a yellowed complexion are also common symptoms.2) (72.1 Mechanism of Action Thrombin (coagulation factor IIa) is a highly specific protease that transforms plasma fibrinogen into fibrin which. >90% of subjects from all surgeries in both study groups had achieved hemostasis. No differences in safety or effectiveness were observed between the elderly and younger patients. in the presence of Factor XIII in the patient’s plasma. Manufacturing pool testing. sterile filtered and aseptically filled and frozen.Immunogenicity In the clinical study.7) 145/153 141/152 Overall (94. 16.01 3 minutes (73. Kiryat Ono 55000. the solution is formulated with calcium chloride. 8. The following results were documented for the 3 minute time point as stratified by surgery and study treatment: (1) cardiovascular surgery. 12.3 Pharmacokinetics Due to the nature of the product. Do not re-freeze EVITHROM® once it has been thawed.63 >4. After nanofiltration. The detection of antibody formation is highly dependent upon the sensitivity and specificity of the assay. and an increased number of runts. Thrombin is a highly specific protease that transforms fibrinogen into fibrin. human Thrombin.8-7.95 5.8) (92. EVITHROM® should be used in pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.4) (97. All tests for HIV. 1. The effect of EVITHROM® on fertility has not been evaluated. Greater susceptibility of older patients to adverse reactions cannot be ruled out. (2) spinal surgery.80. No toxicological effects due to solvent/detergent reagents [tri-n-butyl phosphate (TnBP) and Triton X-100] used in the virus inactivation procedure are expected since the residual levels are less than 5µg/ml. When thawed.000 copies/ml. EVITHROM® has been shown to be stable for up to 24 hours at room temperature. each containing 8001200 units/ml Thrombin. or underlying disease. 1. No embryo-fetal adverse effects were observed at doses up to 300 µg/kg/day TnBP and 1500 µg/kg/day Triton X-100.74 >9. but none had antibodies that cross-reacted with human Factor V/Va.7% of the subjects developing antibodies in the control group (bovine Thrombin). 13. Studies were performed in bacteria to determine mutagenicity of human thrombin alone. The ELISA data were adjudicated by a panel of experts blinded to treatment assignment.4 Pediatric Use Of the 155 patients undergoing liver surgery who were treated in adequate and wellcontrolled studies of EVICEL® Fibrin Sealant (Human). thrombin activates fibrinogen in the patient’s plasma to form fibrin. License No.82 >5. 12. Ramat-Gan POB 888. The first of these is treatment with a solvent/detergent (S/D) mixture (1% tri-n-butyl phosphate.01. Mannitol and human albumin are used to stabilize the solution. HIV 1 & 2 Ab and HCV Ab. studies to evaluate the potential reproductive/developmental toxicity of residual levels of Triton X-100 and tri-n-butyl phosphate (solvent/detergent reagents) were conducted in animals and are summarized in the Non Clinical Toxicology section (13). 17.6) Neurosurgical 60/61 59/60 (Spine) (98. EVITHROM® is manufactured by chromatographic purification of prothrombin from cryo-poor plasma followed by activation with calcium chloride.85 Nanofiltration >4. 450 µg/kg/day) and Triton X-100 (1500-fold human dose.2 Animal Toxicology and/or Pharmacology EVICEL® Fibrin Sealant (Human). HBV.00 0. Distributed by: J&J Wound Management A division of ETHICON. Evidence of hepatitis A may include several days to weeks of poor appetite. Sheba Hospital. was classified as non-irritant in the Primary Cutaneous Irritation Test and slightly irritant in the Ocular Irritation test. Adequate and well-controlled studies in pregnant women have not been performed. The effectiveness of the S/D treatment and nanofiltration procedures for reducing virus content has been assessed using a series of viruses with a range of physico-chemical characteristics. the panel used an algorithm for assigning outcomes for each antigen: seroconversion negative or seroconversion positive. OVERDOSAGE No case of overdose has been reported. vomiting and abdominal pain. both limits of the confidence interval must have been within (0.95 1. No. TnBP and Triton X-100 at doses up to approximately 600-fold human dose of TnBP (900 µg/kg/day) and 3000-fold human dose of Triton X-100 (4500 µg/kg/day) resulted in increased postimplantation loss and an increased number of late resorptions. (3) general surgery. NJ 08876-0151 USA U. the significance of a negative result for these viruses is unknown. The protocol did not specify any comparative analysis for immunogenicity data. Table 3: Efficacy for Intent to Treat (ITT) population Time Interval Treatment Group: Ratio # Successes/N (%) Human/Bovine ® Bovine Thrombin EVITHROM N=153 N=152 149/153 148/152 1. 7. Patients should be encouraged to consult their physician if such symptoms appear. Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of EVITHROM® due to the human origin of thrombin. serum samples were collected at baseline and at 5 weeks postsurgery for evaluation of antibodies to bovine Thrombin. bovine thrombin: 63.16 95% CI is for the ratio of proportions of success For the two treatments to be equivalent. USP. Do not refrigerate EVITHROM® once at room temperature. each manufacturing pool is tested for HBsAg.3) 41/45 44/46 General Surgery (91. and for HCV NAT.2 1. Use only if clearly needed.93. Samples were collected at both time points for 81. 450 µg/kg/day) and Triton X-100 (1500-fold human dose. 8.96. The S/D reagents are removed by cation exchange chromatography. However. 2009 Manufactured by: Omrix Biopharmaceuticals Ltd. respectively. Topical (Human) is a sterile solution. USE IN SPECIFIC POPULATIONS 8.88. 80TZ00M3D2 . Topical (Human): • Vial containing 2 ml.human thrombin: 61.3% of the subjects treated with EVITHROM® developed antibodies to any of the four antigens. double-blinded study of 305 subjects at 22 centers in the US.8) 1 2 Ratio Human/Bovine 95% CI for Ratio Human/Bovine1. 5 ml or 20 ml frozen solution Storage and handling Store frozen vials at -18°C or colder for up to 2 years. If absorbed systemically EVITHROM® could potentially cause blood clotting disorders. 2250 µg/kg/day) resulted in increased resorption rates.85 Factor HIV-1: SBV: BVDV: PRV: EMCV: HAV: CPV: Human Immunodeficiency Virus Type 1 Sindbis Virus Bovine Viral Diarrhea Virus Pseudorabies Virus Encephalomyocarditis virus Hepatitis A Virus Canine Parvovirus 12. Use of EVITHROM® in pediatric patients is supported by these data and by extrapolation of findings for safety and efficacy in adults. P.97.2 Labor and Delivery The safety of EVITHROM® for use during labor and delivery has not been established. Inc. 8. bovine thrombin: 80. 6. CLINICAL PHARMACOLOGY EVITHROM® requires no intermediate physiological agent because it clots the fibrinogen of the blood directly. 200-fold and 1000-fold the human dose. HAV and parvovirus 19. bovine thrombin: 71. Parvovirus B19 most seriously affects pregnant women or immunecompromised individuals.00 10 minutes (97. These studies were negative for both Thrombin and for TnBP or Triton X-100 at all concentrations tested. Somerville. and human Factor V/Va. pH 6. chills and runny nose followed about two weeks later by a rash and joint pain.6) (82. In addition to the screening of plasma units. The results of the validation studies are summarized in the following table: Table 2: Reducing factors of S/D treatment and nanofiltration for a series of viruses Virus HIV-1 SBV BVDV PRV EMCV HAV CPV Reduction factor (log10) 0. Unopened vials can be stored at 2°C to 8°C for up to 30 days. prospective. intended for topical application to the surface of tissue at the surgical site. The manufacturing process includes two targeted steps for inactivation or removal of viruses. The level of parvovirus B19 contamination is not permitted to exceed 10.80. CLINICAL STUDIES EVITHROM® was compared with bovine thrombin in a phase III. Mutagenesis. chromosomal aberrations and micronuclei induction. 1. 13. since the effectiveness of the HBV and HAV NAT methods in detecting low levels of viral material is still under investigation. 7. decreased fetal body weights. compared to 12. Subjects undergoing elective cardiovascular.95 5.4) 145/153 141/152 1. is of lower sensitivity than individual unit testing. Human albumin. This limit is applied to restrict the viral load of parvovirus B19 in the starting plasma pool.4) 1 2 95% CI for Ratio Human/Bovine1.25) Table 4: Efficacy at 6 minutes (ITT population) Surgical Treatment Group: Specialty # Successes/N (%) Human Bovine Thrombin Thrombin 44/47 38/46 Cardiovascular (93. HCV. 11. bovine Factor V/Va.4) (98. HOW SUPPLIED/STORAGE AND HANDLING EVITHROM® is supplied in the following single-use packages.18 >10. 1% Triton X-100) for 6 hours at 26°C to inactivate lipid enveloped viruses. Additionally. Other studies performed with combinations of TnBP (300-fold human dose. which undergoes nanofiltration for removal of both enveloped and non-enveloped viruses. Individual plasma units obtained for production of EVITHROM® are tested by licensed serological tests for HBsAg. eight were pediatric patients.human thrombin: 71. which requires the presence of calcium.S.08 0. All concentrations of the combination of TnBP and Triton X-100 also tested negative in assays performed to determine mammalian cell mutagenicity. Failure to clot blood occurs in the rare case where the primary clotting defect is the absence of fibrinogen itself. and solvent/detergent residues [tri-n-butyl phosphate (TnBP) and Triton X-100. neurologic (spinal) or general surgical procedures were randomized (stratified by surgical specialty) when there was oozing or bleeding of mild intensity that could not be controlled by other surgical techniques and the surgeon determined that a topical hemostatic agent was necessary. Water for injection (WFI) EVITHROM® is made from pooled Human Source Plasma obtained from US licensed plasma collection centers.human thrombin: 83.74 >4.02 6 minutes (94. concomitant medications.0 SD Treatment >5. ISRAEL Issued 01/2009 Art. 1.8) (92.1) (95.47 Global Reduction >10.05 0.82. Treatment with EVITHROM® was as successful as treatment with bovine thrombin in achieving the primary efficacy endpoint: hemostasis within 10 minutes of product application and secondary efficacy endpoints: hemostasis within 6 and 3 minutes of product application.O.96.2 Post Marketing Experience No adverse reactions have been identified from domestic or spontaneous reports.13 1. DRUG INTERACTIONS No drug interactions are known. direct comparison of incidence of antibody development to human or bovine thrombin or Factor V/Va following administration of EVITHROM® with incidence of antibody development following administration of other products may be misleading and the clinical significance of these findings is unknown.7%.72 6. DESCRIPTION EVITHROM® Thrombin. sample handling. Frozen EVITHROM® consists of a white to slightly yellowish opaque mass. including class related products. Discard unused product after 24 hours at room temperature. The fibrin clot is stabilized by cross-linking occurring as a result of activation of the patient’s endogenous factor XIII. INC.36 0. in which EVITHROM® is a component. 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.25) At the 6 minute and 10 minute time points. Other studies performed with combinations of TnBP (300-fold human dose. Studies to evaluate the potential reproductive/developmental toxicity of EVITHROM® have not been performed due to the human origin of thrombin.3% of the subjects. HBV and HAV must be negative (non-reactive). The composition of EVITHROM® is as follows: Active Ingredients: Human thrombin (800-1200 units/ml) Other Ingredients: Calcium chloride. HCV. EVITHROM® is clear to slightly opalescent and colorless to slightly yellowish.1 Pregnancy Teratogenic effects: Pregnancy category C. containing highly purified human thrombin for the activation of clotting.25 Not Done Not Done 6.2.09 0.36 >5. and an increased number of runts.8) 112/153 110/152 1.96. 12. None of the patients treated with EVITHROM® developed detectable antibodies to human thrombin or to human Factor V/Va. PATIENT COUNSELING INFORMATION Some viruses such as hepatitis A virus and parvovirus B19 are particularly difficult to remove or inactivate. The adjudicated results show that 3. 10.5 Geriatric Use Sixty three (63) subjects over 65 years of age received EVITHROM® in the phase III clinical trial. 1.1 Carcinogenesis. Neurotoxicity studies performed with EVITHROM® or with EVICEL® confirmed that intracerebral application of thrombin was not associated with any evidence of neurotoxicity. 1.09 95% CI is for the ratio of proportions of success For the two treatments to be equivalent. 1603 Trademark ETHICON. for an overall ratio of proportions of 1. which includes EVITHROM® as one of the active components. randomized. Of these. Box 151. decreased fetal body weights. Patients should be encouraged to consult their physician for any new or unusual symptoms. Symptoms of parvovirus B19 infection include: fever. Bovine thrombin and EVITHROM® were applied with SURGIFOAM* Absorbable Gelatin Sponge.52% of these subjects developed antibodies to bovine Factor V/Va.94% of the subjects treated with bovine Thrombin (control group) developed antibodies to bovine thrombin and 9.2 Pharmacodynamics Clinical pharmacodynamic studies with Human Thrombin have not been performed as this would be ethically unacceptable with this type of product. both limits of the confidence interval must have been within (0. Mannitol.0%. 1. is crosslinked to form a stable clot. 13. After reviewing all data. only descriptive statistics.31 >4.37 6. 14. respectively. which results in clot formation and hemostasis.