FLOSEAL Hemostatic Matrix
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FLOSEAL Hemostatic Matrix - 1

not inject FLOSEAL Matrix into a vessel or tissue. FLOSEAL Hemostatic Matrix, 10 mL Instructions for Use Caution: Federal Law (United States) restricts this device to sale by or on the order of a licensed healthcare practitioner DO NOT INJECT INTRAVASCULARLY. FLOSEAL Hemostatic Matrix (“FLOSEAL Matrix”) must not be injected into blood vessels. Device Description: The FLOSEAL Matrix kit consists of a bovine-derived Gelatin Matrix component, a human-derived Thrombin component, Applicator tips, and several mixing accessories. The mixing accessories include a syringe, a Luer connector, a Thrombin bowl, and a pre-filled Sodium Chloride Solution syringe and a vial adapter for needle-free reconstitution. The accessories are included to facilitate the reconstitution and mixing of the Thrombin into the Gelatin Matrix. Applicator tips are included to facilitate the delivery of FLOSEAL Matrix to the site to be treated. (For specific package contents, see table in “How Supplied” section.) The Gelatin Matrix consists of cross-linked gelatin granules and is provided sterile and non-pyrogenic in a standard disposable syringe. The Thrombin (Human) is a sterile, nonpyrogenic, freeze-dried, vapor-heated and solvent/detergent treated powder preparation made from pooled human plasma. The Sodium Chloride Solution is a sterile, non-pyrogenic solution. After reconstitution of the lyophilized Thrombin with Sodium Chloride Solution, the resulting Thrombin solution contains 500 units*/mL Thrombin (Human). *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 Organization (WHO) Second International Standard for Thrombin, 01/580. Therefore, a unit used herein is equivalent to an International Unit. Thrombin (Human) is prepared from pooled human plasma through a series of separation and filtration steps followed by incubation of the solution with Calcium Chloride in order to activate prothrombin to Thrombin. The Thrombin (Human) solution subsequently undergoes ultra/diafiltration, vapor heat treatment, solvent/detergent treatment, sterile filtration and freeze-drying. Thrombin (Human) is made from pooled human plasma obtained from U.S. licensed plasma collection centers. The two-step vapor-heated and solvent/detergent treatment used in its manufacture has been shown to be capable of significant viral reduction. However, no procedure has been shown to be completely effective in removing viral infectivity from derivatives of human plasma (see “Warnings”). The manufacturing procedure for FLOSEAL Matrix includes processing steps designed to reduce the risk of viral transmission. Several steps are included in the manufacture of the Gelatin Matrix component that reduces the risk of viral transmission. The virus reduction factors (expressed as log10) for the manufacture of the Gelatin Matrix component are provided in the table below. Reduction Factors for Virus Removal and/or Inactivation During the Manufacture of Gelatin Matrix Virus Reduction Factor of Virus Tested Manufacturing Step Chemical Cross-linking Heat Treatment A two-step vapor-heated and solvent/detergent viral inactivation treatment process is included in the manufacture of Thrombin. The virus reduction factors (expressed as log10) for Thrombin are provided in the table below. Reduction Factors for Virus Removal and/or Inactivation Thrombin Component Mean Reduction Factors [log10] of Virus Tested HIV-1 HAV BVDV PRV MMV B19V Thrombin precursor mass capture Vapor Heat Treatment Solvent/Detergent Treatment Overall Reduction Factor (ORF) n. d. = not determined HIV-1: Human immunodeficiency virus 1; HAV: Hepatitis A virus; BVDV: Bovine viral diarrhea virus, a model for Hepatitis C virus; PRV: Pseudorabies virus, a model for enveloped DNA viruses, among those Hepatitis B virus; MMV: Mice minute virus, a model for Human Parvovirus B19; B19V: Human Parvovirus B19. FLOSEAL Matrix is the combination of the Gelatin Matrix component and the reconstituted Thrombin (Human) component. Thrombin must be added to the Gelatin Matrix component prior to use. FLOSEAL Matrix is biocompatible and resorbed within 6 to 8 weeks, consistent with normal wound healing. FLOSEAL Matrix is intended only for topical administration. Indications: FLOSEAL Matrix is indicated in surgical procedures (other than in ophthalmic) as an adjunct to hemostasis when control of bleeding, by ligature or conventional procedures is ineffective or impractical. Contraindications: • Do not inject or compress FLOSEAL Matrix into blood vessels. Do not apply FLOSEAL Matrix in the absence of active blood flow, e.g., while the vessel is clamped or bypassed, as extensive intravascular clotting and even death may result. • To avoid a risk of allergic-anaphylactoid reaction and/or thromboembolic events, which may be life threatening, do Adverse Events Reported in Greater than 1% of Patients in the FLOSEAL Clinical Trial Adverse Event Warnings: • FLOSEAL Matrix contains Thrombin made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and removing certain viruses. Despite these measures, such products can still potentially transmit disease. Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxter Healthcare Corporation. The physician should discuss the risks and benefits of this product with the patient. • FLOSEAL Matrix is not intended as a substitute for meticulous surgical technique and the proper application of ligatures or other conventional procedures for hemostasis. FLOSEAL is effective on surgical bleeding, from oozing to spurting, and is not intended to be used as a prophylactic hemostatic agent. • Excess FLOSEAL Matrix (material not incorporated in the hemostatic clot) should always be removed by gentle irrigation from the site of application. Meticulous irrigation is required when used in, around, or in proximity to foramina in bone, areas of bony confine, the spinal cord, the brain and/or cranial nerves. • FLOSEAL Matrix swells by approximately 10-20% after product is applied and surgeons should consider its potential effect on the surrounding anatomic areas. Maximum swell volume is achieved within about 10 minutes. • FLOSEAL Matrix should not be used in the presence of infection. FLOSEAL Matrix should be used with caution in contaminated areas of the body. If signs of infection or abscess develop where FLOSEAL Matrix has been applied, re-operation may be necessary in order to remove the infected material and allow drainage. • The safety and effectiveness of FLOSEAL Matrix for use in ophthalmic procedures has not been established. • FLOSEAL Matrix should not be used for controlling postpartum bleeding or menorrhagia. • The safety and effectiveness of FLOSEAL Matrix has not been established in children under 2 years of age and pregnant women. • Do not use air to remove residual FLOSEAL Matrix from Applicator tip. Precautions: General • For single use only. Do not re-sterilize. • As with other hemostatic agents, circumstances that result in a negative peripheral venous pressure (e.g. patient positioning) may draw material into the vascular system, potentially resulting in life-threatening thromboembolic events. • When placed into cavities or closed tissue spaces, gentle approximation is advised. BVDV: Bovine viral diarrhea virus, a model for Hepatitis C virus; PPV Porcine parvovirus, a model for non-enveloped viruses, among those, Hepatitis A virus. Manufacturing Step • Do not use FLOSEAL Matrix in the closure of skin incisions because it may interfere with the healing of the skin edges due to mechanical interposition of gelatin. • Since the Thrombin solution can be denatured by contact with solutions containing alcohol, iodine, or heavy metal ions, FLOSEAL Matrix should not be applied before the application site is cleaned to remove any antiseptics that may contain such substances. Base Treatment (NaOH) • Do not use FLOSEAL Matrix in patients with known allergies to materials of bovine origin. • As with other hemostatic agents, do not aspirate FLOSEAL Matrix into extracorporeal cardiopulmonary bypass circuits or autologous blood salvage circuits. It has been demonstrated that fragments of collagen based hemostatic agents may pass through 40μm transfusion filters of blood scavenging systems. • Do not use FLOSEAL Matrix on bone surfaces where adhesives, such as methylmethacrylate or other acrylic adhesives, will be required to attach a prosthetic device. Microfibrillar collagen has been reported to reduce the strength of methylmethacrylate adhesives used to attach prosthetic devices to bone surfaces. • FLOSEAL Matrix should not be used for the primary treatment of coagulation disorders. • The safety and effectiveness of the combined use of FLOSEAL Matrix with antibiotic solutions or powders has not been established. • The safety and effectiveness for use in neurosurgical and urological procedures has not been established through randomized clinical studies. • In urological procedures, FLOSEAL Matrix should not be left in the renal pelvis or ureters to eliminate the potential foci for calculus formation. • The Applicator tips should not be cut. Information for Patients • Some viruses, such as human parvovirus B19, are particularly difficult to remove or inactivate at this time. Human parvovirus B19 most seriously affects pregnant women, or immune-compromised individuals. Symptoms of human parvovirus B19 infection include fever, drowsiness, chills, and runny nose followed about two weeks later by a rash, and joint pain. Patients should be encouraged to consult their physician if such symptoms appear. Control (Gelatin Sponge + Thrombin) Fibrillation Atrial Urinary Tract Infection Respiratory Distress Dural Tear Fibrillation Ventricular Heart Failure Right Thrombosis Arterial Pleural Effusion Counts reflect number of patients in each treatment group reporting one or more adverse events that map to a Modified COSTART 5th edition body system. At each level of summarization (Adverse Event), patients are only counted once. Other adverse events observed in 1% or less of the FLOSEAL clinical trial patients were myocardial infarction, cellulitis, pneumothorax, pain, cerebrovascular accident, hallucination, paresthesia, bradycardia, abscess, diarrhea, urinary retention, dehiscence, skin ulcer, transfusion reaction, dyspnea, heart arrest, lung edema, back pain, ventricular tachycardia, neuropathy, acute kidney failure, kidney tubule necrosis, gastritis, nausea, nausea and vomiting, skin rash, hyperglycemia, and heel ulcer. The following adverse events, all rated “mild”, were deemed by the surgeon to be “Possibly Related” to the use of FLOSEAL: anemia (2 patients, 1%), mild post-operative bleeding (1 patient, <1%), and local inflammation (1 patient, <1%). No other adverse events were deemed by the surgeon to be related to the use of FLOSEAL. Allergic reactions may be encountered in people who are sensitive to bovine materials. Gelatin-Based Hemostatic Agents Adverse Events: • Gelatin-based hemostatic agents may serve as a nidus for infection and abscess formation and have been reported to potentiate bacterial growth. • Giant cell granulomas have been observed at implant sites when used in the brain. • Compression of the brain and spinal cord resulting from the accumulation of sterile fluid has been observed. • Multiple neurologic events were reported when absorbable gelatin-based hemostatic agents were used in laminectomy operations, including cauda equina syndrome, spinal stenosis, meningitis, arachnoiditis, headaches, paresthesias, pain, bladder and bowel dysfunction, and impotence. • The use of absorbable gelatin-based hemostatic agents during the repair of dural defects associated with laminectomy and craniotomy operations has been associated with fever, infection, leg paresthesias, neck and back pain, bladder and bowel incontinence, cauda equina syndrome, neurogenic bladder, impotence, and paresis. • The use of absorbable gelatin-based hemostatic agents has been associated with paralysis, due to device migration into foramina in the bone around the spinal cord, and blindness, due to device migration in the orbit of the eye, during lobectomy, laminectomy and repair of a frontal skull fracture and lacerated lobe. Patients were randomized only after it was determined that the bleeding could not be controlled using conventional approaches (e.g. direct pressure, sutures and/or cautery) because of their ineffectiveness or impracticality. Success at achieving hemostasis was defined as cessation of bleeding within 10 minutes following application of the agent. The primary endpoint was hemostasis success for the first treated bleeding site. A secondary endpoint was time to hemostasis for the first treated bleeding site. Although multiple bleeding sites in the same patient were treated, only the first treated bleeding site was used to determine primary effectiveness, as this was the only site that was truly randomized. Clinical Study Results: Primary Endpoint: The primary endpoint, cessation of bleeding within 10 minutes of the first lesion, achieved a success rate of 96% in the FLOSEAL group and 77% in the Control group. FLOSEAL and Control were shown to be equivalent using the Blackwelder and Chang test, using a ∆ (clinically significant difference) of 0.15 (p<0.0001). The difference between FLOSEAL and Control was also shown to be statistically significant using the Cochran-Mantel-Haenszel test (p<0.001). Primary endpoint data were stratified for individual surgical specialties, and the results are summarized in the table below: Hemostasis Within 10 Minutes – First Lesion Only (Intent-to-Treat Patients) Patient Category In the cardiac cohort, 88 of the 93 patients (95%) underwent surgery with extracorporeal cardiopulmonary bypass. FLOSEAL was used for hemostasis prior to heparin reversal by the administration of protamine sulfate in 19 of 46 patients. Protamine sulfate reverses the anticoagulative effects of heparin. Results for hemostasis at 10 minutes for the heparinized patients in both the FLOSEAL and Control groups, before and after protamine sulfate reversal of heparin, are shown in the table below: Hemostasis Success at 10 Minutes Before and After Protamine Administration (Cardiac Patients Only) Group Before Protamine After Protamine The success rate for FLOSEAL did not appear to be affected by whether or not the patient had received protamine sulfate administration. This was demonstrated by the fact that the success rate for FLOSEAL before protamine sulfate administration was similar to the success rate after protamine sulfate administration whereas the Control hemostat success rate was clearly lower before protamine sulfate reversal of heparin was administered. Secondary Endpoint: A secondary endpoint was time to hemostasis for the first treated bleeding site. The data for time to hemostasis are summarized in the table below. Cumulative Percent of Patients with Complete Hemostasis First Lesion (Protocol Valid Patients*) Time Interval • Toxic shock syndrome was reported in association with the use of absorbable gelatin-based hemostats in nasal surgery. • Fever, failure of absorption, and hearing loss have been observed when absorbable hemostatic agents were used during tympanoplasty. *Six (6) patients, 3 in the FLOSEAL group and 3 in the Control group, were excluded because of protocol deviations in measuring hemostasis for the first treated bleeding site. • Foreign body reactions, “encapsulation” of fluid, and hematoma have been observed at implant sites. • Excessive fibrosis and prolonged fixation of a tendon have been reported when absorbable gelatin-based sponges were used in severed tendon repair. As with any other plasma derivates, anaphylactoid or anaphylactic reactions may occur in rare cases. No adverse events of this type were reported during the course of clinical trials using a different product containing the same human Thrombin component. Mild reactions can be managed with antihistamines; severe hypotensive reactions require immediate intervention using current principles of shock therapy. In a randomized prospective, concurrently controlled clinical trial using a formulation of FLOSEAL Matrix containing bovine Thrombin, (FLOSEAL), a total of 309 patients received FLOSEAL or the Control (Gelatin Sponge + Thrombin). The most common adverse events recorded during and after the application of the hemostatic agents were anemia, atrial fibrillation, infection, and hemorrhage. The following is a complete list of adverse events reported in greater than 1% of patients that were observed in the pivotal clinical trial for the FLOSEAL group. The corresponding adverse events for the Control group are listed for comparison. None of the adverse events that occurred were judged by the surgeon to be “Probably Related” to the use of FLOSEAL. Patients undergoing surgery in cardiac, vascular or spinal/ orthopedic surgical specialties were included. Human Thrombin Adverse Events: FLOSEAL Matrix Adverse Events: Study Design and Objectives: A prospective, randomized, controlled, multi-center, multi-specialty study was conducted using a formulation of FLOSEAL Matrix containing bovine Thrombin, (FLOSEAL). Three hundred and nine (309) patients were enrolled at 10 centers. The objective of the study was to evaluate the safety and effectiveness of FLOSEAL, compared to a commercially available control hemostat, Absorbable Gelatin Sponge, USP (“Gelatin Sponge”) + Thrombin, in controlling intraoperative bleeding. This study was designed to show that the FLOSEAL success rate was equivalent to the success rate for the Control. • Long-term animal studies to evaluate the carcinogenic potential of FLOSEAL Matrix or studies to determine the effect of FLOSEAL Matrix on fertility have not been performed. • It is not known whether FLOSEAL Matrix can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. FLOSEAL Matrix should be administered to a pregnant woman only if clearly needed. Clinical Studies: Carcinogenesis, Mutagenesis, Impairment of Fertility at each time point. These data points were analyzed using the method of Blackwelder and Chang for proportions. The results for all lesions in all animals showed FLOSEAL Matrix (human Thrombin) and FLOSEAL (bovine Thrombin) were equivalent for each of the time intervals with a p-value of 0.015. Equivalence of Bovine and Human Thrombin: The performance of FLOSEAL Matrix containing human Thrombin was compared to that of original FLOSEAL (containing bovine Thrombin) in a bleeding liver square model in pigs. Blood flow rates for the lesions created in the pig liver model were recorded at specific time points and statistically analyzed by the method of Blackwelder and Chang modified for continuous variables. This analysis demonstrates that the performance of FLOSEAL Matrix (human Thrombin) is equivalent to the performance of FLOSEAL (bovine Thrombin) with a p-value of < 0.001 at each of the time intervals. In addition, each lesion was subjectively scored for bleeding When the data were stratified by surgical specialty, the median times to hemostasis were shorter for the FLOSEAL group than for the Control group in all specialties. The median times are summarized in the table below. Time to Hemostasis First Lesion Only (Protocol Valid Lesions) Median Time to Hemostasis in minutes (95% Confidence Interval*) Patient Category *Confidence interval using a Bonferroni correction.

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