THROMBIN-JMI- thrombin, topical (bovine)
Pfizer Laboratories Div Pfizer Inc
THROMBIN-JMI, Thrombin, Topical (Bovine), is a protein substance produced through a conversion reaction in which prothrombin of bovine origin is activated by tissue thromboplastin of bovine origin in the presence of calcium chloride. It is supplied as a sterile powder that has been freeze-dried in the final container. Also contained in the preparation are mannitol and sodium chloride. Mannitol is included to make the dried product friable and more readily soluble. The product contains no preservative.
THROMBIN-JMI has been chromatographically purified and further processed by ultrafiltration. Analytical studies demonstrate the current manufacturing process' capability to remove significant amounts of extraneous proteins, and result in a reduction of factor Va light chain content to levels below the limit of detection of semi-quantitative Western Blot assay (<92 ng/mL, when reconstituted as directed). The clinical significance of these findings is unknown.
THROMBIN-JMI requires no intermediate physiological agent for its action. It activates platelets and catalyzes the conversion of fibrinogen to fibrin, which are essential steps for clot formation. Failure to clot blood occurs in the case where the primary clotting defect is the absence of fibrinogen itself. The speed with which thrombin clots blood is dependent upon the concentration of both thrombin and fibrinogen.
THROMBIN-JMI is topical bovine thrombin indicated to aid 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, ligature, or cautery) is ineffective or impractical.
In various types of surgeries, solutions of THROMBIN-JMI may be used in conjunction with an Absorbable Gelatin Sponge, USP for hemostasis.
See BOXED WARNING above.
THROMBIN-JMI causes thrombosis if it enters the circulatory system. Apply topically. DO NOT INJECT.
The safety assessment of Thrombin JMI is based primarily on the review of post marketing experience including three (3) randomized controlled clinical trials in which Thrombin JMI was used as a comparator and one (1) observational study. In these studies, the most common adverse reactions (incidence greater than or equal to 2%) following administration of THROMBIN JMI were: hypersensitivity, bleeding, anemia, post-operative wound infection, thromboembolic events, hypotension, pyrexia, tachycardia and thrombocytopenia.
Serious adverse reactions that have been reported to Pfizer from post-marketing experience after the administration of THROMBIN-JMI include: anaphylactic reactions, prolonged prothrombin time, prolonged activated partial thromboplastin time, disseminated intravascular coagulation, factor V deficiency, postprocedural hematoma, swelling and Staphylococcal wound infection.
In a randomized, double-blinded, controlled trial that compared recombinant human thrombin to THROMBIN-JMI, 206 patients received THROMBIN-JMI and 205 patients received recombinant human thrombin as adjuncts to hemostasis in liver resection, spine, peripheral arterial bypass, and dialysis access surgeries. Four hundred one (401) patients completed the trial. The reported adverse reactions in both treatment groups were: cardiac events (18%), hypersensitivity (17%), other infections (15%), bleeding (11%), postoperative wound infection (10%) and thromboembolic events (5%). Among 200 patients who were evaluated for the presence of antibodies to Thrombin-JMI, 10 patient (5%) were positive at baseline and 43 (21.5%) after treatment. The seroconversion rate in THROMBIN-JMI group was 18.4%.
In another multicenter, prospective, randomized, double-blinded, controlled trial that compared plasma-derived human thrombin to THROMBIN-JMI, 152 patients received THROMBIN-JMI and 153 patients received human thrombin applied topically to the target bleeding site with a gelatin sponge. Serious adverse reactions (pyrexia and post-procedural hematoma) were reported in two patients receiving THROMBIN-JMI. In this study, 16 out of 126 (12.7%) patients who received THROMBIN-JMI demonstrated seroconversion for at least one of the four antibodies assayed. The four separate ELISA assays used to detect development of antibodies and the corresponding antibody development rates included: 1) Anti-bovine thrombin 10/126 (7.94%), 2) Anti-bovine factor V/Va 12/126 (9.52%), 3) Anti-human thrombin 3/126 (2.38%) and 4) Anti-human factor V/Va 0/126 (0%).
The effect of repeat exposure was evaluated in a third multi-center, prospective, randomized, double-blinded, controlled trial on 72 patients with diabetic foot ulcers, using a gel prepared with THROMBIN-JMI and autologous platelet rich plasma that was applied weekly for 12 weeks. Forty (40) patients were treated with the gel at fourteen (14) sites. Safety parameters were evaluated during the 12 weeks of treatment and the three month follow-up period. No serious adverse reactions related to the gel treatment were reported.
A total of 554 subjects were enrolled,in a multi-center, open-label, observational study (MOSAIC) conducted to assess the effect of possible exposure to Thrombin JMI on activated partial thromboplastin time (aPTT) at 48 hours post surgery in subjects with likelihood of prior exposure to Thrombin JMI within the past 4 years. Of the 554 subjects, 550 had undergone surgery and completed the study. A total of 384 subjects undergoing vascular surgeries, neurosurgeries and orthopedic surgeries were exposed to THROMBIN-JMI (5,000 international units to 20,000 international units).
In this study, the impact of exposure to THROMBIN-JMI in 78 subjects who were positive for anti-bovine thrombin (aBT) antibodies prior to surgery was compared with 140 subjects who did not have any aBT antibodies and were not exposed to THROMBIN-JMI. The study did not meet the pre-specified primary endpoint, a mean change from baseline in aPTT at 48 hours post surgery. The study was not powered to detect coagulopathy related to an immune response after bovine thrombin use.
A post hoc analysis was performed in which subjects who underwent surgery were re-assigned to one of four exploratory cohorts based on the presence or absence of pre-surgery anti-Bovine factor V/antiBovine factor V active (aBV/Va) antibodies and whether or not they were administered Thrombin-JMI during the study surgery. Non-inferiority (based on aPTT) was observed in these exploratory cohorts at all time points of 48 hours, 4 weeks and 8 weeks post-surgery.
For the primary study cohort (THROMBIN-JMI use in subjects with baseline positive aBT or positive aBV/Va), there was a higher incidence of seroconversion from anti human thrombin (aHT) negative at baseline to post-surgery positive compared to the primary reference cohort (no THROMBIN-JMI use in subjects with baseline negative aBT or negative aBV/Va). This difference was not present at 48 hours after surgery but was evident at 4 weeks and 8 weeks post-surgery. A similar immunological response with aBT and aBV/Va antibodies was observed following THROMBIN-JMI administration.
Secondary immune responses in patients treated with Thrombin-JMI were evidenced by the generation of anti-bovine and anti-human thrombin and factor V/Va antibodies, consistent with known immunogenicity of topical bovine thrombin.
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
For topical use on the surface of bleeding tissue only. Do not inject.
THROMBIN-JMI may be reconstituted with sterile isotonic saline at a recommended concentration of 1,000 to 2,000 International Units/mL. Where bleeding is profuse, as from abraded surfaces of liver or spleen, concentrations of 1,000 International Units per mL may be required. For general use in plastic surgery, dental extractions, skin grafting, etc. solutions containing approximately 100 International Units/mL are frequently used. Intermediate strengths to suit the needs of the case may be prepared by diluting the contents of the THROMBIN-JMI container with an appropriate volume of sterile isotonic saline. In many situations, it may be advantageous to use THROMBIN-JMI in a dry form on oozing surfaces.
In instances where a concentration of approximately 1,000 units/mL is desired, the contents of the vial of sterile isotonic saline diluent may be transferred into the THROMBIN-JMI container with a sterile syringe or sterile transfer device. If the transfer device is used for reconstitution, transfer the diluent in the following manner.
CAUTION: Solutions should be used promptly upon removal from the container. However, the solution may be refrigerated at 2°–8°C for up to 24 hours, or may be stored at room temperature for up to 8 hours after reconstitution.
Refer to THROMBIN-JMI Pump Spray Kit instructions for spray pump assembly and use.
Each spray kit contains one vial of THROMBIN-JMI, one vial of diluent and one spray pump and actuator.
Refer to THROMBIN-JMI Syringe Spray Kit instructions for spray syringe assembly and use. Each syringe kit contains one vial of THROMBIN-JMI, one vial of diluent and one spray tip and syringe.
Refer to THROMBIN-JMI Epistaxis Kit instructions for accessory assembly and use.
Each epistaxis kit contains one vial of THROMBIN-JMI, one vial of diluent and one nasal drug delivery device.
The following techniques are suggested for the topical application of THROMBIN-JMI®.
THROMBIN-JMI may be used in conjunction with Absorbable Gelatin Sponge, USP. Consult the Absorbable Gelatin Sponge, USP labeling for complete information for use prior to utilizing the following thrombin saturated sponge procedure.:
THROMBIN-JMI may also be used with FloSeal™ NT according to the directions for use in the FloSeal™ NT package insert.
THROMBIN-JMI® is supplied in the following packages:
THROMBIN-JMI® Pump Spray Kit is supplied in the following package:
THROMBIN-JMI® Syringe Spray Kit is supplied in the following packages:
THROMBIN-JMI® Epistaxis Kit is supplied in the following package: