THROMBIN-JMI- thrombin, topical (bovine)
Pfizer Laboratories Div Pfizer Inc
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use THROMBIN-JMI safely and effectively. See full prescribing information for THROMBIN-JMI.
THROMBIN-JMI® (Thrombin, Topical (Bovine) U.S.P.), Solution for topical use
Initial U.S. Approval: 1986
WARNING: SEVERE BLEEDING AND THROMBOSIS COMPLICATIONS
See full prescribing information for complete boxed warning
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
THROMBIN-JMI is a topical 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. (1)
THROMBIN-JMI may be used in conjunction with an absorbable gelatin sponge, USP. (1)
DOSAGE AND ADMINISTRATION
For topical use on the surface of bleeding tissue only. Do not inject. (2)
DOSAGE FORMS AND STRENGTHS
WARNINGS AND PRECAUTIONS
Most common adverse reactions (incidence ≥ 2%) are hypersensitivity, bleeding, anemia, post-operative wound infection, thromboembolic events, hypotension, pyrexia, tachycardia and thrombocytopenia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Pregnancy: No human or animal data. Use only if clearly needed. (8.1)
See 17 for PATIENT COUNSELING INFORMATION.
FULL PRESCRIBING INFORMATION: CONTENTS*
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.
For topical use on the surface of bleeding tissue only. Do not inject.
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°C – 8°C for up to 24 hours, or may be stored at room temperature for up to 8 hours after reconstitution.
THROMBIN-JMI PUMP SPRAY KIT
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.
THROMBIN-JMI SYRINGE SPRAY KIT
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.
THROMBIN-JMI EPISTAXIS KIT
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.
Use in conjunction with Absorbable Gelatin Sponge
Consult the Absorbable Gelatin Sponge, USP labeling for complete information for use prior to utilizing the following thrombin saturated sponge procedure.
THROMBIN-JMI (Thrombin, Topical (Bovine) U.S.P.), Solution for topical use is supplied in the following packages:
Vial: 5,000 IU vial with 5 mL diluent.
Vial: 20,000 IU vial with 20 mL diluent.
THROMBIN-JMI Pump Spray Kit is supplied in the following packages:
Pump Spray Kit: 20,000 IU vial with 20 mL diluent, spray pump and actuator.
THROMBIN-JMI Syringe Spray Kit is supplied in the following packages:
Syringe Spray Kit: 5,000 IU vial with 5 mL diluent, spray tip and syringe.
Syringe Spray Kit: 20,000 IU vial with 20 mL diluent, spray tip and syringe.
THROMBIN-JMI Epistaxis Kit is supplied in the following packages:
5,000 IU vial with 5 mL diluent, nasal drug delivery device and syringe.
Warning: Severe Bleeding and Thrombosis Complications
THROMBIN-JMI causes thrombosis if it enters the circulatory system. Apply topically. DO NOT INJECT.
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.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
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 [see Clinical Studies (14)].
The following serious adverse reactions have been identified during post approval use of THROMBIN-JMI: anaphylactic reactions, prolonged prothrombin time, prolonged activated partial thromboplastin time, disseminated intravascular coagulation, factor V deficiency, post-procedural hematoma, swelling and Staphylococcal wound infection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Pregnancy Category C: Animal reproduction studies have not been conducted with THROMBIN-JMI. It is also not known whether THROMBIN-JMI can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. THROMBIN-JMI should be given to a pregnant woman only if clearly needed.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when THROMBIN-JMI is administered to a nursing woman.
Clinical studies of THROMBIN-JMI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
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.
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/anti-bovine 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.
Not made with natural rubber latex.
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:
Because THROMBIN-JMI may cause the formation of clots in blood vessels if absorbed systemically, advise patients to consult their physician if they experience leg tenderness or swelling, chest pain, shortness of breath, or difficulty speaking or swallowing.