Thrombin Human: Package Insert and Label Information

THROMBIN HUMAN- human thrombin powder, for solution
Ethicon, Inc

1 INDICATIONS AND USAGE

EVITHROM® Thrombin, 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, ligature or cautery) is ineffective or impractical.

EVITHROM® Thrombin, Topical (Human), may be used in conjunction with an Absorbable Gelatin Sponge, USP.

2 DOSAGE AND ADMINISTRATION

2.1 Dose

For Topical Use Only. DO NOT INJECT.

The amount of EVITHROM® required depends upon the area of tissue to be treated and the method of application. As an approximate guide, volumes up to 10 ml were used in clinical studies where EVITHROM® was used in conjunction with Absorbable Gelatin Sponge, USP.

2.2 Preparation

  • Use aseptic technique when handling vials and syringes.
  • Remove the flip-off plastic cap from the vial to expose the rubber stopper.
  • Reconstitute the lyophilized human thrombin powder with 2 ml of sterile Water for Injection, USP using the provided reconstitution device.
  • Shake gently until the solution is clear.
  • Reconstituted solution is stable for up to 8 hours at room temperature and should be used within this time period.

2.3 Application Techniques

Apply only on the surface of bleeding tissue.

EVITHROM® Use alone

  • Sponge target surface (do not wipe) or suction free of blood before application.
  • Flood the surface with EVITHROM® using a sterile syringe and small gauge needle.
  • Avoid sponging after treatment, to ensure that the clot remains securely in place.

EVITHROM® in conjunction with Absorbable Gelatin Sponge, USP

  • Prepare the desired shape of the Absorbable Gelatin Sponge, USP. (see Absorbable Gelatin Sponge, USP circular for additional instructions for use).
  • Transfer EVITHROM® into a sterile container using aseptic techniques.
  • Immerse gelatin sponge into the EVITHROM® solution.
  • Vigorously knead the sponge with moistened gloved fingers until all air is expelled and it can return to its original size and shape.
  • Hold the saturated sponge in place with gauze or cotton pledget using moderate pressure until hemostasis is achieved.

3 DOSAGE FORMS AND STRENGTHS

EVITHROM® is a sterile lyophilized powder for solution 2000 (1600-2400) units of lyophilized human thrombin powder for reconstitution. After reconstituted, the final solution contains 1000 (800-1200) units/ml of human thrombin.

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, 01/580. Therefore, a unit used herein is equivalent to an International Unit.

4 CONTRAINDICATIONS

  • Do not use in individuals known to have an anaphylactic or severe systemic reaction to EVITHROM® or to human blood products.
  • Do not use for the treatment of severe or brisk arterial bleeding.

5 WARNINGS AND PRECAUTIONS

5.1 Thrombosis

There is a risk of thrombosis if absorbed systemically. Apply topically only.

5.2 Anaphylactic/Hypersensitivity Reactions

Anaphylactic reactions may occur in rare cases. No adverse events of this type were reported during the conduct of the clinical trials. Severe hypotensive reactions require immediate intervention using current principles of shock therapy.

5.3 Transmission of Infectious Agents

Because this product is made from human plasma, it may carry a risk of transmitting infectious agents, such as viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk of transmitting 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. There is also the possibility that unknown infectious agents may be present in such products.

6 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, increased INR, decreased lymphocyte count, prolonged prothrombin time and increased neutrophil count.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, 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.

In a multicenter, prospective, controlled, randomized, double-blinded clinical trial of 305 subjects where EVITHROM® (n=153) was compared with bovine thrombin (n=152), occurrence of adverse events was not statistically different between the two groups.

Overall, adverse events occurred in similar proportions of subjects in the two groups (see Table 1). No clinically significant differences were seen in age (<65 years, >65 years) or gender subgroup analyses of adverse events.

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. The SAEs reported were associated with post-surgical complications (e.g. 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. Two subjects (1.3%) in EVITHROM® group experienced a treatment emergent severe adverse event: respiratory arrest and post-procedural hematoma (in one subject) and extradural hematoma. Three subjects in the bovine thrombin group experienced a treatment emergent severe adverse event: hyperhidrosis, pyrexia and post-procedural hematoma.

No deaths were reported during the study period.

Viral serology was not monitored during the trial with EVITHROM®. However, no adverse events indicative of infection with transfusion-transmissible agents were reported.

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
System Organ Class/Adverse Event EVITHROM® (n=153) Bovine (n=152) Total (n=305)
Investigations 11 (7.2%) 14 (9.2%) 25 (8.2%)
Activated partial thromboplastin time increased 4 (2.6%) 8 (5.3%) 12 (3.9%)
International normalized ratio increased 4 (2.6%) 5 (3.3%) 9 (3.0%)
Lymphocyte count decreased 4 (2.6%) 2 (1.3%) 6 (2.0%)
Prothrombin time prolonged 4 (2.6%) 8 (5.3%) 12 (3.9%)
Neutrophil count increased 3 (2.0%) 2 (1.3%) 5 (1.6%)
Skin and Subcutaneous Tissue Disorders 1 (0.7%) 3 (2.0%) 4 (1.3%)
Pruritus 1 (0.7%) 3 (2.0%) 4 (1.3%)
General Disorders and Administration Site Conditions 0 3 (2.0%) 3 (1.0%)

Immunogenicity

In the clinical study, serum samples were collected at baseline and at 5 weeks post-surgery for evaluation of antibodies to bovine thrombin, bovine Factor V/Va, human thrombin, and human Factor V/Va. Samples were collected at both time points for 81.3% of the subjects. The ELISA data were adjudicated by a panel of experts blinded to treatment assignment. After reviewing all data, the panel used an algorithm for assigning outcomes for each antigen: seroconversion negative or seroconversion positive.

The protocol did not specify any comparative analysis for immunogenicity data, only descriptive statistics. The adjudicated results show that 3.3% of the subjects treated with EVITHROM® (frozen formulation) developed antibodies to any of the four antigens, compared to 12.7% of the subjects developing antibodies in the control group (bovine thrombin). 7.9% of the subjects treated with bovine thrombin (control group) developed antibodies to bovine thrombin and 9.5% of these subjects developed antibodies to bovine Factor V/Va. A few control subjects had antibodies that cross-reacted with human thrombin, but none had antibodies that crossreacted with human Factor V/Va. None of the patients treated with EVITHROM® developed detectable antibodies to human thrombin or to human Factor V/Va.

The detection of antibody formation is highly dependent upon the sensitivity and specificity of the assay. The observed incidence of a positive signal in an assay may be influenced by several factors including timing of sampling, sample handling, concomitant medications, or underlying disease. Therefore, direct comparison of incidence of antibody development to human thrombin, bovine thrombin, 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.

6.2 Post Marketing Experience

No adverse reactions have been identified from spontaneous post-marketing reports.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no data with EVITHROM® use in pregnant women to inform a drug-associated risk.

Animal reproduction studies have not been conducted with EVITHROM®. It is not known whether EVITHROM® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. EVITHROM® should be given to a pregnant woman only if clearly needed. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation

Risk Summary

There is no information regarding the presence of EVITHROM® in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EVITHROM® and any potential adverse effects on the breastfed infant from EVITHROM® or from the underlying maternal condition.

8.4 Pediatric Use

Of the 155 patients undergoing liver surgery who were treated in adequate and well-controlled studies of EVICEL® Fibrin Sealant (Human), in which EVITHROM® is a component, eight were pediatric patients. Of these, five were less than 2 years old and three were between 2 and 12 years old. Use of EVITHROM® in pediatric patients is supported by these data and by extrapolation of findings for safety and efficacy in adults.

8.5 Geriatric Use

Sixty three (63) subjects over 65 years of age received EVITHROM® in the clinical trial.

No differences in safety or effectiveness were observed between the elderly and younger patients. Greater susceptibility of older patients to adverse reactions cannot be ruled out.

11 DESCRIPTION

EVITHROM® is a sterile lyophilized powder of purified human thrombin (1600-2400 units) of white to slightly yellowish color. When reconstituted, EVITHROM® solution, pH 6.8-7.2, is clear to slightly opalescent and colorless to slightly yellowish. Other inactive ingredients are Calcium chloride, Human albumin, Mannitol, Sodium acetate

EVITHROM® is made from pooled Human Source obtained from US licensed plasma collection centers. Individual plasma units obtained for production of EVITHROM® are tested by licensed serological tests for HBsAg, HIV 1 & 2 Ab and HCV Ab. Additionally, the plasma units are tested by licensed Nucleic Acid Testing (NAT) for HIV-1, HCV, HBV, HAV and parvovirus B19. All tests for HIV, HCV, HBV and HAV must be negative (non-reactive). However, since the effectiveness of the HBV and HAV NAT methods in detecting low levels of viral material is still under investigation, the significance of a negative result for these viruses is unknown. The level of parvovirus B19 contamination is not permitted to exceed 10,000 copies/ml. This limit is applied to restrict the viral load of parvovirus B19 in the starting plasma pool. In addition to the screening of plasma units, each manufacturing pool is tested for HBsAg, HIV-1 & 2 Ab, HCV NAT and for parvovirus B19 by NAT. Manufacturing pool testing, however, is of lower sensitivity than individual unit testing.

EVITHROM® is manufactured by purification of prothrombin from cryo-poor plasma followed by activation with calcium chloride, or alternatively with calcium chloride in combination with Gluconate. The manufacturing process includes two targeted steps for inactivation or removal of viruses. The first of these is treatment with a solvent/detergent (S/D) mixture (1% tri-n-butyl phosphate and 1% Triton X-100 or 1% Polysorbate-80 and 0.3% tri-n-butyl phosphate) for 6 hours at 26°C to inactivate lipid enveloped viruses. The S/D reagents are removed by cation exchange chromatography. Mannitol and human albumin are used to stabilize the solution, which undergoes nanofiltration for removal of both enveloped and non-enveloped viruses. After nanofiltration, the solution is formulated with calcium chloride, sterile filtered and aseptically filled and frozen.

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 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 HIV-1 BVDV PRV EMCV HAV MVM PPV
Reduction factor (log10 )
HIV-1: Human Immunodeficiency Virus Type 1;
BVDV: Bovine Viral Diarrhea Virus;
PRV: Pseudorabies Virus;
EMCV: Encephalomyocarditis Virus;
HAV: Hepatitis A Virus;
MVM: Minute Virus of Mouse;
PPV: Porcine Parvovirus
SD Treatment ≥5.5 >4.6 >4.2 Not Done Not Done Not Done Not Done
Nanofiltration ≥4.6 ≥5.6 ≥5.7 ≥7.4 ≥7.5 ≥6.3 ≥ 5.6
Global Reduction Factor ≥10.1 ≥10.2 ≥9.9 ≥7.4 ≥7.5 ≥6.3 ≥5.6
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