2.1 Dose

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 applied in conjunction with Absorbable Gelatin Sponge, USP.

2.2 Preparation

2.3 Administration

DO NOT INJECT. Apply only on the surface of bleeding tissue.

5.1 Thrombosis

Potential risk of thrombosis if absorbed systemically.

5.2 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. The physician should discuss the risks and benefits of this product with the patient.

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.

Anaphylactic reactions may occur in rare cases. No adverse events of this type were reported during the conduct of the clinical trials. Mild reactions can be managed with anti-histamines. Severe hypotensive reactions require immediate intervention using current principles of shock therapy.

In a phase III multicenter, prospective, controlled, randomized, double-blinded study 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 study 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 study with EVITHROM®. However, no adverse events indicative of infection with transfusion-transmissible agents were reported.

6.2 Post Marketing Experience

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

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Of the 155 patients undergoing liver surgery who were treated in adequate and well controlled clinical 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 phase III 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.

12.1 Mechanism of Action

Thrombin (coagulation factor IIa) is a highly specific protease that transforms plasma fibrinogen into fibrin which, in the presence of Factor XIII in the patient's plasma, is crosslinked to form a stable clot. When applied to a surgical wound where bleeding is present, thrombin activates fibrinogen in the patient's plasma to form fibrin, which results in clot formation and hemostasis. The fibrin clot is stabilized by cross-linking occurring as a result of activation of the patient's endogenous factor XIII, which requires the presence of calcium.

12.2 Pharmacodynamics

Clinical pharmacodynamic studies with human thrombin have not been performed as this would be ethically unacceptable with this type of product.

12.3 Pharmacokinetics

Due to the nature of the product, intended for topical application to the surface of tissue at the surgical site, pharmacokinetic studies were not conducted.

13.1 Carcinogenesis, Mutagenesis, 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.

Studies were performed in bacteria to determine mutagenicity of human thrombin alone, and solvent/detergent residues [tri-n-butyl phosphate (TnBP) and Triton X-100], used in the virus inactivation manufacturing step. These studies were negative for both Thrombin and for TnBP or Triton X-100 at all concentrations tested. All concentrations of the combination of TnBP and Triton X-100 also tested negative in assays performed to determine mammalian cell mutagenicity, chromosomal aberrations and micronuclei induction.

The effect of EVITHROM® on fertility has not been evaluated. 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 post-implantation loss and an increased number of late resorptions. Other studies performed with combinations of TnBP (300-fold human dose, 450 µg/kg/day) and Triton X-100 (1500-fold human dose, 2250 µg/kg/day) resulted in increased resorption rates, decreased fetal body weights, and an increased number of runts. No embryo-fetal adverse effects were observed at doses up to 300 µg/kg/day TnBP and 1500 µg/kg/day Triton X-100, 200-fold and 1000-fold the human dose, respectively.

13.2 Animal Toxicology and/or Pharmacology

EVICEL® Fibrin Sealant (Human), which includes EVITHROM® as one of the active components, was classified as non-irritant in the Primary Cutaneous Irritation Test and slightly irritant in the Ocular Irritation test.

Neurotoxicity studies performed with EVITHROM® or with EVICEL® confirmed that intracerebral application of thrombin was not associated with any evidence of neurotoxicity. 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 5 µg/ml.

Storage and handling

• The vials must be stored in an upright position.
• Store frozen vials at -18°C or colder for up to 2 years.
• Unopened vials can be stored at 2°C to 8°C for up to 30 days.
• EVITHROM® has been shown to be stable for up to 24 hours at room temperature.
• 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.
• Do not re-freeze EVITHROM® once it has been thawed.
• Do not refrigerate EVITHROM® once at room temperature.
• Discard unused product after 24 hours at room temperature.
• Discard if the packaging of EVITHROM® is damaged.