6 ADVERSE REACTIONS
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.
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 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 publications summarizing four (4) randomized controlled clinical trials in which THROMBIN-JMI was used as a comparator2–5, and one (1) observational study6 [see Clinical Studies (14)].
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.2 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 patients (5%) were positive at baseline and 43 (21.5%) after treatment. The seroconversion rate in THROMBIN-JMI group was 18.4%.
In a 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.3 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 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.4 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.
In a prospective, randomized, phase 2, non-inferiority study, topical human thrombin was compared with THROMBIN-JMI during vascular, hepatic, soft tissue, and spinal open surgery procedures.5 A total of 205 patients were randomized in a 2:1 ratio to receive human thrombin (n=137) or THROMBIN-JMI (n=68). The most common treatment-emergent adverse reactions (experienced by >5% patients within a treatment group) were procedural pain, nausea, constipation, pruritus, muscle spasms, insomnia, pyrexia, and vomiting. Two patients in the THROMBIN-JMI group (3.2% of treated patients) showed low-level titers of antibodies to bovine factor V.
6.2 Postmarketing Experience
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.