• Highlights
• Contents
• Indications and Usage
• Dosage and Administration
• Dosage Forms and Strengths
• Contraindications

• Warnings and Precautions
• Adverse Reactions
• Drug Interactions
• Use in Specific Populations
• Description

• Clinical Pharmacology
• Nonclinical Toxicology
• Clinical Studies
• References
• How Supplied/
  Storage and Handling

6.2 Immunogenicity

The development of anti-product antibodies, a pre-specified study endpoint, was monitored in an adequate and well-controlled Phase 3 clinical trial [1]. Blood samples were collected at baseline and at day 29 for 97% of the subjects in both treatment groups. For subjects randomized to Thrombin, topical (Recombinant), the samples were analyzed by ELISA for antibodies to RECOTHROM, Chinese hamster ovary (CHO) host cell protein, and pro-thrombin activator (used in the conversion of single chain precursor to active RECOTHROM). For subjects randomized to bovine thrombin, the samples were analyzed by ELISA for antibodies to bovine thrombin product.

Treatment with RECOTHROM resulted in a statistically significantly lower incidence of specific anti-product antibody development. Three of 198 (1.5%; 95% CI, 0 to 4%) of the patients in the RECOTHROM arm developed specific anti-thrombin product antibodies (1 patient also developed anti-CHO host cell protein antibodies). No subjects developed antibodies to pro-thrombin activator. Forty-three of 200 subjects (22%; 95% CI, 16 to 28%) in the bovine thrombin arm developed specific antibodies to bovine thrombin product. None of the antibodies in the RECOTHROM group neutralized native human thrombin. Antibodies against bovine thrombin product were not tested for neutralization of native human thrombin. Development of antibodies in either group did not lead to any adverse events such as excessive bleeding.

At baseline in the Phase 3 study, 1.5% of subjects (n=3/198) in the RECOTHROM group had positive anti-product antibody titers compared with 5% of subjects in the bovine thrombin group (n=10/200). Of the subjects who had detectable anti-product antibodies at baseline, 0 of 3 in the RECOTHROM group and 8 of 10 in the bovine thrombin group exhibited ≥1.0 titer unit (≥10-fold) increases in antibody levels after study treatment.

In Phase 2 studies, incidence of antibody development following treatment with RECOTHROM was 1.2% (95% CI, 0% to 6.5%) compared to 2.4% (95% CI, 0.1% to 12.9%) for placebo.

The detection of antibody formation is highly dependent upon the sensitivity and specificity of the assay. The absolute immunogenicity rates reported here are difficult to compare with results from studies of other products due to differences in assay methodology, patient populations, and other underlying factors.

Limited data (n=6) are currently available on repeat exposure to RECOTHROM [see NONCLINICAL TOXICOLOGY (13.2)].