Summary of safety profile: Vedolizumab has been studied in three placebo-controlled clinical trials in patients with ulcerative colitis (GEMINI I) or Crohn's disease (GEMINI II and III). In two controlled studies (GEMINI I and II) involving 1,434 patients receiving vedolizumab 300 mg at Week 0, Week 2 and then every eight weeks or every four weeks from Week 6 for up to 52 weeks, and 297 patients receiving placebo for up to 52 weeks, adverse events were reported in 84% of vedolizumab-treated patients and 78% of placebo-treated patients. Over 52 weeks, 19% of vedolizumab-treated patients experienced serious adverse events compared to 13% of placebo-treated patients. Similar rates of adverse events were seen in the every eight week and every four week dosing groups in the Phase 3 clinical trials. The proportion of patients who discontinued treatment due to adverse events was 9% for vedolizumab-treated patients and 10% for placebo-treated patients. In the combined studies of GEMINI I and II the adverse reactions that occurred in ≥5% were nausea, nasopharyngitis, upper respiratory tract infection, arthralgia, pyrexia, fatigue, headache, cough. Infusion-related reactions were reported in 4% of patients receiving vedolizumab.
In the shorter (10 week) placebo controlled induction trial, GEMINI III, the types of adverse reactions reported were similar but occurred at lower frequency than the longer 52 week trials.
A further 279 patients were treated with vedolizumab at Week 0 and Week 2 and then with placebo for up to 52 weeks. Of these patients, 84% experienced adverse events and 15% experienced serious adverse events.
Patients (n=1,822) previously enrolled in Phase 2 or 3 vedolizumab studies were eligible to enrol in an ongoing open-label study and received vedolizumab 300 mg every four weeks.
Tabulated list of adverse reactions: The following listing of adverse reactions is based on the clinical trial experience and are displayed by system organ class. Within the system organ classes, adverse reactions are listed under headings of the following frequency categories: very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
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Description of selected adverse reactions: Infusion-related reactions: In GEMINI I and II controlled studies, 4% of vedolizumab-treated patients and 3% of placebo-treated patients experienced an adverse event defined by the investigator as infusion-related reaction (IRR) (see Precautions). No individual Preferred Term reported as an IRR occurred at a rate above 1%. The majority of IRRs were mild or moderate in intensity and <1% resulted in discontinuation of study treatment. Observed IRRs generally resolved with no or minimal intervention following the infusion. Most infusion related reactions occurred within the first 2 hours. Of those patients who had infusion related reactions, those dosed with vedolizumab had more infusion related reactions with in the first two hours as compared to placebo patients with infusion related reactions. Most infusion related reactions were not serious and occurred during the infusion or within the first hour after infusion is completed.
One serious adverse event of IRR was reported in a Crohn's disease patient during the second infusion (symptoms reported were dyspnoea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate) and was successfully managed with discontinuation of infusion and treatment with antihistamine and intravenous hydrocortisone. In patients who received vedolizumab at Weeks 0 and 2 followed by placebo, no increase in the rate of IRR was seen upon retreatment with vedolizumab after loss of response.
Infections: In GEMINI I and II controlled studies, the rate of infections was 0.85 per patient-year in the vedolizumab-treated patients and 0.70 per patient-year in the placebo-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, sinusitis, and urinary tract infections. Most patients continued on vedolizumab after the infection resolved.
In GEMINI I and II controlled studies, the rate of serious infections was 0.07 per patient year in vedolizumab-treated patients and 0.06 per patient year in placebo-treated patients. Over time, there was no significant increase in the rate of serious infections.
In controlled and open-label studies in adults with vedolizumab, serious infections have been reported, which include tuberculosis, sepsis (some fatal), salmonella sepsis, listeria meningitis, and cytomegaloviral colitis.
Immunogenicity: In GEMINI I and II controlled studies, vedolizumab showed an immunogenicity rate of 4% (56 of 1,434 patients who received continuous treatment with vedolizumab were anti-vedolizumab antibody-positive at any time during treatment). Nine out of 56 patients were persistently positive (anti-vedolizumab antibody-positive at two or more study visits) and 33 patients developed neutralizing anti-vedolizumab antibodies.
The frequency of anti-vedolizumab antibody detected in patients 16 weeks after the last dose of vedolizumab (approximately five half-lives after the last dose) was approximately 10% in GEMINI I and II.
In GEMINI I and II controlled studies, 5% (3 of 61) of the patients who had an adverse event assessed by the investigator as an IRR were persistently anti-vedolizumab antibody-positive.
Overall, there was no apparent correlation of anti-vedolizumab antibody development to clinical response or adverse events. However, the number of patients that developed anti-vedolizumab antibodies was too limited to make a definitive assessment.
Malignancy: Overall, results from the clinical program to date do not suggest an increased risk for malignancy with vedolizumab treatment; however, the number of malignancies was small and long-term exposure was limited. Long-term safety evaluations are ongoing.