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Postmarketing Study Reveals Higher Risk of Blood Clots and Death – FDA Approves Boxed Warning

Like many drugs that undergo clinical trials (even larger trials), rare adverse events may not become apparent until well after the drug is in wider use after approval.  In addition, as a condition of approval, the FDA often requires a post-approval commitment to further study the drug.  Such is the case as described in the updated Safety Communication released today by the Agency as FDA announced it approved “a Boxed Warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR).”

The Safety Communication stated:

When FDA first approved tofacitinib in 2012, we required a postmarketing clinical trial in patients with RA on background methotrexate, to evaluate the risk of heart-related events, cancer, and infections. The trial is studying two different doses of tofacitinib (5 mg twice daily, which is the currently approved dose for RA, and a higher, 10 mg twice daily dosage) in comparison to a TNF blocker.

In an interim analysis of this on-going study, it was determined that patients on a 10-mg twice-daily dose had a higher incidence of blood clots and deaths “compared to patients treated with tofacitinib 5‑mg twice‑daily or a TNF blocker.”  As a result, the 10-mg dose was dropped from the study and patients on the 5‑mg dose are continued to be followed.

The notice described the interim analysis results as of January 2019 as follows:

  • Nineteen cases of blood clots in the lung out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared to three cases out of 3,982 patient-years in patients who received TNF blockers
  • Forty-five cases of death from all causes out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared to twenty-five cases out of 3,982 patient-years in patients who received TNF blockers.

The drugs are approved to treat rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ulcerative colitis.  The Safety Communication goes on to say, “The 10-mg twice-daily dose of tofacitinib is not approved for RA or (PsA).  This dose is only approved for ulcerative colitis for initial treatment and for long-term use in limited situations.”

It is certain that we will hear more about this issue as the study progresses and we will keep you informed of any additional information as the Agency makes it available.