Worldwide Post-marketing Safety Surveillance Experience With Tofacitinib in Ulcerative Colitis

David T. Rubin; Irene Modesto; Séverine Vermeire; Silvio Danese; Siew C. Ng; Kenneth K. Kwok; Nana Koram; Thomas V. Jones


Aliment Pharmacol Ther. 2022;55(3):302-310. 

In This Article

Abstract and Introduction


Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Post-marketing surveillance (PMS) is an important part of monitoring adverse events (AEs).

Aims: To report an analysis of PMS case safety reports for tofacitinib in patients with UC

Methods: Worldwide tofacitinib PMS reports received in the Pfizer safety database from 30 May 2018 (first regulatory approval) to 25 August 2020 were analysed. The type and estimated reporting rate (RR) of serious AEs of interest, including infection, gastrointestinal, vascular, respiratory, neoplasm and cardiac events, were reviewed. Patient-years of exposure (PY) was estimated based on worldwide sales data and the calculated daily regimens of tofacitinib 5 or 10 mg twice daily, immediate- or extended-release formulations.

Results: During the 27-month reporting period, worldwide post-marketing exposure to tofacitinib was 8916 PY. Overall, 4226 case reports were received and included 12 103 AEs, of which 1839 were serious AEs (SAEs). Among the cases reported, 1141 (27.0%) included an SAE and 18 (0.4%) were fatal. The RR (per 100 PY) for SAEs of interest by Medical Dictionary for Regulatory Activities System Organ Class were 3.28 for infections, 1.26 for vascular disorders, 0.74 for respiratory disorders, 0.55 for neoplasms and 0.50 for cardiac disorders.

Conclusions: The types of AEs were consistent with those reported in tofacitinib clinical trials. Most reported AEs were non-serious. Limitations of PMS reports and reliance on estimated RRs due to lack of precise values for exposure, required for incidence rate calculation, should be considered when interpreting these results.


Ulcerative colitis (UC) is a chronic inflammatory disease of the colon and rectum which follows a relapsing and remitting course.[1] Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of UC. The efficacy and safety of tofacitinib in adults with moderately to severely active UC has been evaluated in clinical trials, including a dose-ranging phase 2 induction trial,[2] two 8-week phase 3 induction trials (OCTAVE Induction 1 and 2),[3] a 52-week phase 3 maintenance trial (OCTAVE Sustain),[3] and an open-label, long-term extension trial (OCTAVE Open).[4]

Tofacitinib received its first marketing authorisation in the United States on 30 May 2018 for the treatment of adults with moderately to severely active UC and was approved in the European Union on 1 August 2018. Initially, tofacitinib was only available in an immediate-release formulation (5 and 10 mg tablets), and an extended-release formulation (11 and 22 mg tablets) was approved in the United States for use in patients with moderately to severely active UC in December 2019. The recommended dosage for induction is tofacitinib 10 mg twice daily, or 22 mg once daily for 8 weeks. If needed, induction treatment can be continued for a maximum of 16 weeks.[5] For maintenance treatment, tofacitinib 5 mg twice daily or 11 mg once daily is recommended.[5] For patients with a loss of response during maintenance treatment, tofacitinib 10 mg twice daily or 22 mg once daily may be considered and limited to the shortest duration, with careful consideration of the benefits and risks for the individual patient.[5]

The safety profile of tofacitinib in patients with UC has been characterised in a pooled analysis of tofacitinib-treated patients from phase 2 and 3 trials, and open-label, long-term extension studies (as of May 2019).[6] Adverse events (AEs) of special interest included serious infections, herpes zoster, opportunistic infections, malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, major adverse cardiovascular events (MACE) and gastrointestinal perforations. In this integrated safety analysis, the AE incidence rate remained generally consistent over time.[6,7] Compared with the general population, patients with inflammatory bowel disease have been shown to be at increased risk for herpes zoster,[8] and this risk is elevated in patients with UC treated with tofacitinib.[9] Post-marketing surveillance (PMS), the practice of monitoring drug safety following market release, is important for pharmacovigilance and complements data from clinical trials to establish a real-world safety profile. PMS includes spontaneous and voluntary reporting of AEs, post-marketing observational studies and active surveillance.

We evaluated the safety profile of tofacitinib in patients with UC in the post-marketing setting and compared with previously reported PMS data in patients with rheumatoid arthritis (RA).[10]