Background/Purpose: Post-marketing surveillance is an important part of monitoring adverse events (AEs) following the approval of new drugs. Tofacitinib is an oral Janus kinase inhibitor approved in the United States in November 2012 for the treatment of rheumatoid arthritis (RA). An analysis of the post-marketing spontaneous (PMS) reports, covering a period of 18 months, was conducted to evaluate the safety of tofacitinib in the post-marketing setting.

Methods: Tofacitinib worldwide PMS reports received in the Pfizer safety database from 6 November 2012 to 5 May 2014 were analyzed. The type and estimated reporting rate of serious AEs of interest, including infections, neoplasm events, gastrointestinal (GI), and hepatobiliary disorders, by 6-month interval were reviewed. The reporting rate of SAEs was calculated by dividing the number of SAEs by the estimated patient-years of exposure (PYs). The PYs were estimated based on estimated worldwide sales and an estimated daily regimen of 5 mg twice daily.

Results: A total of 2,496 case reports with 6,295 AEs were received. The majority of reported AEs were non-serious (83.4%). Of the 1,043 SAEs, 21.8% of the events were related to infections, 8.7% were GI disorders, 3.55% were neoplasm events, and 0.6% were hepatobiliary disorders. The reporting rate of serious infections (SIs) was 5.1, 6.2, and 2.48 per 100 PYs for the first/second/third 6-month interval, respectively.  The most commonly reported SI events (n ≥ 10) include pneumonia (33), urinary tract infection (26), sepsis (15), diverticulitis (11), and herpes zoster (HZ) infections (10). A small number of opportunistic infections (OI) were reported including reactivation of tuberculosis (2), disseminated HZ (1), histoplasmosis (1), Cytomegalovirus gastritis/ oesophagitis (1), and unspecified OI (1). The reporting rate of serious neoplasm events across the first/second/third intervals was 0.14, 1.02, and 0.54 per 100 PYs, respectively. The commonly-reported serious neoplasm events (n ≥2) include lymphoma (6), bladder cancer (3), brain neoplasm (3), lung neoplasm malignant (2), basal cell carcinoma (2), and unspecified neoplasm malignant (2). Most of the case reports did not have sufficient information for a causality assessment. In the reports where time to onset was provided, eight events were diagnosed before or within 2 months of the initiation of tofacitinib. Across the reporting period, no significant change in reporting rate was noted for GI and hepatobiliary disorders. Of the 91 reported serious GI events, the most commonly reported events (n ≥ 5) including diarrhea (11), nausea (6), vomiting (6), GI hemorrhage (5), and hematochezia (5).

Conclusion: Review of AEs from PMS reports did not reveal any new safety signal compared with the safety profile identified from tofacitinib RA clinical studies during its development program. SAEs including SIs and malignancy have been reported in the post-marketing setting and the safety profile of tofacitinib will continuously be monitored via pharmacovigilance. Limitations of PMS reports (such as under-reporting and reporting bias) and estimated reporting rate due to lack of denominators should be considered when interpreting these results.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/18-month-worldwide-post-marketing-surveillance-experience-of-tofacitinib/