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Rheumatoid arthritis: integrated safety analysis of Tofacitinib in clinical trials with a cumulative exposure of 12,664 patient-years

Tofacitinib ( Xeljanz ) is an oral Janus kinase ( JAK ) inhibitor for the treatment of rheumatoid arthritis ( RA ). Phase 2, phase 3, and open-label long-term extension ( LTE ) studies have described the safety profile of Tofacitinib and demonstrated that Tofacitinib is effective as monotherapy and in combination with non-biologic disease-modifying antirheumatic drugs ( DMARDs ).

An analysis has described safety data for Tofacitinib in patients from the integrated rheumatoid arthritis clinical trial database based on cumulative exposure in phase 2, phase 3, and LTE studies, with a focus on safety events of special interest according to duration of Tofacitinib exposure.

The analysis was performed on patients who received greater than or equal to 1 dose of Tofacitinib ( doses pooled ), as monotherapy or with background DMARDs, integrated across 6 phase2, 6 phase 3 trials, and in 2 LTE studies ( ongoing; database not locked ) up to April 10, 2013.
Patients switching from placebo, Adalimumab ( Humira ) or Methotrexate to Tofacitinib contributed data following their first dose of Tofacitinib.

The incidence rates ( IR; events/100 patient-years ) for opportunistic infections ( OI ) included herpes zoster ( HZ ) events that were described as disseminated or multidermatomal and excluded events of tuberculosis ( TB ), which were reported separately.

The analysis has included 5,671 patients and has represented an overall 12,664 patient-years of Tofacitinib exposure, with a median exposure of 2.4 years.
The numbers of patients receiving Tofacitinib for at least 12, 24, 36 and greater than 48 months were 4,204 ( 74% ), 3,804 ( 54% ), 1,948 ( 34% ), and 555 ( 10% ) respectively.

Overall 926 ( 16.3% ) discontinued due to adverse events.

The IR for mortality ( within 30 days of last dose ) was 0.28. IRs across discrete 6-month periods of exposure for serious adverse effects and adverse effects of interest, were stable across time intervals.

Serious infections were the most common serious adverse reactions ( IR 2.93 ). IRs for opportunistic infections and tuberculosis were 0.25 and 0.21, respectively.

Of all herpes zoster adverse reactions ( overall IR 4.22 ), 93% were non-serious; disseminated and multidermatomal cases were rare. Rates of all malignancies, excluding non-melanoma skin cancer ( NMSC ), and of lymphoma/lymphoproliferative disorders, were similar across time intervals.
US Surveillance, Epidemiology, and End Results Program ( SEER ) standardised incidence ratios were 1.08 for malignancies excluding non-melanoma skin cancer and 2.58 for lymphoma, and were comparable to those reported from cohorts of rheumatoid arthritis patients treated with tumour necrosis factor inhibitors.

In conclusion, the pattern and rate of serious adverse reactions and adverse effects of special interest observed following greater than 12,000 patient-years of overall exposure was stable across time intervals.
No new risks were identified compared to previous reports.
Longer term follow-up, observational research, and pharmacovigilance activities will further characterise the safety profile of Tofacitinib in rheumatoid arthritis. ( Xagena )

Source: EULAR Meeting - Cohen S et al, Ann Rheum Dis 2014;73(Suppl2)