Worldwide, 3-Year, Post-Marketing Surveillance Experience with Tofacitinib in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic, chronic autoimmune disease associated with joint pain and inflammation, potentially resulting in joint destruction. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. Clinical efficacy and safety of tofacitinib have been established in numerous patient populations with active RA in phase 2 [1] and phase 3 [2‐7] randomized controlled trials (RCTs), and long-term extension (LTE) studies [8, 9].

Tofacitinib received first marketing authorization in the United States (US) on November 6, 2012 for the treatment of adults with moderately to severely active RA and an inadequate response/intolerance to methotrexate. As of November 2015 (data-cut for analysis), tofacitinib was approved in 46 countries and marketed in 29 countries. Tofacitinib has since received marketing authorization in the European Union and is currently approved in over 80 countries worldwide. In most countries, the approved tofacitinib dose for RA is 5 mg twice daily (BID); a 10 mg BID dose is approved in Botswana, Switzerland, and Russia. An extended-release formulation, dosed at 11 mg once daily, has been approved in the US for the same indication.

Post-marketing surveillance (PMS) is integral to adverse event (AE) monitoring following regulatory approval of drugs. PMS complements phase 3 and LTE safety data to establish a real-world safety profile. A pooled analysis of tofacitinib-treated patients during phase 1, 2, 3, and LTE studies (to March 2015) found that AEs were generally stable over time, with no new safety risks versus previous reports [10]. PMS includes spontaneous or voluntary reporting of AEs, post-marketing observational studies, or active surveillance.

We aimed to evaluate the safety of tofacitinib in the post-marketing setting using spontaneous/non-interventional solicited PMS reports (i.e., market research where the product was not offered but AE data were collected) and non-study literature cases (i.e., cases not reported in a study but published as a case report) during the 3 years following first marketing authorization.

During the reporting period, the worldwide post-marketing exposure to tofacitinib, based on estimated worldwide sales and a regimen of tofacitinib 5 mg BID, was 34,223 patient-years. Overall, 9291 case reports were received, including 56.3% reported by healthcare professionals; 9206 (99.1%) were spontaneous reports, 77 (0.8%) were from non-interventional solicited sources, and eight (0.1%) were non-study literature cases. Most originated in the US (73.9%). Other countries with large contributions (> 100) included Canada, Argentina, Colombia, Australia, and Switzerland. Of cases with reported gender (92.9%) or age (79.2%), 78.2% occurred in females, and median age was 60 years. Of the cases where information on medical history was available, in addition to RA, the other most commonly reported (> 150 cases per PT) pre-existing medical conditions by PT included drug hypersensitivity, hypertension, drug ineffective, osteoarthritis, gastroesophageal reflux disease, diabetes mellitus, hypersensitivity, fibromyalgia, and hypothyroidism.

Overall, 25,417 AEs were reported through November 5, 2015; 82.9% were non-serious. The MedDRA SOCs with the most reported AEs included general, GI, and musculoskeletal disorders. The most reported AEs by PT (Fig. 1) included drug ineffective (13.2%), headache (9.0%), pain (6.4%), fatigue (6.0%), nausea (6.0%), condition aggravated (5.9%), diarrhea (5.8%), and arthralgia (5.2%).

Overall, 4352 SAEs were reported; RRs for SAEs of special interest by SOC are presented in Table 1. The most reported SAEs by PT (Fig. 2) included RA (4.5%), condition aggravated (3.4%; any condition [RA or other] that worsened), pneumonia (1.7%), and arthropathy (1.2%).

It is estimated that, as of August 2017, 102,214 patients worldwide have received tofacitinib (data on file); it is therefore important that tofacitinib safety is evaluated in patients with real-world experience. This analysis evaluated PMS reports for tofacitinib in RA over a 3-year period after first marketing authorization. AEs were consistent with the safety profile observed during RCTs [1‐8, 10].

AEs were presented by PT, as opposed to SOC; however, some of the PTs relate to loss of efficacy rather than ADRs. For example, ‘drug ineffective’ was the most reported AE. The most recorded SAEs by SOC also related to loss of efficacy of tofacitinib, followed by serious infections; however, the RR of these events decreased over time. A small number of potential OI SAEs included disseminated HZ and tuberculosis, consistent with the incidence of HZ [11], tuberculosis, and other OIs [12] observed across tofacitinib RA RCTs. Baseline tuberculosis screening status was not included in the PMS reports. Two histoplasmosis cases were recorded in the PMS; this was not reported during tofacitinib RA RCTs, but both cases originated in US regions where histoplasmosis is endemic.

Consistent with the tofacitinib label, the most common GI SAEs by PT were diarrhea, nausea, vomiting, and abdominal pain; all known ADRs for tofacitinib. Pancreatitis and GI perforations were reported in PMS and risk of these events is monitored though pharmacovigilance surveillance; however, potential contributory factors include concomitant medications (e.g., methotrexate and prednisone). Although pancreatitis has been reported in RA RCTs and PMS, data do not indicate an increased risk of pancreatitis with tofacitinib.

The types of malignancies reported in PMS were consistent with tofacitinib RA RCTs. The most common neoplasms reported in both settings were NMSCs. Overall neoplasm rates in the tofacitinib RA clinical program and PMS did not increase with increasing tofacitinib exposure [13]. In PMS, 15 lymphoma cases were reported over approximately 34,000 patient-years of exposure as of November 5, 2015. The RR of lymphoma did not increase over time. Risk of lymphoma with tofacitinib continues to be monitored through routine and enhanced pharmacovigilance activities. Consistent with data from tofacitinib RA LTEs, PMS data do not suggest an increased risk of cardiac events with tofacitinib.

Review of reported deaths did not suggest an increased risk of death with tofacitinib; no new safety information was identified versus RCTs. The most reported causes were consistent with those observed during tofacitinib RA RCTs, including infections and cardiovascular events.

The following limitations should be considered. Case reports are often submitted voluntarily; the magnitude of under-reporting is unknown. Importantly, some clinical information is often missing or incompletely recorded. Patients’ age, pre-existing comorbidities, underlying RA, and concomitant medications could not be excluded as contributing to AEs, and due to the limited information on medical history captured in the spontaneous reports, it is not feasible to analyze the reported events by patients’ pre-existing conditions to tease out any confounding effects. The spontaneous reporting system utilized in PMS yields RRs rather than incidence rates, limiting between-drug comparisons.

Furthermore, RRs were calculated at the event level; there may have been correlations for events that occurred within the same patients. The RR may therefore be different at the patient level, and it cannot be adjusted for patient demographic characteristics. Patient exposure in PMS is calculated based on sales data rather than clinical trial data; comparisons between PMS and integrated safety database rates cannot be made. Additionally, it is difficult to make age- and gender-adjusted comparisons with the non-tofacitinib RA population. PMS data for other biologic therapies for RA have been published in patients with RA; however, in contrast to the worldwide tofacitinib data presented here, these reports only present country-specific data [14, 15]. Additional disproportionality analysis (e.g., proportional reporting ratios) or Multi-Item Gamma Poisson Shrinkage would enable between-drug comparisons, although these are beyond the scope of this analysis. Furthermore, reported rates are based on estimated exposure based on commercial records, rather than actual exposure (i.e., exposure time was not censored at time of event). A known phenomenon in drug reporting is the Weber effect, which predicts higher AE RRs within the first 2 years of drug approval, decreasing thereafter, possibly due to reduced reporting of mild AEs. The data analyzed here were recorded within 3 years of marketing authorization; therefore, the Weber effect should be considered when interpreting early estimated RRs. Finally, an accumulation of AE reports may not necessarily indicate causation by the drug, and may relate to underlying diseases, comorbidities, or other factors. Despite these limitations, PMS data are important for characterizing safety profiles of medications in a real-world setting, including possible detection of new safety signals.

Based on this review of PMS data for tofacitinib in RA, the types of AEs and RRs were consistent with the known tofacitinib safety profile, with no new safety risks identified. Risks identified during the tofacitinib development program continue to be monitored through pharmacovigilance surveillance.