FDA Adds Warning for Higher Dose of Tofacitinib; Researchers Report on Another JAK Inhibitor

The FDA Friday issued a black box warning for the 10-mg, twice-daily dose of tofacitinib, sold under the names Xeljanz or Xeljanz XR; the drug is an oral, small-molecule Janus kinase (JAK) inhibitor. In addition, this week researchers released phase 3 study results of an investigational JAK inhibitor, filgotinib; the drug showed a clinical response, but the researchers said additional work is needed to assess long-term efficacy and safety.

The FDA Friday issued a black box warning for the 10-mg, twice-daily dose of tofacitinib, which is used in patients with ulcerative colitis (UC). Sold under the names Xeljanz or Xeljanz XR by Pfizer, the drug is an oral, small-molecule Janus kinase (JAK) inhibitor.

The warning comes a few months after the FDA said a clinical trial in patients with rheumatoid arthritis (RA) taking an as-yet unapproved 10-mg dose of tofacitinib twice each day found an increased risk of blood clots and death.

In addition, this week researchers released phase 3 study results of an investigational JAK inhibitor, filgotinib, for active RA. Although the drug showed a clinical response in a randomized clinical trial of 448 patients, the researchers, noting safety concerns about this class of drugs overall, said additional research is needed to assess long-term efficacy and safety.

The 10-mg twice-daily dose of tofacitinib is not approved for RA or psoriatic arthritis (PsA). This dose is only approved for UC for initial treatment and for long-term use in limited situations. The increased risks of blood clots and of death seen in RA may also apply to those taking tofacitinib for UC, the FDA said. Therefore, the approved use of tofacitinib for UC will be limited to certain patients who are not treated effectively or who experience severe side effects with certain other medicines, the FDA said.

Tofacitinib, an oral, small-molecule Janus kinase (JAK) inhibitor, was first approved in 2012 to treat adult patients with RA who did not respond well to methotrexate. In 2017, it was cleared for patients with PsA who did not respond well to methotrexate or other similar medicines, and it was approved for UC in 2018.

JAK inhibitors as a class have recently come under closer scrutiny.

Tofacitinib has been widely expected to compete with innovator anti—tumor necrosis factor (TNF) therapies and their emerging biosimilars. Studies have demonstrated that the JAK inhibitor could result in a lower cost to treat RA than cycling anti-TNF drugs in the case of nonresponse, and for many patients, an oral therapy is preferable to either infusion of products like infliximab and its biosimilars or self-administration of injectable biologics like adalimumab (Humira) or etanercept (Enbrel). Additionally, in cases in which ensuring a cold chain for the storage of biologics is difficult, oral small-molecule drugs may be advantageous.

In 2017, the FDA’s Adverse Events Reporting System revealed 18 primary cases of pulmonary embolism in patients taking tofacitinib. And in April 2018, the FDA’s Arthritis Advisory Committee voted to recommend a low dose of Eli Lilly’s JAK inhibitor, baricitinib, but voted against recommending approval of a higher dose given concerns about the potential for dose-dependent adverse events such as thrombosis. The drug was later approved by the FDA at the lower dose, under the name Olumiant, with a black box warning that includes a caution related to deep venous thrombosis, pulmonary embolism, and arterial thrombosis, among other warnings.

Those worries were referenced in the study released this week about filgotinib, published in JAMA.1

At week 12, more patients receiving filgotinib, 200 mg (66.0%) or 100 mg (57.5%), achieved American College of Rheumatology 20% response (placebo, 31.1%; difference vs placebo: 34.9% [95% CI, 23.5%-46.3%] and 26.4% [95% CI, 15.0%-37.9%], respectively; both P&thinsp;<&thinsp;.001), including among patients with prior exposure to 3 or more biologics (70.3%, 58.8%, and 17.6%, respectively; difference vs placebo: 52.6% [95% CI, 30.3%-75.0%] for 200 mg filgotinib and 41.2% [95% CI, 17.3%-65.0%] for 100 mg filgotinib; both P&thinsp;<.001).

The most common adverse events (AEs) were nasopharyngitis (10.2%) for filgotinib, 200 mg; headache, nasopharyngitis, and upper respiratory infection (5.9% each) for filgotinib, 100 mg; and RA (6.1%) for placebo. Four uncomplicated herpes zoster cases and 1 retinal vein occlusion were reported with filgotinib. There were no opportunistic infections, active tuberculosis, malignancies, gastrointestinal perforations, or deaths.

Two major cardiovascular serious AEs (as judged by an independent cardiovascular event adjudication committee) were reported: A mild myocardial ischemia in a 61-year-old man in the filgotinib, 100 mg, group and a moderate subarachnoid hemorrhage in a 53-year-old woman in the placebo group.

The authors said the study was not powered to make statistical comparisons of AEs among the randomized groups, which limits interpretations. There was little difference in the proportion of AEs between treatment groups, and most were mild or moderate; few patients in any group discontinued the study due to an AE.

An accompanying editorial noted that while different theories have emerged, it isn’t yet understood whether and how the inhibition of JAK subtypes may lead to different risks for this class of drugs, and that linking JAK subtype inhibition with specific AEs is difficult.2

The editorial also said these drugs will need to be priced at levels comparable with conventional synthetic disease modifying agents, rather than biologics. Head-to-head comparison of filgotinib with other JAK inhibitors, biologics, and triple conventional disease-modifying therapy will set the most appropriate use of filgotinib for patients with RA by examining the comparative efficacy and safety, the author said.


1. Genovese MC, Kalunian K, Gottenberg JE, et al. Severe rheumatoid arthritis refractory to disease-modifying antirheumatic drug therapy: the FINCH 2 randomized clinical trial. JAMA. 2019;322(4):315-325. doi:10.1001/jama.2019.9055

2. Singh J. Filgotinib, a JAK1 inhibitor, for treatment-resistant rheumatoid arthritis. JAMA. 2019;322(4):309-311. doi:10.1001/jama.2019.9056