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21-08-2019 | Tofacitinib | Feature | Article

Tofacitinib black box warning: A cause for concern?

How FDA alert about pulmonary embolism will affect rheumatoid arthritis treatment decisions

In July 2019, the US FDA added a boxed warning to the label for tofacitinib, to alert physicians and patients to an increased risk for pulmonary embolism and death associated with the 10 mg twice daily dose of the Janus kinase (JAK) inhibitor. This higher dose – currently used for the treatment of inflammatory bowel disease – is not approved for rheumatoid arthritis (RA) or psoriatic arthritis (PsA), but is there reason to think the new warning will impact on rheumatology practice?

Speaking to medwireNews, Roy Fleischmann, Clinical Professor of Medicine at the University of Texas Southwestern Medical Center in Dallas, USA, gives his view, offering some reassurance and guidance on addressing the questions this new warning may raise among patients.

Unchanged risk:benefit ratio

“I wouldn’t be worried about using tofacitinib 5 mg twice daily or 11 mg once daily any more so today than I would have been a month ago,” says Fleischmann.

He stresses that rheumatologists must “remember that the change to the label is for the 10 mg dose, which is used for ulcerative colitis,” but that the 5 mg twice daily dose used for RA and PsA has not yet been associated with an increased risk for pulmonary embolism or death.

Moreover, the risk associated with the 10 mg dose is “relatively small,” he says. The boxed warning is based on interim findings from an ongoing tofacitinib safety trial in RA patients, which identified 19 cases of pulmonary embolism during 3884 patient–years of follow-up among patients who received tofacitinib 10 mg twice daily, compared with three cases during 3982 person–years among those who received tumor necrosis factor (TNF) inhibitors. A total of 45 patients treated with the higher dose of tofacitinib and 25 given TNF inhibitors died [1].

The label update prompted by these findings is “reasonable,” believes Fleischmann, given that the study has demonstrated an increase in mortality and pulmonary embolism risk with the higher tofacitinib dose.

He remarks, however, that the rate of pulmonary embolism seen in the safety study so far for patients treated with tofacitinib 10 mg “is what we might actually expect in a rheumatoid arthritis population,” while rates with the other drugs “were perhaps lower than expected.” He stresses that “we only have some answers from the safety study so far,” and “we won’t know the absolute answer until the study is over and we are able to analyze all the data.”

The FDA says that the safety trial is still ongoing, that patients in the 5 mg tofacitinib and TNF inhibitor groups “continue to be followed,” and that the agency “will reassess these safety issues when the trial has completed and final, verified data are available” [1].

In the meantime, it is important to bear in mind that “the risk of dying from heart disease, untreated RA, and the risk of systemic complications is much higher” than the risks associated with tofacitinib, says Fleischmann, noting that “there is not a single medication I can give a patient which I could tell them it is perfectly safe.”

“I can’t tell them methotrexate is perfectly safe; I can’t tell them that aspirin is perfectly safe; I can’t tell them that etanercept is perfectly safe. I couldn’t even tell them that the bottle of water that they are drinking is perfectly safe!

“The question is what is the risk and what is the risk–benefit?”

Fleischmann emphasizes that “the risk–benefit is clearly in favor of the medications that we use for RA,” regardless of the mechanism of action of the drug in question.

He feels that at present, “as far as the rheumatologist is concerned in treating patients with RA,” the change to the label is “not meaningful as it only relates to the 10 mg twice daily dose.”

Talking to patients about tofacitinib safety

Nonetheless, he thinks that the information about tofacitinib safety may be perceived differently by the general population.

“They may just see tofacitinib causes pulmonary embolism” and not consider the doses, and “the rheumatologists may have more work on their hands explaining to the patient that it is the 10 mg twice daily dose that has raised the extra concern, not the 5 mg dose as yet.”

Fleischmann says that if a patient asks “can you tell me that I should have no concern whatsoever with the 5 mg dose?”, he would say “absolutely not,” because cases of venous thromboembolism have occurred among patients treated with all JAK inhibitors, at all doses, as well as with TNF inhibitors.

“With whatever drug you are treating, there is a risk,” he says, pointing to the 48-week results of the SELECT-COMPARE trial, in which adjudicated exposure-adjusted incidence rates of venous thromboembolism were 0.3 per 100 person–years for patients treated with the JAK inhibitor upadacitinib, and 1.1 per 100 person–years for those given the TNF inhibitor adalimumab [2].

“Is the risk raised with these drugs? I still don’t know the answer to that,” remarks Fleischmann.

He notes, however, that there are certain precautions he would take for specific patient groups. For example, “if a patient has a prior history with a VTE [venous thromboembolism] or pulmonary embolism, I might suggest concomitant treatment with an anticoagulant when I start any DMARD to reduce the risk for VTE,” he says.

“It is always best to use caution,” he emphasizes.

Considerations with other JAK inhibitors

One question rheumatologists and patients may have is whether the potentially increased risk for pulmonary embolism and death associated with the higher dose of tofacitinib may extend to other JAK inhibitors.

Fleischmann says that when baricitinib was under consideration for approval in the USA, “the FDA did a lot of quizzing on the mechanisms,” but neither the FDA nor the manufacturer (Eli Lilly and Company, Indianapolis, Indiana, USA) “were able to come up with mechanisms underlying the VTE or pulmonary embolism observed in RA patients treated with baricitinib.”

“We know that when you take a look at all the JAKs, the incidence rate [of VTE] is about 0.5 [per 100 person– years] which is the same as the general population,” he says. However, he notes that “there was an imbalance” in VTE rates in the placebo-controlled portions of baricitinib trials. In addition, one patient in the baricitinib arm of the RA-BEAM trial experienced thrombophlebitis, and one patient in the RA-BUILD trial experienced pulmonary embolism after switching from placebo to baricitinib [reviewed in 3], whereas there were no thromboembolic events among participants undergoing placebo or adalimumab treatment in these trials.

Click here for a guide to the trials evaluating baricitinib in RA patients

For the JAK1-selective inhibitor upadacitinib, which was approved by the US FDA for the treatment of RA in August 2019, Fleischmann says that the label includes a black box warning for thrombosis risk.

Better understanding of the risks

In order to better understand the risk for VTE among patients treated with tofacitinib, “I think that the only way to do it is to finish the study,” says Fleischmann.

He believes that mandatory post-marketing approval studies may provide the best solution, noting that for “every drug that is approved [in Japan], the first 5000 patients have to be analyzed for safety, but it is only for 6 months.”

He thinks that if “every single patient [treated with tofacitinib] is followed for a period of a year or two, then you could really answer the question” of whether the drug raises VTE risk.

“I won’t be surprised if the FDA doesn’t ask [the manufacturers of] filgotinib and upadacitinib to do a similar type of study, going forwards,” he says.

“They may or may not, but I think that is probably what you need to do.”

By Claire Barnard

medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group

  1. FDA Drug Safety Communication: FDA approves Boxed Warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR). Available at: [Accessed 8 August 2019]
  2. Fleischmann RM, Genovese MC, Enejosa JV, et al. Safety and effectiveness of upadacitinib or adalimumab plus methotrexate in patients with rheumatoid arthritis over 48 weeks with switch to alternate therapy in patients with insufficient response. Ann Rheum Dis 2019; doi:10.1136/annrheumdis-2019-215764.
  3. Scott IC, Hider SL, Scott DL. Thromboembolism with Janus Kinase (JAK) Inhibitors for Rheumatoid Arthritis: How Real is the Risk? Drug Saf 2018; 41: 645–653.