Drug Profile

Baricitinib is a Janus kinase inhibitor and one of the newest members of the disease-modifying antirheumatic drug (DMARD) family. It is a potent suppressor of the immune system and is taken orally.[1]

Baricitinib was approved by the Food and Drug Administration (FDA) in 2018 for the treatment of adults with moderate-to-severe active rheumatoid arthritis who have had an inadequate response to one or more of the injectable biologic DMARDs that block tumor necrosis factor — for example, adalimumab (ABRILADA, AMJEVITA, CYLTEZO, HADLIMA, HULIO, HUMIRA, HYRIMOZ) and etanercept (ENBREL, ERELZI, ETICOVO).[2]

We have designated this drug as Do Not Use because it has unique risks of serious harm — in particular, an increased risk of life-threatening blood clots — without offering any unique advantages over many other available DMARDs.

Baricitinib’s manufacturer, Eli Lilly, originally applied for FDA approval of the drug in January 2016.[3] The company sought approval for two dosages — 2 milligrams (mg) and 4 mg once daily — for treatment of adults with moderate-to-severe active rheumatoid arthritis.

Among the data provided by Eli Lilly in its initial application to the FDA were results from four large randomized clinical trials.[3] Two six-month trials compared baricitinib at a dosage of 2 mg or 4 mg once daily with a placebo once daily. One 12-month trial compared the 4-mg dose of baricitinib with the first-line oral DMARD methotrexate (OTREXUP, RASUVO, TREXALL, XATMEP). A second 12-month trial compared the 4-mg dose of baricitinib with adalimumab and a placebo. Data from the four trials demonstrated that baricitinib at the doses tested was more effective in improving the signs and symptoms of rheumatoid arthritis and physical function compared with a placebo, or with methotrexate and adalimumab. One study also showed that baricitinib slowed the progression of joint damage.[3] Of note, only one of the four trials enrolled patients who previously had an inadequate response to a biologic DMARD that blocks tumor necrosis factor.

These same clinical trials and others demonstrated that baricitinib causes numerous serious adverse effects that are typical of other potent immunosuppressive rheumatoid arthritis drugs, including infections and cancer (see the black-box above from baricitinib’s FDA-approved product labeling).[4]

However, data from the major clinical trials showed that baricitinib, at both the 2-mg and 4-mg doses, increased the risk of dangerous blood clots, including deep venous thrombosis (blood clots forming in large veins, usually in the leg) and pulmonary embolism (blood clots in veins that dislodge, move through the blood and lodge in the lungs).[4] There also were several cases of arterial blood clots in subjects who received baricitinib. No such blood clot events occurred in any subjects who received a placebo. Moreover, FDA reviewers noted that such adverse events had not been seen with any other DMARDs.[3]

The director of the FDA division that reviewed the initial application for approval of baricitinib noted the following in his highly critical assessment of the drug:

“The [blood clot] findings are of particular concern because these events are not predictable, and some were associated with death … There will need to be further safety data generated to understand the thrombosis risk for baricitinib, and it would be reasonable to obtain the data and address this safety risk pre-approval … Given that baricitinib is another member of the DMARD class that has many choices, and baricitinib is not serving an unmet medical need that is above and beyond [biologic] DMARDs and tofacitinib [XELJANZ], it would be reasonable to not approve any of the doses of baricitinib at this time.”[3]

Having concluded that “the overall benefit/risk profile for baricitinib was not favorable” because of the risk of dangerous blood clot events, in April 2017, the FDA rejected Eli Lilly’s application for approval of the drug.[4] Notably, the safety concerns raised by the FDA in its rejection letter could only have been adequately addressed by new clinical trials testing lower dosages of the drug.

In December 2017, Eli Lilly resubmitted an updated application to the FDA for approval of baricitinib. The company again sought approval of the 2-mg and 4-mg once-daily dosages, but narrowed the intended patient population to adults with moderate-to-severe active rheumatoid arthritis who have had an inadequate response to or intolerance of methotrexate.[1]

However, the updated application did not include data from any new clinical trials testing lower dosages of baricitinib. Instead, Eli Lilly provided a series of flawed analyses of data from the previously conducted clinical trials.[4] FDA reviewers identified important deficiencies in each of the new analyses conducted by Eli Lilly.[4] They concluded that the additional data did not substantially alter the evidence on baricitinib’s safety and effectiveness in the original application.

In April 2018, an FDA advisory committee was convened to consider whether baricitinib should be approved. Ten of the 15 committee members concluded that there was not adequate safety data to support approval of the 4-mg dose of baricitinib, whereas six reached the same conclusion for the 2-mg dose.[5] By identical votes of 10 to 5, the committee opposed approval of the 4-mg dose of baricitinib but favored approval of the 2-mg dose. The FDA subsequently approved baricitinib at a dosage of 2 mg daily, but only for treatment of adults with moderate-to-severe active rheumatoid arthritis who have had an inadequate response to one or more of the injectable biologic DMARDs that block tumor necrosis factor.

The drug also may increase the risk of potentially life-threatening gastrointestinal perforations (tears in the stomach or intestines), particularly in patients who have had diverticulitis.[6]

You should avoid starting baricitinib if you are not currently taking it. If you are already taking baricitinib, consult with your doctor about switching to one of the DMARDs that we have designated as Limited Use (see beginning of drug profile).

Regardless of the drug treatment chosen by you and your doctor, you should consider engaging in an exercise program and physical therapy designed within the limits of pain. This will help to strengthen muscles and maintain or improve range of motion in the joints.

In 2023, Annals of the Rheumatic Diseases published an article showing that Janus kinase inhibitor drugs, including baricitinib, were associated with an increased risk of malignancy compared to tumour necrosis factor (TNF) inhibitor drugs. TNF inhibitor drugs are used to suppress inflammation and treat certain autoimmune diseases.[3280]