EMA imposes formal limit on Xeljanz prescription as regulators continue to review safety concerns

Three months after Pfizer flagged blood clot issues and a higher rate of deaths for rheumatoid arthritis patients taking the 10 mg dose of Xeljanz (tofacitinib) in a post-marketing safety study, the EMA has handed down official restrictions in its use.

The agency’s safety committee — pharmacovigilance risk assessment committee, or PRAC — is still in the process of reviewing the evidence, but it is alarmed enough to ban prescription of the 10 mg twice daily regimen in any patients with a high risk of blood clots in the lungs. Those who have heart failure, cancer, a history or predisposition to blood clots are on the list, as are patients taking hormone-based therapies or preparing/recovering from major surgery.

And regulators made sure to be crystal clear about the implications:

The new advice means that, since 10 mg is the only recommended starting dose for ulcerative colitis, patients with this condition who are at high risk of blood clots must not be started on Xeljanz. Patients at high risk currently taking this dose for any condition must be switched to alternative treatments.

The formal — though temporary — restrictions follow an earlier warning, which directed healthcare professionals to monitor patients for signs and symptoms of blood clots in the lungs. Doctors were also advised to stick to the recommended 5 mg dose when treating rheumatoid arthritis.

In February, Pfizer yanked the 10 mg dose from the ongoing A3921133 study in rheumatoid arthritis, switching patients to the 5 mg dose after documenting “a statistically and clinically important difference in the occurrence of pulmonary embolism” as well as an imbalance in the rate of death. In addition to the 5 mg arm, there was also a control group taking a TNF inhibitor.

The FDA sounded its own alarm days later, launching an investigation and urging patients to seek medical care if they experience a blood clot in the lung, chest pains, or start coughing up blood.

Xeljanz was the original JAK inhibitor to hit the market, racking up blockbuster sales in the seven years it’s been approved by the FDA (the EMA nod came much later in 2017). But safety issues have clouded both the drug and the entire class, as manifested by the FDA’s decision to slap down a higher, 4 mg dose of Eli Lilly’s Olumiant (baricitinib) and allow only the 2 mg dose in the market.

None of that has stopped Pfizer from stepping up its JAK game, though. Just this week, the pharma giant touted a positive slate of Phase III data for its JAK1 inhibitor abrocitinib (PF-​04965842) in atopic dermatitis, looking to get into a heated blockbuster race.

AbbVie’s own JAK1, upadacitinib, is now under regulatory review for rheumatoid arthritis on both sides of the Atlantic. Gilead put its bet on filgotinib, widely tapped as a potential blockbuster in its own right. Both companies are giving themselves high marks on safety, signaling a fierce marketing rivalry to come.

Image Source: Pfizer

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Skyhawk Therapeutics Waltham, MA
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