FDA and EMA warn patients taking high dose of Xeljanz

EMA bans 10mg twice-daily maintenance on ulcerative colitis at high risk of blood clots

FDA removes Xeljanz from first-line ulcerative colitis indication, pushes down to second-line

MFDS and Pfizer Korea in talks for patient-safety-first action to take

The European Medicines Agency (EMA) has decided to limit high dose prescription of a Janus kinase (JAK) inhibitor medicine, Xeljanz (tofacitinib citrate), following a similar move by the U.S.

 

Food and Drug Administration (FDA), and now Korean Ministry of Food and Drug Safety (MFDS) is also expected to make a similar decision in response.

 

On Nov.

 

15 (local time), EMA officially confirmed that the maintenance therapy taking 10mg twice daily should not be used in patients with ulcerative colitis who are at high risk of blood clots unless there is no suitable alternative treatment.

 

Previously, EMA’s safety committee, also known as Pharmacovigilance Risk Assessment Committee (PRAC), issued a statement in last May and warned healthcare providers “must not prescribe” 10mg twice daily dose of Xeljanz to patients with high risk of pulmonary embolism (PE), who take combined hormonal contraceptives, are receiving hormone replacement therapy or undergoing major surgery.

 

While 10mg is higher dose only recommended to patients with ulcerative colitis, PRAC has recommended patients with the condition and are at high risk of blood clots “must not” start with Xeljanz, but to choose another option.

 

EMA then stated it would announce a revised guidance as soon as a review result is out.

 

And on Nov.

 

15, the agency officially confirmed its restriction on the JAK inhibitor.

 

On Nov.

 

15, EMA posted an official statement about Xeljanz on its website

In last July, the U.S.

 

FDA also amended one of Xeljanz’s indications as first-line treatment for patients with ulcerative colitis to second-line treatment of the condition.

 

Negotiating with FDA, Pfizer cited the Xeljanz’s risks on its ‘black-box warning’ and revised indication for ulcerative colitis around the same time.

 

With the FDA’s most stringent warning labeled, Xeljanz can now be prescribed to ulcerative colitis patients who took conventional therapy, but did not have a response with tumor necrosis factor (TNF) inhibitor.

 

In a nutshell, Xeljanz in the U.S.

 

has been removed from first-line treatment for ulcerative colitis and was pushed down to second-line, and also the drug has a formal restriction on prescription for patients at high risk of blood clot in Europe.

 

Initially, Xeljanz was approved as a treatment for rheumatoid arthritis, psoriatic arthritis and ulcerative colitis.

 

The approved dose for rheumatoid arthritis is 5mg twice daily, whereas for ulcerative colitis is 10mg twice daily for the first eight weeks and either maintain 10mg or decrease to 5mg twice daily depending on the treatment reaction.

 

Xeljanz treatment for ulcerative colitis previously required starting dose of 10mg for the first eight weeks.

 

But the interim analysis on post-marketing clinical trial studying Xeljanze in comparison to a TNF blocker, a same class as Humira and Remicade, significantly influenced the U.S.

 

and the European health authorities’ decisions to amend approval and restrict prescription.

 

The analysis apparently found concerning reporting of 19 cases of blood clots in the lung and 45 cases of death from all causes out of 3,884 patient-years of follow-up in patients who received Xeljanz, compared to three cases of blood clots in the lung and 25 cases of death out of 3,982 patient-years in patients who received TNF blockers.

 

On the foreign health authorities’ decisions, MFDS and Pfizer Korea officials noted, “We are paying a close attention on the FDA and EMA’s decision and actions.

 

The ministry and the company are in mutually cooperative talks to take an appropriate action considering the safety of Korean patients.” When EMA issued a temporary restriction on the drug in last May, Pfizer Korea disseminated a letter of safety warning and held seminars for healthcare providers in Korea.

 

But the company has not yet made a decision on the news of the drug being pushed down to second-line treatment or prescription restriction on patients at high risk of blood clots.

 

Meanwhile, Japanese Ministry of Health, Labor and Welfare in last August added venous thromboembolism (VTE) as a ‘serious adverse reaction’ on Xeljanz’s label, and recommended doctors to consider other options when prescribing a treatment to a patient at high risk of cardiovascular events.