Take only as directed: high-dose Xeljanz poses PE risk

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High-dose Xeljanz increases the risk of blood clots in the lungs and death among RA patients

High-dose tofacitinib (Xeljanz) has been found in a trial to increase the risk of blood clots in the lungs and death among rheumatoid arthritis patients, according to manufacturer Pfizer.

But for rheumatologists prescribing the drug as approved, “it’s not going to make a scrap of difference”, says rheumatologist Stephen Hall, who is a professor at Monash University.

Pfizer is writing to doctors to alert them about a post-market study to assess the risk of cardiovascular events in RA patients, in which one treatment arm has received 10mg of tofacitinib twice daily and another 5mg daily, with controls receiving a tumour necrosis factor inhibitor.

All patients were over 50, had at least one existing cardiovascular risk factor and were previously treated with methotrexate.

After an undisclosed number of patients on the higher dose experienced pulmonary emboli, patients in that arm will receive the lower dose for the remainder of the study. The FDA and the TGA are monitoring the safety issue.

The 10mg patients “had a statistically and clinically important difference in the occurrence of pulmonary embolism, compared with patients in this study who were treated with a TNFi. The DSMB also noted an increase in overall mortality in the 10 mg twice daily treatment group compared to the tofacitinib 5 mg twice daily and TNFi treatment arms”, Pfizer says.

Tofacitinib, a non-biologic disease-modifying antirheumatic drug or nbDMARD, is PBS-listed and widely prescribed for RA, in tablet form and usually at 5mg daily. It is due to be PBS-listed for psoriatic arthritis.

A Janus kinase inhibitor, it reduces immune as well as inflammatory processes in rheumatoid arthritis and therefore increases the risk of common infections including URTIs and shingles. It can also raise lipid levels in some patients and cause perforations of the gut, according to Pfizer.

Although tofacitinib is not approved at 10mg twice for treating rheumatoid arthritis, it is approved at that dose as a short-term treatment for moderate to severe ulcerative colitis. The product information notes four cases of pulmonary embolism in a long-term study of UC patients, including one fatality.

In its Drug Safety Communication in February, the US Federal Drug Administration says it “still believes the benefits of taking tofacitinib for its approved uses continue to outweigh the risks”.

Professor Hall told The Medical Republic that Pfizer had studied this high dosage in rheumatoid arthritis, inflammatory bowel disease and psoriasis, and found more infections but no signal of increased risk of thromboembolism. While there was a precedent in ulcerative colitis, the results of the current study needed to be pooled with the others before a meaningful interpretation could be made, he said.

“One study without looking at the others doesn’t make a lot of sense,” Professor Hall said. “I’m sure they’ll be pooling their data on their cross-indication experience and come up with something.

“It may have implications for their launch with IBD but not for rheumatologists.”

“In psoriasis you only get good results on the 10 mg twice daily. In IBD you really need the 10 for the induction until you get it under control, and then you reduce the dose.

“So for the gastroenterologists it may be highly relevant, depending on what they conclude is the magnitude of the issue. But for rheumatologists it’s irrelevant.”


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