Rheumatic Drug Safety Updates 2012: FDA at the ACR Meeting


New label changes about hepatic risks with the gout drug febuxostat (Uloric) and uncertainties about the new oral RA drug tofacitinib (Xeljanz) were on the agenda as the most important new drug issues arising this year, as FDA officials spoke at the American College of Rheumatology meeting.

Tofacitinib (Xeljanz), the newly approved oral JAK inhibitor for rheumatoid arthritis, may be an exciting advance for patients, but doctors should be aware of certain realities, a physician with the FDA’s Center for Drug Evaluation Research (CDER) pointed out at the American College of Rheumatology meeting on Monday.

•    If the 5 mg dose fails to help, the 10 mg dose may not make much difference either.

•    Substantial uncertainty remains as to whether or not it slows progression.

The incremental benefit of the 10 mg dose remain “quite small,” said Larrisa Lapteva MD of CDER, achieving DAS28 scores lower than 2.6 for at most 18% of patients.

The drug, approved for use in patients not adequately helped by other medications, may not be taken concurrently with biological DMARDs or with potent immunosuppressants such as azathioprine or cyclosporine.

What’s more, the “vast majority of patients” had no visible improvement in radiographic evidence of progression at 6 months, Lapteva added. Fewer than 40% had changes in total Sharp scores assessing erosion and joint space narrowing, and when FDA analysis removed a few distant outliers from the results provided by Pfizer, the p values for the progression at both dose levels rose above 0.05.

“It may have an effect on radiographic progression,” Lapteva said, but “uncertainty remains.”

Others at the meeting have questioned the FDA’s radiologic standard for progression, observing that it is far easier to assess arthritic progression on MRI than on ordinary x-rays. FDA is reconsidering its approach to radiographic progression, she added, but “the fact is we may not be able to see changes with the patients we have now,” because fewer RA patients show progression overall than was the case years ago. It’s unclear whether anything other than a “superdrug” would be able to achieve evidence of progression in RA today, Lapteva said.

Safety data do not raise infection or hepatic injury as causes for concern, but FDA is monitoring the evidence for lymphoproliferative disorders of the central nervous system and breast, which occurred in 7 patients on the drug but not in the placebo group. The background risk for these conditions is high in RA in any case, Lapteva said, but there is concern about animal studies in which 3 of 8 monkeys in the high-dose group developed similar conditions.

Another speaker at the meeting drew attention to concern about possibly fatal liver failure among some patients taking the gout drug febuxostat (Uloric), which led to a new label warning earlier this month.  Post-marketing cases are insufficient to establish causality, said Sally M. Seymour MD, deputy director for safety at FDA’s Division of Pulmonary, Allergy, and Rheumatology Products. But liver enzyme elevations more than 3 times above the upper limit of normal have been noted and published, she added.

The label change directs physicians to:

•    Perform a baseline liver test panel (serum alanine aminotransferase or ALT, aspartate aminotransferase, alkaline phosphatase, and total bilirubin) before starting ULORIC.

•    Repeat liver tests prompty for patients who report fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.

•    Interrupt treatment if tests are abnormal (>3 times the upper limit of the reference range in the case of ALT) and discontinue the drug unless and until another cause for the abnormalities is found.

•    Use febuxostat “with caution” for patients with lesser elevations of ALT or bilirubin for whom another cause is probable.

Seymour also alerted rheumatologists to safety warnings about anaphylactic reactions to pegloticase and belimumab. The former is the subject of a black box warning issued last April, and the belimumab label was updated in March in response to reports about delayed hypersensitivity reactions.

Also from ACR2012:

ACR2012 Highlights: Rheumatoid Arthritis Comorbidities and Adverse Events ACR2012 Highlights: Rheumatoid Arthritis Diagnosis and Prognosis ACR2012 Highlights: Rheumatoid Arthritis Treatment“Magic Bullet” Approaching for Systemic JIA: But Which One? FDA Panel on Biosimilars: Analytics Should Trump Clinical Trials JAK Inhibitors Newer Than Tofacitinib (and Better?) Wait in the Wings


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