FDA issues warning about increased risk of serious cardiovascular events, malignancy, thrombosis, and death with tofacitinib and other JAK inhibitors
The US Food and Drug Administration (FDA) has issued a warning about an increased risk of serious cardiovascular events, malignancy, thrombosis, and death with tofacitinib and two other Janus kinase (JAK) inhibitors (baricitinib and upadacitinib).
This follows final results from a large randomized safety clinical trial comparing tofacitinib with tumor necrosis factor (TNF)-alpha inhibitors in patients with rheumatoid arthritis. The study found an increased risk of blood clots and death with the lower dose of tofacitinib (5 mg twice daily); this serious event had previously been reported only with the higher dose (10 mg twice daily - the induction dose for ulcerative colitis) in the preliminary analysis.
The FDA advises clinicians to:
Reserve tofacitinib, baricitinib, and upadacitinib for patients who have had an inadequate response or are intolerant to one or more TNF-alpha inhibitors
Consider the patient’s individual benefit-risk profile when deciding to prescribe or continue treatment with these medications, particularly in patients who are current or past smokers, patients with other cardiovascular risk factors, those who develop a malignancy, and those with a known malignancy (other than a successfully treated nonmelanoma skin cancer).
Two other JAK inhibitors, ruxolitinib and fedratinib, are not indicated for the treatment of arthritis and other inflammatory conditions and so are not affected by this warning. A similar safety alert was issued by the European Medicines Agency (EMA) for tofacitinib only in June 2021, based on results from the same study. The EMA advice relates to patients aged >65 years, those who are current or past smokers, patients with other cardiovascular risk factors, and patients with other malignancy risk factors. In these patient groups, tofacitinib should only be used to treat moderate or severe ulcerative colitis, if no suitable treatment alternative is available.
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Ulcerative colitis is a type of inflammatory bowel disease characterized by diffuse inflammation of the colonic mucosa and a relapsing, remitting course.
Patients commonly experience bloody diarrhea, chronic diarrhea (or both), lower abdominal pain, fecal urgency, and extraintestinal manifestations, particularly those related to activity of the colitis.
Diagnosis requires endoscopy with biopsy and negative stool culture.
Relapses are often associated with pathogens; therefore, stool should be obtained for culture in all cases of disease flare-up.
Treatment aims to induce and maintain remission. Drug choice and formulation depends on the severity and extent of disease.
Toxic megacolon can occur with associated risk of perforation. Bowel adenocarcinoma is a complication in 3% to 5% of patients.
Ulcerative colitis (UC) is a type of inflammatory bowel disease that characteristically involves the rectum and extends proximally to affect a variable length of the colon. It is recognized as a multifactorial polygenic disease, as the exact etiology is still unknown. Included in the etiologic theories are environmental factors, immune dysfunction, and a likely genetic predisposition.
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Hesam A. Nooredinvand, MBBS, MRCP, BSc (Hons)
Research Fellow in Gastroenterology
St George's Hospital
HAN declares that he has no competing interests.
Andrew Poullis, BSc, MBBS, MD, FRCP
Department of Gastroenterology
St George’s Hospital
AP is an author of a reference cited in this topic.
Dr Hesam A. Nooredinvand, and Dr Andrew Poullis would like to gratefully acknowledge Dr Ben Shandro, Dr Anet Soubieres, Dr Rhys Hewett, Dr Willem J.S. de Villiers, and Dr Houssam Mardini, previous contributors to this topic.
BS, AS, RH, WJSD, and HM declare that they have no competing interests.
Trevor Winter, MD, PhD
Associate Professor of Medicine
Division of Digestive Diseases and Nutrition
University of Kentucky
TW declares that he has no competing interests.
Sharon Stein, MD
Assistant Professor of Surgery
Division of Colon and Rectal Surgery
University Hospital Case Medical Center
SS received a fee for educational courses on laparoscopic surgery, paid for in part by Covidien, Olympus, and Applied Medical.
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