June 08, 2019 – For some time now, Tofacitinib (Xeljanz) receives intense attention in the media, with regulatory authorities, and patients and treating physicians alike because of serious concerns of increased risk of blood clots in the lungs and increased mortality in patients treated for ulcerative colitis at the 10-mg twice-daily dose of Tofacitinib (Xeljanz).
Tofacitinib (Xeljanz) is a medication used to treat indications such as rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. The active ingredient Tofacitinib is an inhibitor of the enzyme janus kinase 1 (JAK1) and janus kinase 3 (JAK 3), which means that it interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription. In mouse models of established arthritis, Tofacitinib rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. The efficacy in this disease model correlated with the inhibition of both JAK1 and JAK3 signalling pathways, suggesting that Tofacitinib may exert therapeutic benefit via pathways that are not exclusive to inhibition of JAK3. This may be involved in the problem of blood clotting discused here, since in a number of studies cross talking of JAK-STAT signalling pathways with other pathways, some of them involving coagulation factors such factor VIIa have been shown, although the exact molecular mechanisms are not yet well known.
In any case, in clinical practice, Tofacitinib (Xeljanz) may turn out to be associated with increased risk of blood clots in the lungs and increased mortality. This concerns patients who are treated with Tofacitinib (Xeljanz) in the ulcerative colitis indication who receive the 10-mg twice-daily dose of Tofacitinib (Xeljanz) recommended for this indication. These risks were identified in a FDA-mandated Post-Marketing Study (A3921133) on Tofacitinib (Xeljanz) in patients with rheumatoid arthritis , where the 5-mg twice-daily dose of Tofacitinib (Xeljanz), recommended for this indication, was compared to the higher 10-mg twice-daily dose of Tofacitinib (Xeljanz), which is recommended in the ulcerative colitis indication only.
Based on the findings of this Post-Marketing Study, in February of this year, the FDA issued a Drug Safety Communication saying that health care professionals should strictly follow the recommendations in the Tofacitinib (Xeljanz) prescribing information for the specific condition they are treating and monitor patients for signs and symptoms of pulmonary embolism, and advise them to seek medical attention immediately if they experience them. However, patients should not stop or change their dose of Tofacitinib (Xeljanz) without first talking to their health care professional, as doing so may worsen the condition for which they are in treatment. Patients taking Tofacitinib (Xeljanz) should seek medical attention immediately if they experience symptoms of a blood clot in the lungs or other unusual symptoms such as: i) sudden shortness of breath or difficulty breathing, ii) chest pain or pain in the back, iii) coughing up blood, iv) excessive sweating, or v) lammy or bluish colored skin.
In May 2019, the European Medicines Agency (EMA) was putting temporary restrictions on the use of Tofacitinib (Xeljanz) due to risks of pumonary embolisms. Thus, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) was temporarily advising physicians not to prescribe the 10-mg twice-daily dose of Tofacitinib (Xeljanz) to patients at high risk for pulmonary embolism (PE). These include patients with heart failure, cancer, inherited coagulation disorders, a history of venous thromboembolism, either deep venous thrombosis (DVT) or PE, as well as patients taking combined hormonal contraceptives or hormone replacement therapy or who are scheduled to have major surgery. According to EMA, prescribers should also consider other factors that may increase the risk for PE, such as age, obesity, smoking, or immobilization for any reason.
Also the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA), the Federal Institute for Drugs and Medical Devices (BfArM) in Germany, the Swiss Agency for Therapeutic Products (Swissmedic), l’Agence nationale de sécurité du médicament et des produits de santé (ANSM) in France, and Health Canada have issued safety communications along the same lines of argumentation concerning Tofacitinib (Xeljanz).
In the age of personalised and/or precision medicine, it would of course be of outmost interest to know if the patients affected here are carriers of genetic predispositions for abnormal high tendencies of blood clotting. If so, genetic testing may help to identify those individuals at risk even more precise and reduce the number of patients falling victim to pulmonary embolism (PE) even under the higher dose of Tofacitinib (Xeljanz) discussed here.
See here: Just a patient who suffered a clot in the lung (pulmonary embolism):