Tofacitinib (Xeljanz): Dangers of blood clots in the lungs and of death

Last Updated on

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 transcriptionIn 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):

Print Friendly, PDF & Email

Tags: , , , , , , , , , , ,
About the Author
Joseph Gut - thasso Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

Your opinion

Comment

No comments yet

thasso: conditions

thasso: newest tweets

thasso: recent comments

thasso post: magazine

View my Flipboard Magazine.

thasso: categories

thasso: archives

thasso: simple chat

You must be a registered user to participate in this chat.

  • Scientists identify gene linked to thinness that may help resist weight gain May 21, 2020
    While others may be dieting and hitting the gym hard to stay in shape, some people stay slim effortlessly no matter what they eat. In a study publishing May 21 in the journal Cell, researchers use a genetic database of more than 47,000 people in Estonia to identify a gene linked to thinness that may […]
  • Tracking the COVID-19 pandemic in Australia using genomics May 21, 2020
    Using genome sequencing to identify genetic mutations in SARS-CoV-2 cases in Victoria, researchers have identified clusters and transmission networks which has helped limit the spread of the virus, painting an important picture of transmission in Victoria.
  • COVID-19 study looks at genetics of healthy people who develop severe illness May 21, 2020
    To help unravel the mysteries of COVID-19, scientists are sequencing the DNA of young, healthy adults and children who develop severe illness despite having no underlying medical problems. The researchers are looking for genetic defects that could put certain individuals at high risk of becoming severely ill from the novel coronavirus.
  • Scientists discover more than 200 genetic factors that cause heart arrhythmia May 21, 2020
    Hundreds of new links have been found between people's DNA and the heart's electrical activity, according to a study of almost 300,000 people led by researchers at Queen Mary University of London and the Broad Institute of MIT and Harvard.
  • Weight loss surgery may alter gene expression in fat tissue May 21, 2020
    Altered gene expression in fat tissue may help explain why individuals who have regained weight after weight loss surgery still experience benefits such as metabolic improvements and a reduced risk of type 2 diabetes. The findings come from a study published in the Journal of Internal Medicine.
  • New studies reveal extent and risks of laughing gas & stimulant abuse among young people May 23, 2020
    In one study, researchers from Turkey reported increasing stimulant use among medical students approaching their final exams, despite the substantial risks to their health. In the second study, researchers from the Netherlands detailed the neurological outcomes associated with recreational use of laughing gas (nitrous oxide), suggesting that, for some individuals, permanent neurological damage can occur.
  • Sleep-wake disturbances can predict recurrent events in stroke survivors May 23, 2020
    The study, conducted in Switzerland, found that having multiple sleep-wake disturbances such as sleep-disordered breathing, extreme long or short sleep duration, insomnia and restless leg syndrome independently and significantly increased the risk of a new cardio-cerebrovascular event in the two years following a stroke.
  • Does MRI have an environmental impact? May 23, 2020
    Researchers from Tokyo Metropolitan University have surveyed the amount of gadolinium found in river water in Tokyo. Gadolinium is contained in contrast agents given to patients undergoing medical magnetic resonance imaging (MRI) scans, and it has been shown in labs to become toxic when exposed to ultraviolet rays. The researchers found significantly elevated levels, particularly […]
  • New native grass species have been discovered on the Iberian Peninsula and Menorca May 22, 2020
    The new species belong to the genus Aira, delicate herbaceous plants, which enjoy their greatest diversity in the Mediterranean Region. One of them, Aira minoricensis is a native species of the siliceous sands of Menorca. The other new species is called Aira hercynica and is widely found in the area of the Iberia Peninsula which […]
  • Combinatorial screening approach opens path to better-quality joint cartilage May 22, 2020
    High-throughput platform identifies complex conditions with biomaterial compositions, and mechanical and chemical stimuli that help stem cells produce more robust cartilage.
Top