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Xeljanz

The FDA has recently notified the public that some patients with rheumatoid arthritis taking Xeljanz at an unapproved dose in a post-marketing clinical trial were at higher risk of blood clots in the lungs, and death.

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Did you experience complications after taking Xeljanz?

What Is Xeljanz?

Xeljanz and Xeljanz XR, also known as tofacitinib, are drugs indicated for the treatment of adults with moderate to severe rheumatoid arthritis (RA), active psoriatic arthritis (PA), and moderate to severely active ulcerative colitis (UC). Manufactured by Pfizer, Xeljanz was approved by the FDA in 2012 and Xeljanz XR was approved in 2016. Xeljanz is a member of a class of drugs called Janus kinase (JAK) inhibitors.

JAK inhibitors can suppress certain immune responses by blocking JAK pathways, which serve as a messaging system in the immune system. (1) JAK inhibitors are part of the family of medicines called DMARDs (disease-modifying antirheumatic drugs).

All DMARDs attempt to counteract the immune system in patients with autoimmune diseases, in which the body’s immune system is attacking and damaging healthy tissue. Examples of autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, and vasculitis, among many others. (2) (3)

Because they dampen the immune system, JAK inhibitors also leave the body susceptible to infectious disease. For this reason, the label recommends monitoring Xeljanz patients for tuberculosis and other infections during treatment.

The most common serious infections reported with use of Xeljanz are pneumonia, cellulitis, herpes zoster, urinary tract infections, diverticulitis, and appendicitis. In addition, serious opportunistic infections such as tuberculosis have also been reported. (4) (5)

Limitations of Use

Xeljanz and Xeljanz XR are not intended for use with biologic DMARDs or certain strong immunosuppressants. These drugs and biologics include: (6)

  • Tocilizumab: Actemra®.
  • Etanercept: Enbrel®.
  • Adalimumab: Humira®.
  • Infliximab: Remicade®.
  • Rituximab: Rituxan®.
  • Abatacept: Orencia®.
  • Anakinra: Kineret®.
  • Certolizumab: Cimzia®.
  • Golimumab: Simponi®.
  • Ustekinumab: Stelara®.
  • Secukinumab: Cosentyx®.
  • Vedolizumab: Entyvio®.
  • Azathioprine.
  • Cyclosporine.

Live vaccines should also be avoided while on Xeljanz or Xeljanz XR. (7) Consult your doctor before stopping any prescribed medication.

Serious Side Effects

Xeljanz and Xeljanz XR can cause serious and potentially lethal side effects. As an immunosuppressant, Xeljanz can increase the risk of developing a serious infection or worsening/reactivating a serious infection the patient already has. These infections include: (8) (9)

  • Tuberculosis (TB).
  • Hepatitis B or C.
  • Shingles (herpes zoster).
  • Invasive fungal infections (such as cryptococcosis and pneumocystosis).
  • Other bacterial, fungal, and viral infections.
  • Other opportunistic pathogens.

Xeljanz has other serious known side effects, including:

  • Perforations of the stomach or intestines.
  • Lymphoma and other cancers.
  • Liver enzyme elevations.
  • Non-melanoma skin cancers.

Because of the risk of some of these side effects, the label recommends monitoring of patients taking Xeljanz. Monitoring includes bloodwork to check for changes in lymphocyte, neutrophil, and red blood cell counts, as well as routine liver and cholesterol tests. (10)

In addition to the known side effects listed on the label, the FDA recently released a safety announcement about increased risk of pulmonary embolism (PE) and death in rheumatoid arthritis (RA) patients in a postmarketing clinical trial taking 10 mg twice daily doses of Xeljanz. This dose is only approved in the dosing regimen for patients with ulcerative colitis. The studies have been allowed to continue. (11) A different JAK inhibitor, Olumiant®, approved by the FDA in 2018, has a black box warning of PE and other serious and at times fatal blood clots. (12)

Symptoms of PE to Look Out For

A pulmonary embolism (PE) is a blood clot in the lungs. PEs are incredibly dangerous and can be fatal. Signs of PE to be on watch for include:

  • Sudden trouble breathing.
  • Shortness of breath.
  • Chest or back pain.
  • Coughing up blood.
  • Severe sweating.
  • Skin that is clammy or bluish-colored.
  • Rapid or irregular heartbeat.
  • Lightheadedness or dizziness.

PEs can be life-threatening and symptoms can come on suddenly. Seek immediate medical attention if you experience symptoms of a PE. Many PEs may also occur with no symptoms. (13) (14) (15)

Symptoms of DVT to Look Out For

PEs are often preceded by a deep vein thrombosis (DVT). A DVT is a blood clot that occurs deep in the veins, usually of the legs. If a DVT migrates to the lungs, it can become a PE.

There is not currently known data showing an increased risk of DVT when taking Xeljanz. However, because a DVT so commonly occurs before a PE, it is important to know the signs of a DVT, which may include:

  • Swelling in the affected leg.
  • Pain in your leg (feeling like a cramp).
  • Red or discolored skin on the leg.
  • Warmth in the area affected.

Seek immediate medical attention if you experience these symptoms. Like PE, a DVT may also happen without symptoms. (16)

Treatment

Patients with DVTs are typically given a blood thinner, also known as an anticoagulant. Anticoagulants do not break up the clot, but they do stop the clot from getting bigger and prevent new clots from being formed. (17)

In the hospital, patients are typically first given the anticoagulant heparin. Afterwards they may be prescribed an anticoagulant such as warfarin (Coumadin), apixaban (Eliquis), or dabigatran (Pradaxa). Patients on warfarin require regular blood tests to make sure they have the right level of anticoagulation. (18)

Anticoagulation is a balancing act. Too little anticoagulation means there is still risk of the clot growing or new clots forming. Too much anticoagulation can result in dangerous, life-threatening bleeds. This is true of both warfarin and the newer anticoagulants.

The body usually dissolves the clot on its own over time, although the clot may damage the vein. If a clot is very large or life-threatening, a patient may be given a thrombolytic agent, also known as a “clot-buster,” to break up the clot. Thrombolytic agents are administered at a hospital. (19)

Lawsuit Allegations

Lawsuits may soon be filed against Xeljanz and Xeljanz XR’s manufacturer, Pfizer, on behalf of patients who experienced a DVT/PE, or a death from a DVT/PE, after taking Xeljanz or Xeljanz XR.

As DVTs typically precede PEs, any potential lawsuits will likely allege a higher risk of both DVT and PE, as well as a higher risk of death.

The Xeljanz label does not currently warn of a higher risk of DVT or PE. However, on February 25, 2019, the FDA released a safety announcement alerting the public of the postmarketing clinical trial data indicating increased risks of blood clots in the lungs and death in patients with rheumatoid arthritis who were taking 10 mg twice daily doses of Xeljanz. The FDA has not approved this 10 mg twice daily dose for rheumatoid arthritis. The FDA announced an ongoing evaluation of safety information. (20) The European Medicines Agency (EMA) announced a safety review of Xeljanz shortly afterwards, as well. (21)

Recent Studies

An analysis of an ongoing postmarketing study of Xeljanz recently found that rheumatoid arthritis patients taking the 10 mg twice daily dose of Xeljanz “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 [tumor necrosis factor inhibitor]” as well as “an increase in overall mortality … compared to the tofacitinib 5 mg twice daily and TNFi treatment arms.” (22)

On February 19, 2019, Pfizer announced it would modify the postmarketing study by transitioning the rheumatoid arthritis patients taking the 10 mg twice daily dose to the 5 mg twice daily dose due to these safety concerns. (23)

The postmarketing study is designed to examine the risks of cardiovascular events in rheumatoid arthritis patients over 50 years old, with at least one cardiovascular risk factor. The recommended dose of Xeljanz for rheumatoid arthritis patients without moderate or severe renal impairment, or moderate hepatic impairment, is 5 mg twice daily. The 10 mg twice daily dose is currently approved for patients with ulcerative colitis who do not have moderate or severe renal impairment, or moderate hepatic impairment. (24) Ulcerative colitis patients were not part of this postmarketing study.

  1. Prescribing Information. (2018, October). XELJANZ® (tofacitinib) tablets, for oral use. XELJANZ®XR (tofacitinib) extended-release tablets, for oral use. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/203214s020,208246s006lbl.pdf
  2. UpToDate. (2019, February 28). Patient education: Disease-modifying antirheumatic drugs (DMARDs) (Beyond the Basics). Retrieved from https://www.uptodate.com/contents/disease-modifying-antirheumatic-drugs-dmards-beyond-the-basics
  3. WebMD. (2018, August 14). What Are Autoimmune Disorders? Retrieved from https://www.webmd.com/a-to-z-guides/autoimmune-diseases
  4. UpToDate. (2019, February 28). Patient education: Disease-modifying antirheumatic drugs (DMARDs) (Beyond the Basics). Retrieved from https://www.uptodate.com/contents/disease-modifying-antirheumatic-drugs-dmards-beyond-the-basics
  5. Prescribing Information. (2018, October). XELJANZ® (tofacitinib) tablets, for oral use. XELJANZ®XR (tofacitinib) extended-release tablets, for oral use. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/203214s020,208246s006lbl.pdf
  6. Ibid.
  7. Ibid.
  8. Ibid.
  9. Pfizer. (2019, February 19). Pfizer Announces Modification to Ongoing Tofacitinib FDA Post-Marketing Requirement Study in Patients with Rheumatoid Arthritis. Retrieved from https://investors.pfizer.com/investor-news/press-release-details/2019/Pfizer-Announces-Modification-to-Ongoing-Tofacitnib-FDA-Post-Marketing-Requirement-Study-in-Patients-with-Rheumatoid-Arthritis/default.aspx
  10. Prescribing Information. (2018, October). XELJANZ®(tofacitinib) tablets, for oral use XELJANZ®XR (tofacitinib) extended-release tablets, for oral use. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/203214s020,208246s006lbl.pdf
  11. Helfand, C. (2019, February 26). FDA issues red alert on Pfizer's Xeljanz after trial tags higher dose with blood clots, death. Retrieved from https://www.fiercepharma.com/pharma/fda-alerts-public-to-dosing-risks-for-pfizer-s-xeljanz
  12. Prescribing Information. (2018, May). OLUMIANT (baricitinib) tablets, for oral use. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/207924s000lbl.pdf
  13. U.S. Food & Drug Administration. (2019, February 25). Safety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate. Retrieved from https://www.fda.gov/Drugs/DrugSafety/ucm631871.htm
  14. Mayo Clinic. (2018, March 7). Pulmonary embolism. Retrieved from https://www.mayoclinic.org/diseases-conditions/pulmonary-embolism/symptoms-causes/syc-20354647
  15. MedlinePlus. (2018, 10 August). Pulmonary Embolism. Retrieved from https://medlineplus.gov/pulmonaryembolism.html
  16. Mayo Clinic. (2018, March 6). Deep vein thrombosis (DVT). Retrieved from https://www.mayoclinic.org/diseases-conditions/deep-vein-thrombosis/symptoms-causes/syc-20352557
  17. WedMD. (2017, August 17). Treatment for Deep Vein Thrombosis (DVT). Retrieved from https://www.webmd.com/dvt/deep-vein-thrombosis-treatment-dvt
  18. Ibid.
  19. WedMD. (2018, December 22). What's the Treatment for a Pulmonary Embolism? Retrieved from https://www.webmd.com/lung/treatment-for-a-pulmonary-embolism
  20. U.S. Food & Drug Administration. (2019, February 25). Safety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate. Retrieved from https://www.fda.gov/Drugs/DrugSafety/ucm631871.htm
  21. Liu, A. (2019, March 1). EMA follows FDA in putting Pfizer’s Xeljanz under the microscope for safety concerns. Retrieved from https://www.fiercepharma.com/pharma/ema-follows-fda-s-suit-to-reassess-pfizer-s-xeljanz-over-safety-concerns
  22. Pfizer. (2019, February 19). Pfizer Announces Modification to Ongoing Tofacitinib FDA Post-Marketing Requirement Study in Patients with Rheumatoid Arthritis. Retrieved from https://investors.pfizer.com/investor-news/press-release-details/2019/Pfizer-Announces-Modification-to-Ongoing-Tofacitnib-FDA-Post-Marketing-Requirement-Study-in-Patients-with-Rheumatoid-Arthritis/default.aspx
  23. Ibid.
  24. Sagonowsky, E. (2019, February 20). Pharma. Pfizer switches RA patients to lower dose of fast-growing Xeljanz as safety issues arise in postmarketing study. Retrieved from https://www.fiercepharma.com/pharma/postmarketing-study-pfizer-switches-ra-patients-to-lower-xeljanz-dose-safety-concerns