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tofacitinib (Xeljanz)

presumptive DMARD Indications: - treatment of rheumatoid arthritis - for use in combination with methotrexate for patients who have failed TNF inibitor therapy [3] - monotherapy with tofacitinib is superior to methotrexate monotherapy at the cost of increased adverse effects [6] - treatment of psoriatic arthritis [9] - symptomatic benefit - effect on radiologic progression unclear - treatment of ulcerative colitis (UC) [12] * not 1st line therapy for rheumatoid arthritis (RA) * only available ib drug for RA Contraindications: - use in combination with other biologic agent DMARDs, azathioprine or cyclosporin A [5] Pregnancy category: C [7] Dosage: - 5 mg PO BID [13] - box warning for 10 mg BID dose formerly for ulcerative colitis [14] Storage: - store in orginal container (reason unclear) [4] Monitor: - screening for tuberculosis [7] - CBC, basic metabolic panel, serum AST & serum ALT at baseline & every 3 months [7] - lipid panel at 8 weeks then every 6 months [7] Adverse effects: - headache - upper respiratory tract infection - neutropenia, lymphopenia, anemia - possible increased risk of cancer, including lymphoma [6] - increased risk of infection - tuberculosis - Herpes zoster [6,10,15,17] - risk doubles when used in combination with glucocorticoids [15] - prior Herpes zoster vaccine reduces risk [15] - elevated LDL cholesterol* [1,7] - slight elevations in serum creatinine - gastrointestinal distress: diarrhea - increased serum transaminases [7] - possibly myocardial infarction, stroke [10] - increased risk of serious heart-related events & cancer [16] - increased risk for cancer 4.2% vs 2.9% for TNF-alpha inhibitors [17] - 3-4 fold elevations in serum AST & serum ALT - 10 mg BID dosing in patients with rheumatoid arthritis associated with increased risk for pulmonary embolism/thrombosis & death [13,17] - increased risk of myocardial infarction, stroke, cancer, blood clots, & death. * also elevates HDL cholesterol [6] Box warning: - increased risk of blood clots & of death with 10 mg BID [14] Drug interactions: - shingles vaccine - start tofacitinib 2-3 weeks after shingles vaccine [11] Mechanism of action: - Janus kinase inhibitor - preferential JAK1/JAK3 inhibitor [8] Notes: - cost (2014) ~ $30,000/year [6] Management: - whenever possible bring patients up to date on vaccinations prior to initiating biologic immunosuppressive agent [7]

Interactions

drug interactions drug adverse effects of immunosuppressive agents monitor with immunosuppressive agents

General

Janus kinase inhibitor; JAK inhibitor biologic immunosuppressive agent (biologic agent, biologic immune modulator) disease-modifying antirheumatic agent (DMARD)

Database Correlations

PUBCHEM correlations

References

  1. Fleischmann R et al Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 2012 Aug 9; 367:495 PMID: 22873530 - van Vollenhoven RF et al Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012 Aug 9; 367:508 PMID: 22873531 - Fox DA. Kinase inhibition - A new approach to the treatment of rheumatoid arthritis. N Engl J Med 2012 Aug 9; 367:565 PMID: 22873537
  2. FDA News Release: Nov. 6, 2012 FDA approves Xeljanz for rheumatoid arthritis http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm327152.htm
  3. Burmester GR et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: A randomised phase 3 trial. Lancet 2013 Feb 9; 381:451. PMID: 23294500 - Miossec P. Kinase inhibition in rheumatoid arthritis: A big advance? Lancet 2013 Feb 9; 381:429. PMID: 23294499
  4. Prescriber's Letter 21(6): 2014 Oral Meds to Keep in Original Containers Detail-Document#: 300622 (subscription needed) http://www.prescribersletter.com
  5. Pfizer Drug Warning. May 13, 2014
  6. Lee EB et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 2014 Jun 19; 370:2377 PMID: 24941177
  7. Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015
  8. Coblyn JS Baricitinib Might Expand Options for Patients with Refractory Rheumatoid Arthritis NEJM Journal Watch. April 5, 2016 Massachusetts Medical Society (subscription needed) http://www.jwatch.org
  9. Walsh N. FDA Panel Says Yes to Tofacitinib for PsA. Clear efficacy for symptoms, but radiographic progression benefit remains unclear. MedPage Today, August 03, 2017 https://www.medpagetoday.com/Rheumatology/Arthritis/67064
  10. Gladman D, Rigby W, Azevedo VF et al Tofacitinib for Psoriatic Arthritis in Patients with an Inadequate Response to TNF Inhibitors. N Engl J Med 2017; 377:1525-1536. October 19, 2017 PMID: 29045207 http://www.nejm.org/doi/full/10.1056/NEJMoa1615977
  11. Winthrop KL, Wouters AG, Choy EH et al. The safety and immunogenicity of live zoster vaccination in patients with rheumatoid arthritis before starting tofacitinib: A randomized phase II trial. Arthritis Rheumatol 2017 Oct; 69:1969 PMID: 28845577 - Winthrop KL, Curtis JR, Lindsey S et al Herpes Zoster and Tofacitinib: Clinical Outcomes and the Risk of Concomitant Therapy. Arthritis Rheumatol. 2017 Oct;69(10):1960-1968. PMID: 28845604
  12. Brooks M Tofacitinib (Xeljanz) Gets FDA Nod for Ulcerative Colitis. Medscape - May 30, 2018. https://www.medscape.com/viewarticle/897365 - FDA News Release. May 30, 2018 FDA approves new treatment for moderately to severely active ulcerative colitis. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm609225.htm
  13. FDA Safety Alert. Feb 25, 2018 Xeljanz, Xeljanz XR (tofacitinib): Safety Communication - Safety Trial Finds Increased Risk of Blood Clots in the Lungs and Death with Higher Dose in Rheumatoid Arthritis Patients.
  14. FDA Safety Alert. July 26, 2019 Xeljanz, Xeljanz XR (tofacitinib): Drug Safety Communication - Due to an Increased Risk of Blood Clots and Death with Higher Dose. https://www.fda.gov/safety/medwatch-safety-alerts-human-medical-products/xeljanz-xeljanz-xr-tofacitinib-drug-safety-communication-due-increased-risk-blood-clots-and-death - FDA Safety Communiscation. July 26, 2019 FDA approves Boxed Warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR) https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-boxed-warning-about-increased-risk-blood-clots-and-death-higher-dose-arthritis-and
  15. Curtis JR, Xie F, Yang S et al. Risk for herpes zoster in tofacitinib-treated rheumatoid arthritis patients with and without concomitant methotrexate and glucocorticoids. Arthritis Care Res (Hoboken) 2019 Sep; 71:1249 PMID: 30295428 https://onlinelibrary.wiley.com/doi/abs/10.1002/acr.23769
  16. FDA Safety Watch. Feb 4, 2021 Xeljanz, Xeljanz XR (tofacitinib): Drug Safety Communication - Initial Safety Trial Results Find Increased Risk of Serious Heart-related Problems and Cancer with Arthritis and Ulcerative Colitis Medicine. https://www.fda.gov/safety/medical-product-safety-information/xeljanz-xeljanz-xr-tofacitinib-drug-safety-communication-initial-safety-trial-results-find-increased
  17. Ytterberg SR et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med 2022 Jan 27; 386:316. PMID: 35081280 https://www.nejm.org/doi/10.1056/NEJMoa2109927
  18. HIGHLIGHTS OF PRESCRIBING INFORMATION XELJANZ (tofacitinib) tablets, for oral use. http://labeling.pfizer.com/ShowLabeling.aspx?id=959 https://labeling.pfizer.com/ShowLabeling.aspx?id=959#BOX