Pharmacology Update

Tofacitinib Tablets (Xeljanz®)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved a new drug with a novel mechanism of action for the treatment of rheumatoid arthritis in patients intolerant to or who have had inadequate response to methotrexate. Tofacifinib is an oral Janus kinase (JAK) inhibitor and is marketed by Pfizer as Xeljanz.


Tofacitinib is indicated for the treatment of moderately to severely active rheumatoid arthritis in adult patients who are intolerant of or had inadequate response to methotrexate.1 The drug may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). It should not be used in combination with potent immunosuppressive agents such as azathioprine or cyclosporine.


The recommended dose is 5 mg twice daily.1 It may be taken with or without food. The recommended dose is 5 mg once daily in patients with moderate hepatic or moderate-to-severe renal dysfunction.1

Tofacitinib is available as 5 mg tablets.

Potential Advantages

Tofacitinib is an orally active drug with a novel mechanism of action.

Potential Disadvantages

Tofacitinib carries the same warning/precautions as biologic disease-modifying agents in regards to serious infections, malignancies, lymphoproliferative disorder, and tuberculosis. Adverse events associated with tofacitinib include gastrointestional perforation, lymphocytosis, neutropenia, anemia, increase in liver enzymes, and lipids.1 Tofacitinib’s systemic exposure is increased by coadministration with CYP3A4 inhibitors and decreased by inducers.


Tofacitinib is an inhibitor of the Janus kinase family with higher selectivity for JAK-1 and JAK-3 compared to JAK-2.1,2 Inhibition of this signal-transduction pathway effects multiple cytokines affecting lymphocyte activation, proliferation, and function.2 The safety and efficacy of tofacitinib were mainly evaluated in five confirmatory clinical trials.1,3,4,5 These trials varied from 6 months to 24 months, and subjects had moderate-to-severe active rheumatoid arthritis and inadequate response to at least one DMARD, usually methotrexate. Subjects were randomized to tofacitinib 5 mg or 10 mg twice daily or placebo. One study included adalimumab (40 mg every 2 weeks). These studies allowed placebo nonresponders to be randomized to tofacitinib at 3 months and all placebo subjects at 6 months. The primary endpoint was the proportion of subjects achieving American College of Rheumatology scale (ACR20). This represents a 20% improvement in the number of swollen joints, number of tender joints, patient’s pain and global assessment, self-reported functional status (HAQ-DI), physician global assessment, and CPR level. Other endpoints included a disease activity score (DAS28-4[ESR] < 2.6), HAQ-DI, and radiographic assessment of joint damage (mTSS). In subjects who were inadequate responders to nonbiologic or biologic DMARDs (n = 611), ACR20 at 3 months was achieved in 59% and 65% for tofacitinib 5 mg and 10 mg monotherapy, respectively, compared to 26% for placebo.1,4 For methotrexate inadequate responders (n = 797), the proportion of ACR20 achievers at 3 months was 55%, 67%, and 27%, respectively, when tofacitinib or placebo was added to methotrexate.1,5 Results were similar compared to adalimumab added to methotrexate (n = 717). Percent ACR20 was 51.5% (5 mg), 52.6% (10 mg), 47.2% (adalimumab), and 28.3% for placebo.3,5 For TNF inhibitor inadequate responders, values were 41%, 48%, and 24% when tofacitinib or placebo was added to methotrexate.1,5 Tofacitinib (10 mg) appears to reduce progression of structural damage when used in combination with methotrexate.5,6

Onset of activity is seen as early as 2 weeks and persistence of benefit has been observed for up to 3 years.5 Both DAS28-4(ESR) < 2.6 and HAQ-DI were statistically significant in favor of tofacitinib. Tofacitinib (10 mg) had a greater decrease from baseline in HAQ-DI (P = 0.16).5 Most frequently reported adverse events were upper respiratory tract infection, headache, nasopharyngitis, diarrhea, and nausea. Frequency of serious infections were numerically higher for tofacitinib, 3.4% (5 mg), and 4.0% (10 mg), compared to adalimumab (1.5%).3

Clinical Implications

Tofacitinib offers a new option for patients with moderate-to-severe rheumatoid arthritis. It has a novel mechanism of action, but potential for serious adverse events with unknown long-term implications. The FDA requires that Pfizer conduct a controlled clinical trial to evaluate the long-term safety focusing on cardiovascular adverse events, opportunistic infections, and malignancy.


1. Xeljanz Prescribing Information. New York, NY: Pfizer; November 2012.

2. Flanagan ME, et al. Discovery of CP-690,550: A potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection. J Med Chem 2010;53:8468-8484.

3. van Vollenhoven RF, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012;367:508-519.

4. Fleischmann R, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 2012;367:495-507.

5. Accessed December 7, 2012.

6. Labranche TP, et al. JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production. Arthritis Rheum 2012;64: 3531-3542.