Tofacitinib (Xeljanz) 


Indication: Tofacitinib (Xeljanz) is indicated as monotherapy or in combination with other nonbiological disease-modifying antirheumatic drugs (DMARDs) or methotrexate in the treatment of adults with moderate to severe rheumatoid arthritis (RA) who are intolerant of, or have had an inadequate response to, methotrexate therapy.1

Pharmacology: Tofacitinib is an oral Janus kinase (JAK) enzyme inhibitor. JAKs are intracellular enzymes that stimulate hematopoiesis and immune function through signals received from growth factor receptors or cytokines. In response to signals received by cytokines or growth factor receptors, JAKs activate signal transducers and activators of transcription (STATs) that, in turn, regulate intracellular expression and gene activity. Tofacitinib works by inhibiting JAKs by preventing growth-factor or cytokine-mediated immune cell activity or gene expression, ultimately increasing B cells, and reducing the levels of CD16/56+ natural killer cells, C-reactive proteins, and serum; IgG, IgA, and IgM.1  

Clinical Trials: The approval of tofacitinib followed the results of two dose-ranging trials and five confirmatory trials.1 In one of the dose-ranging trials, Kremer and colleagues randomly assigned 507 patients with active RA and an inadequate response to methotrexate to tofacitinib at doses of 1 mg, 3 mg, 5 mg, 10 mg, or 15 mg twice daily, or placebo in combination with methotrexate. The pivotal end point was an improvement in American College of Rheumatology 20% (ACR20) criteria over a 12-week period.  

At week 12, ACR20 response rates for patients receiving all tofacitinib dosages ≥3 mg twice daily (52.9% for 3 mg twice daily, 50.7% for 5 mg twice daily, 58.1% for 10 mg twice daily, 56.0% for 15 mg twice daily, and 53.8% for 20 mg/day) were significantly (P ≤0.05) greater than those for placebo (33.3%). The results also showed sustained improvements at week 24 for the ACR20, ACR50, and ACR70 responses, scores for the Health Assessment Questionnaire disability index (HAQ-DI), the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), and a 3-variable DAS28-CRP of <2.6. 2

Overall treatment-related adverse events were higher in patients taking tofacitinib across all treatment groups (66.7%) compared with patients on placebo. Infections were a common adverse effect noticed in the tofacitinib group, as were dose-dependent abnormal labs when compared with placebo.2

In a 12-month, confirmatory trial, 717 patients who had been receiving stable doses of methotrexate were randomly assigned to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, 40 mg of adalimumab once every 2 weeks, or placebo. At month 3, patients in the placebo group who did not have a 20% reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily; at month 6, all patients still receiving placebo were switched to tofacitinib in a blinded fashion.

Results of this phase-3 study showed that at month 6, ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and among those receiving adalimumab (47.2%) compared with placebo (28.3%) (P<0.001 for all comparisons). Researchers also reported that erythrocyte sedimentation rate (DAS28-4 [ESR]) score of <2.6 at 6 months were higher in the tofacitinib 10-mg twice-daily group (12.6%), compared with adalimumab, tofacitinib 5 mg twice daily, or placebo groups (6.7%, 6.2%, and 1.1%, respectively). There also were greater reductions in HAQ-DI scores among patients in the 5-mg and 10-mg tofacitinib groups (-0.55 and -0.61) compared with the adalimumab or placebo groups (-0.49 and -0.24, respectively). 3

Warnings/Precautions: Neutropenia and anemia have been observed in patients taking tofacitinib. Clinicians should avoid tofacitinib therapy in patients with a baseline absolute neutrophil count (ANC) of <1000 cells/mm3. Should patients present with consistent ANC values of 500-1000 cells/mm3 or an ANC drop <500 cells/mm3, therapy should be withheld until ANC levels have risen >1000 cells/mm3.  Anemia also has been observed with tofacitinib use; therefore, tofacitinib therapy should be avoided in patients with a baseline hemoglobin (Hgb) <9 g/dL. Treatment with tofacitinib should be interrupted in patients who develop an Hgb value < 8g/dL or whose Hgb drops >2 g/dL. Lymphocytopenia has been also observed with tofacitinib use; avoid use in patients with a baseline lymphocyte count of <500 cells/mm3.1

Tofacitinib dose adjustment is required for use in patients with moderate to severe renal impairment as well as with patients with moderate hepatic impairment. Tofacitinib use is contraindicated in patients with severe renal impairment.1

The Food and Drug Administration has issued a Black Box warning due to serious infections and malignancies associated with tofacitinib use. “Patients treated with tofacitinib are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt tofacitinib until the infection is controlled. Reported infections include active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before tofacitinib use and during therapy. Treatment for latent infection should be initiated prior to tofacitinib use. Invasive fungal infections, including cryptococcosis and pneumocystosis, may also occur. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. Bacterial, viral, and other infections due to opportunistic pathogens have been reported in patients with RA. The risks and benefits of treatment with tofacitinib should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tofacitinib, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection before initiating therapy.

Lymphoma and other malignancies have been observed in patients treated with tofacitinib. Epstein-Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with [tofacitinib] and concomitant immunosuppressive medications.”1

Tofacitinib is a pregnancy category C drug. Currently, there are insufficient data on tofacitinib use in pregnant women; therefore, tofacitinib should be used in pregnant women only if benefits outweigh risks. Providers should encourage pregnant mothers taking tofacitinib to register in the Xeljanz Pregnancy Registry by calling 1-877-311-8972.1  

Adverse Reactions: The most common adverse effects associated with tofacitinib are infections (20%), most common of which are upper respiratory tract infections followed by nasopharyngitis and urinary tract infections. While rare, serious infections, including cellulitis, pneumonia, herpes zoster, and tuberculosis, have also been associated with tofacitinib. Also rare but associated with tofacitinib use are malignancies such as breast, lung, colorectal, gastric, prostate, and renal cell cancer as well as malignant melanoma. Tofacitinib use has also been associated with changes in lab panels such as decreased lymphocyte and ANC  as well as increased liver enzymes and dose-dependent elevations in lipids (high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, and triglycerides) and serum creatinine.1 

Drug Interactions: Tofacitinib is major CYP3A4 and minor CYP2C9 substrate. Therefore, concomitant therapy with strong CYP3A4 inducers should be avoided. Similarly, therapy with strong to moderate CYP3A4 inhibitors, or with moderate CYP2C9 inhibitors, also should be avoided; however if concomitant therapy must be required, the tofacitinib dose should be adjusted to 5 mg by mouth once daily. Concomitant therapy with other immunosuppressive drugs can increase immunosuppression in patients; concomitant therapy with strong immunosuppressants such as azathioprine, tacrolimus, and cyclosporine also should be avoided. Additionally, the immunosuppressive properties of tofacitinib may augment the adverse effects of live vaccines, which should not be administered for at least 3 months after tofacitinib therapy. Concomitant tofacitinib use with other biological DMARDs is contraindicated.1

Dosage and Administration: Tofacitinib is dosed at 5 mg by mouth twice daily as monotherapy or combination therapy. When used with strong or moderate CYP3A4 inhibitors or potent CYP2C19 inhibitors, tofacitinib dose should be reduced to 5 mg daily.


  1. Xeljanz [package insert]. New York, NY: Pfizer Inc; 2012.
  2. Kremer JM, Cohen S, Wilkinson BE, et al. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum. 2012;64(4):970-981.
  3. van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367:508-519.

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