Xeljanz (tofacitinib) - 5 indications

Scroll down for more information on each indication:

• for the treatment of moderately to severely active rheumatoid arthritis; approved November 2012
• for active psoriatic arthritis; approved December 2017
• for moderate to severe ulcerative colitis; approved May 2019
• for polyarticular course juvenile idiopathic arthritis; approved September 2020
• for adults with active ankylosing spondylitis; approved December 2021

General Information

Xeljanz (tofacitinib) is a selective, potent inhibitor of the JAK family of enzymes. Inhibiting these enzymes affects the signaling of multiple cytokines that are involved in a broad spectrum of inflammatory and autoimmune diseases.

Xeljanz is specifically indicated for the following indications:

• adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs
• adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drug
• adult patients with moderately to severely active ulcerative colitis who have an inadequate response or who are intolerant to TNF blockers
• children and adolescents 2 years and older with active polyarticular course juvenile idiopathic arthritis
• adults with active ankylosing spondylitis who have had an inadequate response or intolerance to one or more tumor necrosis factor (TNF) blockers

Xeljanz is supplied as a tablet, extended-release tablet or solution for oral administration. Scroll down for recommended dosing/administration for each indication.

Mechanism of Action

Xeljanz (tofacitinib) is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs.

Side Effects

Adverse effects associated with the use of Xeljanz monotherapy or in combination with DMARDs for Rheumatoid, Psoriatic Arthritis and Polyarticular Course Juvenile Idiopathic Arthritis may include, but are not limited to, the following:

• upper respiratory tract infection
• nasopharyngitis
• diarrhea
• headache

Adverse effects associated with the use of Xeljanz for ulcerative colitis may include, but are not limited to, the following:

• nasopharyngitis
• elevated cholesterol levels
• headache
• upper respiratory tract infection
• increased blood creatine phosphokinase
• rash
• diarrhea
• herpes zoster 

The Xeljanz drug label comes with the following Black Box Warning:  Serious infections leading to hospitalization or death, including tuberculosis and bacterial, invasive fungal, viral, and other opportunistic infections, have occurred. If a serious infection develops, interrupt Xeljanz/Xeljanz XR/Xeljanz Oral Solution until the infection is controlled. Prior to starting Xeljanz/Xeljanz XR/Xeljanz Oral Solution, perform a test for latent tuberculosis; if it is positive, start treatment for tuberculosis prior to starting Xeljanz/Xeljanz XR/Xeljanz Oral Solution. Monitor all patients for active tuberculosis during treatment, even if the initial latent tuberculosis test is negative. Thrombosis, including pulmonary embolism, deep venous thrombosis and arterial thrombosis have occurred in patients treated with Xeljanz and other Janus kinase inhibitors. Rheumatoid arthritis patients with at least one cardiovascular (CV) risk factor had a higher rate of all-cause mortality and thrombosis with Xeljanz 10 mg twice daily vs. 5 mg twice daily or TNF blockers. Lymphoma and other malignancies have been observed in patients treated with Xeljanz, including an increased rate of Epstein Barr Virus-associated post-transplant lymphoproliferative disorder.

Indication 1 - for the treatment of moderately to severely active rheumatoid arthritis

approved November 2012

Dosing/Administration

Xeljanz 5 mg twice daily or Xeljanz XR 11 mg once daily. Recommended dosage in patients with moderate and severe renal impairment or moderate hepatic impairment is Xeljanz 5 mg once daily

Clinical Trial Results

The FDA approval of Xeljanz for rheumatoid arthritis was based on two dose-ranging trials and five confirmatory trials.
Overview of Results
In all trials, patients treated with either 5 or 10 mg twice daily Xeljanz had higher ACR20, ACR50, and ACR70 response rates versus placebo, with or without background DMARD treatment, at Month 3 and Month 6. Higher ACR20 response rates were observed within 2 weeks compared to placebo. In the 12-month trials, ACR response rates in Xeljanz-treated patients were consistent at 6 and 12 months. In Study IV, a greater proportion of patients treated with Xeljanz 5 mg or 10 mg twice daily plus MTX achieved a low level of disease activity as measured by a DAS28-4(ESR) less than 2.6 at 6 months compared to those treated with MTX alone. Patients receiving XELJANZ 5 and 10 mg twice daily demonstrated greater improvement from baseline in physical functioning compared to placebo at Month 3. The mean difference from placebo in HAQ-DI improvement from baseline at Month 3 in Study III was -0.22 (-0.35, -0.10) in patients receiving 5 mg Xeljanz twice daily and -0.32 (-0.44, -0.19) in patients receiving 10 mg Xeljanz twice daily. Similar results were obtained in Studies I, II, IV and V. In the 12-month trials, HAQ-DI results in Xeljanz-treated patients were consistent at 6 and 12 months.

Indication 2 - for active psoriatic arthritis

approved December 2017

Dosing/Administration

Xeljanz 5 mg twice daily or Xeljanz XR 11 mg once daily. Recommended dosage in patients with moderate and severe renal impairment or moderate hepatic impairment is Xeljanz 5 mg once daily.

Clinical Trial Results

The FDA approval of Xeljanz for the treatment of adult patients with active PsA was based on data from the Phase 3 Oral Psoriatic Arthritis Trial (OPAL) clinical development program, which consisted of two pivotal studies, OPAL Broaden and OPAL Beyond, as well as available data from an ongoing long-term extension trial, OPAL Balance. Both pivotal studies met their two primary efficacy endpoints, demonstrating statistically significant improvements in American College of Rheumatology 20 (ACR20) response and change from baseline in the Health Assessment Questionnaire–Disability Index (HAQ-DI) score at three months in patients receiving Xeljanz 5 mg BID treatment in combination with a nonbiologic DMARD, compared to those treated with placebo. In OPAL Broaden, 50% of patients taking Xeljanz 5 mg BID achieved an ACR20 response, compared to 33% of patients taking placebo at three months. In OPAL Beyond, 50% of patients achieved an ACR20 response with Xeljanz 5 mg BID, compared to 24% of patients taking placebo at three months. In both studies, statistically significant improvements in ACR20 response was also seen with Xeljanz 5 mg BID compared to placebo at week 2, a secondary endpoint and the first post-baseline assessment (OPAL Broaden: 22% and 6%, respectively; OPAL Beyond: 27% and 13%, respectively).

Indication 3 - for moderate to severe ulcerative colitis

approved May 2019

Dosing/Administration

Induction:

• Xeljanz 10 mg twice daily or Xeljanz  XR 22 mg once daily for 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed, continue Xeljanz  10 mg twice daily or Xeljanz XR 22 mg once daily for a maximum of 16 weeks. Discontinue Xeljanz  10 mg twice daily or Xeljanz  XR 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved. (

Maintenance:

• Xeljanz  5 mg twice daily or Xeljanz  XR 11 mg once daily. For patients with loss of response during maintenance treatment, Xeljanz  10 mg twice daily or Xeljanz  XR 22 mg once daily may be considered and limited to the shortest duration, with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dose needed to maintain response.

Clinical Trial Results

This approval was based on data from three pivotal Phase 3 studies from the Oral Clinical Trials for tofAcitinib in ulceratiVE colitis global clinical development program (OCTAVE Induction 1, OCTAVE Induction 2 and OCTAVE Sustain), and OCTAVE Open, an ongoing open label long-term extension study. Data from all three pivotal Phase 3 studies met their respective primary endpoints, showing a statistically significant, greater proportion of patients in remission at week 8 in the induction studies and in remission at week 52 in the maintenance study in patients with moderately to severely active UC treated with tofacitinib compared to placebo. Remission was defined as a Mayo score of 2 points or lower, with no individual subscore exceeding 1 point, and a rectal bleeding subscore of 0.

Indication 4 - for polyarticular course juvenile idiopathic arthritis

approved September 2020

Dosing/Administration

Xeljanz/Xeljanz Oral Solution 5 mg twice daily or weight-based equivalent twice daily.

Clinical Trial Results

FDA approval for children and adolescents 2 years and older with active polyarticular course juvenile idiopathic arthritis was based on data from a Phase 3 study including two phases: an 18-week open-label, run-in phase (including 225 patients), followed by a 26-week double-blind, placebo-controlled, randomized, withdrawal phase (including 173 patients) for a total duration of 44 weeks. The study evaluated the efficacy and safety of tofacitinib taken as either a 5 mg tablet or as a 1 mg/mL oral solution twice daily based on the subject’s body weight (<40 kg for the oral solution) and/or patient preference. The trial met its primary endpoint showing that in patients with pcJIA who achieved a juvenile idiopathic arthritis (JIA) American College of Rheumatology (ACR) 30 response at the end of the run-in phase, the occurrence of disease flare in patients treated with tofacitinib (31 percent; n/N=27/88) was statistically significantly lower than patients treated with placebo (55 percent; n/N=47/85) at week 44. In this study, disease flare was defined as a 30 percent or more worsening in at least three of the six variables of the JIA ACR core set, with no more than one of the remaining JIA core response variables improving by 30 percent or more (outcome measures used in JIA clinical trials) after randomization.

Indication 5 - adults with active ankylosing spondylitis who have had an inadequate response or intolerance to one or more tumor necrosis factor (TNF) blockers

Approved December of 2021

Dosing/Administration

Xeljanz 5 mg twice daily or Xeljanz XR 11 mg once daily. Recommended dosage in patients with moderate and severe renal impairment or moderate hepatic impairment is Xeljanz 5 mg once daily.

Clinical Trial Results

The approval of Xeljanz for AS was based on data from a Phase 3, multicenter, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of tofacitinib 5 mg twice daily versus placebo in 269 adult patients living with active AS. The study met its primary endpoint showing that at week 16, the percentage of patients achieving an Assessment in SpondyloArthritis international Society (ASAS)20 response was significantly greater with tofacitinib (56.4%, n= 75) versus placebo (29.4%, n=40) (p<0.0001). In addition, the percentage of patients achieving an ASAS40 response was significantly greater with tofacitinib (40.6%, n=54) versus placebo (12.5%, n=17) (p<0.0001), a key secondary endpoint of the study.