Xeljanz (Tofacitinib)
Approved Indications & Off-Label Uses
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Rheumatoid arthritis (RA) | Adults with moderately to severely active RA, inadequate response/intolerance to ≥1 TNF blocker | Monotherapy or with MTX/non-biologic DMARDs | FDA Approved |
| Psoriatic arthritis (PsA) | Adults and pediatric ≥2 yr with active PsA, inadequate response/intolerance to ≥1 TNF blocker | With non-biologic DMARDs | FDA Approved |
| Ankylosing spondylitis (AS) | Adults with active AS, inadequate response/intolerance to ≥1 TNF blocker | Monotherapy or with non-biologic DMARDs | FDA Approved |
| Ulcerative colitis (UC) | Adults with moderately to severely active UC, inadequate response/intolerance to ≥1 TNF blocker | Monotherapy (induction + maintenance) | FDA Approved |
| Polyarticular course JIA (pcJIA) | Pediatric ≥2 yr with active pcJIA, inadequate response/intolerance to ≥1 TNF blocker | With non-biologic DMARDs | FDA Approved |
Tofacitinib was the first JAK inhibitor approved in the United States (November 2012) and remains the most extensively studied, with more than 50 clinical trials accruing over 36,000 patient-years of experience. It is the only JAK inhibitor with direct safety comparison data against TNF blockers from the landmark ORAL Surveillance trial, which resulted in the JAK class-wide boxed warning. For RA, PsA, and AS, only the 5 mg BID (or XR 11 mg QD) dose is approved; the 10 mg BID / 22 mg XR dose is reserved exclusively for UC induction. Tofacitinib is not recommended for use with biologic DMARDs or potent immunosuppressants (azathioprine, cyclosporine).
Following the ORAL Surveillance trial results, the higher dose is no longer recommended for RA, PsA, AS, or pcJIA due to dose-dependent increases in MACE, malignancy, thrombosis, and mortality risk compared with TNF blockers. The 10 mg BID (or 22 mg XR) dose remains available only for UC induction, at the lowest effective dose for the shortest duration needed.
Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| RA / PsA / AS — adults, normal renal and hepatic function | 5 mg PO BID or XR 11 mg PO once daily | 5 mg PO BID or XR 11 mg QD | 5 mg BID (10 mg/day) | With or without food 10 mg BID / 22 mg XR NOT recommended for RA, PsA, AS, or pcJIA |
| RA / PsA / AS — moderate or severe renal impairment (CrCl ≤50 mL/min) | 5 mg PO once daily | 5 mg once daily | 5 mg once daily | Switch from XR to IR tablets Includes patients on haemodialysis (give dose after session) |
| RA / PsA / AS — moderate hepatic impairment (Child-Pugh B) | 5 mg PO once daily | 5 mg once daily | 5 mg once daily | Severe HI (Child-Pugh C): not recommended |
| RA / PsA / AS — with strong CYP3A4 inhibitors (e.g. ketoconazole) | 5 mg PO once daily | 5 mg once daily | 5 mg once daily | Also reduce for moderate CYP3A4 + strong CYP2C19 inhibitors (e.g. fluconazole) |
| UC — induction (adults) | 10 mg PO BID or XR 22 mg QD × ≥8 weeks | Transition to maintenance if response achieved | 10 mg BID up to 16 weeks total | Discontinue if no adequate response by 16 weeks Use lowest effective dose for shortest duration |
| UC — maintenance (adults) | 5 mg PO BID or XR 11 mg QD | 5 mg BID or XR 11 mg QD | 10 mg BID may be considered for loss of response (shortest duration) | Use lowest effective dose needed to maintain response |
| pcJIA / PsA — pediatric ≥2 yr, ≥40 kg | 5 mg PO BID (tablet or oral solution) | 5 mg BID | 5 mg BID | 20–40 kg: 4 mg (4 mL) BID; 10–20 kg: 3.2 mg (3.2 mL) BID |
Initiation Thresholds and Dose Modification for Cytopenias
| Parameter | Do Not Initiate If | Action During Treatment |
|---|---|---|
| Absolute Lymphocyte Count | <500 cells/mm³ | ALC <500 confirmed by repeat: discontinue permanently |
| Absolute Neutrophil Count | <1000 cells/mm³ | ANC 500–1000: interrupt until >1000, then resume. ANC <500: discontinue permanently |
| Haemoglobin | <9 g/dL | Hgb <8 g/dL or drop >2 g/dL: interrupt until normalised |
Tofacitinib is the only JAK inhibitor that was directly compared with TNF blockers in the ORAL Surveillance safety trial, generating the data that led to the entire JAK class boxed warning. Unlike baricitinib (2 mg QD), tofacitinib is dosed at 5 mg BID, requiring twice-daily administration for the IR formulation (though XR 11 mg QD is available). The initiation haemoglobin threshold for tofacitinib is 9 g/dL (vs 8 g/dL for baricitinib), a clinically important distinction. Tofacitinib is more extensively hepatically metabolised (~70% via CYP3A4) than baricitinib (~6% CYP3A4), making drug interactions with CYP3A4 inhibitors clinically relevant and necessitating dose reduction.
Pharmacology
Mechanism of Action
Tofacitinib is a small-molecule, competitive inhibitor of the JAK family kinases that binds the ATP-binding site of the kinase domain. It preferentially inhibits signalling through JAK3 and JAK1, with functional selectivity over JAK2 in cellular settings. By blocking JAK-mediated phosphorylation of STATs, tofacitinib suppresses signalling through the common gamma-chain receptor cytokines (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21) and additional cytokines (IL-6, IFN-gamma), which are central to lymphocyte activation, proliferation, and function. In RA, this results in rapid suppression of CRP levels within the first 1 to 2 weeks and progressive improvements in joint inflammation and structural damage. Tofacitinib does not normalise CYP enzyme activity in RA patients, indicating its anti-inflammatory effect does not reverse the CYP suppression associated with systemic inflammation.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral bioavailability 74%; Tmax 0.5–1 hour (IR). High-fat meal reduces Cmax by 32% but no change in AUC. XR Tmax delayed ~1 hour; Cmax increased ~20–27% with food. | Rapid absorption enables fast onset. Can be administered with or without food. XR tablets must be swallowed whole and intact (non-deformable; GI obstruction risk in pre-existing strictures). |
| Distribution | Vd: 87 L (IV). PPB: ~40% (predominantly albumin). Equal partitioning between red blood cells and plasma. | Large Vd indicates distribution into tissues beyond the vascular compartment. Moderate protein binding with low displacement interaction risk. |
| Metabolism | ~70% hepatic metabolism (CYP3A4 major, CYP2C19 minor). ~30% renal excretion of parent drug. Not an inhibitor or inducer of major CYP enzymes at therapeutic concentrations. | CYP3A4 dependence necessitates dose reduction with strong CYP3A4 inhibitors and with combined moderate CYP3A4 + strong CYP2C19 inhibitors (e.g. fluconazole). Strong CYP3A4 inducers (rifampicin) decrease exposure. |
| Elimination | t½: ~3 hours (IR). Urine: ~80% of radioactive dose (29% unchanged drug). Faeces: ~14% (~1% unchanged). Steady state within 24–48 hours; minimal accumulation. | Short half-life explains twice-daily dosing for IR. Renal impairment increases exposure (~40% in ESRD vs normal) because of reduced renal and metabolic clearance — reduce to 5 mg once daily. XR formulation provides extended absorption, not extended metabolism. |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Overall infections | 20% (5 mg BID); 22% (10 mg BID); 18% placebo | Most commonly URTI, nasopharyngitis, and UTI |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Upper respiratory tract infection | 4% (RA, 0–3 mo) | Most commonly reported individual infection across all indications |
| Nasopharyngitis | 3% (RA, 0–3 mo) | Usually mild, self-limiting |
| Diarrhea | 2.2–6.0% (across Phase 3 RA trials) | Usually mild to moderate; resolves within ~4 weeks |
| Headache | 1.3–5.6% (across Phase 3 RA trials) | Usually mild to moderate; resolves within ~4 weeks |
| Urinary tract infection | 2% (RA, 0–3 mo) | Standard management |
| Herpes zoster | ~3.9% (tofacitinib long-term); higher in Asia/Japan | JAK class effect; interrupt tofacitinib until resolved. Higher with 10 mg BID than 5 mg BID. |
| Adverse Effect | Estimated Frequency (per 100 pt-yr) | Typical Onset | Required Action |
|---|---|---|---|
| Serious infections (pneumonia, cellulitis, HZ, UTI, diverticulitis) | 1.7/100 pt-yr (combined, 0–3 mo) vs 0.5 placebo | Any time during therapy | Interrupt tofacitinib until infection controlled |
| All-cause mortality (including sudden CV death) | 5 mg: 0.88; 10 mg: 1.23 vs TNFi: 0.69 | Variable | Consider risk-benefit; class-wide concern. 10 mg BID not recommended for RA. |
| Malignancy (excluding NMSC) | 5 mg: 1.13; 10 mg: 1.13 vs TNFi: 0.77 | Variable | Consider risk-benefit in smokers. Periodic skin cancer screening. |
| MACE (CV death, MI, stroke) | 5 mg: 0.91 vs TNFi: 0.73 (per FDA PI) | Variable | Discontinue if MI or stroke occurs. Higher risk in patients ≥50 with CV risk factors and smokers. |
| DVT / Pulmonary embolism | Increased vs TNF blockers in ORAL Surveillance | Variable | Avoid in patients at increased thrombosis risk. Discontinue and evaluate promptly if VTE symptoms. |
| Lymphoma | 5 mg: 0.07; 10 mg: 0.11 vs TNFi: 0.02 | Variable | Higher rate than TNF blockers at both doses |
| Lung cancer (current/past smokers) | 5 mg: 0.48; 10 mg: 0.59 vs TNFi: 0.27 | Variable | Current/past smokers at additional increased risk |
| GI perforation | Uncommon | Variable | Evaluate new abdominal symptoms promptly, especially with diverticulitis history |
| Reason | Threshold | Context |
|---|---|---|
| Confirmed ALC <500 cells/mm³ | Confirmed by repeat testing | Permanent discontinuation required |
| Confirmed ANC <500 cells/mm³ | Confirmed by repeat testing | Permanent discontinuation required |
| MI or stroke | Clinical event | Discontinue tofacitinib |
The ORAL Surveillance trial (A3921133) was a large, randomized, postmarketing safety study comparing tofacitinib 5 mg and 10 mg BID with TNF blockers (adalimumab or etanercept) in 4362 RA patients aged 50 and older with at least one cardiovascular risk factor. It demonstrated that tofacitinib at both doses was associated with higher rates of MACE, malignancy (excluding NMSC), thrombosis, and all-cause mortality compared with TNF blockers. These findings led the FDA to apply a class-wide boxed warning to all JAK inhibitors and restrict the 10 mg BID dose to UC only. This trial is the basis for the current positioning of JAK inhibitors as options after TNF blocker failure, rather than as first-line biologics.
Drug Interactions
Unlike baricitinib (~6% CYP metabolism), tofacitinib is extensively hepatically metabolised (~70%), making CYP3A4 and CYP2C19 interactions clinically significant. Tofacitinib does not inhibit or induce major CYP enzymes at therapeutic concentrations, so it is unlikely to alter the metabolism of co-administered drugs.
Monitoring
- CBC (ALC, ANC, Hgb)Baseline; 4–8 weeks; then q3 months
RoutineDo not initiate if ALC <500, ANC <1000, or Hgb <9 g/dL. ALC <500 confirmed: discontinue permanently. ANC <500: discontinue permanently. Hgb <8 or drop >2: interrupt until normalised. - Lipid Panel~4–8 weeks after initiation
RoutineDose-dependent increases in total cholesterol, LDL, and HDL (max effect ~6 weeks). LDL/HDL ratio essentially unchanged. Manage per CV risk guidelines; statins effective. - Hepatic Function (LFTs)Baseline; routine monitoring
RoutineInvestigate liver enzyme elevations promptly to identify potential DILI. Not recommended in severe hepatic impairment. - TB ScreeningBaseline; during therapy
RoutineTest for latent TB before and during therapy. Treat latent TB before initiating tofacitinib. Monitor for active TB even in patients with initially negative test. - Viral Hepatitis ScreeningBaseline
RoutineScreen per clinical guidelines. Postmarketing cases of HBV reactivation reported. - Signs of Thrombosis / CV EventsOngoing clinical assessment
Trigger-basedDVT, PE, arterial thrombosis, MI, and stroke reported at higher rates vs TNF blockers. Educate patients on symptoms. Discontinue if thrombotic or CV event occurs. - Skin ExaminationPeriodic
Trigger-basedNMSCs reported, especially in UC patients on 10 mg BID. Periodic skin examination in at-risk patients.
Contraindications & Cautions
Absolute Contraindications
- None listed in the FDA PI — Section 4 states “None”
Relative Contraindications (Specialist Input Recommended)
- Active, serious infection including localised infections
- Active tuberculosis
- Patients at increased thrombosis risk — DVT, PE, and arterial thrombosis observed at higher rates vs TNF blockers
- Patients ≥50 with ≥1 CV risk factor — ORAL Surveillance showed higher MACE, malignancy, thrombosis, and mortality vs TNF blockers
- Current or past smokers — additional increased risk of malignancy and MACE
- Severe hepatic impairment (Child-Pugh C) — not recommended
Use with Caution
- Chronic or recurrent infection
- History of diverticulitis — GI perforation risk
- Chronic lung disease — may be more prone to infections
- Pre-existing GI strictures — XR formulation is non-deformable (obstruction risk)
In ORAL Surveillance (RA Safety Study 1), RA patients ≥50 years with ≥1 CV risk factor treated with tofacitinib 5 mg or 10 mg BID had higher rates of all-cause mortality (0.88 and 1.23 vs 0.69/100 pt-yr), malignancy excluding NMSC (1.13 and 1.13 vs 0.77/100 pt-yr), MACE, and thrombosis compared with TNF blockers. Lymphoma and lung cancer rates were also higher. Current/past smokers are at additional increased risk. The 10 mg BID / 22 mg XR dose is not recommended for RA, PsA, AS, or pcJIA. For UC, use the lowest effective dose for the shortest duration.
Patient Counselling
Purpose of Therapy
Tofacitinib works by blocking specific enzymes (JAK1 and JAK3) inside immune cells that drive inflammation in your joints (or gut, for ulcerative colitis). By reducing this inflammation, it helps control pain, swelling, and stiffness. It is taken as a tablet twice daily (or once daily as the extended-release form).
How to Take
Take one tablet (5 mg) twice daily, or one extended-release tablet (11 mg) once daily, with or without food. Swallow extended-release tablets whole — do not crush, split, or chew. If you see the ghost tablet shell in your stool, this is normal (the medicine has already been absorbed). Do not receive live vaccines while taking this medicine.
Sources
- XELJANZ (tofacitinib) tablets / XELJANZ XR (tofacitinib) extended-release tablets / XELJANZ (tofacitinib) oral solution. Full Prescribing Information. Pfizer Inc. Revised 01/2026. Pfizer PIPrimary source for all approved indications (RA, PsA, AS, UC, pcJIA), dosing, boxed warnings, ORAL Surveillance data, adverse reactions, and PK.
- European Medicines Agency. Xeljanz (tofacitinib) Summary of Product Characteristics. EMAEU regulatory reference; EU indication requires prior inadequate response or intolerance to ≥1 DMARD (broader than US label).
- Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis (ORAL Solo). N Engl J Med. 2012;367(6):495-507. doi:10.1056/NEJMoa1109071Phase III monotherapy trial (n=611) demonstrating tofacitinib 5 mg BID superiority over placebo for ACR20 at 3 months (59.8% vs 26.7%).
- van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate (ORAL Scan). N Engl J Med. 2013;368(6):194-205. doi:10.1056/NEJMoa1203055Phase III trial (n=797) demonstrating tofacitinib + MTX superiority over placebo + MTX, with inhibition of structural progression at 6 and 12 months.
- Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis (OCTAVE Induction 1 & 2, OCTAVE Sustain). N Engl J Med. 2017;376(18):1723-1736. doi:10.1056/NEJMoa1606910Pivotal UC trials (n=1139 induction, n=593 maintenance) demonstrating tofacitinib 10 mg BID induction and 5/10 mg BID maintenance superiority over placebo.
- Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis (ORAL Surveillance). N Engl J Med. 2022;386(4):316-326. doi:10.1056/NEJMoa2109927Landmark postmarketing safety study (n=4362) demonstrating higher MACE, malignancy, thrombosis, and mortality with tofacitinib 5/10 mg BID vs TNF blockers in RA patients ≥50 with ≥1 CV risk factor.
- Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2021;73(7):924-939. doi:10.1002/acr.24596Conditionally recommends TNF inhibitors over JAK inhibitors for RA, based on longer-term safety data and ORAL Surveillance findings.
- Meyer DM, Jesson MI, Li X, et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond). 2010;7:41. doi:10.1186/1476-9255-7-41Preclinical study establishing tofacitinib’s JAK selectivity profile and anti-inflammatory activity in rodent arthritis models.
- Dowty ME, Lin J, Ryder TF, et al. The pharmacokinetics, metabolism, and clearance mechanisms of tofacitinib, a Janus kinase inhibitor, in humans. Drug Metab Dispos. 2014;42(4):759-773. doi:10.1124/dmd.113.054940Definitive human PK study with radiolabeled tofacitinib establishing t½ 3.2 h, 70% hepatic/30% renal clearance, CYP3A4/CYP2C19 metabolism, and 80% urinary recovery.
- Krishnaswami S, Kudlacz E, Wang R, et al. A supratherapeutic dose of the Janus kinase inhibitor tofacitinib does not prolong QTcF interval in healthy subjects. J Clin Pharmacol. 2012;52(8):1247-1258. doi:10.1177/0091270011412834Phase I PK and QT study confirming dose-proportional PK, rapid absorption (Tmax ~0.5 h), and no QTcF prolongation at supratherapeutic doses.
- Wollenhaupt J, Lee EB, Curtis JR, et al. Safety of tofacitinib in patients with rheumatoid arthritis: interim analysis of the ORAL Sequel long-term extension study. Ann Rheum Dis. 2019;78(2):169-178. doi:10.1136/annrheumdis-2018-214124Interim analysis of ORAL Sequel (n=4481, up to 9.5 years) confirming consistent long-term safety profile across extended tofacitinib exposure.
- Charles-Schoeman C, Gonzalez-Gay MA, Engel B, et al. Tofacitinib 5 mg twice daily in patients with rheumatoid arthritis and inadequate response to DMARDs: comprehensive review of phase 3 efficacy and safety. Clin Rheumatol. 2019;38(10):2603-2621. doi:10.1007/s10067-019-04696-1Comprehensive review of all 5 phase 3 RA trials at the approved 5 mg BID dose, with pooled safety data across 1216 patients.