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AboutAboutHow XELJANZ worksXELJANZ in ActionCytokinesSignalling PathwaysDosingDosingDosing in RADosingPractical ConsiderationsDosing in UCDosingPractical ConsiderationsDosing in PsADosingPractical ConsiderationsDosing in pJIA and jPsADosingPractical ConsiderationsEfficacy & SafetyEfficacy & SafetySafety & TolerabilityOral SurveillanceAdverse EventsClinical Efficacy RAORAL Strategy Study DesignORAL Strategy Efficacy ResultsORAL Strategy Safety OutcomesClinical Efficacy UCOCTAVE Study DesignOCTAVE Sub GroupsOCTAVE InductionOCTAVE SustainPost-hoc AnalysesClinical Efficacy PsAOPAL Broaden & BeyondClinical efficacy pJIA and jPsAJIA-1 study designJIA-1 Efficacy ResultsJIA-1 Safety OutcomesReal World EvidenceReal World EvidenceReal World ExperienceWhy Real-World Data?RWE available for XELJANZEffectiveness in RWESafety in RWEDrug Maintenance in RWESupporting ResourcesSupporting ResourcesGRAPPA GuidelinesMaterialsVideos

XELJANZ® (tofacitinib citrate) Prescribing Information. Adverse event reporting can be found at the bottom of the page.

Overview of Safety and Tolerability

The information on this page applies to XELJANZ use in Rheumatoid Arthritis, Psoriatic Arthritis, Ulcerative Colitis, polyarticular Juvenile Idiopathic Arthiritis and juvenile Psoriatic Arthiritis. Some sections refer to information relevant to adult indications only, in which case this is specified. For additional information relating to prescribing, please refer to the 'Practical considerations for use' pages for Rheumatoid Arthritis (RA) / Ulcerative Colitis (UC) / Psoriatic Arthritis (PsA) / polyarticular Juvenile Idiopathic Arthiritis (pJIA) and juvenile Psoriatic Arthirtitis (jPsA) or the XELJANZ SmPC.

Common adverse events for XELJANZ across adult indications1

The following table applies to Xeljanz use in RA, PsA and UC only.

XELJANZ should only be used in patients over 65 years of age, in patients who are current or past smokers, patients with other cardiovascular risk factors, and patients with other malignancy risk factors, if no suitable treatment alternatives are available.

Scroll left to view table

System organ class

Common (1/100 to <1/10)

Infections and infestations

Pneumonia, influenza, herpes zoster, urinary tract infection, sinusitis, bronchitis, nasopharyngitis, pharyngitis

Blood and lymphatic system disorders

Anaemia

Nervous system disorders

Headache

Vascular disorders

Hypertension

Respiratory, thoracic and mediastinal disorders

Cough

Gastrointestinal disorders

Abdominal pain, vomiting, diarrhoea, nausea, gastritis, dyspepsia

Skin and subcutaneous tissue disorders

Rash

Musculoskeletal and connective tissue disorders

Arthralgia

General disorders and administration site conditions

Oedema peripheral, pyrexia, fatigue

Investigations

Blood creatine phosphokinase increased

The most commonly reported adverse reactions seen in RA patients during the first 3 months in controlled clinical trials were headache (3.9%), upper respiratory tract infections (3.8%), viral upper respiratory tract infection (3.3%), diarrhoea (2.9%), nausea (2.7%), and hypertension (2.2%).

Overall, the safety profile observed in patients with active PsA treated with XELJANZ was consistent with the safety profile observed in patients with RA treated with XELJANZ.

​​​​​​Overall, the safety profile observed in patients with UC treated with tofacitinib was consistent with the safety profile of tofacitinib in RA indication. In UC, the most commonly reported adverse reactions in patients receiving XELJANZ 10 mg twice daily in the induction studies were headache, nasopharyngitis, nausea, and arthralgia.

The adverse reactions in Juvenile Idiopathic Arthiritis (JIA) patients in the clinical development program were consistent in type and frequency with those seen in adult RA patients, with the exception of some infections (influenza, pharyngitis, sinusitis, viral infection) and gastrointestinal or general disorders (abdominal pain, nausea, vomiting, pyrexia, headache, cough), which were more common in JIA paediatric population. MTX was the most frequent concomitant csDMARD used (on Day 1, 156 of 157 patients on csDMARDs took MTX). There are insufficient data regarding the safety profile of tofacitinib used concomitantly with any other csDMARDs.

Serious adverse eventsPolyarticular juvenile idiopathic arthiritis (pJIA) and juvenile psoriatic arthirtitis (jPsA)

In the double-blind portion of the pivotal Phase 3 trial (Study JIA-I), infection was the most commonly reported adverse reaction (44.3%). The infections were generally mild to moderate in severity. 1

Serious Infections:
  • In the integrated safety population, 7 patients had serious infections during treatment with tofacitinib within the reporting period (up to 28 days after the last dose of study medication), representing an incidence rate of 1.92 patients with events per 100 patient-years: pneumonia, epidural empyema (with sinusitis and subperiosteal abscess), pilonidal cyst, appendicitis, escherichia pyelonephritis, abscess limb, and UTI.1
Rheumatoid arthritis (RA) and psoriatic arthritis (PsA)

The most common serious adverse reactions in RA clinical trials were serious infections.1

Overall, the safety profile observed in patients with active PsA treated with XELJANZ was consistent with the safety profile observed in patients with RA treated with XELJANZ.1

Serious Infections:

  • The most common serious infections reported with XELJANZ were pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis; cases of opportunistic infections have been reported.1
  • The most common infections resulting in discontinuation of therapy were herpes zoster and pneumonia.1
  • Combination therapy, 6, 12 or 24-month trials: 3.6 patients with events per 100 patient-years for XELJANZ 5 mg twice daily plus DMARD vs. 1.7 per 100 patient-years for placebo plus DMARD.1
  • Monotherapy, 6-month and 24-month controlled clinical studies: 1.7 patients with events per 100 patient-years for XELJANZ 5 mg twice daily vs. 1.9 per 100 patient-years for MTX.1
  • Long-term safety all-exposure population: 3.1 patients with events per 100 patient-years for XELJANZ 5 mg twice daily.2
Ulcerative colitis (UC)

In the induction and maintenance studies, across XELJANZ and placebo treatment groups, the most common categories of serious adverse reactions were gastrointestinal disorders and infections, and the most common serious adverse reaction was worsening of UC.1

Serious Infections:
  • The incidence rates and types of serious infections in the UC clinical studies were generally similar to those reported in RA clinical studies with XELJANZ monotherapy treatment groups.1
Gastrointestinal perforations
  • In UC clinical trials, the incidence rate of GI perforation was 0.2 (95% CI, 0.0–0.5), based on 3 patients with events (across Ph2 and Ph3+LTE).3
  • XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g. patients with a history of diverticulitis, patients with concomitant use of corticosteroids and/or non-steroidal anti-inflammatory drugs).1
  • Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of gastrointestinal perforation.1
Adverse events of special interest across all indicationsHerpes zoster

Viral reactivation and cases of herpes virus reactivation (e.g. herpes zoster) were observed in clinical studies with XELJANZ. In patients treated with XELJANZ, the incidence of herpes zoster appears to be increased in1:

  • Japanese or Korean patients.
  • Patients with an ALC less than 1,000 cells/mm3.
  • Patients with long standing RA who have previously received two or more biological disease modifying antirheumatic drugs (DMARDs).
  • Patients treated with 10 mg twice daily.

In the RA clinical trials, 703 of 6,194 patients developed herpes zoster (92% involved one dermatome):

  • 53 cases were serious; IR/100 patient years for XELJANZ 5 mg BID was 0.3 (CI 0.2-0.5)2
In the integrated safety population of the JIA1 trial, 3 patients had non-serious events of herpes zoster within the reporting window representing an incidence rate of 0.82 patients with events per 100 patient-years. One (1) additional patient had an event of serious HZ outside the reporting window.1

 

XELJANZ treatment in patients with UC is associated with a dose dependent risk of herpes zoster:

  • During maintenance treatment the incidence rate of herpes zoster was 2.1 for 5 mg BID and 6.6 for 10 mg BID4

In the OCTAVE clinical trial programme, most herpes zoster events were limited to one or two adjacent dermatomes.3,4

Most cases of herpes zoster in the OCTAVE programme (70%) did not require permanent or temporary discontinuation of XELJANZ or dose reduction.3,4

Venous thromboembolism (VTE)Rheumatoid arthritis (RA)

In a large, randomised post-authorisation safety surveillance study of rheumatoid arthritis patients who were 50 years of age and older and had at least one cardiovascular (CV) risk factor, VTE was observed at an increased and dose-dependent incidence in patients treated with XELJANZ compared to TNF inhibitors. The majority of these events were serious and some resulted in death. The incidence rates (95% CI) for PE for XELJANZ 10 mg twice daily, XELJANZ 5 mg twice daily, and TNF inhibitors were 0.54 (0.32‑0.87), 0.27 (0.12‑0.52), and 0.09 (0.02‑0.26) patients with events per 100  patient-years, respectively. Compared with TNF inhibitors, the hazard ratio (HR) for PE was 5.96 (1.75‑20.33) and 2.99 (0.81‑11.06) for XELJANZ 10 mg twice daily and XELJANZ 5 mg twice daily, respectively (see section 5.1 of XELJANZ Summary of Product Characteristics).1

In a subgroup analysis in patients with VTE risk factors in the above-mentioned study, the risk for PE was further increased1. Compared with TNF inhibitors, the HR for PE was 9.14 (2.11‑39.56) for XELJANZ 10 mg twice daily and 3.92 (0.83‑18.48) for XELJANZ 5 mg twice daily.1

Polyarticular juvenile idiopathic arthiritis (pJIA) and juvenile psoriatic arthiritis (jPsA)

There were no cases of thrombotic events (DVT, PE, or ATE) in Study JIA-I.7

Ulcerative colitis (UC)

In the ongoing UC extension trial, cases of PE and DVT have been observed in patients using XELJANZ 10 mg twice daily and with underlying VTE risk factor(s).1

Tuberculosis
  • Active TB is a contraindication to XELJANZ use.1
  • TB has been reported in ≥1/1,000 to <1/100 patients (considered uncommon). Disseminated TB has been reported in ≥1/10,000 to <1/1,000 patients (rare).1
  • The risks and benefits of treatment should be considered prior to initiating XELJANZ in patients:1
    • Who have been exposed to TB
    • Who have resided or travelled in areas of endemic TB
  • Patients should be evaluated and tested for latent or active infection prior to and per application guidelines during administration of XELJANZ.1
  • Antituberculosis therapy should also be considered prior to administration of XELJANZ in patients who test negative for TB but who have a history of latent or active TB and where an adequate course of treatment cannot be confirmed; or those who test negative but who have risk factors for TB infection.1
Major adverse cardiovascular events
  • The incidence rate for MACE with XELJANZ in the RA and PsA phase III trials was similar to placebo group.5,6
  • There were no cases of MACE in Study JIA-I.7
  • There were 2 (0.2%) MACE events in the induction cohort of the UC trials, 1 event in the 5 mg and 10 mg arms in the maintenance trial (0.5%).3
  • XELJANZ should only be used in patients with other cardiovascular risk factors if no suitable treatment alternatives are available.
Malignancies and lymphoproliferative disorder [excluding non-melanoma skin cancer (NMSC)]
  • XELJANZ should only be used in patients with other malignancy risk factors if no suitable treatment alternatives are available.
  • The risks and benefits of XELJANZ treatment should be considered prior to initiating therapy in patients with current, or a history of, malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy. The possibility exists for XELJANZ to affect host defences against malignancies.1
  • Lymphomas have been observed in patients treated with XELJANZ. Patients with RA, particularly those with highly active disease may be at a higher risk (up to several-fold) than the general population for the development of lymphoma. The role of XELJANZ in the development of lymphoma is uncertain.1
  • Other malignancies were observed in clinical studies and the post-marketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer and pancreatic cancer.1
  • There were no cases of malignancies (including NMSC) in Study JIA-I.7
  • The effect of  XELJANZ on the development and course of malignancies is not known.1
Explore More Dosing in RA Loading Dosing in UC Loading Dosing in PsA Loading Dosing in pJIA and jPsA Loading

BID=twice daily; TNFi=tumour necrosis factor inhibitor; UC=ulcerative colitis; AEs=adverse events; MTX=methrotrexate ; csDMARDs= onventional disease-modifying antirheumatic drug; UTI=urinary tract infection.

​​​​​​​References

XELJANZ (tofacitinib citrate) Summary of Product CharacteristicsCohen SB et al. Ann Rheum Dis 2017; 0:1–10andborn WJ et al. Clinical Gastroenterology and Hepatology 2019;17:1541-1550Winthrop KL et al. Inflamm Bowel Dis 2018;24:2248-2265Charles-Schoeman C et al. Semin Arthritis Rheum 2016;46:261–271Kavanaugh A et al. Arthritis and Rheumatology 2016; 68:3504–3506Ruperto N, et al. Lancet 2021; doi:10.1016/S0140-6736(21)01255-1.
XELJANZ Risk Minimisation Programme (RMP) materials, including a Patient Alert Card, Prescriber Checklists and a Prescriber Brochure are available from https://www.medicines.org.uk/emc/. Patients treated with XELJANZ should be given the Patient Alert Card.
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