Safety and Tolerability

Common adverse events for XELJANZ across indications1

Please also refer to the 'Practical considerations for use' tab on the Dosing & Practical Considerations page.

The most commonly reported adverse reactions seen in rheumatoid arthritis (RA) patients during the first 3 months in controlled clinical trials were headache, upper respiratory tract infections, nasopharyngitis, diarrhoea, nausea and hypertension.

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

In ulcerative colitis (UC), the most commonly reported adverse reactions in patients receiving tofacitinib 10 mg twice daily in the induction studies were headache, nasopharyngitis, nausea, and arthralgia.

Serious adverse events

Rheumatoid arthritis (RA) and psoriatic arthritis (PsA)

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

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

Serious Infections:

  • The most common serious infections reported with tofacitinib were pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis; cases of opportunistic infections have been reported.
  • The most common infections resulting in discontinuation of therapy were herpes zoster and pneumonia.
  • 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 DMARD1
  • 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 MTX1
  • 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 tofacitinib 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 tofacitinib monotherapy treatment groups.1
  • In the long-term safety all exposure population, the overall rates of serious infections were 2.4 and 3.0 patients with events per 100 patient-years for 5 mg and 10 mg twice daily XELJANZ groups, respectively.3

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 nonsteroidal anti-inflammatory drugs)
  • Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of gastrointestinal perforation.

Adverse events of special interest across all indications

Herpes zoster:

Viral reactivation and cases of herpes virus reactivation (e.g., herpes zoster) were observed in clinical studies with tofacitinib. In patients treated with tofacitinib, 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

Xeljanz treatment in patients with UC is associated with a dose dependent risk of HZ

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

In the OCTAVE clinical trial programme, most herpes zoster events were limited to one or two adjacent dermatomes3,4

Most cases of herpes zoster in the OCTAVE programme (70%) did not require permanent or temporary discontinuation of Xeljanz or dose reduction3,4

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 tofacitinib compared to TNF inhibitors. The majority of these events were serious and some resulted in death. The incidence rates (95% CI) for PE for tofacitinib 10 mg twice daily, tofacitinib 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 tofacitinib 10 mg twice daily and tofacitinib 5 mg twice daily, respectively (see section 5.1 of XELJANZ Summary of Product Characteristics).

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

Ulcerative colitis (UC)

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

TB

  • Active TB is a contraindication to XELJANZ use
  • 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)
  • The risks and benefits of treatment should be considered prior to initiating XELJANZ in patients:
    • 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
  • 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.

MACE

  • The incidence rate for MACE with XELJANZ in the RA and PsA phase III trials was similar to placebo group5,6.
  • There were 2 (0.2%) MACE events in the induction cohort of the UC trials, 1 event in the 5mg and 10mg arms in the maintenance trial (0.5%)3 

Malignancies and lymphoproliferative disorder [excluding non-melanoma skin cancer (NMSC)]

  • 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
  • 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
  • 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
  • The effect of  XELJANZ on the development and course of malignancies is not known.

The licensed dose of XELJANZ for the treatment of RA and PsA is 5 mg BID, which should not be exceeded.1 XELJANZ 10 mg BID is not licensed for the treatment of RA and PsA.

Please see XELJANZ Summary of Product Characteristics for full information.

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.

BID=twice daily; TNFi=tumour necrosis factor inhibitor; UC=ulcerative colitis; AEs=adverse events.
1: XELJANZ (tofacitinib citrate) Summary of Product Characteristics
2: Cohen SB et al. Ann Rheum Dis 2017; 0:1–10.
3: Sandborn WJ et al. Clinical Gastroenterology and Hepatology 2019;17:1541-1550
4: Winthrop KL et al. Inflamm Bowel Dis 2018;24:2248-2265
5: Charles-Schoeman C et al. Semin Arthritis Rheum 2016;46:261–271
6: Adapted from Kavanaugh A et al. ACR 2016; Poster 2595
 

XELJANZ Prescribing Information

PP-XEL-GBR-2189 February 2020