Overview of Safety and Tolerability

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

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

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

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

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

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

• 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

• The incidence rate for MACE with XELJANZ in the RA and PsA phase III trials was similar to placebo group.^5,6
• 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.

• 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
• The effect of  XELJANZ on the development and course of malignancies is not known.¹