XELJANZ® (tofacitinib citrate)| ORAL Surveillance & Integrated Safety Summary

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ORAL Surveillance and Integrated Safety Summary

ORAL Surveillance Study description¹

ORAL Surveillance study description¹

XELJANZ 5 mg BID or XELJANZ 11 mg prolonged-release once daily tablets are the only approved dosages for the treatment of rheumatoid arthritis.²

MACE defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.

Patients who were treated with tofacitinib 10 mg BID were switched to tofacitinib 5 mg BID.

Patients randomized to TNFi in North America, including United States, Puerto Rico, and Canada received adalimumab 40 mg q2w; in the rest of the world, those randomized to TNFi received etanercept 50 mg qw.

ORAL Surveillance: Baseline Characteristics

ORAL Surveillance: Coprimary Endpoint Results for Adjudicated MACE and Adjudicated Malignancies (Excluding NMSC)¹

For adjudicated MACE and adjudicated malignancies (excluding NMSC), the prespecified noninferiority criterion was not met for the primary comparison of the combined tofacitinib doses to TNFi^a

Adjudicated MACE

The primary analyses included 135 patients with MACE
The most frequently reported MACE for tofacitinib was non-fatal myocardial infarction
A 60-day on-treatment time analysis^b was used to assess the MACE coprimary endpoint

Adjudicated malignancies (excluding NMSC)

The primary analyses included 164 patients with malignancies (excluding NMSC)
The most frequently reported malignancy with tofacitinib was lung cancer
A total time analysis^c was used to assess the malignancy coprimary endpoint

XELJANZ 5 mg BID or XELJANZ 11 mg prolonged-release once daily tablets are the only approved dosages for the treatment of rheumatoid arthritis.²

Pfizer continues to work with the EMA and other regulatory agencies to update XELJANZ labeling in their respective markets based on their ongoing review of the complete ORAL Surveillance results.

The noninferiority criterion was not met for the primary comparison of the combined tofacitinib doses to TNFi since the upper limit of the 95% Cl exceeded the pre-specified noninferiority criterion of 1.8 (ie, for MACE: 1.94>1.8, for malignancy: 2.09>1.8).

Defined as the time from the first dose of a trial drug until the end of the risk period (ie, last contact date or last trial dose plus 60 days, whichever was earliest).

Defined as the time from the first dose of a trial drug until the last contact date. The last contact date was the latest of the following: the start date of an AE, the end date of an AE, the date of the last trial visit, the withdrawal date, the telephone contact date, or the date of death.

Based on Cox proportional hazard model.

NNH over a period of 5 years was the number of patients who would need to be treated for that duration with tofacitinib rather than a TNFi to result in one additional adverse event; calculations were performed post hoc.

ORAL Surveillance: Adverse Events of Special Interest¹

A 28-day on-treatment period analysis was used to assess AEs^a

XELJANZ 5 mg BID or XELJANZ 11 mg prolonged-release once daily tablets are the only approved dosages for the treatment of rheumatoid arthritis.²

Pfizer continues to work with the EMA and other regulatory agencies to update XELJANZ labeling in their respective markets based on their ongoing review of the complete ORAL Surveillance results.

Defined as the minimum of the date of last contact or the date of the last dose of a trial treatment plus 28 days.

Based on Cox proportional hazard model.

Also included are opportunistic herpes zoster and tuberculosis events.

Included are herpes zoster adjudicated as an opportunistic infection and nonadjudicated herpes zoster events.

Safety profile from the RA clinical trial programs³

Limitations of pooled and long-term extension (LTE) data

Pooled, post hoc analysis of studies from the RA clinical trial program are subject to certain limitations. First, unlike ORAL Surveillance, the patient population is not limited to a high-risk population but includes all enrolled patients. Second, endpoints of interest (such as MACE and malignancy for ORAL Surveillance) were not all specifically defined or adjudicated. Additionally, ORAL Surveillance was a long-term safety study (vs RCT phase 3 which are short term and designed to test efficacy). Resultant incidence rates in ORAL Surveillance differed from rates seen from pooled study data, suggesting the pooled data may be obscuring information about predictors of events given adverse rates may differ from one patient population to another and may change over time
LTE studies may provide useful data, however, conduct of open-label LTE studies where both treatment and dose are known to both investigator and patient is subject to certain biases and limitations. Most participants were known to have responded to, and tolerated, XELJANZ® (all had completed a qualifying study), hence our findings might not be generalizable to patients new to XELJANZ
Biases include, but are not limited to, patient selection (patient willingness or ineligibility to enroll, which may be due to a prior serious AE), prior treatment, volunteer, observer, initial dose or study drug, investigator/patient expectation and study duration. Limitations include, but are not limited to, AE frequencies and incidence rates subject to change over time due to patient entry/exit, dose changes influenced by both investigator and patient, dose restrictions in certain countries, the number of patients and exposure for a specific safety event possibly differing depending on the timing of censored events, and the number of observed patients with longer exposure times becoming lower

Integrated safety summary (ISS)⁴

The ISS and analysis of adverse events of special interest includes pooled data from patients exposed to ≥1 dose of XELJANZ in phase 1, 2, 3, or 3b/4 clinical trials, and LTE studies in RA⁴
In LTE studies, dose adjustments for XELJANZ or concomitant medications were allowed at the investigator’s discretion for efficacy or safety reasons⁴

Adverse reactions occurring in ≥2% of patients receiving XELJANZ 5 mg BID and ≥1% greater than that observed in patients on placebo (XELJANZ 5 mg BID and placebo± csDMARDs).²

Includes XELJANZ 5 mg BID and 10 mg BID treatment arms ± csDMARDs. XELJANZ 5 mg BID or XELJANZ 11 mg prolonged-release once daily tablets are the only approved dosages for the treatment of rheumatoid arthritis.
10 mg BID is not licensed for RA.²

Final data for the RA cohorts are from April 18, 2019.⁴

All doses in RA included XELJANZ 1 mg, 3 mg, 5 mg, 10 mg, 15 mg, 30 mg BID; 10 mg or 20 mg QD; or 11 mg MR QD.⁴

XELJANZ 5 mg BID or 11 mg prolonged release QD are the only approved dosages for the treatment of RA, which should not be exceeded. 10 mg BID is not licensed for RA.²

Adjudicated events.⁴

Composite MACE defined as any myocardial infarction, stroke, or cardiovascular death.⁴

XELJANZ 5 mg BID or XELJANZ 11 mg prolonged-release once daily tablets are the only approved dosages for the treatment of rheumatoid arthritis. 10 mg BID is not licensed for RA.²

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Please refer to the XELJANZ Summary of Product Characteristics for full prescribing information

ACS=acute coronary syndrome; ATE=arterial thromboembolism; bDMARD=biologic disease-modifying antirheumatic drug; BMl=body mass index; BID=twice daily; CAD=coronary artery disease; CABG=coronary artery bypass grafting; CHD=coronary heart disease; CRP=C-reactive protein; csDMARD=conventional synthetic disease-modifying antirheumatic drug; CV=cardiovascular; DVT=deep vein thrombosis; EMA=European Medicines Agency; HZ=herpes zoster; MACE=major adverse cardiovascular event; Ml=myocardial infarction; MTX=methotrexate; NMSC=nonmelanoma skin cancer; NNH=number needed to harm; PE=pulmonary embolism; pt-yr=patient year; QD=once daily; qw=once a week; q2wk=every 2 weeks; RA=rheumatoid arthritis; RCT=randomised controlled trial; SD= standard deviation; TB=tuberculosis; TNFi=tumor necrosis factor inhibitor; UA=unstable angina; VTE=venous thromboembolism.

References:

Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386(4):316-326.

XELJANZ Summary of Product Characteristics.

Wollenhaupt J, Lee E-B, Curtis JR, et al. Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-term extension study. Arthritis Res Ther. 2019;21(1}:89. doi:10.1186/s13075-019-1866-2

Burmester GR, Nash P, Sands BE, et al. Adverse events of special interest in clinical trials of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and psoriasis with 37 066 patient-years of tofacitinib exposure. RMD Open. 2021;7:e001595. doi:10.1136/rmdopen-2021-001595

Clinical Efficacy RA

SAFETY

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PP-XEL-IRL-0777 January 2023

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