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HomeAboutTofacitinib Pfizer Mechanism of ActionEfficacyClinical Efficacy RARapid Data (ACR20)Head-to-Head Noninferiority Data (ACR50)Clinical Efficacy PsAACR20 DataPASI75 DataEnthesitis and Dactylitis DataClinical Efficacy ASASAS20/40 DataASDAS(CRP) DataClinical Efficacy UC8-Week EfficacyOnset of Action Data52-Week EfficacyOCTAVE Study DesignSafetyImportant Safety InformationSafety and TolerabilitySafety in RASafety in PsASafety in UCSafety in ASDosingDosing in RADosingPractical ConsiderationsDosing in PsADosingPractical ConsiderationsDosing in ASDosingPractical ConsiderationsDosing in UCDosingPractical ConsiderationsMedical InformationVisit the Pfizer Medical Information Africa Website for Healthcare ProfessionalsSubmit a medical question to Pfizer

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Safety in RA, including ORAL Surveillance postmarketing data​​​​​​​ORAL Surveillance study description1
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Design Phase IIIb/IV randomized, open-label, non-inferiority, postauthorization safety endpoint-driven study
Primary objective Evaluate the safety of tofacitinib at 2 doses (5 mg BID and 10 mg BID) compared with a TNFi in patients with RA who were 50 years of age or older and had at least 1 additional CV risk factor
Coprimary endpoints Adjudicated MACEa and adjudicated malignancies (excluding NMSC)
Statistical plan Determine whether the upper limit of the 95% CI for the primary comparison of the combined tofacitinib doses compared to TNFi exceeded the pre-specified non-inferiority criterion of 1.8
Regulatory update Pfizer continues to work with the EMA and other regulatory agencies to update Tofacitinib Pfizer labeling in their respective markets based on their ongoing review of the complete ORAL Surveillance results 
The approved dose of tofacitinib for RA is 5 mg BID.2MACE 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.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: Baseline Characteristics
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  Treated patients
(N=4362)
Female, n (%) 3410 (78.2)
Median age, years (range) 60.0 (50.0-88.0)
Mean disease duration, years (SD) 10.4 (9.1)
Mean BMI, kg/m2 (SD) 29.8 (6.5)
Current/ex-smokers, n (%) 2103 (48.2)
Selected comorbidities, n (%)
    History of CHD 497 (11.4)
    History of diabetes mellitus 759 (17.4)
    History of hypertension 2878 (66.0)
    History of extra-articular disease  1605 (36.8)
ORAL Surveillance: Coprimary Endpoint Results for Adjudicated MACE and Adjudicated Malignancies (Excluding NMSC)1For adjudicated MACE and adjudicated malignancies (excluding NMSC), the prespecified noninferiority criterion was not met for the primary comparison of the combined tofacitinib doses to TNFiaAdjudicated 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 analysisb 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 analysisc was used to assess the malignancy coprimary endpoint
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Tofacitinib
5 mg BID		 Tofacitinib 10 mg BID
(includes patients switched to 5 mg BID dose per Feb 2019 protocol amendment)		 Tofacitinib Doses Combined TNFi
Adjudicated MACE
No. of pts with first event/total no. (%) 47/1455 (3.2) 51/1456 (3.5) 98/2911 (3.4) 37/1451 (2.5)
No. of patient-years 5166.32 4871.96 10,038.28 5045.27
Incidence rate per 100 patient-year (95% CI) 0.91
(0.67, 1.21)		 1.05 
(0.78, 1.38)		 0.98 
(0.79, 1.19)		 0.73
(0.52, 1.01)
Hazard ratio for tofacitinib vs TNFi
(95% CI)d		 1.24
(0.81, 1.91)		 1.43
(0.94, 2.18)		 1.33
(0.91, 1.94)a
Noninferiority margin for primary comparison
(criterion not met; 1.94>1.8)
NNH (over 5-year period) vs TNFie 113 64


Adjudicated malignancies (excluding NMSC)
No. of pts with first event/total no. (%) 62/1455 (4.3) 60/1456 (4.1) 122/2911 (4.2) 42/1451 (2.9)
No. of patient-years 5491.48 5311.71 10,803.19 5482.30
Incidence rate per 100 patient-year (95% CI) 1.13
(0.87, 1.45)		 1.13
(0.86, 1.45)		 1.13
(0.94, 1.35)		 0.77
(0.55, 1.04)
Hazard ratio for tofacitinib vs TNFi
(95% CI)d 		 1.47
(1.00, 2.18)		 1.48
(1.00, 2.19)		 1.48
(1.04, 2.09)a
Noninferiority margin for primary comparison 
(criterion not met; 2.09>1.8)
NNH (over 5-year period) vs TNFie 55 55

The approved dose of tofacitinib for RA is 5 mg BID.2 Pfizer continues to work with the EMA and other regulatory agencies to update Tofacitinib Pfizer 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% CI 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 Interest1A 28-day on-treatment period analysis was used to assess AEs a 
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Tofacitinib
5 mg BID		 Tofacitinib 10 mg BID (N=1456)
(includes patients switched to 
5 mg BID per Feb 2019 protocol amendment)		 TNFi (N=1451)
Serious AE, n (%) 351 (24.1) 306 (21.1) 306 (21.1)

AEs of special interest, n (%)
Hazard ratio for tofacitinib vs TNFi (95% CI)b

Serious infection 141 (9.7)
1.17 (0.92, 1.50)		 169 (11.6)
1.48 (1.17, 1.87)		 119 (8.2)
—
Adjudicated opportunistic infectionc 39 (2.7)
1.82 (1.07, 3.09)		 44 (3.0)
2.17 (1.29, 3.66)		 21 (1.4)
—
All herpes zosterd
(non-serious/serious)		 180 (12.4)
3.28 (2.44, 4.41)		 178 (12.2)
3.39 (2.52, 4.55)		 58 (4.0)
—
Adjudicated hepatic event 46 (3.2)
1.29 (0.83, 2.00)		 72 (4.9)
2.14 (1.43, 3.21)		 35 (2.4)
—
Adjudicated NMSC 31 (2.1)
1.90 (1.04, 3.47)		 33 (2.3)
2.16 (1.19, 3.92)		 16 (1.1)
—
Adjudicated pulmonary embolism 9 (0.6) 2.93 (0.79, 10.83) 24 (1.6)
8.26 (2.49, 27.43)		 3 (0.2)
—
Adjudicated deep vein thrombosis  11 (0.8)
1.54 (0.60, 3.97)		 15 (1.0)
2.21 (0.90, 5.43)		 7 (0.5)
—
Adjudicated venous thromboembolism 17 (1.2) 1.66 (0.76, 3.63) 34 (2.3)
3.52 (1.74, 7.12)		 10 (0.7)
—
Adjudicated death from 
any cause		 26 (1.8) 1.49 (0.81, 2.74) 39 (2.7)
2.37 (1.34, 4.18)		 17 (1.2)
—
The approved dose of tofacitinib for RA is 5 mg BID.2 Pfizer continues to work with the EMA and other regulatory agencies to update Tofacitinib Pfizer 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
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Most common adverse reactions in the first
3 months of 2 phase 2 and 5 phase 3 clinical trials3,a
  Tofacitinib Pfizer® 5 mg BID
(n=1336)  		 Placebo
(n=809)  
Upper respiratory tract infection 4% 3%
Headache 4% 2%
Diarrhea 4% 2%
Nasopharyngitis 4% 3%
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Adverse events (AEs)[all-cause] and serious adverse events (SAEs) in patients receiving Tofacitinib Pfizer over more than 9 years4
  All Tofacitinib Pfizerb (n=4481) 16,291 pt-yrs Tofacitinib Pfizer 5 mg BID (n=1123) 4683 pt-yrs
Patients with AEs (any cause), n (%) 4036 (90.1) 1015 (90.4)
Discontinuation due to AEs, n (%) 1120 (25.0) 315 (28.0)
SAEs, patients with events/100 pt-yrs (95% CI) 9.0 (8.6, 9.5) 8.2 (7.3, 9.1)
Limitations of pooled and long-term extension (LTE) data5
  • 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, Tofacitinib Pfizer (all had completed a qualifying study), hence our findings might not be generalizable to patients new to Tofacitinib Pfizer
  • 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): baseline characteristics and demographics6
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Characteristics RA | All Tofacitinib Pfizer® Dosesa,b
(N=7964)
Mean age, years 52.6
≥65 at baseline, n (%) 1270 (15.9)
Female, n (%) 6522 (81.9)
BMI (kg/m2), mean 27.1
Disease duration (years), mean (range) 8.1 (0.00-65.7)
CRP (mg/L). median (Q1-Q3) 9.2 (3.8-22.8)
Current/ past smokers, n (%) 2754 (34.6)
Prior therapy. n (%)  
    Methotrexate 6657 (83.6)
    Non-bDMARD(non-methotrexate) 3739 (46.9)
    TNFi 1245 (15.6)
    Non-TNFi bDMARD 414 (5.2)
Concomitant corticosteroids, n (%) 4254 (53.4)
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  • The ISS and analysis of adverse events of special interest includes pooled data from patients exposed to ≥1 dose of Tofacitinib Pfizer in phase 1, 2, 3, or 3b/4 clinical trials, and LTE studies in RA6
  • In LTE studies, dose adjustments for Tofacitinib Pfizer or concomitant medications were allowed at the investigator’s discretion for efficacy or safety reasons6
Adverse reactions occurring in ≥2% of patients receiving Tofacitinib Pfizer5 mg BID and ≥1% greater than that observed in patients on placebo (Tofacitinib Pfizer 5 mg BID and placebo ± csDMARDs).3Includes Tofacitinib Pfizer 5 mg BID and 10 mg BID treatment arms ± csDMARDs2; Tofacitinib Pfizer 5 mg BID is the recommended dose in most countries.4Final data for the RA cohorts are from April 18, 2019.6​​​​​​​All doses in RA included Tofacitinib Pfizer 1 mg, 3 mg, 5 mg, 10 mg, 15 mg, 30 mg BID; 10 mg or 20 mg QD; or 11 mg MR QD.8Tofacitinib Pfizer 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 RA2Adjudicated events.6​​​​​​​Composite MACE defined as any myocardial infarction, stroke, or cardiovascular death.6​​​​​​​Tofacitinib Pfizer 5 mg BID and 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.Explore more Dosing and administration in RA See recommended dosing
ACR=American College of Rheumatology; ATE=arterial thromboembolism; BID=twice daily; csDMARD=conventional synthetic disease-modifying antirheumatic drug; CV=cardiovascular; DSMB=Data Safety Monitoring Board; DVT=deep vein thrombosis; EMA=European Medicines Agency; HZ=herpes zoster; IR=inadequate response; JAKi=Janus kinase inhibitor; MACE=major adverse cardiovascular event; MR=modified release; MTX=methotrexate; NMSC=nonmelanoma skin cancer; PsA=psoriatic arthritis; pt-yr=patient year; QD=once daily; qw=once a week; q 2 wk=every 2 weeks; RA=rheumatoid arthritis; TB=tuberculosis; TNF=tumor necrosis factor; UC=ulcerative colitis; VTE=venous thromboembolism.References:Ytterberg SR, Deepak L Bhatt DL, Mikuls T, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med. 2022;386:316-26.Tofacitinib Pfizer [summary of product characteristics]. Bruxelles, PfizerTofacitinib Pfizer [prescribing information]. PfizerWollenhaupt 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/s13075-019-1866-2Data on file. PfizerBurmester 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-2021-001595Mease P, Charles-Schoeman C, Cohen S, et al. Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programmes and from real-world data. Ann Rheum Dis. 2020;79(11):1400-1413.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. [supplementary appendix]. RMD Open. 2021;7(2):1-36.
Safety and Tolerability
EFFICACY

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