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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.

ORAL Surveillance Postmarketing DataORAL 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 XELJANZ labeling in their respective markets based on their ongoing review of the complete ORAL Surveillance results 

The recommended dose of XELJANZ in RA is 5 mg administed BID, or 11 mg administed OD, which should not be exceeded.2
a MACE defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. 
b Patients who were treated with tofacitinib 10 mg BID were switched to tofacitinib 5 mg BID.
c Patients randomised 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.
d Based on Cox proportional hazard model.
e 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 Characteristics1
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  Treated patients
(N=4362)
Female 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 extra-articular disease 1605 (36.8)
History of hypertension 2878 (66.0)
ORAL Surveillance: Coprimary Endpoint Results for Adjudicated MACE and Adjudicated Malignancies (Excluding NMSC)1

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

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 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 recommended dose of XELJANZ in RA is 5 mg administed BID, or 11 mg administed OD, which should not be exceeded.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. 
a 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).
b 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). 
c 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. 
d Based on Cox proportional hazard model.
e 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-treament period analysis was used to assess AEsa

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Xeljanz 5 mg BID
(N=1455)

 
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)

390 (26.8)

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 

9 (0.6) 2.93 (0.79, 10.83)

15 (1.0)
2.21 (0.90, 5.43)

7 (0.5)

Adjudicated pulmonary embolism

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 recommended dose of XELJANZ in RA is 5 mg administed BID, or 11 mg administed OD, which should not be exceeded.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. 
a Defined as the minimum of the date of last contact or the date of the last dose of a trial treatment plus 28 days.
b Based on Cox proportional hazard model.
c Also included are opportunistic herpes zoster and tuberculosis events.
d Included are herpes zoster adjudicated as an opportunistic infection and nonadjudicated herpes zoster events.

Safety profile from the RA clinical trial programs2
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Most common adverse reactions in the first
3 months of phase 2 and 5 phase 3 clinical trials

 

XELJANZ 5 
mg BID 
(n=1336)

Upper respiritary tract infections

4%

Headache

4%

Viral upper respiratory tract infection

3%

Diarrhoea

3%

Nausea

3%

Hypertension

2%

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Adverse events - all-cause and serious adverse events in patients recieving XELJANZ for more than 9 years3

 

 

XELJANZ 5 mg BID
(n=1123)
4683 pt-yrs
​​​​

Patients with AEs (any cause), n (%)

1015 (90.4)

Discontinuation due to AEs, n (%)

315 (28.0)

SAEs, patients with events/100 pt-yrs (95% Cl)

8.2 (7.3, 9.1)

Limitations of pooled and long-term extension (LTE) data4
  • 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
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Incidence rates, patients with events/100 pt-yrs (95% CI) for safety events of interest through March 20175

 

XELJANZ 5 mg BIDa
(N=3066) ​​​​8171pt-yrs

Serious infectionsa

2.8 (2.5, 3.2)

HZ (nonserious and serious)

3.5 (3.1, 3.9)

TB

0.1 (0.1, 0.2)

Opportunistic infections (excluding TB)

0.3 (0.2, 0.5)

Malignancies (excluding NMSC)

0.8 (0.6, 1.0)

NMSC

0.4 (0.3, 0.6)

MACE

0.4 (0.3, 0.6)

VTEb

0.2 (0.1, 04)

DVT

0.2 (0.1, 0.3)

PE

0.1 (0.0, 0.2)

Gastrointestinal perforation

0.1 (0.0, 0.2)

a Average dosing was based on average daily dose; some patients recieved 10 mg BID during the LTE.
b Patients with a DVT event, a PE event, or both DVT and PE events. A total of 5 patients experienced a DVT and PE event (may not have occurred at the same time).1

​​​​​XELJANZ 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 RA2.​​​​​​

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.XELJANZ (tofacitinib citrate) 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/s13075-019-1866-2Data on file. Pfizer Inc., New York, NY.Cohen SB et al. RMD Open: 2020; 6 (3)
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.
PP-XEL-GBR-3727. June 2022
Safety & Tolerability ORAL Surveillance study in Ulcerative Colitis | Professor Charlie Lees

In this video, Professor Charlie Lees, consultant gastroenterologist at the Edinburgh IBD Unit talks about the ORAL Surveillance study and its implications for the use of tofacitinib in the treatment of ulcerative colitis. He offers an overview of the study design and a summary of the results, before offering his own clinical interpretation and how this affects his prescribing decisions specifically with UC patients.

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Prescribing Information

ORAL Surveillance study in Rheumatoid Arthritis | Dr James Galloway

In this video, Dr James Galloway, respected rheumatologist and researcher talks about the ORAL Surveillance study and its implications for the use of tofacitinib in the treatment of RA. He offers an overview of the study design and a summary of the results, before offering his own clinical interpretation and how this affects his prescribing decisions.

Watch NowLoading

Prescribing Information

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard or search 

for MHRA Yellow Card in Google Play or Apple App Store


Adverse events should also be reported to Pfizer Medical Information on 01304 616161

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