UC Efficacy & Safety | XELJANZ® (tofacitinib)

OCTAVE Trial Design

Week 8 & Week 2 Data

Week 52 Data

Open-Label Extension Data

Trial Design

OCTAVE CLINICAL PROGRAM^1-4

Patients eligible for immediate enrollment in OLE

Completed OCTAVE Induction but did not achieve clinical
response
Completed OCTAVE Sustain
Withdrew early from OCTAVE Sustain due to treatment failure

Remission was defined as a total Mayo score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0⁵
Clinical response was defined as a decrease from baseline in the total Mayo score ≥3 points and ≥30%, with an accompanying decrease in the subscore for rectal bleeding of ≥1 point or an absolute subscore for rectal bleeding of 0 or 1⁵

Please scroll down for information pertaining to each study in the OCTAVE Clinical Program.

^aThe total number of patients does not include those who received XELJANZ 15 mg twice daily (n=22).
XELJANZ 15 mg twice daily is not an approved dose.^4,5

^bPatients who completed one of the OCTAVE Induction studies (UC-I or UC-II) but did not achieve clinical response.⁴

^cFinal open-label extension data (August 2020).²

OCTAVE Clinical Program Study Design

The efficacy and safety of XELJANZ in UC were evaluated in the OCTAVE clinical program,
which included three phase 3, randomized, double-blind, placebo-controlled clinical trials:

OCTAVE Induction 1 (UC-I), OCTAVE Induction 2 (UC-II),

OCTAVE Sustain (UC-III), and an open-label, long-term

extension study (UC-IV)^1,5

OCTAVE Induction 1 and 2⁵

OCTAVE Sustain⁵

OCTAVE Open^2,3

All patients in the Oral Clinical Trials for tofAcitinib in ulceratiVE colitis (OCTAVE) clinical program were adults with a confirmed diagnosis of moderately to severely active UC for at least 4 months, which was defined as a Mayo score of 6 to 12, with a rectal bleeding subscore ≥1 and an endoscopic subscore ≥2. Patients were required to have experienced treatment failure with or intolerance to at least 1 of the following agents: oral or intravenous corticosteroids, azathioprine, 6-MP, or TNF blocker. Endoscopic results were centrally read in the induction trials and OCTAVE Sustain.

OCTAVE Induction 1 and 2⁵
In 2 identical, 8-week induction studies, 1139 patients with moderately to severely active UC (598 and 541 patients, respectively) were randomized to XELJANZ 10 mg twice daily or placebo (4:1 ratio). The primary endpoint was remission (primary endpoint at Week 8 UC-I and UC-II, and primary endpoint at Week 52 UC-III). During the induction trials, patients who were on stable doses of oral aminosalicylates and corticosteroids (prednisone daily dose up to 25 mg equivalent) were permitted to continue on their stable dosing. Concomitant immunosuppressants (immunomodulators or biological therapies) were not permitted for UC patients during the induction studies.

OCTAVE Sustain⁵
In a 52-week maintenance study, 593 patients who had completed the induction studies and achieved clinical response were rerandomized to XELJANZ 10 mg twice daily, XELJANZ 5 mg twice daily, or placebo (1:1:1 ratio). XELJANZ 5 mg twice daily is the recommended dosage for maintenance therapy. For patients with loss of response during maintenance treatment, a dosage of 10 mg twice daily may be considered and limited to the shortest duration. The primary endpoint was remission. Sustained corticosteroid-free remission (key secondary endpoint at both Week 24 and Week 52 UC-III) was a key secondary endpoint. Patients were permitted to use stable doses of oral aminosalicylates, but initiation of corticosteroid tapering was required upon entrance to this study for patients who were receiving corticosteroids at baseline. Concomitant immunosuppressants (immunomodulators or biological therapies) were not permitted.

OCTAVE Open^2,3
In this open-label, long-term extension trial of 944 patients with moderately to severely active UC, 175 and 769 patients were assigned XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily, respectively. The primary objective was to assess the safety and tolerability of long-term XELJANZ therapy, and safety endpoints included incidence and severity of AEs and clinical laboratory abnormalities. There were no primary efficacy endpoints. Patients eligible for immediate enrollment in this trial included those who completed or withdrew due to treatment failure from OCTAVE Sustain (UC-III) and those who completed OCTAVE Induction studies (UC-I or UC-II) but did not achieve clinical response.

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Total patient population included patients with and without prior TNF blocker failure⁵

Prior TNF blocker failure was defined in this program as inadequate response, loss of response, or intolerance to TNF blocker therapy
Patients without prior TNF blocker failure had failed one or more conventional therapies
(corticosteroid, azathioprine, 6-MP) but did not have a history of prior failure of TNF blocker therapy

In 2016, the US Food and Drug Administration (FDA) published guidance recommending use of the modified Mayo (mMayo) score as an endpoint for UC clinical trials.^a,b

The mMayo score removes the PGA, which is considered to be a subjective measure and thus potentially limiting in assessing UC disease severity.⁶

Since the pivotal trials for XELJANZ (OCTAVE Induction 1 and 2, which were conducted between 2012-2016) used only Mayo score, a post hoc analysis was performed to evaluate XELJANZ efficacy using both mMayo and Mayo scores with pooled data from OCTAVE Induction 1 and 2. Evaluating efficacy post hoc using the mMayo score may allow physicians to better contextualize these data.

^aD’Haens G, Sandborn WJ, Feagan BG, et al. A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis.
Gastroenterology. 2007; 132: 763–786.

^bU.S. Department of Health and Human Services, Food and Drug Administration and Center for Drug Evaluation and Research (CDER). Ulcerative colitis: clinical trial endpoints. Guidance for industry. http://www.fda.gov/downloads/Drugs/Guidances/UCM515143.pdf (2016, accessed 8 Jul 2021). U.S. Food and Drug Administration. The FDA is responsible for protecting and promoting the public health.

Post Hoc Analysis of OCTAVE Trial Data Through Week 8^6a

In the post hoc analysis (post hoc analysis is cited in Sandborn 2022, Therapeutic Advances in Gastroenterology; Vol. 15: 1–13), remission at Week 8 was based on Mayo and mMayo score:

Objectives:
The subjectivity of the Physician Global Assessment (PGA) is a limitation of the Mayo score in assessing severity of UC. Treatment efficacy was compared using endpoint definitions based on modified Mayo (mMayo) score, versus those based on Mayo score, using data from the tofacitinib OCTAVE program.

Design:
This post hoc analysis included data from two 8-week induction studies (OCTAVE Induction 1 and 2) and a 52-week maintenance study (OCTAVE Sustain).

Methods:
Remission and clinical response [with nonresponder imputation (NRI)] were assessed using mMayo (without PGA) and Mayo scores, and further stratified by prior tumor necrosis factor inhibitor (TNFi) failure status.

DEFINITIONS:
In the post hoc analysis, remission at Week 8 was based on Mayo and mMayo score⁶:

Mayo score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0
mMayo score, with an endoscopic subscore of ≤1, a stool frequency subscore of ≤1, and a rectal bleeding subscore of 0

Limitations:

Post hoc analyses are not prespecified, potentially introducing inherent bias⁶
Clinical data in these post hoc analyses were pooled from 2 different studies and were not adjusted for multiplicity; therefore, the resultant data should be considered cautiously, and statistical conclusions should not be drawn⁶
NRI was applied in this analysis, a conservative method that avoids bias by assuming that the patient is a nonresponder at the time of trial withdrawal, which may limit the differences between scoring definitions compared with the use of observed data⁶

^aThis work was supported by Pfizer. These studies were sponsored by Pfizer. Medical writing support was funded by Pfizer.

OCTAVE Trial Design

Week 8 & Week 2 Data

Week 52 Data

Open-Label Extension Data

Week 8 Data

XELJANZ is approved for use in patients with inadequate response or intolerance to TNF blockers.⁵

^aTotal population includes patients without prior TNF blocker failure.⁵

^bPrior TNF blocker failure was defined as inadequate response, loss of response, or intolerance to TNF blocker therapy.⁵

^cLimitations: While these subgroup analyses were predefined, the pooled data are post hoc analyses.¹

XELJANZ is approved for use in patients with inadequate response or intolerance to TNF blockers.¹

^bTotal population includes patients without prior TNF blocker failure.⁵

^cLimitations: While these subgroup analyses were predefined, the pooled data are post hoc analyses.¹

XELJANZ is approved for use in patients with inadequate response or intolerance to TNF blockers.⁵
Clinical response was defined as a decrease from baseline in the total Mayo score of ≥3 points and ≥30%, with an accompanying decrease in the subscore for rectal bleeding of ≥1 point or an absolute subscore for rectal bleeding of 0 or 1.⁵

^aTotal population includes patients without prior TNF blocker failure.⁵

^bPrior TNF blocker failure was defined as inadequate response, loss of response, or intolerance to TNF blocker therapy.⁵

^cLimitations: While these subgroup analyses were predefined, the pooled data are post hoc analyses.¹

XELJANZ is approved for use in patients with inadequate response or intolerance to TNF blockers.⁵
Improvement of endoscopic appearance of the mucosa was defined as Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern).⁵

^aTotal population includes patients without prior TNF blocker failure.⁵

^bPrior TNF blocker failure was defined as inadequate response, loss of response, or intolerance to TNF blocker therapy.⁵

^cLimitations: While these subgroup analyses were predefined, the pooled data are post hoc analyses.¹

Week 2 Data

MAYO RECTAL BLEEDING AND STOOL FREQUENCY SUBSCORES METHODOLOGY

Patients used a phone-based interactive voice recording system to record daily bowel movement data and rectal bleeding^1,7

• In the OCTAVE clinical program, patients were asked to record:

“Normal” number of stools per day when not having a flare (only at screening)

Number of bathroom visits for bowel movements per day

Presence of blood in stools (if any)

Description of blood in stools (if any)

Daily bowel movement data that were collected from the patients were used to calculate the Mayo stool frequency and rectal bleeding subscores^1,7

Mayo rectal bleeding and stool frequency subscores for exploratory endpoints¹

Mayo scores were calculated based on the data recorded over the 3 prior consecutive days

Mayo rectal bleeding and stool frequency subscores for post hoc analyses⁷

Baseline values were derived using average data from 3 of the 5 days before first dose
Change from baseline was determined based on diary data for each day during the first 15 days of therapy
Reported for total patient population and TNF blocker subgroups (patients with prior TNF blocker failure and patients without prior TNF blocker failure)
Limitations exist for post hoc analysis. See limitations with data below

XELJANZ is approved for use in patients with inadequate response or intolerance to TNF blockers.⁵

^aTotal population includes patients without prior TNF blocker failure.⁵

^bLimitations: While these endpoints were predefined in OCTAVE 1 and 2, the pooled data are post hoc analyses.^1,7

XELJANZ is approved for use in patients with inadequate response or intolerance to TNF blockers.⁵

^aTotal population includes patients without prior TNF blocker failure.⁵

^bLimitations: While these endpoints were predefined in OCTAVE 1 and 2, the pooled data are post hoc analyses.^1,7

POST HOC ANALYSIS

Percent of Patients With a Reduction From Baseline in the Mayo Stool Frequency Subscore ≥ 1 Total Population (Pooled Data)^1,6,a,b

XELJANZ is approved for use in patients with inadequate response or intolerance to TNF blockers.⁵
Post Hoc Analysis From OCTAVE Induction Trials in UC

Limitations of post hoc analysis
These analyses were post hoc, and data were based on daily telephone diary entries. Onset of XELJANZ efficacy in the wider population of patients with UC may differ. XELJANZ plasma concentration may not be at steady state until 24 to 48 hours after initial dosing. Therefore, these analyses should be interpreted with caution.^1,7

POST HOC ANALYSIS

XELJANZ is approved for use in patients with inadequate response or intolerance to TNF blockers.⁵
Post Hoc Analysis From OCTAVE Induction Trials in UC

At day 3, 31% (133/434) of patients with prior TNF blocker failure taking XELJANZ 10 mg BID had a reduction from baseline of ≥1 point in Mayo rectal bleeding subscore vs 13% (14/112) of patients on placebo (pooled data; subgroup population)^1,6,a,c
At day 15, 58% (239/415) of patients with prior TNF blocker failure taking XELJANZ 10 mg BID had a reduction from baseline of ≥1 point in Mayo rectal bleeding subscore vs 36% (39/110) on placebo (pooled data; subgroup population)^2,7,a,c

^aProportion of patients with a reduction from baseline in the Mayo rectal bleeding subscore ≥1 point excludes
patients with a baseline Mayo rectal bleeding subscore of 0.^1,7

^bTotal population includes patients without prior TNF blocker failure.⁵

^cPrior TNF blocker failure was defined as inadequate response, loss of response, or intolerance to TNF blocker
therapy.⁵

References

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POST HOC ANALYSIS

Percent of Patients With a Reduction From Baseline in the Mayo Stool Frequency Subscore ≥ 1 Point With Prior TNF Blocker Failure (Pooled Data of Subgroup Population)^1,6,a,b

XELJANZ is approved for use in patients with inadequate response or intolerance to TNF blockers.⁵
Post Hoc Analysis From OCTAVE Induction Trials in UC

Example

XELJANZ is approved for use in patients with inadequate response or intolerance to TNF blockers.⁵
Post Hoc Analysis From OCTAVE Induction Trials in UC

At day 3, 27% (117/437) of patients with prior TNF blocker failure taking XELJANZ 10 mg BID had a reduction from baseline of ≥1 point in Mayo stool frequency subscore vs 14% (16/114) of patients on placebo (pooled data; subgroup population)^1,6,a,c
At day 15, 47% (196/417) of patients with prior TNF blocker failure taking XELJANZ 10 mg BID had a reduction from baseline of ≥1 point in Mayo stool frequency subscore vs 28% (31/112) on placebo (pooled data; subgroup population)^1,6,a,c

^aProportion of patients with a reduction from baseline in the Mayo stool frequency subscore ≥1 point excludes patients with a baseline Mayo stool frequency subscore of 0.^1,7

^bTotal population includes patients without prior TNF blocker failure.⁵

^cPrior TNF blocker failure was defined as inadequate response, loss of response, or intolerance to TNF blocker therapy.⁵

OCTAVE Trial Design

Week 8 & Week 2 Data

Week 52 Data

Open-Label Extension Data

Week 52 Data

XELJANZ is approved for use in patients with inadequate response or intolerance to TNF blockers.⁵
Remission was defined as a total Mayo score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0.⁵

Recommended Maintenance Dosing: For patients with loss of response during maintenance treatment, a dosage of 10 mg BID may be considered and limited to the shortest duration. Use the lowest effective dose needed to maintain response.⁵ The recommended maintenance dosing is XELJANZ 5 mg BID or XELJANZ XR 11 mg once daily. For patients with loss of response during maintenance treatment, XELJANZ 10 mg BID or XELJANZ XR 22 mg once daily may be considered and limited to the shortest duration, with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dose needed to maintain response.⁵
Changes between XELJANZ and XELJANZ XR should be made by the healthcare provider.⁵ See full dosing recommendations, including adjustments, in the XELJANZ full Prescribing Information here.

^aTotal population includes patients without prior TNF blocker failure.⁵

^bPrior TNF blocker failure was defined as inadequate response, loss of response, or intolerance to TNF blocker therapy.⁵

XELJANZ is approved for use in patients with inadequate response or intolerance to TNF blockers.⁵
Sustained corticosteroid-free remission was defined as remission (a total Mayo score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0) and not taking corticosteroids for at least 4 weeks prior to the visit at both Week 24 and Week 52 among patients in remission at baseline.⁵

^aTotal population includes patients without prior TNF blocker failure.⁵

^bPrior TNF blocker failure was defined as inadequate response, loss of response, or intolerance to TNF blocker therapy.⁵

XELJANZ is approved for use in patients with inadequate response or intolerance to TNF blockers.⁵

Improvement of endoscopic appearance of the mucosa was defined as Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern).

^aTotal population includes patients without prior TNF blocker failure.⁵

^bPrior TNF blocker failure was defined as inadequate response, loss of response, or intolerance to TNF blocker therapy.⁵

OCTAVE Trial Design

Week 8 & Week 2 Data

Week 52 Data

Open-Label Extension Data

OCTAVE CLINICAL PROGRAM TRIAL DESIGN WITH MAINTENANCE OF REMISSION AND RECAPTURE OF RESPONSE SUBPOPULATIONS^1-5,9

The approved dosage of XELJANZ for maintenance therapy is 5 mg twice daily. For patients with loss of response during maintenance treatment, a dosage of 10 mg twice daily may be considered and limited to the shortest duration, with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dose needed to maintain response⁵

See full dosage recommendations, including adjustments in the full Prescribing Information.

Loss of response was assessed in OCTAVE Open as treatment failure^9,c

^aThe total number of patients does not include those who received XELJANZ 15 mg twice daily (n=22). XELJANZ 15 mg twice daily is not an approved dose.^4,5

^bPatients who completed one of the OCTAVE Induction studies (UC-I or UC-II) but did not achieve clinical response.⁴

^cRemission was defined as Mayo score ≤2, with no individual subscore >1 and rectal bleeding subscore of 0.⁹

^dTreatment failure was defined as a ≥3-point increase from baseline total Mayo score, plus a ≥1-point increase in rectal bleeding and endoscopic subscores (centrally read), and an absolute endoscopic subscore ≥2 after ≥8 weeks of maintenance therapy. Patients who withdrew from the study due to insufficient clinical response also qualified for the event of treatment failure.³

^eEfficacy outcomes were assessed in the maintenance of remission subpopulation, which consisted of those who received either 10 mg twice daily or 5 mg twice daily during OCTAVE Sustain (n=142); safety was assessed in patients who received ≥1 dose of XELJANZ 5 mg twice daily in OCTAVE Open (n=175 [142 patients in the maintenance of remission subpopulation, 21 patients who received placebo during OCTAVE Sustain and completed in remission, and 12 patients who received XELJANZ 5 mg twice daily in the OLE as protocol deviations]).³

^fFinal OLE data (August 2020).⁴

^gThere were no primary efficacy endpoints.⁴

LIMITATIONS AND BIASES OF OPEN-LABEL/LONG-TERM EXTENSION STUDIES

LTE studies may provide useful data on rare and long-latency AEs, as well as trends over exposure time
However, conduct of LTE studies where both treatment and dose are known to both investigator and patient is subject to certain biases and limitations and, therefore, data should be interpreted with caution

SUMMARY OF SAFETY IN OCTAVE OPEN—PRIMARY OBJECTIVE

In the long-term extension study, malignancies (including solid cancers, lymphomas, and NMSC) were observed in patients treated with XELJANZ 5 mg and 10 mg twice daily. Five cases of pulmonary embolism were reported in patients taking XELJANZ  10 mg twice daily, including one fatality in a patient with advanced cancer²

LIMITATIONS: In this study, between-group comparisons were limited by baseline differences between dose groups and by the fact that, due to study design, 81.5% of patients were assigned to and received XELJANZ 10 mg twice daily at baseline of the open-label, long-term extension study. Comparisons were also limited by the fact that dose groups were classified based on initial treatment assignment; patients were permitted to switch dose during the study, with no fixed treatment groups for comparison. Dose dependency of IRs could not be firmly concluded from the data presented here, as dose changes were permitted during the study. Finally, this was an open-label study with no placebo or active comparator arm, and so does not allow direct comparison of XELJANZ with other treatments.²

XELJANZ/XELJANZ XR has a BOXED WARNING for Serious Infections, Mortality, Malignancy, MACE, and Thrombosis.

LIMITATIONS: In this study, between-group comparisons were limited by baseline differences between dose groups and by the fact that, due to study design, 81.5% of patients were assigned to and received XELJANZ 10 mg twice daily at baseline of the open-label, long-term extension study. Comparisons were also limited by the fact that dose groups were classified based on initial treatment assignment; patients were permitted to switch dose during the study, with no fixed treatment groups for comparison. Dose dependency of IRs could not be firmly concluded from the data presented here, as dose changes were permitted during the study. Finally, this was an open-label study with no placebo or active comparator arm, and so does not allow direct comparison of XELJANZ with other treatments.³

XELJANZ/XELJANZ XR has a BOXED WARNING for Serious Infections, Mortality, Malignancy, MACE, and Thrombosis.

^aAll patients underwent endoscopy at Month 2; induction nonresponders were mandated to discontinue if they failed to achieve clinical response by Month 2.²

^bA total of 944 patients received at least one dose of XELJANZ (for up to 7.0 years; range, 1-2561 days) upon entry into OCTAVE Open.²

^cOther reasons for withdrawal from OCTAVE Open included: no longer willing to participate in study, pregnancy, protocol violation, lost to follow-up, not meeting entrance criteria, adverse events not related to study drug, other.²

^dAdverse events of worsening ulcerative colitis leading to discontinuation were designated as insufficient clinical response.²

^eRelated to study drug in 12 (6.9%) patients who received XELJANZ 5 mg twice daily and 46 (6.0%) patients who received XELJANZ 10 mg twice daily.²

^fTwo patients in the 5 mg twice daily arm of OCTAVE Open were enrolled in RIVETING in error.²

Percentage of Patients Who Were Remitters in OCTAVE Sustain After 52 Weeks on Either 5 mg Twice Daily or 10 mg Twice Daily and Maintained Remission in OCTAVE Open on 5 mg Twice Daily³

LIMITATIONS: Post hoc analyses and open-label studies have inherent biases. For this analysis from the OLE study, both treatment and dose were known to both investigator and patient; there was no comparator arm; the sample size was small; endoscopies were read locally rather than centrally; and efficacy was not a primary endpoint. This analysis should be interpreted with caution while taking these considerations into account.

Nonresponder imputation (NRI) was applied for patients with missing data or who discontinued. Thus, these patients were recorded as having failed the endpoint.³
Last observation carried forward (LOCF) was applied for patients who discontinued and transferred to another study. LOCF used the patients’ data from the last observation to the date of this data cut, with the assumption that the response status remained after the discontinuation.³
Observed case analysis shows data without these imputations.³
Remission was defined as a total Mayo score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0³

Nonresponder imputation (NRI) was applied for patients with missing data or who discontinued. Thus, these patients were recorded as having failed the endpoint.³
Last observation carried forward (LOCF) was applied for patients who discontinued and transferred to another study. LOCF used the patients’ data from the last observation to the date of this data cut, with the assumption that the response status remained after the discontinuation.³
Observed case analysis shows data without these imputations.³
Remission was defined as a total Mayo score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0³

^aTotal population includes patients in the maintenance of remission efficacy subpopulation of OCTAVE Open who received XELJANZ 5 mg twice daily or 10 mg twice daily during OCTAVE Sustain and 5 mg twice daily during OCTAVE Open.³

^bAt Month 36 (observed case analysis), 84.6% (33/39) and 94.4% (34/36) of patients who received XELJANZ 5 mg twice daily and 10 mg twice daily, respectively, during OCTAVE Sustain were in remission.³

^cFour patients dropped out of the open-label extension between Month 24 and Month 36 to enroll in Study 1288 or the Japan postmarketing surveillance study, or due to regulatory approval in Japan. These patients’ results were carried forward at Month 36 for the NRI-LOCF analysis.¹

^dOne patient had not reached Month 36 at the time of this interim analysis. Data are from an interim analysis of the May 27, 2019 data cut.³

^eAt Month 36 (NRI-LOCF analysis), 53.0% (35/66) and 48.0% (36/75) of patients who received XELJANZ 5 mg twice daily and 10 mg twice daily, respectively, during OCTAVE Sustain were in remission.³

Percentage of Patients With Clinical Response or Remission in OCTAVE Open on XELJANZ 10 mg Twice Daily Who Had Lost Response During the Prior Study, OCTAVE Sustain, on XELJANZ 5 mg Twice Daily^9,b

Clinical response was defined as a decrease from baseline (in Induction 1 and 2 studies) in the total Mayo score of ≥3 points and ≥30%, plus a decrease in the subscore for rectal bleeding of ≥1 point or an absolute subscore for rectal bleeding of 0 or 1⁹
Remission was defined as a total Mayo score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0⁹

See UC Safety Data

See ORAL Surveillance Safety Data

AE=adverse event; BID=twice daily; CIR=cumulative incidence rate; IR=incidence rate; LTE=long-term extension; NMSC=nonmelanoma skin cancer; NRI-LOCF=nonresponder imputation-last observation carried forward; OLE=open-label extension; TNF=tumor necrosis factor; UC=ulcerative colitis.

^aPatients with loss of response were those who experienced treatment failure between Week 8 and Week 52 of OCTAVE Sustain. Treatment failure was defined as a ≥3-point increase from baseline total Mayo score, plus a ≥1-point increase in rectal bleeding and endoscopic subscores (centrally read), and an absolute endoscopic subscore ≥2 after ≥8 weeks of maintenance therapy. Patients who withdrew from OCTAVE Sustain due to insufficient clinical response also qualified for the event of treatment failure.⁹

^bPatients in the recapture efficacy subpopulation of OCTAVE Open were responders to XELJANZ 10 mg twice daily during OCTAVE Induction who received XELJANZ 5 mg twice daily during OCTAVE Sustain and experienced treatment failure, then received XELJANZ 10 mg twice daily during OCTAVE Open.⁹

^cNonresponder imputation (NRI) was applied for patients with missing data or who discontinued. Thus, these patients were recorded as having failed the endpoint. Data are from an interim analysis of the November 2017 data cut.⁹

References:

Data on file. Pfizer Inc., New York, NY.

Sandborn WJ, Lawendy N, Danese S, et al. Safety and efficacy of tofacitinib for treatment of ulcerative colitis: final analysis of OCTAVE Open, an open-label, long-term extension study with up to 7.0 years of treatment. Aliment Pharmacol Ther. 2022;55(4):464-478.

Colombel J-F, Osterman MT, Thorpe AJ, et al. Maintenance of remission with tofacitinib therapy in patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2022;20(1):116-125.

Sandborn WJ, Su C, Sands BE, et al; for the OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain Investigators. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376(18):1723-1736.

XELJANZ [prescribing information]. New York, NY: Pfizer Inc., May 2024.

Sandborn WJ, Sands BE, Vermeire S, et al. Modified Mayo score versus Mayo score for evaluation of treatment efficacy in patients with ulcerative colitis: data from the tofacitinib OCTAVE program. Therap Adv Gastroenterol. 2022;15:1-13.

Hanauer S, Panaccione R, Danese S, et al. Tofacitinib induction therapy reduces symptoms within 3 days for patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2019;17(1):139-147.

Dhanda AD, Creed TJ, Greenwood R, Sands BE, Probert CS. Can endoscopy be avoided in the assessment of ulcerative colitis in clinical trials? Inflamm Bowel Dis. 2012;18(11):2056-2062.

Sands BE, Armuzzi A, Marshall JK, et al. Efficacy and safety of tofacitinib dose de-escalation and dose escalation for patients with ulcerative colitis: results from OCTAVE Open. Aliment Pharmacol Ther. 2020;51(2):271-280.

Safety Profile

Safety Data in OCTAVE Induction Trials

Safety Data in OCTAVE Sustain Trials

Pooled Safety Data From 6 Clinical Trials

ORAL Surveillance Safety Data (RA) and Pooled Safety Analysis (UC)

XELJANZ SAFETY PROFILE

XELJANZ has a BOXED WARNING for Serious Infections, Mortality, Malignancy, MACE, and Thrombosis. See Important Safety Information and full Prescribing Information for additional details.

To review the full XELJANZ safety profile below, select "Read more" to expand each box.

SERIOUS INFECTIONS^1,2

Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ until the infection is controlled.
Reported infections include:

Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ use.
Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

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MORTALITY²

In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular (CV) risk factor comparing XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden CV death, was observed with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day. A XELJANZ 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA. For UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

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MALIGNANCY²

Malignancies, including lymphomas and solid tumors, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. In RA patients, a higher rate of malignancies (excluding NMSC) was observed in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day compared with TNF blockers.

Lymphoma and lung cancers were observed at a higher rate in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day in RA patients compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.

Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy while on treatment, and patients who are current or past smokers. A XELJANZ 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA.

Other malignancies were observed in clinical studies and the postmarketing setting including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. NMSCs have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC.

Read less

MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE)²

RA patients 50 years of age and older with at least one cardiovascular (CV) risk factor, treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily, had a higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke), compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue XELJANZ in patients that have experienced a myocardial infarction or stroke.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ, particularly in patients who are current or past smokers and patients with other CV risk factors. Inform patients about the symptoms of serious CV events. A XELJANZ 10 mg twice a day (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA.

Read less

THROMBOSIS²

Thrombosis, including pulmonary embolism, deep vein thrombosis, and arterial thrombosis, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death. RA patients 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily compared to TNF blockers had an observed increase in incidence of these events. Avoid XELJANZ in patients at risk. Discontinue XELJANZ and promptly evaluate patients with symptoms of thrombosis.

A XELJANZ 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA. In a long-term extension study in UC, five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one death in a patient with advanced cancer. For UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

Read less

GI PERFORATIONS²

Gastrointestinal perforations have been reported in XELJANZ clinical trials, although the role of JAK inhibition is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). There was no discernible difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids. 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 or taking NSAIDs).

Read less

HYPERSENSITIVITY²

Angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ and some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction.

Read less

LAB ABNORMALITIES²

Lymphocyte Abnormalities: Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts. Avoid initiation of XELJANZ treatment in patients with a count less than 500 cells/mm³. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm³, treatment with XELJANZ is not recommended. Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Monitor lymphocyte counts at baseline and every 3 months thereafter.

Neutropenia: Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm³) compared to placebo. Avoid initiation of XELJANZ treatment in patients with an ANC less than 1000 cells/mm³. For patients who develop a persistent ANC of 500-1000 cells/mm³, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm³. In patients who develop an ANC less than 500 cells/mm³, treatment with XELJANZ is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Anemia: Avoid initiation of XELJANZ treatment in patients with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Liver Enzyme Elevations: Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. If drug-induced liver injury is suspected, the administration of XELJANZ should be interrupted until this diagnosis has been excluded. Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury.

Lipid Elevations: Treatment with XELJANZ was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. There were no clinically relevant changes in LDL/HDL cholesterol ratios. Manage patients with hyperlipidemia according to clinical guidelines. Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ therapy.

Read less

VACCINATIONS²

Avoid use of live vaccines concurrently with XELJANZ. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.

Read less

Safety Profile

Safety Data in OCTAVE Induction Trials

Safety Data in OCTAVE Sustain Trials

Pooled Safety Data From 6 Clinical Trials

ORAL Surveillance Safety Data (RA) and Pooled Safety Analysis (UC)

SAFETY DATA: OCTAVE INDUCTION 1 AND 2 TRIALS

XELJANZ/XELJANZ XR has a BOXED WARNING for Serious Infections, Mortality, Malignancy, MACE, and Thrombosis.

^aThe rates of the 4 most frequent adverse events occurring in the OCTAVE Sustain trial are listed for OCTAVE Induction 1 and 2.³

^bThese data include patients who discontinued treatment because of worsening ulcerative colitis.³

^cLaboratory data were missing for some patients.³

^dLLN denotes lower limit of the normal range; ULN denotes upper limit of the normal range.³

Safety Profile

Safety Data in OCTAVE Induction Trials

Safety Data in OCTAVE Sustain Trials

Pooled Safety Data From 6 Clinical Trials

ORAL Surveillance Safety Data (RA) and Pooled Safety Analysis (UC)

XELJANZ/XELJANZ XR has a BOXED WARNING for Serious Infections, Mortality, Malignancy, MACE, and Thrombosis.

SAFETY DATA: OCTAVE SUSTAIN TRIAL

XELJANZ/XELJANZ XR has a BOXED WARNING for Serious Infections, Mortality, Malignancy, MACE, and Thrombosis.

^aThe rates of the 4 most frequent adverse events occurring in the OCTAVE Sustain trial are listed for OCTAVE Induction 1 and 2.³

^bThese data include patients who discontinued treatment because of worsening ulcerative colitis.³

^cLaboratory data were missing for some patients.³

^dLLN denotes lower limit of the normal range; ULN denotes upper limit of the normal range.³

Safety Profile

Safety Data in OCTAVE Induction Trials

Safety Data in OCTAVE Sustain Trials

Pooled Safety Data From 6 Clinical Trials

ORAL Surveillance Safety Data (RA) and Pooled Safety Analysis (UC)

XELJANZ/XELJANZ XR has a BOXED WARNING for Serious Infections, Mortality, Malignancy, MACE, and Thrombosis.

LIMITATIONS: In this integrated safety analysis, only patients who initially participated in the OCTAVE clinical trials were included. Due to study design, 82.5% of patients in the Overall + P3b/4 Cohort received XELJANZ 10 mg BID, which limited between-group comparisons. Dose-dependency of IRs could not be firmly concluded from the data presented here, as dose changes were permitted during the OCTAVE Open and RIVETING studies. Finally, the studies included in the UC clinical program were not designed to be of sufficient size and duration to evaluate rare events, or those with long latency.⁴
For the Induction and Maintenance Cohorts, events that occurred >28 days after the last dose of the study drug were excluded; for the Overall (Dec 2016) and Overall + P3b/4 (2020) Cohorts, all events, including those outside the 28-day risk period, were included.⁴

^bThe "Overall + P3b/4 Cohort" comprised all patients who received one or more doses of XELJANZ 5 mg or 10 mg twice daily in any phase (2/3/OLE or phase 3b/4 study), and included final data from OCTAVE Open plus data from the 6-month interim analysis of the RIVETING study (interim data cutoff: February 20, 2020).⁴

^cAt baseline.⁴

^dData are reported for all AEs by preferred term, which occurred in ≥10% of patients in a treatment group in the Overall + P3b/4 Cohort.⁴

See ORAL Surveillance Safety Data

AE=adverse event; AS=ankylosing spondylitis; BID=twice daily; CV=cardiovascular; DMARD=disease-modifying antirheumatic drugs; GI=gastrointestinal; JAK=Janus kinase; MACE=major adverse cardiovascular event; NMSC=nonmelanoma skin cancer; PsA=psoriatic arthritis; RA=rheumatoid arthritis; TB=tuberculosis; TNF=tumor necrosis factor; UC=ulcerative colitis; XR=extended release.

References:

Data on file. Pfizer Inc., New York, NY.

XELJANZ [prescribing information]. New York, NY: Pfizer Inc., May 2024.

Sandborn WJ, D'Haens GR, Sands BE, et al. Tofacitinib for the treatment of ulcerative colitis: an integrated summary of up to 7.8 years of safety data from the global clinical programme. J Crohns Colitis. 2023;17(3):338-351.

Ulcerative Colitis

XELJANZ®/XELJANZ® XR (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC), who have had an inadequate response or intolerance to one or more TNF blockers.
Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Rheumatoid Arthritis

XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more TNF blockers.
Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic disease-modifying antirheumatic drugs (DMARDs) or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Psoriatic Arthritis

XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to one or more TNF blockers.
Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Ankylosing Spondylitis

XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active ankylosing spondylitis (AS) who have had an inadequate response or intolerance to one or more TNF blockers.
Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Polyarticular Course Juvenile Idiopathic Arthritis

XELJANZ/XELJANZ Oral Solution is indicated for the treatment of active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers.
Limitations of Use: Use of XELJANZ/XELJANZ Oral Solution in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

Indications

SERIOUS INFECTIONS

Patients treated with XELJANZ* are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ until the infection is controlled.

Reported infections include:

Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ use.
Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Avoid use of XELJANZ in patients with an active, serious infection, including localized infections.

In the UC population, XELJANZ 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily. Opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with XELJANZ 10 mg twice daily.

The risks and benefits of treatment with XELJANZ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection, or those who have lived or traveled in areas of endemic TB or mycoses. Viral reactivation including herpes virus and hepatitis B reactivation have been reported. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infection.

MORTALITY

In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular (CV) risk factor comparing XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden CV death, was observed with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day. A XELJANZ 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA. For UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

MALIGNANCIES

Malignancies, including lymphomas and solid tumors, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. In RA patients, a higher rate of malignancies (excluding NMSC) was observed in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day compared with TNF blockers.

Lymphoma and lung cancers were observed at a higher rate in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day in RA patients compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.

Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy while on treatment, and patients who are current or past smokers. A XELJANZ 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA.

Other malignancies were observed in clinical studies and the postmarketing setting including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. NMSCs have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC.

MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE)

RA patients 50 years of age and older with at least one CV risk factor, treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily, had a higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke), compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue XELJANZ in patients that have experienced a myocardial infarction or stroke.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ, particularly in patients who are current or past smokers and patients with other CV risk factors. Inform patients about the symptoms of serious CV events. A XELJANZ 10 mg twice a day (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA.

THROMBOSIS

Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death. RA patients 50 years of age and older with at least one CV risk factor treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily compared to TNF blockers had an observed increase in incidence of these events. Avoid XELJANZ in patients at risk. Discontinue XELJANZ and promptly evaluate patients with symptoms of thrombosis.

A XELJANZ 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA. In a long-term extension study in UC, five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one death in a patient with advanced cancer. For UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

GASTROINTESTINAL PERFORATIONS

Gastrointestinal perforations have been reported in XELJANZ clinical trials, although the role of JAK inhibition is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). There was no discernible difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids. 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 or taking NSAIDs).

HYPERSENSITIVITY

Angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ and some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction.

LABORATORY ABNORMALITIES

Lymphocyte Abnormalities: Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts. Avoid initiation of XELJANZ treatment in patients with a count less than 500 cells/mm³. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm³, treatment with XELJANZ is not recommended. Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Monitor lymphocyte counts at baseline and every 3 months thereafter.

Neutropenia: Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm³) compared to placebo. Avoid initiation of XELJANZ treatment in patients with an ANC less than 1000 cells/mm³. For patients who develop a persistent ANC of 500-1000 cells/mm³, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm³. In patients who develop an ANC less than 500 cells/mm³, treatment with XELJANZ is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Anemia: Avoid initiation of XELJANZ treatment in patients with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Liver Enzyme Elevations: Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. If drug-induced liver injury is suspected, the administration of XELJANZ should be interrupted until this diagnosis has been excluded. Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury.

Lipid Elevations: Treatment with XELJANZ was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. There were no clinically relevant changes in LDL/HDL cholesterol ratios. Manage patients with hyperlipidemia according to clinical guidelines. Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ therapy.

VACCINATIONS

Avoid use of live vaccines concurrently with XELJANZ. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.

PATIENTS WITH GASTROINTESTINAL NARROWING

Caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended-release formulation.

HEPATIC and RENAL IMPAIRMENT

Use of XELJANZ in patients with severe hepatic impairment is not recommended. For patients with moderate hepatic impairment or with moderate or severe renal impairment taking XELJANZ 5 mg twice daily or XELJANZ XR 11 mg once daily, reduce to XELJANZ 5 mg once daily. For UC patients with moderate hepatic impairment or with moderate or severe renal impairment taking XELJANZ 10 mg twice daily, reduce to XELJANZ 5 mg twice daily. If taking XELJANZ XR 22 mg once daily, reduce to XELJANZ XR 11 mg once daily.

ADVERSE REACTIONS

The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials in patients with RA with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in greater than or equal to 2% of patients treated with XELJANZ with or without DMARDs) were upper respiratory tract infection, nasopharyngitis, diarrhea, headache, and hypertension. The safety profile observed in patients with active PsA treated with XELJANZ was consistent with the safety profile observed in RA patients.

Adverse reactions reported in ≥5% of patients treated with either 5 mg or 10 mg twice daily of XELJANZ and ≥1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials for UC were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.

USE IN PREGNANCY

Available data with XELJANZ use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with rheumatoid arthritis and UC in pregnancy. In animal studies, tofacitinib at 6.3 times the maximum recommended dose of 10 mg twice daily demonstrated adverse embryo-fetal findings. The relevance of these findings to women of childbearing potential is uncertain. Consider pregnancy planning and prevention for females of reproductive potential.

SERIOUS INFECTIONS

Patients treated with XELJANZ® (tofacitinib)* are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ until the infection is controlled.

Reported infections include:

Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ use.
Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Avoid use of XELJANZ in patients with an active, serious infection, including localized infections.

In the UC^† population, XELJANZ 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily. Opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with XELJANZ 10 mg twice daily.

The risks and benefits of treatment with XELJANZ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection, or those who have lived or traveled in areas of endemic TB or mycoses. Viral reactivation including herpes virus and hepatitis B reactivation have been reported. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infection.

MORTALITY

In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA)^‡ patients 50 years of age and older with at least one cardiovascular (CV) risk factor comparing XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden CV death, was observed with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day. A XELJANZ 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA^§. For UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

MALIGNANCIES

Malignancies, including lymphomas and solid tumors, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. In RA patients, a higher rate of malignancies (excluding NMSC) was observed in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day compared with TNF blockers.

Lymphoma and lung cancers were observed at a higher rate in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day in RA patients compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.

Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy while on treatment, and patients who are current or past smokers. A XELJANZ 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA.

Other malignancies were observed in clinical studies and the postmarketing setting including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. NMSCs have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC.

MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE)

RA patients 50 years of age and older with at least one CV risk factor, treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily, had a higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke), compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue XELJANZ in patients that have experienced a myocardial infarction or stroke.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ, particularly in patients who are current or past smokers and patients with other CV risk factors. Inform patients about the symptoms of serious CV events. A XELJANZ 10 mg twice a day (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA.

THROMBOSIS

Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death. RA patients 50 years of age and older with at least one CV risk factor treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily compared to TNF blockers had an observed increase in incidence of these events. Avoid XELJANZ in patients at risk. Discontinue XELJANZ and promptly evaluate patients with symptoms of thrombosis.

A XELJANZ 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA. In a long-term extension study in UC, five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one death in a patient with advanced cancer. For UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

GASTROINTESTINAL PERFORATIONS

Gastrointestinal perforations have been reported in XELJANZ clinical trials, although the role of JAK inhibition is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). There was no discernible difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids. 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 or taking NSAIDs).

HYPERSENSITIVITY

Angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ and some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction.

LABORATORY ABNORMALITIES

Lymphocyte Abnormalities: Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts. Avoid initiation of XELJANZ treatment in patients with a count less than 500 cells/mm³. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm³, treatment with XELJANZ is not recommended. Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Monitor lymphocyte counts at baseline and every 3 months thereafter.

Neutropenia: Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm³) compared to placebo. Avoid initiation of XELJANZ treatment in patients with an ANC less than 1000 cells/mm³. For patients who develop a persistent ANC of 500-1000 cells/mm³, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm³. In patients who develop an ANC less than 500 cells/mm³, treatment with XELJANZ is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Anemia: Avoid initiation of XELJANZ treatment in patients with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Liver Enzyme Elevations: Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. If drug-induced liver injury is suspected, the administration of XELJANZ should be interrupted until this diagnosis has been excluded. Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury.

Lipid Elevations: Treatment with XELJANZ was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. There were no clinically relevant changes in LDL/HDL cholesterol ratios. Manage patients with hyperlipidemia according to clinical guidelines. Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ therapy.

VACCINATIONS

Avoid use of live vaccines concurrently with XELJANZ. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.

PATIENTS WITH GASTROINTESTINAL NARROWING

Caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended-release formulation.

HEPATIC and RENAL IMPAIRMENT

Use of XELJANZ in patients with severe hepatic impairment is not recommended. For patients with moderate hepatic impairment or with moderate or severe renal impairment taking XELJANZ 5 mg twice daily or XELJANZ XR 11 mg once daily, reduce to XELJANZ 5 mg once daily. For UC patients with moderate hepatic impairment or with moderate or severe renal impairment taking XELJANZ 10 mg twice daily, reduce to XELJANZ 5 mg twice daily. If taking XELJANZ XR 22 mg once daily, reduce to XELJANZ XR 11 mg once daily.

ADVERSE REACTIONS

The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials in patients with RA with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in greater than or equal to 2% of patients treated with XELJANZ with or without DMARDs) were upper respiratory tract infection, nasopharyngitis, diarrhea, headache, and hypertension. The safety profile observed in patients with active PsA treated with XELJANZ was consistent with the safety profile observed in RA patients.

Adverse reactions reported in ≥5% of patients treated with either 5 mg or 10 mg twice daily of XELJANZ and ≥1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials for UC were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.

USE IN PREGNANCY

Available data with XELJANZ use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with rheumatoid arthritis and UC in pregnancy. In animal studies, tofacitinib at 6.3 times the maximum recommended dose of 10 mg twice daily demonstrated adverse embryo-fetal findings. The relevance of these findings to women of childbearing potential is uncertain. Consider pregnancy planning and prevention for females of reproductive potential.

^*Unless otherwise stated, “XELJANZ” in the Important Safety Information refers to XELJANZ, XELJANZ XR, and XELJANZ Oral Solution.

UC=ulcerative colitis. XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active UC, who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

RA=rheumatoid arthritis. XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

PsA=psoriatic arthritis. XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

Important Safety Information