HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`These highlights do not include all the information needed to use
`
`
`XELJANZ/XELJANZ XR safely and effectively. See full prescribing
`information for XELJANZ/XELJANZ XR.
`
`XELJANZ® (tofacitinib) tablets, for oral use
`
`XELJANZ® XR (tofacitinib) extended-release tablets, for oral use
`
`
`
`
`
`
`Initial U.S. Approval: 2012
`
`
`
`
`WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY
`AND THROMBOSIS
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`
`
` Serious infections leading to hospitalization or death, including
`
`tuberculosis and bacterial, invasive fungal, viral, and other
`
`
`opportunistic infections, have occurred. (5.1)
`
`If a serious infection develops, interrupt XELJANZ/XELJANZ XR
`
`
`until the infection is controlled. (5.1)
`
` Prior to starting XELJANZ/XELJANZ XR, perform a test for latent
`
`
`
`
`
`tuberculosis; if it is positive, start treatment for tuberculosis prior to
`
`
`
`starting XELJANZ/XELJANZ XR. (5.1)
`
`
` Monitor all patients for active tuberculosis during treatment, even if
`
`
`the initial latent tuberculosis test is negative. (5.1)
`
`
` Rheumatoid arthritis patients with at least one cardiovascular (CV)
`
`
`
`
`risk factor had a higher rate of all-cause mortality and thrombosis
`with XELJANZ 10 mg twice daily vs. 5 mg twice daily or TNF
`
`
`
`blockers. (5.2, 5.4)
` Lymphoma and other malignancies have been observed in patients
`
`
`treated with XELJANZ, including an increased rate of Epstein Barr
`
`
`
`Virus-associated post-transplant lymphoproliferative disorder in
`renal transplant patients treated with XELJANZ and concomitant
`
`
`
`immunosuppressive medications. (5.3)
`
`
`--------------------------- RECENT MAJOR CHANGES ---------------------------
`
`
`
`Boxed Warning
`07/2019
`
`07/2019
`Indications and Usage (1)
`
`10/2018
`Dosage and Administration (2.2)
`
`
`07/2019
`Dosage and Administration (2.3)
`
`
`10/2018
`Warnings and Precautions (5.1)
`
`
`07/2019
`Warnings and Precautions (5.2)
`
`
`07/2019
`Warnings and Precautions (5.4)
`
`
`10/2018
`Warnings and Precautions (5.6)
`
`
`
`--------------------------- INDICATIONS AND USAGE----------------------------
`
`
`
`XELJANZ/XELJANZ XR is a Janus kinase (JAK) inhibitor.
`
` 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
`
`methotrexate. It may be used as monotherapy or in combination with
`
`
`
`
`methotrexate or other nonbiologic disease-modifying antirheumatic drugs
`
`
`(DMARDs).
`
`
`○ Limitations of Use: Use of XELJANZ/XELJANZ XR in combination
`with biologic DMARDs or potent immunosuppressants such as
`
`azathioprine and cyclosporine is not recommended. (1)
`
`
` 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 methotrexate or other
`
`
`
`disease-modifying antirheumatic drugs (DMARDs).
`
`
`
`○ Limitations of Use: Use of XELJANZ/XELJANZ XR in combination
`with biologic DMARDs or potent immunosuppressants such as
`
`azathioprine and cyclosporine is not recommended. (1)
`
`
` Ulcerative Colitis: XELJANZ is indicated for the treatment of adult
`
`patients with moderately to severely active ulcerative colitis (UC), who
`
`
`have had an inadequate response or who are intolerant to TNF blockers.
`
`
`○ Limitations of Use: Use of XELJANZ in combination with biological
`therapies for UC or with potent immunosuppressants such as
`
`
`azathioprine and cyclosporine is not recommended. (1)
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION -----------------------
`
`Administration Instructions
`
` Do not initiate XELJANZ/XELJANZ XR if absolute lymphocyte count
`
`
`<500 cells/mm3, an absolute neutrophil count (ANC) <1000 cells/mm3 or
`
`hemoglobin <9 g/dL. (2.1)
`Recommended Dosage
`Rheumatoid Arthritis
`
` XELJANZ 5 mg twice daily or XELJANZ XR 11 mg once daily. (2.2)
`
`
`
`
`
`
`
`Reference ID: 4484853
`
`
` Recommended dosage in patients with moderate and severe renal
`
`
`impairment or moderate hepatic impairment is XELJANZ 5 mg once
`
`
`daily. (2, 8.7, 8.8)
`
`
`Psoriatic Arthritis (in combination with nonbiologic DMARDs)
`
` XELJANZ 5 mg twice daily or XELJANZ XR 11 mg once daily. (2.2)
`
`
`
`
`
` Recommended dosage in patients with moderate and severe renal
`
`
`impairment or moderate hepatic impairment is XELJANZ 5 mg once
`
`
`daily. (2, 8.7, 8.8)
`
`
`Ulcerative Colitis
`
`
`Induction: XELJANZ 10 mg twice daily for 8 weeks; evaluate patients
`
`
`
`
`
`
`and transition to maintenance therapy depending on therapeutic response.
`
`
`If needed, continue 10 mg twice daily for a maximum of 16 weeks.
`
`
`
`Discontinue 10 mg twice daily after 16 weeks if adequate therapeutic
`
`
`
`
`response is not achieved. (2.3)
`
`
` Maintenance: XELJANZ 5 mg twice daily. Limit use of 10 mg twice
`
`
`
`daily beyond induction to those with loss of response. (2.3)
`
`
`
`
` Recommended dosage in patients with moderate and severe renal
`
`impairment or moderate hepatic impairment: half the total daily dosage
`recommended for patients with normal renal and hepatic function. (2.3,
`
`
`
`8.7, 8.8)
`Dosage Adjustment
`
` See the full prescribing information for dosage adjustments by indication
`
`
`for patients receiving CYP2C19 and/or CYP3A4 inhibitors; in patients
`with moderate or severe renal impairment or moderate hepatic impairment;
`
`
`and patients with lymphopenia, neutropenia, or anemia. (2.2, 2.3)
`
`
`
`
`
`
`
` Use of XELJANZ/XELJANZ XR in patients with severe hepatic
`
`impairment is not recommended in any patient population. (2.2, 2.3, 8.8)
`
`
`
`
`
`
`
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS ---------------------
`
`
`
`XELJANZ Tablets: 5 mg, 10 mg tofacitinib (3)
`XELJANZ XR Tablets: 11 mg tofacitinib (3)
`
`------------------------------ CONTRAINDICATIONS ------------------------------
`
`
`
`None (4)
`
`----------------------- WARNINGS AND PRECAUTIONS -----------------------
`
`
`
`
` Serious Infections: Avoid use of XELJANZ/XELJANZ XR during an
`
`
`
`active serious infection, including localized infections. (5.1)
`
`
`
`
`
` Thrombosis, including pulmonary, deep venous and arterial, some fatal:
`
`Reported more commonly in patients treated with XELJANZ 10 mg twice
`
`
`
`daily compared to 5 mg twice daily. Avoid XELJANZ/XELJANZ XR in
`
`
`
`
`
`patients at risk. Promptly evaluate patients with symptoms of thrombosis
`
`and discontinue XELJANZ/XELJANZ XR. (5.4)
`
`
`
` Gastrointestinal Perforations: Use with caution in patients that may be at
`
`increased risk. (5.5)
`
`
` Laboratory Monitoring: Recommended due to potential changes in
`
`lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. (5.7)
`
`
`
`
`
`
`
`
`Immunizations: Live vaccines: Avoid use with XELJANZ/XELJANZ
`
`
`XR. (5.8)
`
`
`
`------------------------------ ADVERSE REACTIONS ------------------------------
`
`
`
`Most common adverse reactions are:
`
` Rheumatoid and Psoriatic Arthritis: Reported during the first 3 months in
`rheumatoid arthritis controlled clinical trials and occurring in ≥2% of
`patients treated with XELJANZ monotherapy or in combination with
`
`
`DMARDs: upper respiratory tract infection, nasopharyngitis, diarrhea,
`
`
`
`and headache. (6.1)
`
`
` Ulcerative Colitis: 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:
`
`nasopharyngitis, elevated cholesterol levels, headache, upper respiratory
`
`tract infection, increased blood creatine phosphokinase, rash, diarrhea,
`
`
`
`and herpes zoster. (6.1)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at
`
`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`------------------------------ DRUG INTERACTIONS-------------------------------
`
`
`See full prescribing information for clinically relevant drug interactions. (2, 7)
`
`
`
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`
`
`Lactation: Advise not to breastfeed. (8.2)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`
`
`Revised: 08/2019
`
`
`
`

`

`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`
`8.2
`Lactation
`
`Females and Males of Reproductive Potential
`
`8.3
`
`
`Pediatric Use
`
`8.4
`8.5 Geriatric Use
`
`8.6 Use in Diabetics
`
`
`8.7 Renal Impairment
`
`
`8.8 Hepatic Impairment
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Rheumatoid Arthritis
`
`14.2 Psoriatic Arthritis
`
`
`
`14.3 Ulcerative Colitis
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the Full Prescribing Information
`
`are not listed.
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: SERIOUS INFECTIONS, MORTALITY,
`
`
`MALIGNANCY AND THROMBOSIS
`
`
`1
`INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1
`Important Administration Instructions
`
`
`2.2 Recommended Dosage in Rheumatoid Arthritis and Psoriatic
`
`Arthritis
`
`
`2.3 Recommended Dosage in Ulcerative Colitis
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`Serious Infections
`
`5.1
`
`5.2 Mortality
`
`5.3 Malignancy and Lymphoproliferative Disorders
`
`
`Thrombosis
`
`5.4
`5.5 Gastrointestinal Perforations
`
`
`5.6 Hypersensitivity
`
`5.7
`Laboratory Abnormalities
`
`5.8 Vaccinations
`
`5.9 Risk of Gastrointestinal Obstruction with a Non-Deformable
`
`Extended-Release Formulation such as XELJANZ XR
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`6.2
`Postmarketing Experience
`
`7 DRUG INTERACTIONS
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4484853
`
`2
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY AND
`
`THROMBOSIS
`
`
`
`SERIOUS INFECTIONS
`Patients treated with XELJANZ/XELJANZ XR are at increased risk for developing
`serious infections that may lead to hospitalization or death [see Warnings and Precautions
`(5.1), Adverse Reactions (6.1)]. Most patients who developed these infections were taking
`concomitant immunosuppressants such as methotrexate or corticosteroids.
`
`If a serious infection develops, interrupt XELJANZ/XELJANZ XR 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/XELJANZ XR use
`and during therapy. Treatment for latent infection should be initiated prior to
`XELJANZ/XELJANZ XR 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 risks and benefits of treatment with XELJANZ/XELJANZ XR should be carefully
`
`considered prior to initiating therapy in patients with chronic or recurrent infection.
`
`Patients should be closely monitored for the development of signs and symptoms of
`infection during and after treatment with XELJANZ/XELJANZ XR, including the possible
`development of tuberculosis in patients who tested negative for latent tuberculosis infection
`prior to initiating therapy [see Warnings and Precautions (5.1)].
`
`MORTALITY
`Rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular
`
`(CV) risk factor treated with XELJANZ 10 mg twice a day had a higher rate of all-cause
`mortality, including sudden CV death, compared to those treated with XELJANZ 5 mg
`given twice daily or TNF blockers in a large, ongoing, postmarketing safety study [see
`Warnings and Precautions (5.2)].
`
`
`MALIGNANCIES
`Lymphoma and other malignancies have been observed in patients treated with
`XELJANZ. 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 [see Warnings and Precautions (5.3)].
`
`
`Reference ID: 4484853
`
`3
`
`
`

`

`
`
`THROMBOSIS
`Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial
`
`
`thrombosis, has been observed at an increased incidence in rheumatoid arthritis patients
`who were 50 years of age and older with at least one CV risk factor treated with XELJANZ
`
`10 mg twice daily compared to XELJANZ 5 mg twice daily or TNF blockers in a large,
`ongoing postmarketing safety study. Many of these events were serious and some resulted
`in death. Avoid XELJANZ/XELJANZ XR in patients at risk. Discontinue
`
`
`XELJANZ/XELJANZ XR and promptly evaluate patients with symptoms of thrombosis
`[see Warnings and Precautions (5.4)].
`
`For patients with ulcerative colitis, use XELJANZ at the lowest effective dose and for the
`
`shortest duration needed to achieve/maintain therapeutic response [see Dosage and
`Administration (2.3)].
`
`
`1 INDICATIONS AND USAGE
`
`
`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
`methotrexate. It may be used as monotherapy or in combination with methotrexate or other
`nonbiologic disease-modifying antirheumatic drugs (DMARDs).
`
` 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.
`
`
`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 methotrexate or other
`disease-modifying antirheumatic drugs (DMARDs).
`
` 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.
`
`
`Ulcerative Colitis
`
`
`XELJANZ is indicated for the treatment of adult patients with moderately to severely active
`ulcerative colitis (UC), who have an inadequate response or who are intolerant to TNF blockers.
`
` Limitations of Use: Use of XELJANZ in combination with biological therapies for UC or
`with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
`
`
`
`
`Reference ID: 4484853
`
`4
`
`
`

`

`
`
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`2.1 Important Administration Instructions
`
` Do not initiate XELJANZ/XELJANZ XR in patients with an absolute lymphocyte count
`less than 500 cells/mm3, an absolute neutrophil count (ANC) less than 1000 cells/mm3 or
`who have hemoglobin levels less than 9 g/dL.
`
` Dose interruption is recommended for management of lymphopenia, neutropenia, and
`anemia [see Warnings and Precautions (5.7), Adverse Reactions (6.1)].
`Interrupt use of XELJANZ/XELJANZ XR if a patient develops a serious infection until
`the infection is controlled [see Warnings and Precautions (5.1)].
`
`
`
` Take XELJANZ/XELJANZ XR with or without food [see Clinical Pharmacology
`
`(12.3)].
`
`
` Swallow XELJANZ XR tablets whole and intact. Do not crush, split, or chew.
`
`
`2.2 Recommended Dosage in Rheumatoid Arthritis and Psoriatic Arthritis
`
`
`Table 1 displays the recommended adult daily dosage of XELJANZ and XELJANZ XR and
`dosage adjustments for patients receiving CYP2C19 and/or CYP3A4 inhibitors, in patients with
`moderate or severe renal impairment (including but not limited to those with severe insufficiency
`who are undergoing hemodialysis) or moderate hepatic impairment, with lymphopenia,
`neutropenia, or anemia.
`
`Table 1: Recommended Dosage of XELJANZ and XELJANZ XR in Patients with
`
`Rheumatoid Arthritis1 and Psoriatic Arthritis2
`
`
` XELJANZ
`5 mg twice daily
`
`
`
`
`
`
`Adult patients
` Patients receiving:
`
`
`  Strong CYP3A4 inhibitors (e.g.,
`
`
` ketoconazole), or
`
` a moderate CYP3A4 inhibitor(s)
`
` with a strong CYP2C19
` inhibitor(s) (e.g., fluconazole)
`
` [see Drug Interactions (7)]
`
`
`
`Patients with:
`
`
`
` moderate or severe renal
`
`impairment [see Use in Specific
`
`
`Populations (8.7)]
`
` moderate hepatic impairment
`
`[see Use in Specific Populations
`(8.8)]*
`
`
` Patients with lymphocyte count less
` than 500 cells/mm3, confirmed by
`
`repeat testing
`
`Patients with ANC 500 to
`1000 cells/mm3
`
`
`
` Patients with ANC less than
`
` 500 cells/mm3
`
`
`
`
` XELJANZ XR
` 11 mg once daily
`
`
`
`
`5 mg once daily
`
`
`5 mg once daily
`
`
`For patients undergoing
`
`hemodialysis, dose should be
`
`administered after the dialysis
`session on dialysis days. If a dose
`was taken before the dialysis
`
`procedure, supplemental doses are
`not recommended in patients after
`
`
`
`dialysis.
`
`Switch to
`
`
`XELJANZ 5 mg once daily
`
`
`Switch to
`
`
`XELJANZ 5 mg once daily
`
`
`Discontinue dosing.
`
` Interrupt dosing.
`
`
` Interrupt dosing.
`
`
`
` When ANC is greater than 1000,
`
` When ANC is greater than 1000,
` resume 11 mg once daily.
`
`
`resume 5 mg twice daily.
`Discontinue dosing.
`
`
`
`
`
`Reference ID: 4484853
`
`5
`
`

`

`
`
`XELJANZ
`
`
`XELJANZ XR
`
`
`
`
`
` Interrupt dosing until hemoglobin values have normalized.
`
`
`
`
`Patients with hemoglobin less than
`
`8 g/dL or a decrease of more than
`2 g/dL
`
`
` 1 XELJANZ/XELJANZ XR may be used as monotherapy or in combination with methotrexate or other
`
` nonbiologic disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis.
`
`
`
`2 XELJANZ/XELJANZ XR is used in combination with nonbiologic disease modifying antirheumatic drugs
`
`
`
`(DMARDs) in psoriatic arthritis. The efficacy of XELJANZ/XELJANZ XR as a monotherapy has not been
`
`
`
`
`
`studied in psoriatic arthritis.
`
`* Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended.
`
`
`
`
`
`
`
`
`
`Switching from XELJANZ Tablets to XELJANZ XR Tablets
`Patients treated with XELJANZ 5 mg twice daily may be switched to XELJANZ XR 11 mg once
`daily the day following the last dose of XELJANZ 5 mg.
`
`2.3 Recommended Dosage in Ulcerative Colitis
`Table 2 displays the recommended adult daily dosage of XELJANZ and dosage adjustments for
`
` patients receiving CYP2C19 and/or CYP3A4 inhibitors, with moderate or severe renal
`impairment (including but not limited to those with severe insufficiency who are undergoing
`
` hemodialysis) or moderate hepatic impairment, with lymphopenia, neutropenia or anemia.
`
`Table 2: Recommended Dosage of XELJANZ in Patients with UC
`
`Ulcerative Colitis
` XELJANZ
`Induction
`Adult patients
`
`
`
`10 mg twice daily for 8 weeks [see Clinical Studies (14.3)]; evaluate
`
`
`patients and transition to maintenance therapy depending on
`
`
`therapeutic response. If needed, continue 10 mg twice daily for a
`
`
`
`maximum of 16 weeks. Discontinue 10 mg twice daily after 16 weeks
`
`if adequate therapeutic response is not achieved.
`
`Maintenance
`
`
`
`5 mg twice daily. Use of 10 mg twice daily beyond induction should
`
`
`be limited to those with loss of response and used for the shortest
`
`
`
`duration, with careful consideration of the benefits and risks for the
`
`
`
`
`individual patient. Use the lowest effective dose needed to maintain
`
`response [see Warnings and Precautions (5.1, 5.3, 5.4, 5.7)].
`
`
`
`
` Patients receiving:
`
`
`  Strong CYP3A4 inhibitors (e.g.,
`
`
` ketoconazole), or
`
` a moderate CYP3A4 inhibitor(s)
`with a strong CYP2C19 inhibitor(s)
`(e.g., fluconazole)
`
`
`[see Drug Interactions (7)]
`
`
`Patients with:
`
` moderate or severe renal impairment
`
`[see Use in Specific Populations
`
`
`(8.7)]
`
` moderate hepatic impairment [see
`Use in Specific Populations (8.8)]*
`
`
`
`
`
` If taking 10 mg twice daily, reduce to 5 mg twice daily.
`
`If taking 5 mg twice daily, reduce to 5 mg once daily.
`
`
`
`
`If taking 10 mg twice daily, reduce to 5 mg twice daily.
`
`
`If taking 5 mg twice daily, reduce to 5 mg once daily.
`
`
`
`
`For patients undergoing hemodialysis, dose should be administered
`
`
`after the dialysis session on dialysis days. If a dose was taken before
`
`the dialysis procedure, supplemental doses are not recommended in
`
`
`patients after dialysis.
`
`Reference ID: 4484853
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`Ulcerative Colitis
`
` Patients with lymphocyte count less
` than 500 cells/mm3, confirmed by
`
`repeat testing
`
`Patients with ANC 500 to
`1000 cells/mm3
`
`
`
`XELJANZ
`
`
`Discontinue dosing.
`
` If taking 10 mg twice daily, reduce to 5 mg twice daily.
`
`
` When ANC is greater than 1000, increase to 10 mg twice daily based
`on clinical response.
`
` If taking 5 mg twice daily, interrupt dosing. When ANC is greater than
`
`1000, resume 5 mg twice daily.
`Discontinue dosing.
`
`
`
`
`
`
`
`
`
`
`
`Interrupt dosing until hemoglobin values have normalized.
`
` Patients with ANC less than
`
` 500 cells/mm3
`
`Patients with hemoglobin less than
`
`8 g/dL or a decrease of more than 2
`g/dL
`*Use in patients with severe hepatic impairment is not recommended.
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`XELJANZ Tablets:
`
`○ 5 mg tofacitinib: White, round, immediate-release film-coated tablets, debossed with
`
`
`“Pfizer” on one side, and “JKI 5” on the other side.
`
`
`
`
`
`
`○ 10 mg tofacitinib: Blue, round, immediate-release film-coated tablets, debossed with
`“Pfizer” on one side, and “JKI 10” on the other side.
`
`
`XELJANZ XR Tablets:
`
`○ 11 mg tofacitinib: Pink, oval, extended-release film-coated tablets with a drilled hole at
`one end of the tablet band and “JKI 11” printed on one side of the tablet.
`
`
`
`
`4 CONTRAINDICATIONS
`
`None.
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Serious Infections
`Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or
`other opportunistic pathogens have been reported in patients receiving XELJANZ. The most
`common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes
`zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections,
`tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal
`candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK
`virus infection, and listeriosis were reported with XELJANZ. Some patients have presented with
`disseminated rather than localized disease, and were often taking concomitant
`immunomodulating agents such as methotrexate or corticosteroids.
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`Reference ID: 4484853
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`In the UC population, XELJANZ treatment with 10 mg twice daily was associated with greater
`risk of serious infections compared to 5 mg twice daily. Additionally, opportunistic herpes zoster
`infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were
`seen in patients who were treated with XELJANZ 10 mg twice daily.
`
`Other serious infections that were not reported in clinical studies may also occur (e.g.,
`
`coccidioidomycosis).
`
`Avoid use of XELJANZ/XELJANZ XR in patients with an active, serious infection, including
`localized infections. The risks and benefits of treatment should be considered prior to initiating
`XELJANZ/XELJANZ XR in patients:
`• with chronic or recurrent infection
`
`• who have been exposed to tuberculosis
`
`• with a history of a serious or an opportunistic infection
`
`• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
`
`• with underlying conditions that may predispose them to infection.
`
`
`Patients should be closely monitored for the development of signs and symptoms of infection
`during and after treatment with XELJANZ/XELJANZ XR. XELJANZ/XELJANZ XR should be
`interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A
`patient who develops a new infection during treatment with XELJANZ/XELJANZ XR should
`undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient;
`appropriate antimicrobial therapy should be initiated, and the patient should be closely
`monitored.
`
`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 infections.
`
`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.
`Discontinuation and monitoring criteria for lymphopenia are recommended [see Dosage and
`
`Administration (2.2, 2.3)].
`
`Tuberculosis
`Patients should be evaluated and tested for latent or active infection prior to and per applicable
`guidelines during administration of XELJANZ/XELJANZ XR.
`
`Anti-tuberculosis therapy should also be considered prior to administration of
`
`XELJANZ/XELJANZ XR in patients with a past history of latent or active tuberculosis in whom
`an adequate course of treatment cannot be confirmed, and for patients with a negative test for
`latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a
`physician with expertise in the treatment of tuberculosis is recommended to aid in the decision
`about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
`
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`Reference ID: 4484853
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`Patients should be closely monitored for the development of signs and symptoms of tuberculosis,
`including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
`
`Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before
`administering XELJANZ/XELJANZ XR.
`
`
` Viral Reactivation
`
`Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were
`observed in clinical studies with XELJANZ. Postmarketing cases of hepatitis B reactivation have
`been reported in patients treated with XELJANZ. The impact of XELJANZ/XELJANZ XR on
`chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or
`C were excluded from clinical trials. Screening for viral hepatitis should be performed in
`
`accordance with clinical guidelines before starting therapy with XELJANZ/XELJANZ XR. The
`risk of herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR and appears
`to be higher in patients treated with XELJANZ in Japan and Korea.
`
`
`5.2 Mortality
`Rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular (CV) risk
`factor treated with XELJANZ 10 mg twice a day had a higher rate of all-cause mortality,
`including sudden CV death, compared to those treated with XELJANZ 5 mg given twice daily or
`TNF blockers in a large, ongoing, postmarketing safety study.
`
`A dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not
`recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].
`
`For the treatment of UC, use XELJANZ at the lowest effective dose and for the shortest duration
`needed to achieve/maintain therapeutic response [see Dosage and Administration (2.3)].
`
`5.3 Malignancy and Lymphoproliferative Disorders
`Consider the risks and benefits of XELJANZ/XELJANZ XR treatment prior to initiating therapy
`in patients with a known malignancy other than a successfully treated non-melanoma skin cancer
`(NMSC) or when considering continuing XELJANZ/XELJANZ XR in patients who develop a
`malignancy. Malignancies were observed in clinical studies of XELJANZ [see Adverse
`
`Reactions (6.1)].
`
`In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma
`
`were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to
`0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group
`during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in
`the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ.
`
`During the 2 PsA controlled clinical studies there were 3 malignancies (excluding NMSC) in
`474 patients receiving XELJANZ plus nonbiologic DMARD (6 to 12 months exposure)
`compared with 0 malignancies in 236 patients in the placebo plus nonbiologic DMARD group
`(3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus nonbiologic
`DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also
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`Reference ID: 4484853
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`been observed in the long-term extension study in psoriatic arthritis patients treated with
`
` XELJANZ.
`
`During the UC controlled clinical studies (8-week induction and 52-week maintenance studies),
`
`which included 1220 patients, 0 cases of solid cancer or lymphoma were observed in
`
`XELJANZ-treated patients. In the long-term extension study, malignancies (including solid
`
`
`cancers and lymphomas) were observed more often in patients treated with XELJANZ 10 mg
`
`
`
`
`twice daily.
`
`
`In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom
`
`
`received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid
`
`products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was
`
`observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of
`
`111 patients treated with cyclosporine.
`
`
`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.
`
`
`Non-Melanoma Skin Cancer
`
`Non-melanoma skin cancers (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.
`
`
`5.4 Thrombosis
`Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis,
`was observed at an increased incidence in patients with rheumatoid arthritis 50 years of age and
`older with at least one CV risk factor treated with XELJANZ 10 mg twice daily compared to
`XELJANZ 5 mg twice daily or TNF blockers in a large, ongoing postmarketing study. Many of
`these events were serious and some resulted in death [see Warnings and Precautions (5.2)].
`
`A dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not
`recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].
`
`In a long-term extension study in patients with UC, four cases of pulmonary embolism were
`reported in patients taking XELJANZ 10 mg twice daily, including one death in a patient with
`advanced cancer.
`
`Promptly evaluate patients with symptoms of thrombosis and discontinue XELJANZ/XELJANZ
`XR in patients with symptoms of thrombosis.
`
`Avoid XELJANZ/XELJANZ XR in patients that may be at increased risk of thrombosis. For the
`treatment of UC, use XELJANZ at the lowest effective dose and for the shortest duration needed
`to achieve/maintain therapeutic response [see Dosage and Administration (2.3)].
`
`
`Reference ID: 4484853
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`10
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`5.5 Gastrointestinal Perforations
`
`Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ,
`although the role of JAK inhibition in these events is not known. In these studies, many patients
`with rheumatoid arthritis were receiving background therapy with Nonsteroidal
`Anti-Inflammatory Drugs (NSAIDs).
`
`There was no discernable 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/XELJANZ XR 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).
`Patients presenting with new onset abdominal symptoms should be evaluated promptly for early
`identification of gastrointestinal perforation [see Adverse Reactions (6.1)].
`
`
`5.6 Hypersensitivity
`Reactions such as angioedema and urticaria