`
`
`
` 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
`
`
`
`
`
`
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`
`
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`
` 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)
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`
`
`
`
` ------------------------------ RECENT MAJOR CHANGES------------------------------
`
`
` 07/2019
`
` Boxed Warning
`
`
` Indications and Usage (1)
`
` 07/2019
`
`
` Dosage and Administration (2.2)
`
` 10/2018
`
`
`
` Dosage and Administration (2.3)
`
` 07/2019
` Warnings and Precautions (5.1)
`
` 10/2018
`
`
`
`
` Warnings and Precautions (5.2)
`
`
`
` 07/2019
`
` Warnings and Precautions (5.4)
`
`
`
` 07/2019
`
` Warnings and Precautions (5.6)
`
`
`
` 10/2018
`
`
`
`
`
`
`
` -------------------------------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)
`
`
`
`
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`
`
`Reference ID: 4467787
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` • 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.
`
`
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`
`
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`
`
`
`
`
` 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: 07/2019
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
` 8 USE IN SPECIFIC POPULATIONS
`Pregnancy
`
`
`
`8.1
`Lactation
`
`
`
`8.2
`
` Females and Males of Reproductive Potential
`
`
`8.3
`
` Pediatric Use
`
`
`
`8.4
`
` Geriatric Use
`
`
`
`8.5
`
` Use in Diabetics
`
`
`
`8.6
`
` Renal Impairment
`
`
`
`8.7
` Hepatic Impairment
`
`
`
`8.8
` 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.
`
`
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`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`
`
`
`
` WARNING: SERIOUS INFECTIONS, MORTALITY,
`
`
`
` MALIGNANCY AND THROMBOSIS
`
`
` INDICATIONS AND USAGE
`1
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
`
` Important Administration Instructions
`
`
`
`2.1
`
` Recommended Dosage in Rheumatoid Arthritis and Psoriatic
`
`
`2.2
`
`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
`
`
`
`5.4
`Thrombosis
`
`
`
` Gastrointestinal Perforations
`
`5.5
`Hypersensitivity
`
`
`
`5.6
`
`Laboratory Abnormalities
`
`5.7
`Vaccinations
`
`
`
`5.8
`
`
`
`
` 5.9 Risk of Gastrointestinal Obstruction with a Non-Deformable
`
` Extended-Release Formulation such as XELJANZ XR
`
`
`
`
`
`
` 6 ADVERSE REACTIONS
`
`
`
` Clinical Trials Experience
`
`
`
`
`6.1
`
`
` Postmarketing Experience
`
`6.2
` 7 DRUG INTERACTIONS
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4467787
`
`
`
` 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 us e
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
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`
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`
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`
`
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`
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`
`
`
`
`
`
`
`
`
`
`
`
` The risks and benefits oftreatment 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 ofsigns and symptoms of
`
`
`
`
`
` infection during and after treatment with XELJANZ/XELJANZ XR, including the possible
`
`
`
`
`
`
` development oftuberculosis 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 ofage 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: 4467787
`
`
`
` 3
`
`
`

`

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`
`
` 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 re sulted
`
`
`
`
`
`
`
`
`
`
`
`
` 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 XELJANZat 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: 4467787
`
`
`
` 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 ofXELJANZand XELJANZ XR in Patients with
`
`
` Rheumatoid Arthritis 1 and Psoriatic Arthritis 2
`
`
`
` XELJANZ
`
` 5 mg twice daily
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` XELJANZ XR
`
` 11 mg once daily
`
`
`
`
`
`
`
`
`
`
`
` 5 mg once daily
`
`
`
`
`
`
`
` Switch to
`
` XELJANZ 5 mg once daily
`
`
`
`
`
`
`
` Switch to
`
` XELJANZ 5 mg once 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 lymphocytecount less
` than 500 cells/mm3, confirmed by
`
`
`
`
`
` repeat testing
`
`
` Patients with ANC500 to
`
`
`
` 1000 cells/mm3
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Patients with ANCless than
` 500 cells/mm3
`
`
`
`
`
`
`
` 5 mg once daily
`
`
`
`
`
`
`
`
` For patients undergoing
`
`
` hemodialysis, doseshould be
`
`
`
` administered after the dialysis
`
`
`
` session on dialysis days. If a dose
`
`
`
`
`
` was taken before thedialysis
`
`
`
`
`
`
` procedure, supplemental doses are
`
`
`
`
` not recommended in patients after
`
`
`
`
` dialysis.
`
`
`
`
`
`
` Discontinue dosing.
`
`
`
` Interrupt dosing.
`
`
` Interrupt dosing.
`
`
`
` When ANCis greater than 1000,
`
`
`
`
`
`
`
` When ANCis greater than 1000,
`
`
`
` resume 11 mg once daily.
`
`
`
`
`
`
` resume 5 mg twice daily.
`
`
`
`
` Discontinue dosing.
`
`
`
`
`Reference ID: 4467787
`
`
`
` 5
`
`

`

`
`
` XELJANZ
`
`
`
`
`
` XELJANZ XR
`
`
`
`
`
`
`
`
`
`
`
` Interrupt dosing untilhemoglobin values have normalized.
`
`
`
`
`
` 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 renalimpairment
`
`
` [see Use in Specific Populations
`
`
`
`
`
` (8.7)]
`
`
`
` • moderate hepatic impairment [see
`
`
`
` Use in Specific Populations (8.8)]*
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Patients with hemoglobin less than
`
`
`
`
`
` 8 g/dLor a decreaseof more than
`
`
`
`
`
`
`
` 2 g/dL
`
`
`
`
`
`
`
`
`
`
`
` 1 XELJANZ/XELJANZ XR may be used as monotherapyorin combinationwith methotrexate orothernonbiologic
`
`
` disease-modifyingantirheumatic drugs (DMARDs)in rheumatoid arthritis.
`
`
`
`
`
`
`
`
`
` 2 XELJANZ/XELJANZ XR is used in combination with nonbiologic disease modifyingantirheumatic drugs
`
`
`
`
`
`
`
`
`
`
`
` (DMARDs)in psoriatic arthritis. The efficacyofXELJANZ/XELJANZ XRas a monotherapy has notbeen
`
`
`
`
`
`
`
`
`
`
`
`
`
` studiedin psoriatic arthritis.
`
`
`
`
` * Use ofXELJANZ/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 ofXELJANZin Patients with UC
`
`
` Ulcerative Colitis
`
`
` XELJANZ
` Adult patients
`
`
`
` Induction
`
`
`
`
`
`
` 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, continue10 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 responseand used for the shortest duration,
`
`
`
`
`
`
`
`
`
`
`
` with carefulconsideration of the benefits and risks for the individual
`
`
`
`
`
`
`
`
`
`
`
` patient. Use thelowest effective dose needed to maintain response [see
`
`
`
`
`
`
`
`
`
`
` Warnings and Precautions (5.1, 5.3, 5.4, 5.7)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`
`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` If taking 10 mg twice daily, reduce to 5 mg twice daily.
`
`
`
`
` If taking 5 mg twice daily, reduce to 5 mg once daily.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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: 4467787
`
`
`
` 6
`
`

`

`
`
`
`
` Ulcerative Colitis
`
`
`
` Patients with lymphocytecount less than
`
`
`
`
` 500 cells/mm3, confirmed by repeat
`
`
`
` testing
`
` Patients with ANC500 to
`
`
`
`
` 1000 cells/mm3
`
`
`
`
`
`
`
`
`
`
` XELJANZ
`
`
`
`
`
` Discontinue dosing.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` If taking 10 mg twice daily, reduce to 5 mg twice daily.
`
` When ANCis greater than 1000, increase to 10 mg twice daily based on
`
`
`
`
`
`
`
`
`
` clinical response.
`
`
`
`
`
`
`
`
` If taking 5 mg twice daily, interrupt dosing. When ANCis greater than
`
` 1000, resume 5 mg twice daily.
`
`
`
`
` Discontinue dosing.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Patients with ANCless than
` 500 cells/mm3
`
`
`
`
`
` Patients with hemoglobin less than
`
`
`
`
`
` Interrupt dosing untilhemoglobin values have normalized.
`
`
` 8 g/dLor a decreaseof 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4467787
`
`
`
` 7
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
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`• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
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`• with underlying conditions that may predispose them to infection.
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` Patients should be closely monitored for the development of signs and symptoms of infection
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` during and after treatment with XELJANZ/XELJANZ XR. XELJANZ/XELJANZ XR should be
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` interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A
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` patient who develops a new infection during treatment with XELJANZ/XELJANZ XR should
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` undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient;
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` appropriate antimicrobial therapy should be initiated, and the patient should be closely
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` monitored.
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` Caution is also recommended in patients with a history of chronic lung disease, or in those who
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` develop interstitial lung disease, as they may be more prone to infections.
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` Risk of infection may be higher with increasing degrees of lymphopenia and consideration
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` should be given to lymphocyte counts when assessing individual patient risk of infection.
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` Discontinuation and monitoring criteria for lymphopenia are recommended [see Dosage and
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` Administration (2.2, 2.3)].
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` Tuberculosis
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` Patients should be evaluated and tested for latent or active infection prior to and per applicable
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` Anti-tuberculosis therapy should also be considered prior to administration of
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` XELJANZ/XELJANZ XR in patients with a past history of latent or active tuberculosis in whom
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` an adequate course of treatment cannot be confirmed, and for patients with a negative test for
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` latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a
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` physician with expertise in the treatment of tuberculosis is recommended to aid in the decision
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` about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
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` Patients should be closely monitored for the development of signs and symptoms of tuberculosis,
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` including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
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`Reference ID: 4467787
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` 8
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` Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before
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` administering XELJANZ/XELJANZ XR.
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` Viral Reactivation
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` Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were
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` observed in clinical studies with XELJANZ. Postmarketing cases of hepatitis B reactivation have
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` been reported in patients treated with XELJANZ. The impact of XELJANZ/XELJANZ XR on
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` chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or
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` C were excluded from clinical trials. Screening for viral hepatitis should be performed in
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` accordance with clinical guidelines before starting therapy with XELJANZ/XELJANZ XR. The
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` risk of herpes zoster