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)
`
`
`• Thrombosis, including pulmonary embolism, deep venous thrombosis
`
`
`
`and arterial thrombosis have occurred in patients treated with
`
`
`
`XELJANZ and other Janus kinase inhibitors. 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. (5.3)
`
`
`
`
`---------------------------RECENT MAJOR CHANGES --------------------------­
`
`
`
`
`Boxed Warning
`07/2019
`
`
`Indications and Usage (1)
`12/2019
`
`
`Dosage and Administration (2.2)
`12/2019
`
`
`
`Dosage and Administration (2.3)
`12/2019
`
`
`07/2019
`Warnings and Precautions (5.2)
`
`
`
`Warnings and Precautions (5.4)
`07/2019
`
`
`
`
`--------------------------- 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/XELJANZ XR 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/XELJANZ XR 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)
`
`
`
`
`
`• 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)
`
`
`Reference ID: 4532973
`
`
`
`
`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 or XELJANZ XR 22 mg once
`•
`
`
`
`daily for 8 weeks; evaluate patients and transition to maintenance therapy
`
`
`
`
`depending on therapeutic response. If needed, continue XELJANZ 10 mg
`
`
`
`
`
`
`twice daily or XELJANZ XR 22 mg once daily for a maximum of
`
`
`
`
`
`
`
`16 weeks. Discontinue XELJANZ 10 mg twice daily or XELJANZ XR
`
`
`
`
`
`
`22 mg once daily after 16 weeks if adequate therapeutic response is not
`
`achieved. (2.3)
`
`
`
`
`• Maintenance: XELJANZ 5 mg twice daily or XELJANZ XR 11 mg once
`daily. For patients with loss of response during maintenance treatment,
`
`
`
`
`
`
`XELJANZ 10 mg twice daily 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. (2.3)
`
`
`
`
`
`
`
`• Dosage adjustment is needed in patients with moderate and severe renal
`
`
`
`impairment or moderate hepatic impairment: see full prescribing
`
`
`information. (2.3)
`
`
`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, 8.7, 8.8)
`
`
`
`
`• 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, 22 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: 12/2019
`
`
`
`

`

`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: SERIOUS INFECTIONS, MORTALITY,
`
`
`
`MALIGNANCY AND THROMBOSIS
`
`
`INDICATIONS AND USAGE
`1
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`Important Administration Instructions
`
`2.1
`
`
`
`
`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
`
`
`
`5.1
`Serious Infections
`
`
`
`5.2 Mortality
`
`
`
`5.3 Malignancy and Lymphoproliferative Disorders
`
`
`
`5.4
`Thrombosis
`
`
`
`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
`
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`
`8.2
`Lactation
`
`
`
`
`
`8.3
`Females and Males of Reproductive Potential
`
`
`
`8.4
`Pediatric Use
`
`
`
`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.
`
`Reference ID: 4532973
`
`

`

`
`
`
`
` 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: 4532973
`
`
`3
`
`

`

`
`
` 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. 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 had an observed increase in incidence of these events. 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/XELJANZ XR 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/XELJANZ XR in combination with biological
`
`
`
`
`therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is
`
`
`
`not recommended.
`
`
`
`
`
`Reference ID: 4532973
`
`
`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)]*
`
`
`
`
`
`
`
`
`
` XELJANZ XR
`
` 11 mg once daily
`
`
`
`
` 5 mg once daily
`
`
`
` Reduce to
` XELJANZ 5 mg once daily
`
`
`
`
`
`
`
`
` 5 mg once daily
`
`
`
`
`
` Reduce to
` XELJANZ 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: 4532973
`
`
`5
`
`

`

`
`
`
` Patients with lymphocyte count less
`
`
` than 500 cells/mm3, confirmed by
`
` repeat testing
`
` Patients with ANC 500 to
`
` 1000 cells/mm3
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` XELJANZ
`
`
`
` XELJANZ XR
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
` 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/XELJANZ XR 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.
`
`
`Reference ID: 4532973
`
`
`6
`
`

`

`
`
`
`
`
`
`
`
`
`
` Table 2: Recommended Dosage of XELJANZ/XELJANZ XR in Patients with UC
`
`
`
`Reference ID: 4532973
`
`
`7
`
`

`

`
`
` XELJANZ
`
`Induction:10 mg twice daily for at
`
`
`
`
` least 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.
`
`
`
` 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 response.
`
`If taking 10 mg twice daily, reduce
`
` to 5 mg twice daily.
`
` If taking 5 mg twice daily, reduce
`
`
` to 5 mg once daily.
`
` .
`
`
`
` XELJANZ XR
`
`Induction: 22 mg once daily for at
`
`
`
`
` least 8 weeks; evaluate patients and
`
`
` transition to maintenance therapy
`
`
`
` depending on therapeutic response.
`
` If needed continue 22 mg once
`
` daily for a maximum of 16 weeks.
` Discontinue 22 mg once daily after
`
`
`16 weeks if adequate therapeutic
`
`
` response is not achieved.
`
`Maintenance: 11 mg once daily.
`
`
`
`
` For patients with loss of response
`
` during maintenance treatment, a
` dosage of 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.
`
`
`
`
` If taking 22 mg once daily, reduce
`
` to 11 mg once daily.
`
`
`
` If taking 11 mg once daily, reduce
` to XELJANZ 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.
`
` Discontinue dosing
`
`
` If taking 22 mg once daily, reduce
`
` to 11 mg once daily.
`
`
`
` If taking 11 mg once daily, reduce
` 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 lymphocyte count less
`
`
` than 500 cells/mm3, confirmed by
`
` repeat testing
`
`
`
`
`
`Reference ID: 4532973
`
`
`8
`
`

`

` XELJANZ
`
`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.
`
`
`
` XELJANZ XR
`
`
` If taking 22 mg once daily, reduce
` to 11 mg once daily. When ANC is
`
`
`
` greater than 1000, increase to
`
` 22 mg once daily based on clinical
`
`
` response.
`
`
` If taking 11 mg once daily,
`
`
` interrupt dosing. When ANC is
` greater than 1000, resume 11 mg
`
`
`
` once daily.
`
`
`
`
` Patients with ANC 500 to
`
`
` 1000 cells/mm3
`
`
`
`
`
`
`
`
`
`
`
` 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 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. Patients treated with XELJANZ 10 mg
`
`
`
`
` twice daily may be switched to XELJANZ XR 22 mg once daily the day following the last dose
`
`
`
`
`
` of XELJANZ 10 mg.
`
`
`
`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.
`
`
`
`
`○ 22 mg tofacitinib: Beige, oval, extended-release film-coated tablets with a drilled hole at
`one end of the tablet band and “JKI 22” printed on one side of the tablet.
`
`
`
`
`
`4 CONTRAINDICATIONS
`
`
`None.
`
`
`
`Reference ID: 4532973
`
`
`9
`
`

`

`
`
`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.
`
`
`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)].
`
`
`Reference ID: 4532973
`
`
`10
`
`

`

`
`
`
`
` 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.
`
`
`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)].
`
`
`Reference ID: 4532973
`
`
`11
`
`

`

`
`
` 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 exposur