`
`
`
`
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
`
` XELJANZ/XELJANZ XR/XELJANZ Oral Solution safely and
`
`
`
` effectively. See full prescribing information for XELJANZ/XELJANZ
` XR/XELJANZ Oral Solution.
`
`
` XELJANZ® (tofacitinib) tablets, for oral use
`
`
`
` XELJANZ® XR (tofacitinib) extended-release tablets, for oral use
`
`
`
`XELJANZ® (tofacitinib) Oral Solution
`
`
`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/XELJANZ Oral Solution until the infection is controlled. (5.1)
`
`
`
`
`
`
`
`
`
` Prior to starting XELJANZ/XELJANZ XR/XELJANZ Oral Solution,
`
`
`
`
`
`
`
`perform a test for latent tuberculosis; if it is positive, start treatment
`
`
`
`for tuberculosis prior to starting XELJANZ/XELJANZ
`
`XR/XELJANZ Oral Solution. (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
`9/2020
`
`Indications and Usage (1)
`9/2020
`
`
`
`
`Dosage and Administration (2.1)
`9/2020
`
`
`Dosage and Administration (2.2)
`12/2019
`
`
`Dosage and Administration (2.3)
`12/2019
`
`
`Dosage and Administration (2.4)
`9/2020
`
`
`Warnings and Precautions (5.1)
`9/2020
`
`
`
`Warnings and Precautions (5.2)
`9/2020
`
`
`
`Warnings and Precautions (5.3)
`9/2020
`
`
`
`Warnings and Precautions (5.4)
`9/2020
`
`
`
`Warnings and Precautions (5.5)
`9/2020
`
`
`
`Warnings and Precautions (5.7)
`9/2020
`
`
`
`9/2020
`Warnings and Precautions (5.8)
`
`
`
`
`--------------------------- INDICATIONS AND USAGE----------------------------
`
`
`
`XELJANZ/XELJANZ XR/XELJANZ Oral Solution is a Janus kinase (JAK)
`
`
`
`inhibitor indicated for:
`
` 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.
`
`○ 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)
`
`
`
`
`
`
`
`
`Reference ID: 4676373
`
`
` Polyarticular Course Juvenile Idiopathic Arthritis: XELJANZ/XELJANZ
`
`
`Oral Solution is indicated for the treatment of active polyarticular course
`
`
`
`
`
`
`
`juvenile idiopathic arthritis (pcJIA) in patients 2 years of age and older.
`
`
`
`
`
`
`○ Limitations of Use: Use of XELJANZ/XELJANZ Oral Solution in
`
`
`
`
`
`
`combination with biologic DMARDs or potent immunosuppressants
`
`
`
`such as azathioprine and cyclosporine is not recommended. (1)
`
`
`
`
`
`
`
`
`
`
`
`----------------------- DOSAGE AND ADMINISTRATION -----------------------
`
`
`
`Administration Instructions
`
`
` XELJANZ XR (tofacitinib extended-release tablets) is not
`
`
`
`
`
`interchangeable or substitutable with XELJANZ Oral Solution. (2.1)
`
`
`
` Changes between XELJANZ and XELJANZ XR should be made by the
`
`
`
`
`
`
`
`
`
`
`healthcare provider. (2.1)
`
`
` Do not initiate XELJANZ/XELJANZ XR/XELJANZ Oral Solution 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)
`
`
`
`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)
`
`
`Polyarticular Course Juvenile Idiopathic Arthritis
`
`
`
` XELJANZ/XELJANZ Oral Solution 5 mg twice daily or weight-based
`
`
`
`equivalent twice daily. (2.4)
`
`
` Dosage adjustment is needed in patients with moderate and severe renal
`
`
`
`
`impairment or moderate hepatic impairment: see full prescribing
`
`
`
`
`information. (2.4)
`
`
`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, 2.4, 8.7,
`
`
`
`
`
`8.8)
`
`
` Use of XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients
`
`
`with severe hepatic impairment is not recommended in any patient
`
`
`
`
`
`
`population. (2.2, 2.3, 2.4, 8.8)
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS----------------------
`
`
`
`
`XELJANZ Tablets: 5 mg, 10 mg tofacitinib (3)
`
`
`
`
`
`
`
`XELJANZ XR Tablets: 11 mg, 22 mg tofacitinib (3)
`
`
`
`
`
`
`
`
`XELJANZ Oral Solution: 1 mg/mL tofacitinib (3)
`
`
`
`
`
`------------------------------ CONTRAINDICATIONS ------------------------------
`
`
`None (4)
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS -----------------------
`
`
`
` Serious Infections: Avoid use of XELJANZ/XELJANZ XR/XELJANZ
`
`
`
`
`
`
`Oral Solution 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/XELJANZ Oral Solution in patients at risk. Promptly evaluate
`
`
`
`
`

`

`
`
`
` patients with symptoms of thrombosis and discontinue
`
`
`
`
`
`
` XELJANZ/XELJANZ XR/XELJANZ Oral Solution. (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/XELJANZ Oral Solution. (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)
`
`
`
`
`  Polyarticular Course Juvenile Idiopathic Arthritis: Consistent with
`
`
`common adverse reactions reported in adult rheumatoid arthritis patients.
`
`
`(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: 9/2020
`
`
`
`Reference ID: 4676373
`
`

`

`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`2.3
`
`2.4
`
`
`
`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
`
`
`Recommended Dosage in Ulcerative Colitis
`
`
`Recommended Dosage in Polyarticular Course Juvenile
`
`
`Idiopathic Arthritis
`
`
`
`
`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
`
`
`
`5.5
`Gastrointestinal Perforations
`
`
`
`5.6 Hypersensitivity
`
`
`Laboratory Abnormalities
`
`5.7
`
`
`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
`
`
`
`Postmarketing Experience
`
`6.2
`
`
`7 DRUG INTERACTIONS
`
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1
`Pregnancy
`
`8.2
`Lactation
`
`Females and Males of Reproductive Potential
`
`8.3
`
`
`
`Pediatric Use
`
`8.4
`
`
`Geriatric Use
`
`8.5
`
`
`8.6 Use in Diabetics
`
`
`
`
`Renal Impairment
`
`8.7
`
`
`
`
`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
`
`
`
`
`14.4 Polyarticular Course Juvenile Idiopathic Arthritis
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`*Sections or subsections omitted from the Full Prescribing Information
`
`
`
`are not listed.
`
`
`
`Reference ID: 4676373
`
`2
`
`

`

`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
` WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY AND
`
`THROMBOSIS
`
`
`
`
`SERIOUS INFECTIONS
`
`
`Patients treated with XELJANZ/XELJANZ XR/XELJANZ Oral Solution 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/XELJANZ Oral
`
`Solution 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/XELJANZ Oral Solution use and during therapy. Treatment for latent infection
`
`
` should be initiated prior to XELJANZ/XELJANZ XR/XELJANZ Oral Solution 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/XELJANZ Oral
`
`
`
`
`Solution 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/XELJANZ Oral
`
`
`Solution, 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
`
`Reference ID: 4676373
`
`3
`
`

`

`
`
`
`
` has been observed at an increased rate in renal transplant patients treated with XELJANZ
`
`
`
`and concomitant immunosuppressive medications [see Warnings and Precautions (5.3)].
`
`
`
`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/XELJANZ Oral Solution in patients at risk. Discontinue XELJANZ/XELJANZ
`
`
`XR/XELJANZ Oral Solution 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.
`
`
` Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic
`
`
`disease-modifying antirheumatic drugs (DMARDs) or with potent immunosuppressants such
`as azathioprine and cyclosporine is not recommended.
`
`
`Psoriatic Arthritis
`
`XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic
`
`arthritis (PsA) who have had an inadequate response or intolerance to 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: 4676373
`
`4
`
`

`

`
`
` Polyarticular Course Juvenile Idiopathic Arthritis
`
`
`XELJANZ/XELJANZ Oral Solution is indicated for the treatment of active polyarticular course
`
`juvenile idiopathic arthritis (pcJIA) in patients 2 years of age and older.
`
`
` Limitations of Use: Use of XELJANZ/XELJANZ Oral Solution in combination with biologic
`
`DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not
`recommended.
`
`
`
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Important Administration Instructions
`
` XELJANZ XR (tofacitinib extended-release tablets) is not interchangeable or
`substitutable with XELJANZ Oral Solution.
`
` Changes between XELJANZ and XELJANZ XR should be made by the healthcare
`provider [see Dosage and Administration (2.2)].
`
` Do not initiate XELJANZ/XELJANZ XR/XELJANZ Oral Solution 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/XELJANZ Oral Solution if a patient develops
`a serious infection until the infection is controlled [see Warnings and Precautions (5.1)].
`
` Take XELJANZ/XELJANZ XR/XELJANZ Oral Solution 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 Arthritis and Psoriatic Arthritis1
`
`
` XELJANZ
`
`tablet
`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)]
`
`
`
`
`
` XELJANZ XR
`
`extended-release tablet
`11 mg once daily
`
`
`5 mg once daily
`
`Reduce to
`
`XELJANZ 5 mg once daily
`
`Reference ID: 4676373
`
`5
`
`

`

`
`
`
`
`
`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
`
`XELJANZ
`
`tablet
`
`XELJANZ XR
`
`extended-release tablet
`
`
`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.
`
`Discontinue dosing.
`
`
` Interrupt dosing.
`
`
` Interrupt dosing.
`
` When ANC is greater than 1000,
` When ANC is greater than 1000,
`
` resume 5 mg twice daily.
`
`resume 11 mg once daily.
`Discontinue dosing.
`
`
`
`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 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.
`
`
`
`
`
`
`
`Interrupt dosing until hemoglobin values have normalized.
`
`
` Switching from XELJANZ Tablets to XELJANZ XR Extended-Release Tablets
`
`Patients treated with XELJANZ tablets 5 mg twice daily may be switched to XELJANZ XR
`
` extended-release tablets 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: 4676373
`
`6
`
`

`

`
`
`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
`
`
`
`
` Table 2: Recommended Dosage of XELJANZ/XELJANZ XR in Patients with UC
`
` XELJANZ XR
`
`
`
`XELJANZ
`extended-release tablet
`tablet
`
`Induction: 10 mg twice daily for
`Induction: 22 mg once daily for
`
`
`at least 8 weeks [see Clinical
`
`at least 8 weeks; evaluate patients
`
`Studies (14.3)]; evaluate patients
`
`and transition to maintenance
`
`and transition to maintenance
`
`therapy depending on therapeutic
`
`therapy depending on therapeutic
`response. If needed continue 22
`response. If needed continue
`
`mg once daily for a maximum of
`10 mg twice daily for a maximum
`
`16 weeks. Discontinue 22 mg
`
`of 16 weeks. Discontinue 10 mg
`
`once daily after 16 weeks if
`
`
`twice daily after 16 weeks if
`
`adequate therapeutic response is
`
`adequate therapeutic response is
`
`not achieved.
`
`not achieved.
`
`Maintenance: 11 mg once daily.
`
`
`Maintenance: 5 mg twice daily.
`
`
`
`
`For patients with loss of response
`
`
`For patients with loss of response
`
`
`
`during maintenance treatment, a
`
`
`
`during maintenance treatment, a
`
`dosage of 22 mg once daily may
`
`dosage of 10 mg twice daily may
`be considered and limited to the
`be considered and limited to the
`
`shortest duration, with careful
`
`shortest duration, with careful
`consideration of the benefits and
`consideration of the benefits and
`
`
`risks for the individual patient.
`
`
`risks for the individual patient.
`Use the lowest effective dose
`
`
`Use the lowest effective dose
`needed to maintain response.
`
`
`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.
`
`
`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.
`
`
`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.
`
` 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.
`
`
`Reference ID: 4676373
`
`7
`
`

`

`
`
`
`
`
`
`Patients with ANC 500 to
`1000 cells/mm3
`
`
`
`
`
`XELJANZ
`tablet
`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.
`
`XELJANZ XR
`
`extended-release tablet
`
`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 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.
`
`
`
`
`Discontinue dosing.
`
`
`
`
`Interrupt dosing until hemoglobin values have normalized.
`
`
` Switching from XELJANZ Tablets to XELJANZ XR Extended-Release Tablets
`
`Patients treated with XELJANZ 5 mg tablets twice daily may be switched to XELJANZ XR
`
`extended-release tablets 11 mg once daily the day following the last dose of XELJANZ tablets
`5 mg. Patients treated with XELJANZ 10 mg tablets twice daily may be switched to XELJANZ
`XR extended-release tablets 22 mg once daily the day following the last dose of XELJANZ
`
`10 mg.
`
`
`2.4 Recommended Dosage in Polyarticular Course Juvenile Idiopathic Arthritis
`Table 3 displays the recommended body weight-based dosages for XELJANZ tablets/XELJANZ
`
`Oral Solution and dosage adjustments for patients receiving CYP2C19 and/or CYP3A4
`inhibitors [see Drug Interactions (7)], in patients with moderate or severe renal impairment,
`including but not limited to those undergoing hemodialysis [see Use in Specific Populations
`(8.7)], with moderate hepatic impairment [see Use in Specific Populations (8.8)], with
`
`lymphopenia, neutropenia, or anemia.
`
`
`Reference ID: 4676373
`
`8
`
`

`

`Table 3: Recommended Dosage of XELJANZ/XELJANZ Oral Solution in Patients with
`pcJIA
`
`
`
`
`
`
`
`
`pcJIA patients
`
`
`
` XELJANZ tablets/XELJANZ Oral Solution
`
` 10 kg ≤ body weight <20 kg:
`
`
`
`
`
`3.2 mg (3.2 mL oral solution) twice daily
`
`
`
` 20 kg ≤ body weight <40 kg:
`
`
`
`
`
`
`4 mg (4 mL oral solution) twice daily
`
`
`
` Body weight ≥40 kg:
`
`
`5 mg (one 5 mg tablet or 5 mL oral solutionb) twice
`
`
`daily
`If taking 3.2 mg twice daily, reduce to 3.2 mg once daily.
`
`
`
`
`If taking 4 mg twice daily, reduce to 4 mg once daily.
`
`
`If taking 5 mg twice daily, reduce to 5 mg once daily.
`
`If taking 3.2 mg twice daily, reduce to 3.2 mg once daily.
`
`
`
`
`If taking 4 mg twice daily, reduce to 4 mg once 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.
` Interrupt dosing until ANC is greater than
`
`1000 cells/mm3.
`Discontinue dosing.
`
`Patients with ANC less than 500 cells/mm3
`
`
`
`
`Interrupt dosing until hemoglobin values have
`Patients with hemoglobin less than 8 g/dL or a
`
`normalized.
`decrease of more than 2 g/dL
`
`
` a XELJANZ/XELJANZ Oral Solution is not recommended for patients with severe hepatic impairment.
`b Patients treated with 5 mL XELJANZ Oral Solution may be switched to a XELJANZ 5 mg tablet.
`
`
`
`
`
`
`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)]a
`
`
`
`
`Patients with lymphocyte count less than
`500 cells/mm3, confirmed by repeat testing
`
`
`Patients with ANC 500 to 1000 cells/mm3
`
`
`
`
`
`
`Administer XELJANZ Oral Solution using the included press-in bottle adapter and oral dosing
`syringe [see Instructions for Use].
`
`
`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.
`
`Reference ID: 4676373
`
`9
`
`

`

`
`
` 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.
`
`
`XELJANZ Oral Solution:
`
`1 mg/mL tofacitinib: Clear, colorless oral solution.
`
`
`
`
`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.
`
`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/XELJANZ Oral Solution 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/XELJANZ Oral Solution in patients:
`
`• with c