XELJANZ (tofacitinib) tablet, film coated
Pfizer Laboratories Div Pfizer Inc

Pfizer Laboratories Div Pfizer Inc
Viatris Pharmaceuticals LLC
Viatris Pharmaceuticals LLC
Pfizer Ireland Pharmaceuticals
Pfizer Manufacturing Deutschland GmbH
Pharmacia & Upjohn Company LLC
Pfizer Asia Manufacturing Pte Ltd
Pfizer Ireland Pharmaceuticals
Pfizer Inc
XELJANZ
tofacitinib
TOFACITINIB CITRATE
TOFACITINIB
MICROCRYSTALLINE CELLULOSE
LACTOSE MONOHYDRATE
CROSCARMELLOSE SODIUM
MAGNESIUM STEARATE
TITANIUM DIOXIDE
TRIACETIN
POLYETHYLENE GLYCOL 3350
HYPROMELLOSE 2910 (6 MPA.S)
white to off-white
PFIZER;JKI5
XELJANZ
XR
tofacitinib
TOFACITINIB CITRATE
TOFACITINIB
SORBITOL
HYDROXYETHYL CELLULOSE (140 MPA.S AT 5%)
COPOVIDONE K25-31
MAGNESIUM STEARATE
CELLULOSE ACETATE
HYDROXYPROPYL CELLULOSE (1600000 WAMW)
TITANIUM DIOXIDE
HYPROMELLOSE 2910 (6 MPA.S)
TRIACETIN
FERRIC OXIDE RED
SHELLAC
AMMONIA
PROPYLENE GLYCOL
FERROSOFERRIC OXIDE
pink
JKI11
XELJANZ
tofacitinib
TOFACITINIB CITRATE
TOFACITINIB
MICROCRYSTALLINE CELLULOSE
LACTOSE MONOHYDRATE
CROSCARMELLOSE SODIUM
MAGNESIUM STEARATE
TITANIUM DIOXIDE
TRIACETIN
POLYETHYLENE GLYCOL 3350
HYPROMELLOSE 2910 (6 MPA.S)
FD&C BLUE NO. 1
FD&C BLUE NO. 2
PFIZER;JKI10
XELJANZ
XR
tofacitinib
TOFACITINIB CITRATE
TOFACITINIB
SORBITOL
HYDROXYETHYL CELLULOSE (140 MPA.S AT 5%)
COPOVIDONE K25-31
MAGNESIUM STEARATE
CELLULOSE ACETATE
HYDROXYPROPYL CELLULOSE (1600000 WAMW)
TITANIUM DIOXIDE
HYPROMELLOSE 2910 (6 MPA.S)
TRIACETIN
FERRIC OXIDE RED
SHELLAC
AMMONIA
PROPYLENE GLYCOL
FERROSOFERRIC OXIDE
FD&C BLUE NO. 2 ALUMINUM LAKE
FERRIC OXIDE YELLOW
beige
JKI22
XELJANZ
tofacitinib
TOFACITINIB CITRATE
TOFACITINIB
WINE GRAPE
HYDROCHLORIC ACID
LACTIC ACID, UNSPECIFIED FORM
WATER
SODIUM BENZOATE
SUCRALOSE
XYLITOL
natural grape

WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, and THROMBOSIS

WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE), and THROMBOSIS

See full prescribing information for complete boxed warning.

  • Increased risk of serious bacterial, fungal, viral, and opportunistic infections leading to hospitalization or death, including tuberculosis (TB). Interrupt treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution if serious infection occurs until the infection is controlled. Test for latent TB before and during therapy; treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative latent TB test. (5.1)
  • Higher rate of all-cause mortality, including sudden cardiovascular death with XELJANZ vs. TNF blockers in rheumatoid arthritis (RA) patients. (5.2)
  • Malignancies have occurred in patients treated with XELJANZ. Higher rate of lymphomas and lung cancers with XELJANZ vs. TNF blockers in RA patients. (5.3)
  • Higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) with XELJANZ vs. TNF blockers in RA patients. (5.4)
  • Thrombosis has occurred in patients treated with XELJANZ. Increased incidence of pulmonary embolism, venous and arterial thrombosis with XELJANZ vs. TNF blockers in RA patients. (5.5)

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

In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular risk factor comparing XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day [see Warnings and Precautions (5.2)]. A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].

MALIGNANCIES

Malignancies, including lymphomas and solid tumors, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. In RA patients, a higher rate of malignancies (excluding NMSC) was observed in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day compared with TNF blockers [see Warnings and Precautions (5.3)].

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

Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications [see Warnings and Precautions (5.3)].

MAJOR ADVERSE CARDIOVASCULAR EVENTS

RA patients 50 years of age and older with at least one cardiovascular risk factor, treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily, had a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke), compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients that have experienced a myocardial infarction or stroke [see Warnings and Precautions (5.4)].

THROMBOSIS

Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death. RA patients 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily compared to TNF blockers had an observed increase in incidence of these events. Avoid XELJANZ/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 (5.5)].

1 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 one or more TNF blockers.
    • o Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. (1.1)
  • 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 one or more TNF blockers.
    • o Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. (1.2)
  • Ankylosing Spondylitis: XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active ankylosing spondylitis who have had an inadequate response or intolerance to one or more TNF blockers.
    • o Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. (1.3)
  • 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 intolerance to one or more TNF blockers.
    • o 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. (1.4)
  • 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 who have had an inadequate response or intolerance to one or more TNF blockers.
    • o 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. (1.5)

1.1 Rheumatoid Arthritis

XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more TNF blockers.

  • Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic disease-modifying antirheumatic drugs (DMARDs) or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

1.2 Psoriatic Arthritis

XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to one or more TNF blockers.

  • Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

1.3 Ankylosing Spondylitis

XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active ankylosing spondylitis (AS) who have had an inadequate response or intolerance to one or more TNF blockers.

  • Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

1.4 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 intolerance to one or more TNF blockers.

  • Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

1.5 Polyarticular Course Juvenile Idiopathic Arthritis

XELJANZ/XELJANZ Oral Solution is indicated for the treatment of active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers.

  • Limitations of Use: Use of XELJANZ/XELJANZ Oral Solution in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

2 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)

Ankylosing Spondylitis

  • 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)

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 (5.8), 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, Psoriatic Arthritis, and Ankylosing Spondylitis

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, Psoriatic ArthritisXELJANZ/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., and Ankylosing Spondylitis
XELJANZ
tablet
XELJANZ XR
extended-release tablet

Adult patients

5 mg twice daily

11 mg once daily

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)]

5 mg once daily

Reduce to XELJANZ 5 mg once daily

Patients with:

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.

Patients with lymphocyte count less than 500 cells/mm3, confirmed by repeat testing

Discontinue dosing.

Patients with ANC 500 to 1000 cells/mm3

Interrupt dosing.
When ANC is greater than 1000, resume 5 mg twice daily.

Interrupt dosing.
When ANC is greater than 1000, resume 11 mg once daily.

Patients with ANC less than 500 cells/mm3

Discontinue dosing.

Patients with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL

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.

Table 2: Recommended Dosage of XELJANZ/XELJANZ XR in Patients with UC
XELJANZ
tablet
XELJANZ XR
extended-release tablet

Adult patients

Induction: 10 mg twice daily for at least 8 weeks [see Clinical Studies (14.4)]; 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.

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.

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)]

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

Patients with:

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.

Patients with lymphocyte count less than 500 cells/mm3, confirmed by repeat testing

Discontinue dosing.

Patients with ANC 500 to 1000 cells/mm3

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.

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

Discontinue dosing.

Patients with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL

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.

Table 3: Recommended Dosage of XELJANZ/XELJANZ Oral Solution in Patients with pcJIA
XELJANZ tablets/XELJANZ Oral Solution

pcJIA patients

  • 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 solutionPatients treated with 5 mL XELJANZ Oral Solution may be switched to a XELJANZ 5 mg tablet.) twice daily

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)]

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.

Patients with:

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.

Patients with lymphocyte count less than 500 cells/mm3, confirmed by repeat testing

Discontinue dosing.

Patients with ANC 500 to 1000 cells/mm3

Interrupt dosing until ANC is greater than 1000 cells/mm3.

Patients with ANC less than 500 cells/mm3

Discontinue dosing.

Patients with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL

Interrupt dosing until hemoglobin values have normalized.

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, 10 mg tofacitinib (3)
  • XELJANZ XR Tablets: 11 mg, 22 mg tofacitinib (3)
  • XELJANZ Oral Solution: 1 mg/mL tofacitinib (3)

XELJANZ Tablets:

  • o5 mg tofacitinib: White, round, immediate-release film-coated tablets, debossed with "Pfizer" on one side, and "JKI 5" on the other side.
  • o10 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:

  • o11 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.
  • o22 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.

None (4)

5 WARNINGS AND PRECAUTIONS

  • Serious Infections: Avoid use of XELJANZ/XELJANZ XR/XELJANZ Oral Solution during an active serious infection, including localized infections. (5.1)
  • Gastrointestinal Perforations: Use with caution in patients that may be at increased risk. (5.6)
  • Laboratory Monitoring: Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. (5.8)
  • Immunizations: Live vaccines: Avoid use with XELJANZ/XELJANZ XR/XELJANZ Oral Solution. (5.9)

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 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 Oral Solution. XELJANZ/XELJANZ XR/XELJANZ Oral Solution 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/XELJANZ Oral Solution 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, 2.4)].

Tuberculosis

Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of XELJANZ/XELJANZ XR/XELJANZ Oral Solution.

Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ/XELJANZ XR/XELJANZ Oral Solution 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/XELJANZ Oral Solution.

Viral Reactivation

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ/XELJANZ Oral Solution. Postmarketing cases of hepatitis B reactivation have been reported in patients treated with XELJANZ. The impact of XELJANZ/XELJANZ XR/XELJANZ Oral Solution 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/XELJANZ Oral Solution. The risk of herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR/XELJANZ Oral Solution 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 risk factor treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day had a higher observed rate of all-cause mortality, including sudden cardiovascular death, compared to those treated with TNF blockers in a large, randomized, postmarketing safety study (RA Safety Study 1). The incidence rate of all-cause mortality per 100 patient-years was 0.88 for XELJANZ 5 mg twice a day, 1.23 for XELJANZ 10 mg twice a day, and 0.69 for TNF blockers [see Clinical Studies (14.6)]. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ/XELJANZ XR/XELJANZ Oral Solution.

A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA, PsA, or AS [see Dosage and Administration (2.2)].

For the treatment of UC, use XELJANZ/XELJANZ XR 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

Malignancies, including lymphomas and solid cancers, were observed in clinical studies of XELJANZ [see Adverse Reactions (6.1)].

In RA Safety Study 1, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day as compared with TNF blockers. The incidence rate of malignancies (excluding NMSC) per 100 patient-years was 1.13 for XELJANZ 5 mg twice a day, 1.13 for XELJANZ 10 mg twice a day, and 0.77 for TNF blockers. Patients who are current or past smokers are at additional increased risk [see Clinical Studies (14.6)].

Lymphomas and lung cancers, which are a subset of all malignancies in RA Safety Study 1, were observed at a higher rate in patients treated with XELJANZ 5 mg twice a day and XELJANZ 10 mg twice a day compared to those treated with TNF blockers. The incidence rate of lymphomas per 100 patient-years was 0.07 for XELJANZ 5 mg twice a day, 0.11 for XELJANZ 10 mg twice a day, and 0.02 for TNF blockers. The incidence rate of lung cancers per 100 patient-years among current and past smokers was 0.48 for XELJANZ 5 mg twice a day, 0.59 for XELJANZ 10 mg twice a day, and 0.27 for TNF blockers [see Clinical Studies (14.6)].

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ/XELJANZ XR/XELJANZ Oral Solution, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy while on treatment, and patients who are current or past smokers. A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].

In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

Other malignancies were observed in clinical studies and the postmarketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer.

Non-Melanoma Skin Cancer

Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC.

5.4 Major Adverse Cardiovascular Events

In RA Safety Study 1, RA patients who were 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily had a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke, compared to those treated with TNF blockers. The incidence rate of MACE per 100 patient-years was 0.91 for XELJANZ 5 mg twice a day, 1.11 for XELJANZ 10 mg twice a day, and 0.79 for TNF blockers. The incidence rate of fatal or non-fatal myocardial infarction per 100 patient-years was 0.36 for XELJANZ 5 mg twice a day, 0.39 for XELJANZ 10 mg twice a day, and 0.20 for TNF blockers [see Clinical Studies (14.6)]. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ/XELJANZ XR/XELJANZ Oral Solution, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients that have experienced a myocardial infarction or stroke. A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].

5.5 Thrombosis

Thrombosis, including pulmonary embolism (PE), deep venous thrombosis (DVT), and arterial thrombosis, have occurred in patients treated with XELJANZ and other Janus kinase (JAK) inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death [see Warnings and Precautions (5.2)].

Patients with rheumatoid arthritis 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ at both 5 mg or 10 mg twice daily compared to TNF blockers in RA Safety Study 1 had an observed increase in incidence of these events. The incidence rate of DVT per 100 patient-years was 0.22 for XELJANZ 5 mg twice a day, 0.28 for XELJANZ 10 mg twice a day, and 0.16 for TNF blockers. The incidence rate of PE per 100 patient-years was 0.18 for XELJANZ 5 mg twice a day, 0.49 for XELJANZ 10 mg twice a day, and 0.05 for TNF blockers [see Clinical Studies (14.6)].

A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA, PsA, or AS [see Dosage and Administration (2.2)].

In a long-term extension study in patients with UC, five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one death in a patient with advanced cancer.

Promptly evaluate patients with symptoms of thrombosis and discontinue XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients with symptoms of thrombosis.

Avoid XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients that may be at increased risk of thrombosis. For the treatment of UC, use XELJANZ/XELJANZ XR at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response [see Dosage and Administration (2.3)].

5.6 Gastrointestinal Perforations

Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ, although the role of JAK inhibition in these events is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).

There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids.

XELJANZ/XELJANZ XR/XELJANZ Oral Solution should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation [see Adverse Reactions (6.1)].

5.7 Hypersensitivity

Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ/XELJANZ XR. Some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction [see Adverse Reactions (6.2)].

5.8 Laboratory Abnormalities

Lymphocyte Abnormalities

Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean absolute lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.

Avoid initiation of XELJANZ/XELJANZ XR/XELJANZ Oral Solution treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3). In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution is not recommended.

Monitor lymphocyte counts at baseline and every 3 months thereafter. For recommended modifications based on lymphocyte counts [see Dosage and Administration (2.2, 2.3, 2.4)].

Neutropenia

Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo.

Avoid initiation of XELJANZ/XELJANZ XR/XELJANZ Oral Solution treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3). For patients who develop a persistent ANC of 500 to 1000 cells/mm3, interrupt XELJANZ/XELJANZ XR/XELJANZ Oral Solution dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution is not recommended.

Monitor neutrophil counts at baseline and after 4–8 weeks of treatment and every 3 months thereafter. For recommended modifications based on ANC results [see Dosage and Administration (2.2, 2.3)].

Anemia

Avoid initiation of XELJANZ/XELJANZ XR/XELJANZ Oral Solution treatment in patients with a low hemoglobin level (i.e., less than 9 g/dL). Treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment.

Monitor hemoglobin at baseline and after 4–8 weeks of treatment and every 3 months thereafter. For recommended modifications based on hemoglobin results [see Dosage and Administration (2)].

Liver Enzyme Elevations

Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.

Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of XELJANZ/XELJANZ XR/XELJANZ Oral Solution should be interrupted until this diagnosis has been excluded.

Lipid Elevations

Treatment with XELJANZ was associated with dose-dependent increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. There were no clinically relevant changes in LDL/HDL cholesterol ratios. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

Assessment of lipid parameters should be performed approximately 4–8 weeks following initiation of XELJANZ/XELJANZ XR/XELJANZ Oral Solution therapy.

Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.

5.9 Vaccinations

Avoid use of live vaccines concurrently with XELJANZ/XELJANZ XR/XELJANZ Oral Solution. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

A patient experienced dissemination of the vaccine strain of varicella zoster virus, 16 days after vaccination with live attenuated (Zostavax) virus vaccine and 2 days after treatment start with tofacitinib 5 mg twice daily. The patient was varicella virus naïve, as evidenced by no previous history of varicella infection and no anti-varicella antibodies at baseline. Tofacitinib was discontinued and the patient recovered after treatment with standard doses of antiviral medication.

Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ/XELJANZ XR/XELJANZ Oral Solution therapy.

5.10 Risk of Gastrointestinal Obstruction with a Non-Deformable Extended-Release Formulation such as XELJANZ XR

As with any other non-deformable material, caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended-release formulation.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Most common adverse reactions are:

  • Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis: Reported during the first 3 months in rheumatoid arthritis placebo-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.

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

Rheumatoid Arthritis

The clinical studies described in the following sections were conducted using XELJANZ. Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is 5 mg twice daily. The recommended dose for XELJANZ XR is 11 mg once daily. A dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not a recommended regimen for the treatment of rheumatoid arthritis [see Dosage and Administration (2.2)]. In RA Safety Study 1, 1455 patients were treated with XELJANZ 5 mg twice daily, 1456 patients were treated with 10 mg twice daily, and 1451 patients were treated with a TNF blocker for a median of 4.0 years [see Clinical Studies (14.6)].

The following data includes two Phase 2 and five Phase 3 double-blind, placebo-controlled, multicenter trials. In these trials, patients were randomized to doses of XELJANZ 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, XELJANZ 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven placebo-controlled protocols included provisions for patients taking placebo to receive treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore, some analyses that follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of a given interval. Comparisons between placebo and XELJANZ were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure.

The long-term safety population includes all patients who participated in a double-blind, placebo-controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose.

The most common serious adverse reactions were serious infections [see Warnings and Precautions (5.1)].

The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for patients taking XELJANZ and 3% for placebo-treated patients.

Overall Infections

In the seven placebo-controlled trials, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group.

The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).

Serious Infections

In the seven placebo-controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily XELJANZ group minus placebo.

In the seven placebo-controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.

The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection [see Warnings and Precautions (5.1)].

Tuberculosis

In the seven placebo-controlled trials, during the 0 to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ.

In the seven placebo-controlled trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of XELJANZ and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.

Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days) [see Warnings and Precautions (5.1)].

Opportunistic Infections (excluding tuberculosis)

In the seven placebo-controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ.

In the seven placebo-controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.

The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days) [see Warnings and Precautions (5.1)].

Malignancy

In the seven placebo-controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined 5 mg and 10 mg twice daily XELJANZ group minus placebo.

In the seven placebo-controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with XELJANZ 10 mg twice daily.

The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma [see Warnings and Precautions (5.3)].

Laboratory Abnormalities

Lymphopenia

In the placebo-controlled clinical trials, confirmed decreases in absolute lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.

Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections [see Warnings and Precautions (5.8)].

Neutropenia

In the placebo-controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.

There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group.

There was no clear relationship between neutropenia and the occurrence of serious infections.

In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the placebo-controlled clinical trials [see Warnings and Precautions (5.8)].

Liver Enzyme Elevations

Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3× ULN) were observed in patients treated with XELJANZ. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalization of liver enzymes.

In the placebo-controlled monotherapy trials (0–3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg twice daily groups.

In the placebo-controlled background DMARD trials (0–3 months), ALT elevations greater than 3× ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3× ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively.

One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3× ULN and bilirubin elevations greater than 2× ULN, which required hospitalizations and a liver biopsy.

Lipid Elevations

In the placebo-controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the placebo-controlled clinical trials are summarized below:

  • Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.
  • Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.
  • Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.

In a placebo-controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.

In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the placebo-controlled clinical trials.

Serum Creatinine Elevations

In the placebo-controlled clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.

Other Adverse Reactions

Adverse reactions occurring in 2% or more of patients on 5 mg twice daily or 10 mg twice daily XELJANZ and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in Table 4.

Table 4: Common Adverse Reactionsreported in ≥2% of patients treated with either dose of XELJANZ and ≥1% greater than that reported for placebo. in Clinical Trials of XELJANZ for the Treatment of Rheumatoid Arthritis With or Without Concomitant DMARDs (0–3 Months)
Preferred Term XELJANZ
5 mg Twice Daily
XELJANZ
10 mg Twice Daily the recommended dose of XELJANZ for the treatment of rheumatoid arthritis is 5 mg twice daily [see Dosage and Administration (2)].
Placebo
N = 1336
(%)
N = 1349
(%)
N = 809
(%)
N reflects randomized and treated patients from the seven placebo-controlled clinical trials.

Upper respiratory tract infection

4

4

3

Nasopharyngitis

4

3

3

Diarrhea

4

3

2

Headache

4

3

2

Hypertension

2

2

1

Other adverse reactions occurring in placebo-controlled and open-label extension studies included:

Blood and lymphatic system disorders: Anemia

Infections and infestations: Diverticulitis

Metabolism and nutrition disorders: Dehydration

Psychiatric disorders: Insomnia

Nervous system disorders: Paresthesia

Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with rheumatoid arthritis and some were fatal)

Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea

Hepatobiliary disorders: Hepatic steatosis

Skin and subcutaneous tissue disorders: Rash, erythema, pruritus

Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling

Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancers

General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema

Clinical Experience in Methotrexate-Naïve Patients

Study RA-VI was an active-controlled clinical trial in methotrexate-naïve patients [see Clinical Studies (14)]. The safety experience in these patients was consistent with Studies RA-I through V.

Psoriatic Arthritis

XELJANZ 5 mg twice daily and 10 mg twice daily were studied in 2 double-blind Phase 3 clinical trials in patients with active psoriatic arthritis (PsA). Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is 5 mg twice daily. The recommended dose for XELJANZ XR is 11 mg once daily. A dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended for the treatment of PsA [see Dosage and Administration (2.2)].

Study PsA-I (NCT01877668) had a duration of 12 months and enrolled patients who had an inadequate response to a nonbiologic DMARD and who were naïve to treatment with a TNF blocker. Study PsA-I included a 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months.

Study PsA-II (NCT01882439) had a duration of 6 months and enrolled patients who had an inadequate response to at least one approved TNF blocker. This clinical trial included a 3-month placebo-controlled period.

In these combined Phase 3 clinical trials, 238 patients were randomized and treated with XELJANZ 5 mg twice daily and 236 patients were randomized and treated with XELJANZ 10 mg twice daily. All patients in the clinical trials were required to receive treatment with a stable dose of a nonbiologic DMARD [the majority (79%) received methotrexate]. The study population randomized and treated with XELJANZ (474 patients) included 45 (9.5%) patients aged 65 years or older and 66 (13.9%) patients with diabetes at baseline.

During the 2 PsA controlled clinical trials, there were 3 malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus non-biologic DMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus non-biologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus non-biologic DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also been observed in the long-term extension study in psoriatic arthritis patients treated with XELJANZ.

The safety profile observed in patients with active psoriatic arthritis treated with XELJANZ was consistent with the safety profile observed in rheumatoid arthritis patients.

Ankylosing Spondylitis

XELJANZ 5 mg twice daily was studied in patients with active ankylosing spondylitis (AS) in a confirmatory double-blind placebo-controlled Phase 3 clinical trial (Study AS-I) and in a dose-ranging Phase 2 clinical trial (Study AS-II).

Study AS-I (NCT03502616) had a duration of 48 weeks and enrolled patients who had an inadequate response to at least 2 NSAIDs. Study AS-I included a 16-week double-blind period in which patients received XELJANZ 5 mg or placebo twice daily and a 32-week open-label treatment period in which all patients received XELJANZ 5 mg twice daily.

Study AS-II (NCT01786668) had a duration of 16 weeks and enrolled patients who had an inadequate response to at least 2 NSAIDs. This clinical trial included a 12-week treatment period in which patients received either XELJANZ 2 mg, 5 mg, 10 mg, or placebo twice daily.

In the combined Phase 2 and Phase 3 clinical trials, a total of 420 patients were treated with either XELJANZ 2 mg, 5 mg, or 10 mg twice daily. Of these, 316 patients were treated with XELJANZ 5 mg twice daily for up to 48 weeks. In the combined double-blind period, 185 patients were randomized to and treated with XELJANZ 5 mg twice daily and 187 to placebo for up to 16 weeks. Concomitant treatment with stable doses of nonbiologic DMARDs, NSAIDs, or corticosteroids (≤10 mg/day) was permitted. The study population randomized and treated with XELJANZ included 13 (3.1%) patients aged 65 years or older and 18 (4.3%) patients with diabetes at baseline.

The safety profile observed in patients with AS treated with XELJANZ was consistent with the safety profile observed in RA and PsA patients.

Ulcerative Colitis

XELJANZ has been studied in patients with moderately to severely active UC in 4 randomized, double-blind, placebo-controlled trials (UC-I, UC-II, UC-III, and dose-ranging UC-V) and an open-label long-term extension study (UC-IV) [see Clinical Studies (14.4)].

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

Induction Trials (Study UC-I, UC-II, and UC-V):

Common adverse reactions reported in ≥2% of patients treated with XELJANZ 10 mg twice daily and ≥1% greater than that reported in patients receiving placebo in the 3 induction trials were: headache, nasopharyngitis, elevated cholesterol levels, acne, increased blood creatine phosphokinase, and pyrexia.

Maintenance Trial (Study UC-III)

Common adverse reactions reported in ≥4% of patients treated with either dose of XELJANZ and ≥1% greater than reported in patients receiving placebo are shown in Table 5.

Table 5: Common Adverse Reactionsreported in ≥4% of patients treated with either dose of XELJANZ and ≥1% greater than reported for placebo. in -UC Patients during the Maintenance Trial (Study UC-III)
Preferred Term XELJANZ
5 mg Twice Daily
XELJANZ
10 mg Twice Daily
Placebo
N = 198
(%)
N = 196
(%)
N = 198
(%)

Nasopharyngitis

10

14

6

Elevated cholesterol levelsincludes hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low density lipoprotein increased, low density lipoprotein abnormal, or lipids increased.

5

9

1

Headache

9

3

6

Upper respiratory tract infection

7

6

4

Increased blood creatine phosphokinase

3

7

2

Rash

3

6

4

Diarrhea

2

5

3

Herpes zoster

1

5

1

Gastroenteritis

3

4

3

Anemia

4

2

2

Nausea

1

4

3

Dose-dependent adverse reactions seen in patients treated with XELJANZ 10 mg twice daily, in comparison to 5 mg twice daily, include the following: herpes zoster infections, serious infections, and NMSC [see Warnings and Precautions (5.1, 5.3)].

During the UC controlled clinical studies (8-week induction and 52-week maintenance studies), which included 1220 patients, 0 cases of solid cancer or lymphoma were observed in XELJANZ-treated patients.

In the long-term extension study, malignancies (including solid cancers, lymphomas and NMSC) were observed in patients treated with XELJANZ 5 mg and 10 mg twice daily [see Warnings and Precautions (5.3)]. Five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one fatality in a patient with advanced cancer [see Warnings and Precautions (5.5)].

Polyarticular Course Juvenile Idiopathic Arthritis

XELJANZ/XELJANZ Oral Solution 5 mg twice daily or weight-based equivalent twice daily was studied in 225 patients from 2 years to 17 years of age in Study pcJIA-I [see Clinical Studies (14.5)] and one open-label extension study. The total patient exposure (defined as patients who received at least one dose of XELJANZ/XELJANZ Oral Solution) was 351 patient-years.

In general, the types of adverse drug reactions in patients with pcJIA were consistent with those seen in adult RA patients [see Adverse Reactions (6.1)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of XELJANZ/XELJANZ XR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: Drug hypersensitivity (events such as angioedema and urticaria have been observed)

Skin and subcutaneous tissue disorders: Acne

7 DRUG INTERACTIONS

Table 6 includes drugs with clinically important drug interactions when administered concomitantly with XELJANZ/XELJANZ XR/XELJANZ Oral Solution and instructions for preventing or managing them.

Table 6: Clinically Relevant Interactions Affecting XELJANZ/XELJANZ XR/XELJANZ Oral Solution When Coadministered with Other Drugs

Strong CP3A4 Inhibitors (e.g., ketoconazole)

Clinical Impact

Increased exposure to tofacitinib

Intervention

Dosage adjustment of XELJANZ/XELJANZ XR/XELJANZ Oral Solution is recommended
[see Dosage and Administration (2), Clinical Pharmacology, Figure 3 (12.3)]

Moderate CYP3A4 Inhibitors Coadministered with Strong CYP2C19 Inhibitors (e.g., fluconazole)

Clinical Impact

Increased exposure to tofacitinib

Intervention

Dosage adjustment of XELJANZ/XELJANZ XR/XELJANZ Oral Solution is recommended
[see Dosage and Administration (2), Clinical Pharmacology, Figure 3 (12.3)]

Strong CYP3A4 Inducers (e.g., rifampin)

Clinical Impact

Decreased exposure to tofacitinib and may result in loss of or reduced clinical response

Intervention

Coadministration with XELJANZ/XELJANZ XR/XELJANZ Oral Solution is not recommended
[see Clinical Pharmacology, Figure 3 (12.3)]

Immunosuppressive Drugs (e.g., azathioprine, tacrolimus, cyclosporine)

Clinical Impact

Risk of added immunosuppression; coadministration with biologic DMARDs or potent immunosuppressants has not been studied in patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, UC, or pcJIA.

Intervention

Coadministration with XELJANZ/XELJANZ XR/XELJANZ Oral Solution is not recommended
[see Indications and Usage (1), Clinical Pharmacology, Figure 3 (12.3)]

See full prescribing information for clinically relevant drug interactions. (2, 7)

8 USE IN SPECIFIC POPULATIONS

All information provided in this section is applicable to XELJANZ/XELJANZ XR/XELJANZ Oral Solution as they contain the same active ingredient (tofacitinib).

Lactation: Advise not to breastfeed. (8.2)

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to XELJANZ/XELJANZ XR/XELJANZ Oral Solution during pregnancy. Patients should be encouraged to enroll in the XELJANZ/XELJANZ XR/XELJANZ Oral Solution pregnancy registry if they become pregnant. To enroll or obtain information from the registry, patients can call the toll free number 1-877-311-8972.

Risk Summary

Available data with XELJANZ/XELJANZ XR/XELJANZ Oral Solution use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with rheumatoid arthritis and UC in pregnancy (see Clinical Considerations). In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively. Further, in a peri- and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dose of 5 mg twice daily and approximately 36 times the maximum recommended dose of 10 mg twice daily, respectively (see Data).

The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis or ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Data

Animal Data

In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the recommended dose of 5 mg twice daily, and approximately 73 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the recommended dose of 5 mg twice daily, and approximately 29 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats).

In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the recommended dose of 5 mg twice daily, and approximately 6.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the recommended dose of 5 mg twice daily, and approximately 1.5 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits).

In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the recommended dose of 5 mg twice daily, and approximately 36 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the recommended dose of 5 mg twice daily, and approximately 8.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats).

8.2 Lactation

Risk Summary

There are no data on the presence of tofacitinib in human milk, the effects on a breastfed infant, or the effects on milk production. Tofacitinib is present in the milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Given the serious adverse reactions seen in patients treated with XELJANZ/XELJANZ XR/XELJANZ Oral Solution, such as increased risk of serious infections, advise patients that breastfeeding is not recommended during treatment and for at least 18 hours after the last dose of XELJANZ/XELJANZ Oral Solution or 36 hours after the last dose of XELJANZ XR (approximately 6 elimination half-lives).

Data

Following administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum, and were approximately 2 times higher in milk relative to maternal serum at all time points measured.

8.3 Females and Males of Reproductive Potential

Contraception

Females

In an animal reproduction study, tofacitinib at AUC multiples of 13 times the recommended dose of 5 mg twice daily and 6.3 times the maximum recommended dose of 10 mg twice daily demonstrated adverse embryo-fetal findings [see Use in Specific Populations (8.1)]. However, there is uncertainty as to how these animal findings relate to females of reproductive potential treated with the recommended clinical dose. Consider pregnancy planning and prevention for females of reproductive potential.

Infertility

Females

Based on findings in rats, treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution may result in reduced fertility in females of reproductive potential. It is not known if this effect is reversible [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of XELJANZ/XELJANZ Oral Solution for the treatment of active pcJIA have been established in patients 2 years to 17 years of age. Use of XELJANZ/XELJANZ Oral Solution for the treatment of pediatric patients with active pcJIA in this age group is supported by evidence from adequate and well-controlled studies of XELJANZ in adult RA patients with additional data from a clinical trial of XELJANZ/XELJANZ Oral Solution in pediatric patients (2 years to 17 years of age) with active pcJIA consisting of an 18-week, open label, run-in period followed by a 26-week placebo-controlled, randomized withdrawal period [see Clinical Studies (14.5)]. The safety and effectiveness of XELJANZ/XELJANZ Oral Solution have not been established in pcJIA patients less than 2 years of age.

Adverse reactions observed in pediatric patients receiving XELJANZ/XELJANZ Oral Solution were consistent with those reported in RA patients [see Adverse Reactions (6.1)].

Safety and efficacy of XELJANZ/XELJANZ Oral Solution in pediatric patients for indications other than pcJIA have not been established.

The safety and effectiveness of XELJANZ XR in pediatric patients have not been established.

8.5 Geriatric Use

Of the 3315 patients who enrolled in rheumatoid arthritis Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among XELJANZ-treated subjects 65 years of age and older was higher than among those under the age of 65.

Of the 1156 XELJANZ-treated patients in the UC program, a total of 77 patients (7%) were 65 years of age or older. The number of patients aged 65 years and older was not sufficient to determine whether they responded differently from younger patients.

As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly [see Warnings and Precautions (5.1)].

8.6 Use in Diabetics

As there is a higher incidence of infection in diabetic population in general, caution should be used when treating patients with diabetes.

8.7 Renal Impairment

Moderate and Severe Impairment

XELJANZ-treated patients with moderate or severe renal impairment had greater tofacitinib blood concentrations than XELJANZ-treated patients with normal renal function. Therefore, dosage adjustment of XELJANZ/XELJANZ XR/XELJANZ Oral Solution is recommended in patients with moderate or severe renal impairment (including but not limited to those with severe insufficiency who are undergoing hemodialysis) [see Dosage and Administration (2.2, 2.3, 2.4)].

Mild impairment

No dosage adjustment is required in patients with mild renal impairment.

8.8 Hepatic Impairment

Severe Impairment

XELJANZ/XELJANZ XR/XELJANZ Oral Solution has not been studied in patients with severe hepatic impairment; therefore, use of XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients with severe hepatic impairment is not recommended.

Moderate Impairment

XELJANZ-treated patients with moderate hepatic impairment had greater tofacitinib blood concentration than XELJANZ-treated patients with normal hepatic function [see Clinical Pharmacology (12.3)]. Higher blood concentrations may increase the risk of some adverse reactions. Therefore, dosage adjustment of XELJANZ/XELJANZ XR/XELJANZ Oral Solution is recommended in patients with moderate hepatic impairment [see Dosage and Administration (2.2, 2.3, 2.4)].

Mild Impairment

No dosage adjustment of XELJANZ/XELJANZ XR/XELJANZ Oral Solution is required in patients with mild hepatic impairment.

Hepatitis B or C Serology

The safety and efficacy of XELJANZ/XELJANZ XR/XELJANZ Oral Solution have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.

10 OVERDOSAGE

There is no specific antidote for overdose with XELJANZ/XELJANZ XR/XELJANZ Oral Solution. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions.

In a study in subjects with end stage renal disease (ESRD) undergoing hemodialysis, plasma tofacitinib concentrations declined more rapidly during the period of hemodialysis and dialyzer efficiency, calculated as dialyzer clearance/blood flow entering the dialyzer, was high [mean (SD) = 0.73 (0.15)]. However, due to the significant non-renal clearance of tofacitinib, the fraction of total elimination occurring by hemodialysis was small, and thus limits the value of hemodialysis for treatment of overdose with XELJANZ/XELJANZ XR/XELJANZ Oral Solution.

11 DESCRIPTION

XELJANZ/XELJANZ XR (tofacitinib) tablets and XELJANZ (tofacitinib) Oral Solution are formulated with the citrate salt of tofacitinib, a JAK inhibitor.

Tofacitinib citrate is a white to off-white powder with the following chemical name: (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino)-ß-oxo-1-piperidinepropanenitrile, 2-hydroxy-1,2,3-propanetricarboxylate (1:1).

The solubility of tofacitinib citrate in water is 2.9 mg/mL.

Tofacitinib citrate has a molecular weight of 504.5 Daltons (or 312.4 Daltons as the tofacitinib free base) and a molecular formula of C16H20N6O∙C6H8O7. The chemical structure of tofacitinib citrate is:

Chemical Structure

XELJANZ is supplied for oral administration as a 5 mg white round, immediate-release film-coated tablet. Each tablet of XELJANZ contains 5 mg tofacitinib (equivalent to 8.08 mg tofacitinib citrate) and the following inactive ingredients: croscarmellose sodium, HPMC 2910/Hypromellose 6cP, lactose monohydrate, macrogol/PEG3350, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin.

XELJANZ is supplied for oral administration as a 10 mg blue round, immediate-release film-coated tablet. Each 10 mg tablet of XELJANZ contains 10 mg tofacitinib (equivalent to 16.16 mg of tofacitinib citrate) and the following inactive ingredients: croscarmellose sodium, FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, FD&C Blue #2/Indigo Carmine Aluminum Lake, HPMC 2910/Hypromellose 6cP, lactose monohydrate, macrogol/PEG3350, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin.

XELJANZ XR is supplied for oral administration as a 11 mg pink, oval, extended-release film-coated tablet with a drilled hole at one end of the tablet band. Each 11 mg tablet of XELJANZ XR contains 11 mg tofacitinib (equivalent to 17.77 mg tofacitinib citrate) and the following inactive ingredients: cellulose acetate, copovidone, hydroxyethyl cellulose, hydroxypropyl cellulose, HPMC 2910/Hypromellose, magnesium stearate, red iron oxide, sorbitol, titanium dioxide and triacetin. Printing ink contains, ammonium hydroxide, ferrosoferric oxide/black iron oxide, propylene glycol, and shellac glaze.

XELJANZ XR is supplied for oral administration as a 22 mg beige, oval, extended-release film-coated tablet with a drilled hole at one end of the tablet band. Each 22 mg tablet of XELJANZ XR contains 22 mg tofacitinib (equivalent to 35.54 mg tofacitinib citrate) and the following inactive ingredients: cellulose acetate, copovidone, FD&C Blue #2 Aluminum Lake, hydroxyethyl cellulose, hydroxypropyl cellulose, HPMC 2910/Hypromellose, magnesium stearate, red iron oxide, sorbitol, titanium dioxide, triacetin, and yellow iron oxide. Printing ink contains ammonium hydroxide, ferrosoferric oxide/black iron oxide, propylene glycol, and shellac glaze.

XELJANZ Oral Solution is supplied for oral administration as a 1 mg/mL clear, colorless solution. Each 1 mL of XELJANZ Oral Solution contains 1 mg of tofacitinib (equivalent to 1.62 mg tofacitinib citrate) and the following inactive ingredients: grape flavor (natural), hydrochloric acid, lactic acid, purified water, sodium benzoate, sucralose, and xylitol.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.

12.2 Pharmacodynamics

Treatment with XELJANZ was associated with dose-dependent reductions of circulating CD16/56+ natural killer cells, with estimated maximum reductions occurring at approximately 8–10 weeks after initiation of therapy. These changes generally resolved within 2–6 weeks after discontinuation of treatment. Treatment with XELJANZ was associated with dose-dependent increases in B cell counts. Changes in circulating T-lymphocyte counts and T-lymphocyte subsets (CD3+, CD4+ and CD8+) were small and inconsistent. The clinical significance of these changes is unknown.

Total serum IgG, IgM, and IgA levels after 6-month dosing in patients with rheumatoid arthritis were lower than placebo; however, changes were small and not dose-dependent.

After treatment with XELJANZ in patients with rheumatoid arthritis, rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout dosing. Changes in CRP observed with XELJANZ treatment do not reverse fully within 2 weeks after discontinuation, indicating a longer duration of pharmacodynamic activity compared to the pharmacokinetic half-life.

Similar changes in T cells, B cells, and serum CRP have been observed in patients with active psoriatic arthritis although reversibility was not assessed. Total serum immunoglobulins were not assessed in patients with active psoriatic arthritis.

12.3 Pharmacokinetics

XELJANZ/XELJANZ Oral Solution

Following oral administration of XELJANZ/XELJANZ Oral Solution, peak plasma concentrations are reached within 0.5–1 hour, elimination half-life is about 3 hours and a dose-proportional increase in systemic exposure was observed in the therapeutic dose range. Steady state concentrations are achieved in 24–48 hours with negligible accumulation after twice daily administration.

XELJANZ XR

Following oral administration of XELJANZ XR, peak plasma concentrations are reached at 4 hours and half-life is about 6 to 8 hours. Steady state concentrations are achieved within 48 hours with negligible accumulation after once daily administration.

Table 7: Pharmacokinetic Parameters of XELJANZ/ XELJANZ XR Following Multiple Oral Dosing
PK Parameters Values represent the geometric mean, except T max, for which is the median (range) is shown. (CV%) XELJANZ XELJANZ XR
Dosing Regimen 5 mg
Twice Daily
10 mg
Twice Daily
11 mg
Once Daily
22 mg
Once Daily
Abbreviations: AUC24 = area under the concentration-time profile from time 0 to 24 hours; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; Tmax = time to Cmax; CV = Coefficient of variation.

AUC24 (ng.hr/mL)

263.4 (15)

539.6 (22)

269.0 (18)

596.6 (19)

Cmax (ng/mL)

42.7 (26)

84.7 (18)

38.2 (15)

83.8 (25)

Cmin (ng/mL)

1.41 (40)

3.10 (54)

1.07 (69)

3.11 (43)

Tmax (hours)

1.0
(0.5 to14.0Values beyond 12 hours were after the evening dose which was administered 12 hours after the morning dose of twice-daily XELJANZ)

0.8
(0.5 to 14.0

)

4.0
(3.0 to 4.0)

4.0
(2.0 to 4.0)

Absorption

XELJANZ

The absolute oral bioavailability of XELJANZ is 74%. Coadministration of XELJANZ with a high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical trials, XELJANZ was administered without regard to meals [see Dosage and Administration (2.1)].

XELJANZ XR

Coadministration of XELJANZ XR 11 and 22 mg with a high-fat meal resulted in no changes in AUC while Cmax was increased by 27% and 19% respectively. Tmax was extended by approximately 1 hour for both XELJANZ XR 11 and 22 mg.

Distribution

After intravenous administration, the volume of distribution is 87 L. The protein binding of tofacitinib is approximately 40%. Tofacitinib binds predominantly to albumin and does not appear to bind to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.

Metabolism and Excretion

Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule.

Pharmacokinetics in Patient Populations

Population pharmacokinetic analyses indicated that pharmacokinetic characteristics were similar between patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and UC. The coefficient of variation (%) in AUC of tofacitinib were generally similar across different disease patients, ranging from 22% to 34% (Table 8).

Table 8: XELJANZ Exposure in Patient Populations at 5 mg Twice Daily and 10 mg Twice Daily Doses
Pharmacokinetic Parameters Pharmacokinetic parameters estimated based on population pharmacokinetic analysis. Geometric Mean
(CV%)
XELJANZ 5 mg
Twice Daily
XELJANZ 10 mg
Twice Daily
Rheumatoid Arthritis Psoriatic Arthritis Ankylosing Spondylitis Ulcerative Colitis Ulcerative Colitis
Abbreviations: AUC0–24,ss=area under the plasma concentration-time curve over 24 hours at steady state; CV=coefficient of variation.

AUC0–24,ss
(ng∙h/mL)

504
(22.0%)

419
(34.1%)

381
(25.4%)

423
(22.6%)

807
(24.6%)

Specific Populations

Covariate evaluation as part of population PK analyses in adult patient populations indicated no clinically relevant change in tofacitinib exposure, after accounting for differences in renal function (i.e., creatinine clearance) between patients, based on age, weight, gender and race (Figure 1). An approximately linear relationship between body weight and volume of distribution was observed, resulting in higher peak (Cmax) and lower trough (Cmin) concentrations in lighter patients. However, this difference is not considered to be clinically relevant.

Covariate evaluation as part of population PK analyses in pcJIA patients identified body weight significantly impacting tofacitinib exposure, which supports weight-based dosing in this population. No additional dose adjustment is needed based on age, gender, race, or disease severity in pcJIA patients.

The effect of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of tofacitinib is shown in Figure 1.

Figure 1: Impact of Intrinsic Factors on Tofacitinib Pharmacokinetics

Note: Reference values for weight, age, gender, and race comparisons are 70 kg, 55 years, male, and white, respectively; reference groups for renal and hepatic impairment data are subjects with normal renal and hepatic function.
a Refer to Dosage and Administration (2.2, 2.3, 2.4) for dosage adjustment in RA, PsA, AS, UC, and pcJIA patients.
Figure 1

In subjects with ESRD maintained on hemodialysis, mean AUC was approximately 40% higher compared with historical healthy subject data, consistent with approximately 30% contribution of renal clearance to the total clearance of tofacitinib. Dose adjustment is recommended in RA, PsA, AS, UC, and pcJIA patients with ESRD maintained on hemodialysis [see Dosage and Administration (2.2, 2.3, 2.4)].

Figure 1

Drug Interaction Studies

Potential for XELJANZ/XELJANZ XR/XELJANZ Oral Solution to Influence the PK of Other Drugs

In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the major human drug-metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations corresponding to the steady state Cmax of a 10 mg twice daily dose. These in vitro results were confirmed by a human drug interaction study showing no changes in the pharmacokinetics of midazolam, a highly sensitive CYP3A4 substrate, when coadministered with XELJANZ.

In vitro studies indicate that tofacitinib does not significantly inhibit the activity of the major human drug-metabolizing uridine 5'-diphospho-glucuronosyltransferases (UGTs) [UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7] at concentrations exceeding 250 times the steady state Cmax of a 10 mg twice daily dose.

In rheumatoid arthritis patients, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in rheumatoid arthritis patients. Therefore, coadministration with XELJANZ/XELJANZ XR is not expected to result in clinically relevant increases in the metabolism of CYP substrates in rheumatoid arthritis patients.

In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, organic anionic or cationic transporters at therapeutic concentrations is low.

Dosing recommendations for coadministered drugs following administration with XELJANZ/XELJANZ XR/XELJANZ Oral Solution are shown in Figure 2.

Figure 2: Impact of Tofacitinib on the Pharmacokinetics of Other Drugs

Note: Reference group is administration of concomitant medication alone; OCT = Organic Cationic Transporter; MATE = Multidrug and Toxic Compound Extrusion.
Figure 2
Figure 2

Potential for Other Drugs to Influence the Pharmacokinetics of Tofacitinib

Since tofacitinib is metabolized by CYP3A4, interaction with drugs that inhibit or induce CYP3A4 is likely. Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to substantially alter the pharmacokinetics of tofacitinib (see Figure 3).

Figure 3: Impact of Other Drugs on the Pharmacokinetics of Tofacitinib

Note: Reference group is administration of tofacitinib alone.
a [see Dosage and Administration (2.2, 2.3, 2.4), Drug Interactions (7)].
Figure 3
Figure 3

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 39-week toxicology study in monkeys, tofacitinib at exposure levels approximately 6 times the recommended dose of 5 mg twice daily, and approximately 3 times the 10 mg twice daily dose (on an AUC basis at oral doses of 5 mg/kg twice daily) produced lymphomas. No lymphomas were observed in this study at exposure levels 1 times the recommended dose of 5 mg twice daily, and approximately 0.5 times the 10 mg twice daily dose (on an AUC basis at oral doses of 1 mg/kg twice daily).

The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib, at exposure levels approximately 34 times the recommended dose of 5 mg twice daily, and approximately 17 times the 10 mg twice daily dose (on an AUC basis at oral doses of 200 mg/kg/day) was not carcinogenic in mice.

In the 24-month oral carcinogenicity study in Sprague-Dawley rats, tofacitinib caused benign Leydig cell tumors, hibernomas (malignancy of brown adipose tissue), and benign thymomas at doses greater than or equal to 30 mg/kg/day (approximately 42 times the exposure levels at the recommended dose of 5 mg twice daily, and approximately 21 times the 10 mg twice daily dose on an AUC basis). The relevance of benign Leydig cell tumors to human risk is not known.

Tofacitinib was not mutagenic in the bacterial reverse mutation assay. It was positive for clastogenicity in the in vitro chromosome aberration assay with human lymphocytes in the presence of metabolic enzymes, but negative in the absence of metabolic enzymes. Tofacitinib was negative in the in vivo rat micronucleus assay and in the in vitro CHO-HGPRT assay and the in vivo rat hepatocyte unscheduled DNA synthesis assay.

In rats, tofacitinib at exposure levels approximately 17 times the recommended dose of 5 mg twice daily, and approximately 8.3 times the 10 mg twice daily dose (on an AUC basis at oral doses of 10 mg/kg/day) reduced female fertility due to increased post-implantation loss. There was no impairment of female rat fertility at exposure levels of tofacitinib equal to the recommended dose of 5 mg twice daily, and approximately 0.5 times the 10 mg twice daily dose (on an AUC basis at oral doses of 1 mg/kg/day). Tofacitinib exposure levels at approximately 133 times the recommended dose of 5 mg twice daily, and approximately 67 times the 10 mg twice daily dose (on an AUC basis at oral doses of 100 mg/kg/day) had no effect on male fertility, sperm motility, or sperm concentration.

14 CLINICAL STUDIES

14.1 Rheumatoid Arthritis

The XELJANZ clinical development program included six confirmatory trials. Although other doses have been studied, the recommended dose of XELJANZ is 5 mg twice daily. XELJANZ 10 mg twice daily is not recommended for the treatment of rheumatoid arthritis [see Dosage and Administration (2.2)].

Confirmatory Trials

Study RA-I (NCT00814307) was a 6-month monotherapy trial in which 610 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a DMARD (nonbiologic or biologic) received XELJANZ 5 or 10 mg twice daily or placebo. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, changes in Health Assessment Questionnaire – Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) less than 2.6.

Study RA-II (NCT00856544) was a 12-month trial in which 792 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a nonbiologic DMARD received XELJANZ 5 or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppressive treatments such as azathioprine or cyclosporine). At the Month 3 visit, nonresponding patients were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. At the end of Month 6, all placebo patients were advanced to their second predetermined treatment in a blinded fashion. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, changes in HAQ-DI at Month 3, and rates of DAS28-4(ESR) less than 2.6 at Month 6.

Study RA-III (NCT00853385) was a 12-month trial in 717 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX. Patients received XELJANZ 5 or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.

Study RA-IV (NCT00847613) was a 2-year trial with a planned analysis at 1 year in which 797 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, mean change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.

Study RA-V (NCT00960440) was a 6-month trial in which 399 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to at least one approved TNF blocking biologic agent received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, HAQ-DI, and DAS28-4(ESR) less than 2.6.

Study RA-VI (NCT01039688) was a 2-year monotherapy trial with a planned analysis at 1 year in which 952 MTX-naïve patients with moderate to severe active rheumatoid arthritis received XELJANZ 5 or 10 mg twice daily or MTX dose-titrated over 8 weeks to 20 mg weekly. The primary endpoints were mean change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at Month 6 and the proportion of patients who achieved an ACR70 response at Month 6.

Clinical Response

The percentages of XELJANZ-treated patients achieving ACR20, ACR50, and ACR70 responses in Studies RA-I, IV, and V are shown in Table 9. Similar results were observed with Studies RA-II and III. In trials RA-I through V, patients treated with 5 mg twice daily XELJANZ had higher ACR20, ACR50, and ACR70 response rates versus placebo, with or without background DMARD treatment, at Month 3 and Month 6. Higher ACR20 response rates were observed within 2 weeks compared to placebo. In the 12-month trials, ACR response rates in XELJANZ-treated patients were consistent at 6 and 12 months.

Table 9: Proportion of Patients with an ACR Response
Percent of Patients
Monotherapy in Nonbiologic or Biologic DMARD Inadequate Responders Inadequate response to at least one DMARD (biologic or nonbiologic) due to lack of efficacy or toxicity. MTX Inadequate Responders Inadequate response to MTX defined as the presence of sufficient residual disease activity to meet the entry criteria. TNF Blocker Inadequate Responders Inadequate response to a least one TNF blocker due to lack of efficacy and/or intolerance.
Study I Study IV Study V
N N is number of randomized and treated patients. PBO XELJANZ
5 mg Twice Daily
PBO + MTX XELJANZ
5 mg Twice Daily + MTX
PBO + MTX XELJANZ
5 mg Twice Daily + MTX
122 243 160 321 132 133

ACR20

Month 3

26%

59%

27%

55%

24%

41%

Month 6

NANA Not applicable, as data for placebo treatment is not available beyond 3 months in Studies I and V due to placebo advancement.

69%

25%

50%

NA

51%

ACR50

Month 3

12%

31%

8%

29%

8%

26%

Month 6

NA

42%

9%

32%

NA

37%

ACR70

Month 3

6%

15%

3%

11%

2%

14%

Month 6

NA

22%

1%

14%

NA

16%

In Study RA-IV, a greater proportion of patients treated with XELJANZ 5 mg twice daily plus MTX achieved a low level of disease activity as measured by a DAS28-4(ESR) less than 2.6 at 6 months compared to those treated with MTX alone (Table 10).

Table 10: Proportion of Patients with DAS28-4(ESR) Less Than 2.6 with Number of Residual Active Joints
Study IV
DAS28-4(ESR) Less Than 2.6 Placebo + MTX XELJANZ 5 mg Twice Daily + MTX
160 321

Proportion of responders at Month 6 (n)

1% (2)

6% (19)

Of responders, proportion with 0 active joints (n)

50% (1)

42% (8)

Of responders, proportion with 1 active joint (n)

0

5% (1)

Of responders, proportion with 2 active joints (n)

0

32% (6)

Of responders, proportion with 3 or more active joints (n)

50% (1)

21% (4)

The results of the components of the ACR response criteria for Study RA-IV are shown in Table 11. Similar results were observed for XELJANZ in Studies RA-I, II, III, V, and VI.

Table 11: Components of ACR Response at Month 3
Study IV
XELJANZ
5 mg
Twice Daily + MTX
Placebo + MTX
N=321 N=160
Component (mean) Data shown is mean (Standard Deviation) at Month 3. Baseline Month 3
Baseline Month 3

Number of tender joints
(0–68)

24
(14)

13
(14)

23
(13)

18
(14)

Number of swollen joints
(0–66)

14
(8)

6
(8)

14
(9)

10
(9)

PainVisual analog scale: 0 = best, 100 = worst.

58
(23)

34
(23)

55
(24)

47
(24)

Patient global assessment

58
(24)

35
(23)

54
(23)

47
(24)

Disability index
(HAQ-DI)Health Assessment Questionnaire Disability Index: 0 = best, 3 = worst; 20 questions; categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.

1.41
(0.68)

0.99
(0.65)

1.32
(0.67)

1.19
(0.68)

Physician global assessment

59
(16)

30
(19)

56
(18)

43
(22)

CRP (mg/L)

15.3
(19.0)

7.1
(19.1)

13.7
(14.9)

14.6
(18.7)

The percent of ACR20 responders by visit for Study RA-IV is shown in Figure 4. Similar responses were observed for XELJANZ in Studies RA-I, II, III, V, and VI.

Figure 4: Percentage of ACR20 Responders by Visit for Study RA-IV

Figure 4
Figure 4

Radiographic Response

Two studies were conducted to evaluate the effect of XELJANZ on structural joint damage. In Study RA-IV and Study RA-VI, progression of structural joint damage was assessed radiographically and expressed as change from baseline in mTSS and its components, the erosion score and joint space narrowing score, at Months 6 and 12. The proportion of patients with no radiographic progression (mTSS change less than or equal to 0) was also assessed.

In Study RA-IV, XELJANZ 5 mg twice daily reduced the mean progression of structural damage (not statistically significant) as shown in Table 12. Analyses of erosion and joint space narrowing scores were consistent with the overall results.

In the placebo plus MTX group, 74% of patients experienced no radiographic progression at Month 6 compared to 84% of patients treated with XELJANZ plus MTX 5 mg twice daily.

In Study RA-VI, XELJANZ monotherapy inhibited the progression of structural damage compared to MTX at Months 6 and 12 as shown in Table 12. Analyses of erosion and joint space narrowing scores were consistent with the overall results.

In the MTX group, 55% of patients experienced no radiographic progression at Month 6 compared to 73% of patients treated with XELJANZ 5 mg twice daily.

Table 12: Radiographic Changes at Months 6 and 12

Study IV

Placebo
N=139
Mean (SD) SD = Standard Deviation

XELJANZ 5 mg Twice Daily
N=277
Mean (SD)

XELJANZ 5 mg Twice Daily
Mean Difference from Placebo Difference between least squares means XELJANZ minus placebo or MTX (95% CI = 95% confidence interval) (CI)

mTSSMonth 6 and Month 12 data are mean change from baseline.

Baseline

33 (42)

31 (48)

-

Month 6

0.5 (2.0)

0.1 (1.7)

-0.3 (-0.7, 0.0)

Study VI

MTX
N=166
Mean (SD)

XELJANZ 5 mg Twice Daily
N=346
Mean (SD)

XELJANZ 5 mg Twice Daily
Mean Difference from MTX

(CI)

mTSS

Baseline

17 (29)

20 (40)

-

Month 6

0.8 (2.7)

0.2 (2.3)

-0.7 (-1.0, -0.3)

Month 12

1.3 (3.7)

0.4 (3.0)

-0.9 (-1.4, -0.4)

Physical Function Response

Improvement in physical functioning was measured by the HAQ-DI. Patients receiving XELJANZ 5 mg twice daily demonstrated greater improvement from baseline in physical functioning compared to placebo at Month 3.

The mean (95% CI) difference from placebo in HAQ-DI improvement from baseline at Month 3 in Study RA-III was -0.22 (-0.35, -0.10) in patients receiving 5 mg XELJANZ twice daily. Similar results were obtained in Studies RA-I, II, IV and V. In the 12-month trials, HAQ-DI results in XELJANZ-treated patients were consistent at 6 and 12 months.

Other Health-Related Outcomes

General health status was assessed by the Short Form health survey (SF-36). In Studies RA-I, IV, and V, patients receiving XELJANZ 5 mg twice daily demonstrated greater improvement from baseline compared to placebo in physical component summary (PCS), mental component summary (MCS) scores and in all 8 domains of the SF-36 at Month 3.

14.2 Psoriatic Arthritis

The XELJANZ clinical development program to assess efficacy and safety included 2 multicenter, randomized, double-blind, placebo-controlled confirmatory trials in 816 patients 18 years of age and older (PsA-I and PsA-II). Although other doses have been studied, the recommended dose of XELJANZ is 5 mg twice daily. XELJANZ 10 mg twice daily is not recommended for the treatment of psoriatic arthritis [see Dosage and Administration (2.2)]. All patients had active psoriatic arthritis for at least 6 months based upon the Classification Criteria for Psoriatic Arthritis (CASPAR), at least 3 tender/painful joints and at least 3 swollen joints, and active plaque psoriasis. Patients randomized and treated across the 2 clinical trials represented different psoriatic arthritis subtypes at screening, including <5 joints or asymmetric involvement (21%), ≥5 joints involved (90%), distal interphalangeal (DIP) joint involvement (61%), arthritis mutilans (8%), and spondylitis (19%). Patients in these clinical trials had a diagnosis of psoriatic arthritis for a mean (SD) of 7.7 (7.2) years. At baseline, 80% and 53% of patients had enthesitis and dactylitis, respectively. At baseline, all patients were required to receive treatment with a stable dose of a nonbiologic DMARD (79% received methotrexate, 13% received sulfasalazine, 7% received leflunomide, 1% received other nonbiologic DMARDs). In both clinical trials, the primary endpoints were the ACR20 response and the change from baseline in HAQ-DI at Month 3.

Study PsA-I was a 12-month clinical trial in 422 patients who had an inadequate response to a nonbiologic DMARD (67% and 33% were inadequate responders to 1 nonbiologic DMARD and ≥2 nonbiologic DMARDs, respectively) and who were naïve to treatment with a TNF blocker. Patients were randomized in a 2:2:2:1:1 ratio to receive XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, adalimumab 40 mg subcutaneously once every 2 weeks, placebo to XELJANZ 5 mg twice daily treatment sequence, or placebo to XELJANZ 10 mg twice daily treatment sequence, respectively; study drug was added to background nonbiologic DMARD treatment. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a predetermined XELJANZ dose of 5 mg or 10 mg twice daily. Study PsA-I was not designed to demonstrate noninferiority or superiority to adalimumab.

Study PsA-II was a 6-month clinical trial in 394 patients who had an inadequate response to at least 1 approved TNF blocker (66%, 19%, and 15% were inadequate responders to 1 TNF blocker, 2 TNF blockers and ≥3 TNF blockers, respectively). Patients were randomized in a 2:2:1:1 ratio to receive XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, placebo to XELJANZ 5 mg twice daily treatment sequence, or placebo to XELJANZ 10 mg twice daily treatment sequence, respectively; study drug was added to background nonbiologic DMARD treatment. At the Month 3 visit, placebo patients were advanced in a blinded fashion to a predetermined XELJANZ dose of 5 mg or 10 mg twice daily as in Study PsA-I.

Clinical Response

At Month 3, patients treated with XELJANZ 5 mg twice daily had higher (p≤0.05) response rates versus placebo for ACR20, ACR50, and ACR70 in Study PsA-I and for ACR20 and ACR50 in Study PsA-II; ACR70 response rates were also higher for XELJANZ 5 mg twice daily versus placebo in Study PsA-II, although the differences versus placebo were not statistically significant (p>0.05) (Tables 13 and 14).

Table 13: Proportion of Patients with an ACR Response in Study PsA-ISubjects received one concomitant nonbiologic DMARD. [Nonbiologic DMARD Inadequate Responders (TNF Blocker-Naïve)]
Treatment Group Placebo XELJANZ
5 mg
Twice Daily
N N is number of randomized and treated patients. 105 107
Response Rate Response Rate Difference (%)
95% CI from Placebo
Subjects with missing data were treated as non-responders.

Month 3

  ACR20

33%

50%

17.1 (4.1, 30.2)

  ACR50

10%

28%

18.5 (8.3, 28.7)

  ACR70

5%

17%

12.1 (3.9, 20.2)

Table 14: Proportion of Patients with an ACR Response in Study PsA-IISubjects received one concomitant nonbiologic DMARD. (TNF Blocker Inadequate Responders)
Treatment Group Placebo XELJANZ
5 mg
Twice Daily