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  • RA: Efficacy data

    Radiographic data in phase 3 trials

    Inhibited the progression of structural joint damage as monotherapy vs MTX1,2,a 

    ORAL Start (Study RA-VI) in MTX-naïve patients1
    XELJANZ is not indicated in MTX-naïve patients.​​​​​​​1

    *P=0.0006 vs MTX
    • Mean baseline mTSS scores1: XELJANZ 5 mg BID: 20; MTX:​​​​​ 17
    More patients receiving XELJANZ had no radiographic progression vs MTX at year 2 (secondary endpoint)1,2
    72%b,c
       XELJANZ
    (n=250/348)
    57%b,c
         MTX
    (n=97/171)
    More patients receiving XELJANZ had no radiographic progression vs MTX at year 2 (secondary endpoint)1,2
       72%b,c
      XELJANZ
    (n=250/348)
      57%b,c
         MTX
    (n=97/171)

    More patients receiving XELJANZ monotherapy had no radiographic progression vs MTX at month 6 (primary endpoint) and at year 1 and year 2 (secondary endpoint)1,2

    • 73%, 73%, and 72% of patients treated with XELJANZ 5 mg BID at month 6, year 1, and year 2, respectively, had no radiographic progression vs 55%, 61%, and 57% with MTX, respectivelyb,c

    No radiographic progression was defined as mean change from baseline in mTSS ≤0.00.1

    Nonprogression was a secondary endpoint at month 6, year 1, and year 2. Mean change from baseline in mTSS was a primary endpoint at month 6 and a secondary endpoint at year 1 and year 2.2,3

    Patients treated with XELJANZ showed less progression from baseline in both erosion and joint space narrowing at month 6 compared with MTX. Changes from baseline in erosion and joint space narrowing were secondary endpoints at month 6.1,2 Patient baseline clinical characteristics included mean disease duration of 2.9 years for XELJANZ 5 mg BID and 2.7 years for MTX; 37% of patients who received XELJANZ 5 mg BID had been previously treated with DMARDs other than MTX.2

    Mean MTX dose at end of titration (month 3)=18.5 mg/week.2

    aStable doses of antimalarial agents allowed.2
    bIn the absence of an acceptable radiograph, the results from previous radiographs were extrapolated linearly.2
    cIn year 1, all X-rays were read by independent, blinded readers. In year 2, all X-rays were re-read by independent, blinded readers beginning at study baseline. Data not available in year 1 for a few patients became available for 2-year analyses.2​​​​​​​​​​​​​​

    A 24-month, randomized, double-blind, active-controlled, multicenter, parallel-group trial in which 952 patients with moderately to severely active RA who were MTX-naïve, and who had ≥3 hand or foot erosions or were seropositive, received XELJANZ 5 mg BID or 10 mg BID or MTX (XELJANZ 10 mg BID is not approved for RA). Stable low-dose oral glucocorticoids allowed. MTX dose started at 10 mg/week, titrated by 5 mg q 4 wk as tolerated to 20 mg/week by week 8. All DMARDs were washed out before baseline visit, except stable doses of antimalarial agents were permitted (XELJANZ 5 mg 12%; MTX 16%). The 2 coprimary endpoints were change in mTSS and ACR70 response rate at month 6. Nonresponder imputation was applied to missing sign/symptom data.1-3

    XELJANZ/XELJANZ XR is not indicated in MTX-naïve patients.1

    ACR=American College of Rheumatology; BID=twice daily; DMARD=disease-modifying antirheumatic drug; mTSS=modified Total Sharp Score; MTX=methotrexate; q 4 wk=every 4 weeks; RA=rheumatoid arthritis.
    References:
    1. XELJANZ [prescribing information]. New York, NY: Pfizer Inc., October 2020.
    2. Data on file. Pfizer Inc., New York, NY. 
    3. Lee EB, Fleischmann R, Hall S, et al; for the ORAL Start Investigators. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370(25):2377-2386.

    ORAL Start (Study RA-VI) study design


    Reduced the progression of structural joint damage1,2,4

    ORAL Scan (Study IV) in MTX-IR patients1

    • Mean baseline mTSS scores1: XELJANZ 5 mg BID: 31; placebo: 33
    A greater proportion of patients receiving XELJANZ + MTX had no radiographic progression vs placebo + MTX at month 6 (secondary endpoint)1,2 
        84%a,b
    XELJANZ + MTX
       (n=232/277)
        74%a
    Placebo + MTX
      (n=103/139)
    A greater proportion of patients receiving XELJANZ + MTX had no radiographic progression vs placebo + MTX at month 6 (secondary endpoint)1,2 ​​​​​​​
          84%a,b​​​​​​​
    XELJANZ + MTX
       (n=232/277)
           74%a​​​​​​​
    PLACEBO + MTX
        (n=103/139)

    No radiographic progression was defined as mean change from baseline in mTSS ≤0.00.1

    Nonprogression was a secondary endpoint at month 6. Mean change from baseline in mTSS was a primary endpoint at month 6.1,2

    XELJANZ 5 mg BID + MTX reduced mean progression of structural damage vs placebo + MTX at month 6 (not statistically significant). Analyses of erosion and joint space narrowing scores were consistent with the overall results.1

    Patient baseline clinical characteristics for the XELJANZ 5 mg BID dose included mean disease duration of 9 years; percent of patients on prior medications: MTX, 100%; other nonbiologic DMARDs, 60%; TNFi, 19%.2​​​​​​​

    aIn the absence of an acceptable radiograph, the results from previous radiographs were extrapolated linearly.2
    b
    Statistical significance was not declared because the primary radiographic endpoint of mean change in mTSS was not met for XELJANZ 5 mg BID.2

    A 24-month, randomized, double-blind, placebo-controlled, multicenter trial in which 797 patients with moderately to severely active RA who had an inadequate response to MTX, and who had ≥3 hand or foot erosions or were seropositive, received XELJANZ 5 mg BID or 10 mg BID or placebo (all patients on stable background MTX, the only permitted background DMARD). Stable low-dose oral glucocorticoids allowed. At 3 months, nonresponding placebo patients were advanced blindly to XELJANZ 5 mg or 10 mg BID (XELJANZ 10 mg BID is not approved for RA). At 6 months, all remaining placebo patients were advanced similarly. The 4 coprimary endpoints were ACR20 response rate, change in mTSS, and rate of DAS28-4(ESR) <2.6 (each at month 6), and HAQ-DI change at month 3. Nonresponder imputation was applied to missing sign/symptom data, plus an advancement penalty for 3-month nonresponders.1,2

    ACR=American College of Rheumatology; BID=twice daily; DAS28-4(ESR)=Disease Activity Score for 28-joint counts based on erythrocyte sedimentation rate; DMARD=disease-modifying antirheumatic drug; HAQ-DI=Health Assessment Questionnaire–Disability Index; mTSS=modified Total Sharp Score; MTX=methotrexate; RA=rheumatoid arthritis.
    References:
    1. XELJANZ [prescribing information]. New York, NY: Pfizer Inc., October 2020.
    2. van der Heijde D, Tanaka Y, Fleischmann R, et al; and the ORAL Scan Investigators. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four–month phase III randomized radiographic study. Arthritis Rheum. 2013;65(3):559-570.

    ORAL Scan (Study RA-IV) study design

    MTX-withdrawal data 

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    RA: Efficacy data

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    Dosing considerations in RA/PsA

    Dosing and lab monitoring information

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    See JAKi market experience for XELJANZ—#1 most prescribed JAK inhibitor for moderate to severe RA.1,2,a

    aInternal calculations by Pfizer based on IQVIA database of new prescription (NRx) and total prescription (TRx) JAK inhibitors prescribed for RA, monthly as of December 2020.2

    BID=twice daily; DMARD=disease-modifying antirheumatic drug; JAK=Janus kinase; JAKi=Janus kinase inhibitor; mTSS=modified Total Sharp Score; MTX=methotrexate; RA=rheumatoid arthritis; TNFi=tumor necrosis factor inhibitor.
    References:
    1. XELJANZ [prescribing information]. New York, NY: Pfizer Inc., October 2020.
    2. Data on file. Pfizer Inc., New York, NY. 
    3. Lee EB, Fleischmann R, Hall S, et al; for the ORAL Start Investigators. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370(25):2377-2386.  
    4. van der Heijde D, Tanaka Y, Fleischmann R, et al; and the ORAL Scan Investigators. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four–month phase III randomized radiographic study. Arthritis Rheum. 2013;65(3):559-570. 

    SERIOUS INFECTIONS

    Patients treated with XELJANZ* are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

    If a serious infection develops, interrupt XELJANZ 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 use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ 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 most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Avoid use of XELJANZ in patients with an active, serious infection, including localized infections, or with chronic or recurrent infection.

    In the UC population, XELJANZ 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily. Opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with XELJANZ 10 mg twice daily.

    The risks and benefits of treatment with XELJANZ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection, or those who have lived or traveled in areas of endemic TB or mycoses. Viral reactivation including herpes virus and hepatitis B reactivation have been reported. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy.

    Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

    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 infection.

    MORTALITY

    Rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular (CV) risk factor treated with XELJANZ 10 mg twice a day had a higher rate of all-cause mortality, including sudden CV death, compared to those treated with XELJANZ 5 mg given twice daily or TNF blockers in a large, ongoing, postmarketing safety study. XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended for the treatment of RA or PsA. For UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

    MALIGNANCIES

    Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

    Consider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy.

    Malignancies (including solid cancers and lymphomas) were observed more often in patients treated with XELJANZ 10 mg twice daily dosing in the UC long-term extension study.

    Other malignancies were observed in clinical studies and the post-marketing setting including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. NMSCs have been reported in patients treated with XELJANZ. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

    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. RA patients who were 50 years of age and older with at least one CV risk factor treated with XELJANZ 10 mg twice daily compared to XELJANZ 5 mg twice daily or TNF blockers in a large, ongoing postmarketing safety study had an observed increase in incidence of these events. Many of these events were serious and some resulted in death. Avoid XELJANZ in patients at risk. Discontinue XELJANZ and promptly evaluate patients with symptoms of thrombosis. For patients with UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response. XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended for the treatment of RA or PsA. In a long-term extension study in UC, four cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one death in a patient with advanced cancer.

    GASTROINTESTINAL PERFORATIONS

    Gastrointestinal perforations have been reported in XELJANZ clinical trials, although the role of JAK inhibition 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 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).

    HYPERSENSITIVITY

    Angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ and some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction.

    LABORATORY ABNORMALITIES

    Lymphocyte Abnormalities: Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts. Avoid initiation of XELJANZ treatment in patients with a count less than 500 cells/mm3. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ is not recommended. 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. Monitor lymphocyte counts at baseline and every 3 months thereafter.

    Neutropenia: Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo. Avoid initiation of XELJANZ treatment in patients with an ANC less than 1000 cells/mm3. For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ 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 is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

    Anemia: Avoid initiation of XELJANZ treatment in patients with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ 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.

    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. If drug-induced liver injury is suspected, the administration of XELJANZ should be interrupted until this diagnosis has been excluded. 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.

    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. Manage patients with hyperlipidemia according to clinical guidelines. Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ therapy.

    VACCINATIONS

    Avoid use of live vaccines concurrently with XELJANZ. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.

    PATIENTS WITH GASTROINTESTINAL NARROWING

    Caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing. 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.

    HEPATIC and RENAL IMPAIRMENT

    Use of XELJANZ in patients with severe hepatic impairment is not recommended.

    For patients with moderate hepatic impairment or with moderate or severe renal impairment taking XELJANZ 5 mg twice daily, reduce to XELJANZ 5 mg once daily.

    For UC patients with moderate hepatic impairment or with moderate or severe renal impairment taking XELJANZ 10 mg twice daily, reduce to XELJANZ 5 mg twice daily.

    ADVERSE REACTIONS

    The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials in patients with RA with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in greater than or equal to 2% of patients treated with XELJANZ with or without DMARDs) were upper respiratory tract infection, nasopharyngitis, diarrhea, headache, and hypertension. The safety profile observed in patients with active PsA treated with XELJANZ was consistent with the safety profile observed in RA patients.

    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 for UC were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.

    USE IN PREGNANCY

    Available data with XELJANZ 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. In animal studies, tofacitinib at 6.3 times the maximum recommended dose of 10 mg twice daily demonstrated adverse embryo-fetal findings. The relevance of these findings to women of childbearing potential is uncertain. Consider pregnancy planning and prevention for females of reproductive potential.

    *Unless otherwise stated, “XELJANZ” in the Important Safety Information refers to XELJANZ, XELJANZ XR, and XELJANZ Oral Solution.


    Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

    Rheumatoid Arthritis (RA)

    • XELJANZ®/XELJANZ® XR (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.
    • Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

    Psoriatic Arthritis (PsA)

    • XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs).
    • Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

    Ulcerative Colitis (UC)

    • XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC), who have had an inadequate response or who are intolerant to TNF blockers.
    • Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

    Polyarticular Course Juvenile Idiopathic Arthritis (pcJIA)

    • XELJANZ/XELJANZ Oral Solution is indicated for the treatment of active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients 2 years of age and older.
    • Limitations of Use: Use of XELJANZ/XELJANZ Oral Solution in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

    INDICATIONS AND LIMITATIONS OF USE FOR RA, PsA, UC, AND pcJIA

    Please see full Prescribing Information including BOXED WARNING and Medication Guide.

    Rheumatoid Arthritis (RA): XELJANZ®/XELJANZ® XR (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.

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

    Psoriatic Arthritis (PsA): XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs).

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

    Ulcerative Colitis (UC): XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response or who are intolerant to TNF blockers.

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

    Polyarticular Course Juvenile Idiopathic Arthritis (pcJIA): XELJANZ/XELJANZ Oral Solution is indicated for the treatment of active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients 2 years of age and older.

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