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  • UC: Efficacy data

    OCTAVE clinical program design

    Study designs

    The efficacy and safety of XELJANZ in UC were evaluated in the OCTAVE clinical program, which included 3 phase 3, randomized, double-blind, placebo-controlled clinical trials (OCTAVE Induction 1 [UC-I], OCTAVE Induction 2 [UC-II], and OCTAVE Sustain [UC-III]), and an open-label, long-term extension study (UC-IV).1,2 

    All patients in the Oral Clinical Trials for tofAcitinib in ulceratiVE colitis (OCTAVE) clinical program were adults with a confirmed diagnosis of moderately to severely active UC for at least 4 months, which was defined as a Mayo score of 6 to 12, with a rectal bleeding subscore ≥1 and an endoscopic subscore ≥2. Patients were required to have experienced treatment failure with or intolerance to at least 1 of the following agents: oral or intravenous corticosteroids, azathioprine, 6-MP, or TNF blocker. XELJANZ is indicated for patients who have an inadequate response or who are intolerant to TNF blockers. Endoscopic results were centrally read in the induction trials and OCTAVE Sustain. Patients who completed OCTAVE Induction 1 or 2 and had a clinical response were eligible to participate in OCTAVE Sustain. During the OCTAVE clinical program, patients were not allowed to take concomitant immunomodulators or biological therapies.

    aThe total number of patients does not include those who received XELJANZ 15 mg twice daily (n=22). XELJANZ 15 mg twice daily is not an approved dose.1,3
    bPatients who completed one of the OCTAVE Induction studies (UC-I or UC-II) but did not achieve clinical response.3
    cRemission was defined as Mayo score ≤2 with no individual subscore >1 and rectal bleeding subscore=0.4
    dThese N values are from May 27, 2019 data cut.4

    Total patient population included patients with and without prior TNF blocker failure. XELJANZ is not indicated for use in patients without prior TNF blocker failure.1

    • Prior TNF blocker failure was defined in this program as inadequate response, loss of response, or intolerance to TNF blocker therapy 
    • Patients without prior TNF blocker failure had failed one or more conventional therapies (corticosteroid, azathioprine, 6-MP) but did not have a history of prior failure of TNF blocker therapy​​​​​​​

    In 2 identical, 8-week induction studies, 1139 patients with moderately to severely active UC (598 and 541 patients, respectively) were randomized to XELJANZ 10 mg twice daily or placebo (4:1 ratio). The primary endpoint of Study UC-I and Study UC-II was the proportion of patients in remission at Week 8, and the key secondary endpoint was the proportion of patients with improvement of endoscopic appearance of the mucosa at Week 8. During the induction trials, patients who were on stable doses of oral aminosalicylates and corticosteroids (prednisone daily dose up to 25 mg equivalent) were permitted to continue on their stable dosing. Concomitant immunosuppressants (immunomodulators or biological therapies) were not permitted for UC patients during the induction studies.​​​​​​​ Disease activity was assessed by Mayo scoring index (0 to 12) which consists of four subscores (0 to 3 for each subscore): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment. An endoscopic subscore of 2 was defined by marked erythema, absent vascular pattern, any friability, and erosions; an endoscopic subscore of 3 was defined by spontaneous bleeding and ulceration.

    OCTAVE Induction 1 and 21

    In a 52-week maintenance study, 593 patients who had completed the induction studies and achieved clinical response were rerandomized to XELJANZ 10 mg twice daily, XELJANZ 5 mg twice daily, or placebo (1:1:1 ratio). XELJANZ 5 mg twice daily is the recommended dosage for maintenance therapy. 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. The primary endpoint was the proportion of patients in remission at Week 52. There were 2 key secondary endpoints: the proportion of patients with improvement of endoscopic appearance at Week 52, and the proportion of patients with sustained corticosteroid-free remission at both Week 24 and Week 52 among patients in remission at baseline of Study UC-III. Patients were permitted to use stable doses of oral aminosalicylates, but initiation of corticosteroid tapering was required upon entrance to this study for patients who were receiving corticosteroids at baseline. Concomitant immunosuppressants (immunomodulators or biological therapies) were not permitted.

    OCTAVE Sustain1

    Study

    Endpoint

    Definition

    OCTAVE Induction 1 and 21

    Remission (primary)

    A total Mayo score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0 at Week 8 

    Improvement of endoscopic appearance of the mucosa (key secondary)

    A Mayo endoscopic subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern) at Week 8

    Clinical response (secondary)

    A decrease from baseline in the total Mayo score ≥3 points and ≥30% with an accompanying decrease in the subscore for rectal bleeding ≥1 point or an absolute subscore for rectal bleeding of 0 or 1 at Week 8

    OCTAVE Sustain1

    Remission (primary)

    A total Mayo score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0 at Week 52

    Improvement of endoscopic appearance of the mucosa (key secondary)

    A Mayo endoscopic subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern) at Week 52

    Sustained corticosteroid-free remission (key secondary)

    Remission (a total Mayo score ≤ 2, with no individual subscore >1 and a rectal bleeding subscore of 0) and not taking corticosteroids for at least 4 weeks prior to the visit at both Week 24 and Week 52 among patients in remission at baseline

    Maintenance of clinical response

    Clinical response (a decrease from baseline in the total Mayo score ≥3 points and ≥30%, with an accompanying decrease in the subscore for rectal bleeding ≥1 point or an absolute subscore for rectal bleeding of 0 or 1) at both baseline and Week 52 

    Maintenance of remission

    Remission (a total Mayo score ≤ 2, with no individual subscore >1 and a rectal bleeding subscore of 0) at both baseline and Week 52

    Study

    OCTAVE Induction 1 and 21

    Endpoint

    Definition

    Remission (primary)

    A total Mayo score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0 at Week 8 

    Improvement of endoscopic appearance of the mucosa (key secondary)

    A Mayo endoscopic subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern) at Week 8

    Clinical response (secondary)

    A decrease from baseline in the total Mayo score ≥3 points and ≥30% with an accompanying decrease in the subscore for rectal bleeding ≥1 point or an absolute subscore for rectal bleeding of 0 or 1 at Week 8

    Study

    OCTAVE Sustain1

    Endpoint​​​​​​​

    Definition​​​​​​​

    Remission (primary)​​​​​​​

    A total Mayo score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0 at Week 52

    Improvement of endoscopic appearance of the mucosa (key secondary)​​​​​​​

    A Mayo endoscopic subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern) at Week 52​​​​​​​

    Sustained corticosteroid-free remission (key secondary)

    Remission (a total Mayo score ≤ 2, with no individual subscore >1 and a rectal bleeding subscore of 0) and not taking corticosteroids for at least 4 weeks prior to the visit at both Week 24 and Week 52 among patients in remission at baseline

    Maintenance of clinical response

    Clinical response (a decrease from baseline in the total Mayo score ≥3 points and ≥30%, with an accompanying decrease in the subscore for rectal bleeding ≥1 point or an absolute subscore for rectal bleeding of 0 or 1) at both baseline and Week 52 

    Maintenance of remission

    Remission (a total Mayo score ≤ 2, with no individual subscore >1 and a rectal bleeding subscore of 0) at both baseline and Week 52

    Key Endpoints and Definitions1

    Notable aspects

    Select patient characteristics

    aConcomitant use of immunosuppressants was prohibited in OCTAVE Induction 1 and 2 and in OCTAVE Sustain.3 
    bThe maximum corticosteroid dose at baseline in OCTAVE Sustain was 25 mg/day of oral prednisone or equivalent, and 9 mg/day of budesonide. Tapering corticosteroids was mandatory starting the first week of the study at the following rates. The daily dose of prednisone or equivalent was decreased at a rate of 5 mg per week until the dose reached 20 mg/day, then by 2.5 to 5.0 mg per week until the dose reached 10 mg/day, and then by 2.5 mg per week until the dose was 0 mg. The daily dose of oral budesonide was decreased at a rate of 3 mg every 3 weeks until the dose reached 0 mg.3

    • Oral corticosteroids were received as concomitant treatment for UC by 47% of patients (45% in OCTAVE Induction 1 and 48% in OCTAVE Induction 2) and 71% were receiving concomitant aminosalicylates as treatment for UC (71% in OCTAVE Induction 1 and 72% in OCTAVE Induction 2)1 
    • The baseline clinical characteristics were generally similar between the XELJANZ-treated patients and patients receiving placebo1
    • Prior TNF blocker failure was defined in this program as inadequate response, loss of response, or intolerance to TNF blocker therapy. Primary nonresponse was defined as a failure to achieve a response; secondary nonresponse was a failure to maintain a response. Intolerance may have been due to an adverse event1,2

    Safety data in UC

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    The first and only oral JAK inhibitor approved for moderately to severely active UC1,2


    6-MP=6-mercaptopurine; FDA=Food and Drug Administration; TNF=tumor necrosis factor; UC=ulcerative colitis.

    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.