Sign Out
All patients in these studies had moderate to severe rheumatoid arthritis. The study XELJANZ population had a mean age of 52.1 years and 83.2% were female.
The long-term safety population includes all patients who participated in a double-blind, controlled study (including earlier development phase studies) and then participated in one of two long-term safety studies.
A total of 6194 patients (Phase 1, 2, 3, and long-term extension studies) were treated with any dose of XELJANZ with a mean duration of 3.13 years, with 19,405.8 patient-years of accumulated total drug exposure based on more than 8 years of continuous exposure to XELJANZ.
Safety information is also included for one large (N=4362), randomized Post-authorization safety study (PASS) in RA patients who were 50 years or older with at least one additional cardiovascular risk factor (CV risk factors defined as: current cigarette smoker, diagnosis of hypertension, diabetes mellitus, family history of premature coronary heart disease, history of coronary artery disease including a history of revascularization procedure, coronary artery bypass grafting, myocardial infarction, cardiac arrest, unstable angina, acute coronary syndrome, and presence of extra-articular disease associated with RA, e.g., nodules, Sjögren's syndrome, anemia of chronic disease, pulmonary manifestations), and were on a stable background dose of methotrexate. The majority (more than 90%) of tofacitinib patients who were current or past smokers had a smoking duration of more than 10 years and a median of 35.0 and 39.0 smoking years, respectively.
Patients were randomized to open-label tofacitinib 10 mg twice daily, tofacitinib 5 mg twice daily, or a TNF inhibitor (TNF inhibitor was either etanercept 50 mg once weekly or adalimumab 40 mg every other week) in a 1:1:1 ratio. The co-primary endpoints are adjudicated malignancy (excluding NMSC) and adjudicated major adverse cardiovascular events (MACE); cumulative incidence and statistical assessment of endpoints are blinded. The study is an event-powered study that also requires at least 1500 patients to be followed for 3 years. The study treatment of tofacitinib 10 mg twice daily has been stopped and the patients were switched to 5 mg twice daily because of a dose dependent signal of PE.
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).
Study PsA-I had a duration of 12 months and included 422 patients who had an inadequate response to a csDMARD and who were naïve to treatment with a TNF-inhibitor (TNFi) biologic DMARD. 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 had a duration of 6 months and included 394 patients who had an inadequate response to at least one approved TNFi. Study PsA-II included a 3-month placebo-controlled period. All patients in the clinical trials were required to receive treatment with a stable dose of a csDMARD [the majority received methotrexate (78.2%)]. In the Phase 3 clinical trials, patients were randomized and treated with XELJANZ 5 mg twice daily (238 patients) or XELJANZ 10 mg twice daily (236 patients). 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.
An additional long-term, open-label clinical trial was conducted which included 680 patients with psoriatic arthritis who originally participated in either of the 2 double-blind, controlled clinical trials. Patients who participated in this open-label clinical trial were initially treated with XELJANZ 5 mg twice daily. Starting at Month 1, escalation to XELJANZ 10 mg twice daily was permitted at investigator discretion; subsequent dose reduction to 5 mg twice daily was also permitted. This limits the interpretation of the long-term safety data with respect to dose.
Of the 783 patients (as of 10 May 2016) who received XELJANZ doses of 5 mg twice daily or 10 mg twice daily in psoriatic arthritis clinical trials, 665 received treatment for 6 months or longer, of whom 437 received treatment for one year or longer, of whom 44 received treatment for greater than or equal to 24 months.
Ankylosing Spondylitis: XELJANZ 5 mg twice daily was studied in patients with active ankylosing spondylitis (AS) in a randomized double-blind placebo-controlled Phase 3 clinical trial (Study AS-I) and included in a randomized dose-ranging double-blind placebo-controlled Phase 2 clinical trial (Study AS-II).
Study AS-I enrolled patients who had an inadequate response to at least 2 NSAIDs. Study AS-I included a 16-week double-blind treatment 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 enrolled patients who had an inadequate response to at least 2 NSAIDs. This clinical trial included a 12-week double-blind treatment period in which patients received either XELJANZ 2 mg, 5 mg, 10 mg, or placebo twice daily. This trial also included a 4-week follow-up period.
In the safety population of the combined Phase 2 and the 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. Among these 316 patients, 253 received treatment for 6 months or longer, and among these 253 patients, 108 received treatment for 12 months or longer. In the combined double-blind placebo-controlled period, 185 patients were randomized to and treated with XELJANZ 5 mg twice daily and 187 were randomized to and treated with placebo for up to 16 weeks. Concomitant treatment with stable doses of cDMARDs, NSAIDs, or corticosteroids (≤10 mg/day) was permitted. The study population of 420 patients randomized and treated with XELJANZ included 13 (3.1%) patients aged 65 years or older and 18 (4.3%) patients with diabetes at baseline.
Ulcerative Colitis: The following safety data were based on 4 randomized, double-blind, placebo-controlled studies: 2 Phase 3 induction studies of identical design (UC-I and UC-II), a Phase 3 maintenance study (UC-III), and 1 dose-ranging Phase 2 induction study (UC-V). Patients with moderately to severely active ulcerative colitis were enrolled in the Phase 2 and Phase 3 induction studies. In the induction studies, randomized patients received treatment with XELJANZ 10 mg twice daily (938 patients combined) or placebo (282 patients combined) for up to 8 weeks. Patients who completed either Study UC-I or Study UC-II and achieved clinical response entered Study UC-III. In Study UC-III, patients were re-randomized, such that 198 patients received XELJANZ 5 mg twice daily, 196 patients received XELJANZ 10 mg twice daily, and 198 patients received placebo for up to 52 weeks. Concomitant use of immunosuppressants or biologics was prohibited during these studies. Concomitant stable doses of oral corticosteroids were allowed in the induction studies, with taper of corticosteroids to discontinuation mandated within 15 weeks of entering the maintenance study. In addition to the induction and maintenance studies, long-term safety was evaluated in an open-label long-term extension study (Study UC-IV).
Polyarticular Course Juvenile Idiopathic Arthritis: The following-safety data were based on the double-blind, placebo-controlled Phase 3 clinical trial (Study pcJIA-I) in a total of 225 pcJIA patients (56 male and 169 female) 2 to <18 years of age, treated with XELJANZ dosed at 5 mg twice daily or weight based equivalent twice daily with or without concomitant MTX.
Clinical Trials Experience: The most common category of serious adverse reactions in rheumatoid arthritis, psoriatic arthritis and polyarticular course juvenile idiopathic arthritis was serious infections (see Precautions).
In induction and maintenance studies, across all treatment groups, the most common categories of serious adverse reactions in ulcerative colitis were gastrointestinal disorders and infections.
Rheumatoid Arthritis: In rheumatoid arthritis, the most commonly reported adverse reactions during the first 3 months in controlled clinical trials (occurring in ≥2% of patients treated with XELJANZ monotherapy or in combination with DMARDs) were headache, upper respiratory tract infections, nasopharyngitis, hypertension, nausea, and diarrhea.
The proportion of patients who discontinued treatment due to any adverse reactions during first 3 months of the double-blind, placebo or methotrexate-controlled studies was 3.8% for patients taking XELJANZ and 3.2% for placebo-treated patients. The most common infections resulting in discontinuation of therapy were herpes zoster and pneumonia.
Psoriatic Arthritis: In active psoriatic arthritis, the most commonly reported adverse reactions during the first 12 weeks in placebo-controlled clinical trials (occurring in ≥2% of patients treated with XELJANZ and at least 1% greater than the rate observed in patients on placebo) were bronchitis, diarrhea, dyspepsia, fatigue, headache, nasopharyngitis, pharyngitis.
The proportion of patients who discontinued treatment due to any adverse reactions during the first 12 weeks of the double-blind placebo-controlled studies was 3.2% for XELJANZ treated patients and 2.5% for placebo-treated patients. The most common infection resulting in discontinuation of therapy was sinusitis.
Overall, the safety profile observed in patients with active psoriatic arthritis treated with XELJANZ was consistent with the safety profile in patients with rheumatoid arthritis.
Ankylosing Spondylitis: In active ankylosing spondylitis, the most commonly reported adverse reactions during the first 16 weeks in the controlled clinical trials (occurring in ≥2% of patients treated with XELJANZ and at least 1% greater than the rate observed in patients on placebo) were upper respiratory tract infection, influenza, and fatigue.
Ulcerative Colitis: The adverse reactions that occurred in at least 2% of patients receiving XELJANZ 10 mg twice daily and at least 1% greater than that observed in patients receiving placebo in the induction studies (Study UC-I, Study UC-II, and Study UC-V) were increased blood creatine phosphokinase, nasopharyngitis, pyrexia, and headache.
In induction and maintenance studies, across all treatment groups, the most common categories of serious adverse reactions were gastrointestinal disorders and infections, and the most common serious adverse reaction was worsening of ulcerative colitis.
In the controlled clinical studies for ulcerative colitis, 1 case of breast cancer was reported in a placebo-treated patient and no cases of solid cancers or lymphoma were observed in XELJANZ-treated patients. Malignancies have also been observed in the long-term extension study in patients with ulcerative colitis treated with XELJANZ, including solid cancers and lymphoma.
In induction and maintenance studies, the most frequent reason for study discontinuation was worsening of ulcerative colitis. Excluding discontinuations due to worsening of ulcerative colitis, the proportion of patients who discontinued due to adverse reactions was less than 5% in any of the XELJANZ or placebo treatment groups in these studies.
Overall, the safety profile observed in patients with ulcerative colitis treated with XELJANZ was consistent with the safety profile of XELJANZ across indications.
Polyarticular Course Juvenile Idiopathic Arthritis: In the pivotal Phase 3 (Study pcJIA-I [A3921104]), in patients with juvenile idiopathic arthritis aged 2 to <18 years of age, the most commonly reported adverse reactions occurring in ≥5% of patients treated with tofacitinib dosed at 5 mg twice daily or weight-based equivalent twice daily were upper respiratory tract infections, headache, nasopharyngitis, pyrexia, nausea and vomiting.
The Adverse Drug Reactions (ADRs) listed in Table 20 are presented by System Organ Class (SOC). Within each SOC, undesirable effects are presented in order of decreasing seriousness.
The Adverse Drug Reactions (ADRs) listed in the table as follows are presented by System Organ Class (SOC) and frequency categories, defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) or rare (≥1/10,000 to <1/1,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
ADRs BY SOC AND CIOMS FREQUENCY CATEGORY LISTED IN ORDER OF DECREASING MEDICAL SERIOUSNESS OR CLINICAL IMPORTANCE WITHIN EACH FREQUENCY CATEGORY AND SOC. (See Table 20.)
Click on icon to see table/diagram/imageOverall Infections: Rheumatoid Arthritis: In the 6-month and 24-month, controlled Phase 3 clinical studies the rates of infections in the 5 mg twice daily (total 616 patients) and 10 mg twice daily (total 642 patients) XELJANZ monotherapy group were 16.2% (100 patients), and 17.9% (115 patients), respectively, compared to 18.9% (23 patients) in the placebo group (total 122 patients). In studies of 6-month, 12-month, or 24-month duration with background DMARDs, the rates of infections in the 5 mg twice daily (total 973 patients) and 10 mg twice daily (total 969 patients) XELJANZ plus DMARD group were 21.3% (207 patients) and 21.8% (211 patients), respectively, compared to 18.4% (103 patients) in the placebo plus DMARD group (total 559 patients).
The most commonly reported infections were upper respiratory tract infections and nasopharyngitis (3.7% and 3.2%, respectively).
The overall rate of infections with XELJANZ in the long-term safety all exposure population (total 4867 patients) was 46.1 patients with events per 100 patient-years (43.8 and 47.2 patients with events for 5 mg and 10 mg twice daily, respectively). For patients (total 1750) on monotherapy, the rates were 48.9 and 41.9 patients with events per 100 patient-years for 5 mg and 10 mg twice daily, respectively. For patients (total 3117) on background DMARDs, the rates were 41.0 and 50.3 patients with events per 100 patient-years for 5 mg and 10 mg twice daily, respectively.
Infections were also reported in a large, randomized PASS in RA patients who were 50 years or older with at least one additional cardiovascular risk factor (see Pharmacology: Pharmacodynamics under Actions).
Psoriatic Arthritis: In the controlled Phase 3 studies of up to 6-month and up to 12-month, the frequency of infections in the XELJANZ 5 mg twice daily (238 patients) and XELJANZ 10 mg twice daily (236 patients) groups were 37.8% and 44.5%, respectively. The frequency of infections in the 3-month placebo-controlled period was 23.5% for XELJANZ 5 mg twice daily (238 patients), 28.8% for XELJANZ 10 mg twice daily (236 patients) and 15.7% in the placebo group (236 patients).
The most commonly reported infections in the 3-month placebo-controlled period were nasopharyngitis (5.9% and 5.5% in the 5 mg twice daily and 10 mg twice daily dose groups, respectively) and upper respiratory tract infections (5.0% and 4.7% in the 5 mg twice daily and 10 mg twice daily dose groups, respectively).
As of May 2016, the overall rate of infections with XELJANZ in the long-term safety population for combined doses was 63.5 patients with events per 100 patient-years.
Ankylosing Spondylitis: In the combined Phase 2 and Phase 3 clinical trials, during the placebo-controlled period of up to 16 weeks, the frequency of infections in the XELJANZ 5 mg twice daily group (185 patients) was 27.6% and the frequency in the placebo group (187 patients) was 23.0%. In the combined Phase 2 and Phase 3 clinical trials, among the 316 patients treated with XELJANZ 5 mg twice daily for up to 48 weeks, the frequency of infections was 35.1%.
Ulcerative Colitis: In the randomized 8-week Phase 2/3 induction studies, the proportions of patients with infections were 21.1% for XELJANZ 10 mg twice daily compared with 15.2% for placebo. In the randomized 52-week Phase 3 maintenance study, the proportion of patients with infections were 35.9% for XELJANZ 5 mg twice daily, 39.8% for XELJANZ 10 mg twice daily, and 24.2% for placebo. In the entire treatment experience with XELJANZ in the ulcerative colitis program, the overall incidence rate of infection was 65.7 events per 100 patient-years (involving 47.9% of patients). The most common infection was nasopharyngitis, occurring in 16.8% of patients.
Polyarticular Course Juvenile Idiopathic Arthritis: In the double-blind portion of the pivotal Phase 3 Study pcJIA-I, infection was the most commonly reported adverse reaction with 44.3% of patients treated with tofacitinib as compared with 30.6% of patients on placebo. The infections were generally mild to moderate in severity.
Serious Infections: Rheumatoid Arthritis: In the 6-month and 24-month, controlled clinical studies, the rate of serious infections in the 5 mg twice daily XELJANZ monotherapy group was 1.7 patients with events per 100 patient-years. In the 10 mg twice daily XELJANZ monotherapy group, the rate was 1.6 patients with events per 100 patient-years, the rate was 0 events per 100 patient-years for the placebo group and the rate was 1.9 patients with events per 100 patient-years for the methotrexate group.
In studies of 6-, 12- or 24-month duration, the rates of serious infections in the 5 mg twice daily and 10 mg twice daily XELJANZ plus DMARD groups were 3.6 and 3.4 patients with events per 100 patient-years, respectively, compared to 1.7 patients with events per 100 patient-years in the placebo plus DMARD group.
In the long-term safety all exposure population comprised of phase 2 and phase 3 clinical trials and long-term extension studies, the overall rates of serious infections were 2.4 and 3.0 patients with events per 100 patient-years for 5 mg and 10 mg twice daily XELJANZ groups, respectively. The most common serious infections reported with XELJANZ included pneumonia, herpes zoster, urinary tract infection, cellulitis, gastroenteritis, and diverticulitis. Cases of opportunistic infections have been reported (see Precautions).
Of the 4271 patients who enrolled in Studies I to VI, a total of 608 rheumatoid arthritis patients were 65 years of age and older, including 85 patients 75 years and older. The frequency of serious infection among XELJANZ-treated patients 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.
Serious infections were also reported in a large, randomized PASS in RA patients who were 50 years or older with at least one additional cardiovascular risk factor (see Pharmacology: Pharmacodynamics under Actions).
Psoriatic Arthritis: In the 6-month and 12-month Phase 3 studies, the rate of serious infections in the XELJANZ 5 mg twice daily group was 1.30 patients with events per 100 patient-years. In the XELJANZ 10 mg twice daily group, the rate was 2.0 patients with events per 100 patient-years.
In the long-term safety population, the overall rate of serious infections was 1.4 patients with events per 100 patient-years for XELJANZ treated patients. The most common serious infection reported with XELJANZ was pneumonia.
Ankylosing Spondylitis: In the combined Phase 2 and Phase 3 clinical trials, among the 316 patients treated with XELJANZ 5 mg twice daily for up to 48 weeks, there was one serious infection (aseptic meningitis) yielding a rate of 0.43 patients with events per 100 patient-years.
Ulcerative Colitis: In the randomized 8-week Phase 2/3 induction studies, the proportion of patients with serious infections in patients treated with XELJANZ 10 mg twice daily was 0.9% (8 patients) compared with 0.0% in patients treated with placebo. In the randomized 52-week Phase 3 maintenance study, the incidence rates of serious infections in patients treated with XELJANZ 5 mg twice daily (1.35 events per 100 patient-year) and in patients treated with XELJANZ 10 mg twice daily (0.64 events per 100 patient-year) were not higher than that for placebo (1.94 events per 100 patient-year). The incidence rate of serious infections in the entire treatment experience with XELJANZ in patients with ulcerative colitis was 2.05 events per 100 patient-year. There was no apparent clustering into specific types of serious infections.
Polyarticular Course Juvenile Idiopathic Arthritis: In the pivotal Phase 3 Study pcJIA-I, four patients had serious infections during treatment with tofacitinib, representing an incidence rate of 3.25 events per 100 patient-years: pneumonia, epidural empyema (with sinusitis and subperiosteal abscess), pilonidal cyst, and appendicitis.
Viral Reactivation: In XELJANZ clinical trials, Japanese and Korean patients appear to have a higher rate of herpes zoster than that observed in other populations. Events of herpes zoster were reported in a large, randomized PASS in RA patients who were 50 years or older with at least one additional cardiovascular risk factor (see Pharmacology: Pharmacodynamics under Actions).
Venous Thromboembolism: Rheumatoid Arthritis: Events of PE and DVT were reported in a large, randomized PASS in RA patients who were 50 years or older with at least one additional cardiovascular risk factor (see Pharmacology: Pharmacodynamics under Actions).
Completed Rheumatoid Arthritis Studies: In the 4 to 12 week placebo period of randomized controlled studies of 4 weeks to 24 months duration, the IRs (95% CI) for tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and placebo for PE were 0.00 (0.00, 0.57), 0.00 (0.00, 0.77), and 0.40 (0.01, 2.22) patients with events per 100 PYs respectively; the IRs (95% CI) for DVT were 0.00 (0.00, 0.57), 0.21 (0.01,1.16), and 0.40 (0.01, 2.22) patients with events per 100 PYs respectively.
In the full randomized period of controlled studies of 4 weeks to 24 months duration, the IRs (95% CI) for tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for PE were 0.12 (0.02, 0.34) and 0.15 (0.03, 0.44) patients with events per 100 PYs respectively; the IRs (95% CI) for DVT were 0.15 (0.04, 0.40) and 0.10 (0.01, 0.36) patients with events per 100 PYs respectively.
In the long term safety population that includes exposure during completed randomized controlled studies and open label long-term extension studies, the IRs (95% CI) for tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for PE were 0.12 (0.06, 0.22) and 0.13 (0.08, 0.21) patients with events per 100 PYs respectively; the IRs (95% CI) for DVT were 0.17 (0.09, 0.27) and 0.15 (0.09, 0.22) patients with events per 100 PYs respectively.
Psoriatic arthritis: In the 3 month placebo period of completed randomized controlled studies of 6 to 12 months duration, the IRs (95% CI) for tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and placebo for PE were 0.00 (0.00, 6.75), 0.00 (0.00, 6.78), and 0.00 (0.00, 6.87) patients with events per 100 PYs respectively; the IRs (95% CI) for DVT were 0.00 (0.00, 6.75), 0.00 (0.00, 6.78), and 0.00 (0.00, 6.87) patients with events per 100 PYs respectively.
In the full randomized period of completed controlled studies of 6 to 12 months, the IRs (95% CI) for tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for PE were 0.00 (0.00, 1.83) and 0.00 (0.00, 1.87) patients with events per 100 PYs respectively; the IRs (95% CI) for DVT were 0.00 (0.00, 1.83) and 0.51 (0.01, 2.83) patients with events per 100 PYs respectively.
In the long-term safety population that includes exposure during completed randomized controlled studies and ongoing open label long-term extension study, the IRs (95% CI) for tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for PE were 0.11 (0.00, 0.60) and 0.00 (0.00, 0.58) patients with events per 100 PYs respectively; the IRs (95% CI) for DVT were 0.00 (0.00, 0.40) and 0.16 (0.00, 0.87) patients with events per 100 PYs respectively.
Ankylosing Spondylitis: In the combined Phase 2 and Phase 3 randomized controlled clinical trials, there were no VTE events in 420 patients (233 patient-years of observation) receiving XELJANZ up to 48 weeks.
Ulcerative Colitis: In the completed randomized placebo-controlled induction studies of 8 weeks duration, the IR (95% CI) for tofacitinib 10 mg twice daily and placebo for PE were 0.00 (0.00, 2.22) and 1.98 (0.05, 11.04) patients with events per 100 PYs; the IR (95% CI) for DVT were 0.00 (0.00, 2.22) and 1.99 (0.05, 11.07) patients with events per 100 PYs respectively.
In the completed randomized maintenance study of 52 weeks duration, the IRs (95% CI) for tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for PE were 0.00 (0.00, 2.48) and 0.00 (0.00, 2.35) patients with events per 100 PYs respectively; the IRs (95% CI) for DVT were 0.00 (0.00, 2.48) and 0.00 (0.00, 2.35) patients with events per 100 PYs respectively.
In the long-term safety population that includes exposure during completed randomized controlled studies and ongoing open label long-term extension study, the IRs (95% CI) for tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for PE were 0.00 (0.00, 0.54) and 0.20 (0.05, 0.52) patients with events per 100 PYs respectively; the IRs (95% CI) for DVT were 0.00 (0.00, 0.54) and 0.05 (0.00, 0.28) patients with events per 100 PYs respectively.
Clinical Experience in Methotrexate-Naïve Rheumatoid Arthritis Patients: Study VI was an active-controlled clinical trial in methotrexate-naïve RA patients (see Pharmacology: Pharmacodynamics under Actions). The safety experience in these patients was consistent with Studies I-V.
Laboratory Tests: In the clinical trials in psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis changes in lymphocytes, neutrophils, and lipids observed with XELJANZ treatment were similar to the changes observed in clinical trials in rheumatoid arthritis.
In the clinical trials in psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis, changes in liver enzyme tests observed with XELJANZ treatment were similar to the changes observed in clinical trials in rheumatoid arthritis where patients received background DMARDs.
Rheumatoid Arthritis: Lymphocytes: In the controlled clinical studies in rheumatoid arthritis, confirmed decreases in lymphocyte counts below 500 cells/mm3 occurred in 0.23% of patients for the 5 mg twice daily and 10 mg twice daily doses combined. In the controlled clinical trials in psoriasis, confirmed decreases in absolute lymphocyte count below 500 cells/mm3 occurred in 3 patients (0.1%) for XELJANZ and none in placebo, during the first 0 to 12-16 weeks of exposure.
In the long-term safety population in rheumatoid arthritis, confirmed decreases in lymphocyte counts below 500 cells/mm3 occurred in 1.3% of patients for the 5 mg twice daily and 10 mg twice daily doses combined. In the long-term safety population in psoriasis, confirmed decreases in lymphocyte counts below 500 cells/mm3 occurred in 0.7% of patients for the combined dose groups.
Confirmed lymphocyte counts <500 cells/mm3 were associated with an increased incidence of treated and serious infections (see Precautions).
Neutrophils: In the controlled clinical studies in rheumatoid arthritis, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.08% of patients for the 5 mg twice daily and 10 mg twice daily doses combined. In the controlled clinical trials for psoriasis, no patients had confirmed neutrophil levels below 1000 cells/mm3 in either of the XELJANZ treatment groups or placebo group during the first 0 to 12-16 weeks 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 controlled clinical studies (see Precautions).
Liver Enzyme Tests: Rheumatoid Arthritis: Confirmed increases in liver enzymes >3 times the upper limit of normal (3x ULN) were uncommonly observed. 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 controlled portion of the Phase 3 monotherapy study (0-3 months), (Study I, see Pharmacology: Pharmacodynamics under Actions), ALT elevations >3x ULN were observed in 1.65%, 0.41%, and 0% of patients receiving placebo, XELJANZ 5 mg and 10 mg twice daily, respectively. In this study, AST elevations >3x ULN were observed in 1.65%, 0.41% and 0% of patients receiving placebo, XELJANZ 5 mg, and 10 mg twice daily, respectively.
In the Phase 3 monotherapy study (0-24 months) (Study VI, see Pharmacology: Pharmacodynamics under Actions), ALT elevations >3x ULN were observed in 7.1%, 3.0%, and 3.0% of patients receiving methotrexate, XELJANZ 5 mg, and 10 mg twice daily, respectively. In this study, AST elevations >3x ULN were observed in 3.3%, 1.6% and 1.5% of patients receiving methotrexate, XELJANZ 5 mg, and 10 mg twice daily, respectively.
In the controlled portion of the Phase 3 studies on background DMARDs (0-3 months), (Studies II-V, see Pharmacology: Pharmacodynamics under Actions), ALT elevations >3x ULN were observed in 0.9%, 1.24% and 1.14% of patients receiving placebo, XELJANZ 5 mg, and 10 mg twice daily, respectively. In these studies, AST elevations >3x ULN were observed in 0.72%, 0.50% and 0.31% of patients receiving placebo, XELJANZ 5 mg, and 10 mg twice daily, respectively.
Elevations of ALT and AST were reported in a large, randomized PASS in RA patients who were 50 years or older with at least one additional cardiovascular risk factor (see Pharmacology: Pharmacodynamics under Actions).
Lipids: Elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were first assessed at one month following initiation of XELJANZ in the controlled double-blind clinical trials of rheumatoid arthritis. Increases were observed at this time point and remained stable thereafter.
Rheumatoid Arthritis: Changes in lipid parameters from baseline through the end of the study (6-24 months) in the controlled clinical studies in rheumatoid arthritis are summarized as follows: Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 20% in the XELJANZ 10 mg twice daily arm at Month 12, and increased by 16% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm at Month 24.
Mean HDL cholesterol increased by 17% in the XELJANZ 5 mg twice daily arm and 18% in the XELJANZ 10 mg twice daily arm at Month 12, and increased by 19% in the XELJANZ 5 mg twice daily arm and 20% in the XELJANZ 10 mg twice daily arm at Month 24.
Mean LDL cholesterol/HDL cholesterol ratios and Apolipoprotein B (ApoB)/ApoA1 ratios were essentially unchanged in XELJANZ-treated patients.
Elevations of LDL cholesterol, and HDL cholesterol, were reported in a large, randomized PASS in RA patients who were 50 years or older with at least one additional cardiovascular risk factor (see Pharmacology: Pharmacodynamics under Actions).
In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.
In the long-term safety populations, elevations in the lipid parameters remained consistent with what was seen in the controlled clinical studies.
View ADR Reporting Link
Continue with Google