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All patients in these studies had moderate to severe rheumatoid arthritis. The study tofacitinib population had a mean age of 52.7 years and 84.1% 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 5305 patients (Phase 1, 2, 3 (excluding A3921069), and long-term extension studies) were treated with any dose of tofacitinib with a mean duration of 3.16 years, with 16785.8 patient-years of accumulated total drug exposure based on more than 8 years of continuous exposure to tofacitinib.
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: Tofacitinib 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.
Study PsA-I (OPAL BROADEN) 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 (OPAL BROADEN) included a 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months. Study PsA-II (OPAL BEYOND) had a duration of 6 months and included 394 patients who had an inadequate response to at least one approved TNFi. Study PsA-II (OPAL BEYOND) 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 tofacitinib 5 mg twice daily (238 patients) or tofacitinib 10 mg twice daily (236 patients). The study population randomized and treated with tofacitinib (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 686 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 tofacitinib 5 mg twice daily. Starting at Month 1, escalation to tofacitinib 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 who received tofacitinib doses of 5 mg twice daily or 10 mg twice daily in psoriatic arthritis clinical trials, 713 received treatment for 6 months or longer, of whom 635 received treatment for one year or longer, of whom 335 received treatment for greater than or equal to 24 months.
Ulcerative Colitis: The following safety data were based on 4 randomized, double-blind, placebo-controlled studies: 2 Phase 3 induction studies of identical design (OCTAVE Induction 1 and OCTAVE Induction 2), a Phase 3 maintenance study (OCTAVE Sustain), 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 tofacitinib 10 mg twice daily (938 patients combined) or placebo (282 patients combined) for up to 8 weeks. Patients who completed either OCTAVE Induction 1 or OCTAVE Induction 2 and achieved clinical response entered OCTAVE Sustain. In OCTAVE Sustain, patients were re-randomized, such that 198 patients received tofacitinib 5 mg twice daily, 196 patients received tofacitinib 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 (OCTAVE Open).
Clinical Trials Experience: The most common category of serious adverse reactions in rheumatoid 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 tofacitinib 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-controlled studies was 4.2% for patients taking tofacitinib 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 tofacitinib 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 tofacitinib-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 tofacitinib was consistent with the safety profile in patients with rheumatoid arthritis.
Ulcerative Colitis: The adverse reactions that occurred in at least 2% of patients receiving tofacitinib 10 mg twice daily and at least 1% greater than that observed in patients receiving placebo in the induction studies (OCTAVE Induction 1, OCTAVE Induction 2), 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 tofacitinib-treated patients. Malignancies have also been observed in the long-term extension study in patients with ulcerative colitis treated with tofacitinib, 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 tofacitinib or placebo treatment groups in these studies.
Overall, the safety profile observed in patients with ulcerative colitis treated with tofacitinib was consistent with the safety profile of tofacitinib across indications.
Serious Infections: In the seven 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 tofacitinib 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 tofacitinib group minus placebo.
In the seven 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 tofacitinib and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib.
The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection (see Precautions).
Tuberculosis: In the seven controlled trials, during the 0 to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of tofacitinib, or 10 mg twice daily of tofacitinib.
In the seven controlled trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of tofacitinib and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib.
Cases of disseminated tuberculosis were also reported. The median tofacitinib exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days) (see Precautions).
Opportunistic Infections (Excluding Tuberculosis): In the seven controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of tofacitinib, or 10 mg twice daily of tofacitinib.
In the seven 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 tofacitinib and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib.
The median tofacitinib exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days) (see Precautions).
Malignancy: In the seven 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 tofacitinib 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 tofacitinib group minus placebo.
In the seven 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 tofacitinib and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with tofacitinib 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 Precautions).
The Adverse Drug Reactions (ADRs) listed in the tables as follows are presented by System Organ Class (SOC) and Council for International Organization of Medical Science (CIOMS) frequency category. Within each SOC, undesirable effects are presented in order of decreasing seriousness. (See Tables 14 and 15.)
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Click on icon to see table/diagram/imageOverall Infections: Rheumatoid Arthritis: In the 6-month, controlled Phase 3 clinical study the rates of infections in the 5 mg twice daily (total 243 patients) and 10 mg twice daily (total 245 patients) tofacitinib monotherapy group were 16.5% (40 patients), and 19.2% (47 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) tofacitinib 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 (4.1% and 3.4%, respectively).
The overall rate of infections with tofacitinib 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 tofacitinib 5 mg twice daily (238 patients) and tofacitinib 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 tofacitinib 5 mg twice daily (238 patients), 28.8% for tofacitinib 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).
The overall rate of infections with tofacitinib in the long-term safety population for combined doses was 52.3 patients with events per 100 patient-years.
Ulcerative Colitis: In the randomized 8-week Phase 2/3 induction studies, the proportions of patients with infections were 21.1% for tofacitinib 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 tofacitinib 5 mg twice daily, 39.8% for tofacitinib 10 mg twice daily, and 24.2% for placebo. In the entire treatment experience with tofacitinib 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.
Serious Infections: Rheumatoid Arthritis: In the 6-month, controlled clinical study, the rate of serious infections in the 5 mg twice daily tofacitinib monotherapy group was 0.85 patients with events per 100 patient-years. In the 10 mg twice daily tofacitinib monotherapy group, the rate was 3.5 patients with events per 100 patient-years, and the rate was 0 events per 100 patient-years for the placebo group.
In studies of 6-, 12- or 24-months duration, the rates of serious infections in the 5 mg twice daily and 10 mg twice daily tofacitinib 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 tofacitinib groups, respectively. The most common serious infections reported with tofacitinib included pneumonia, herpes zoster, urinary tract infection, cellulitis, gastroenteritis, and diverticulitis. Cases of opportunistic infections have been reported (see Precautions).
Of the 3315 patients who enrolled in 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 tofacitinib-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 tofacitinib 5 mg twice daily group was 1.30 patients with events per 100 patient-years. In the tofacitinib 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 tofacitinib-treated patients. The most common serious infection reported with tofacitinib was pneumonia.
Ulcerative Colitis: In the randomized 8-week Phase 2/3 induction studies, the proportion of patients with serious infections in patients treated with tofacitinib 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 tofacitinib 5 mg twice daily (1.35 events per 100 patient-year) and in patients treated with tofacitinib 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 tofacitinib in patients with ulcerative colitis was 2.05 events per 100 patient-year. There was no apparent clustering into specific types of serious infections.
Viral Reactivation: In tofacitinib 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.
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.
Laboratory Tests: In the clinical trials in psoriatic arthritis and ulcerative colitis, changes in lymphocytes, neutrophils, and lipids observed with tofacitinib treatment were similar to the changes observed in clinical trials in rheumatoid arthritis.
In the clinical trials in psoriatic arthritis and ulcerative colitis, changes in liver enzyme tests observed with tofacitinib 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, confirmed decreases in lymphocyte counts below 500 cells/mm3 occurred in 0.26% of patients for the 5 mg twice daily and 10 mg twice daily doses combined.
In the long-term safety population, 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.
Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections (see Precautions).
Neutrophils: In the controlled clinical studies 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. 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: 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 tofacitinib, or reduction in tofacitinib 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, tofacitinib 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, tofacitinib 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, tofacitinib 5 mg, and 10 mg twice daily, respectively. In these studies, AST elevations >3x ULN were observed in 0.72%, 0.52% and 0.31% of patients receiving placebo, tofacitinib 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 tofacitinib in the controlled double-blind clinical trials. Increases were observed at this time point and remained stable thereafter.
Changes in lipid parameters from baseline through the end of the study (6-24 months) in the controlled clinical studies are summarized as follows: Mean LDL cholesterol increased by 14% in the tofacitinib 5 mg twice daily arm and 20% in the tofacitinib 10 mg twice daily arm at Month 12, and increased by 14% in the tofacitinib 5 mg twice daily arm and 15% in the tofacitinib 10 mg twice daily arm at Month 24.
Mean HDL cholesterol increased by 16% in the tofacitinib 5 mg twice daily arm and 18% in the tofacitinib 10 mg twice daily arm at Month 12, and increased by 18% in the tofacitinib 5 mg twice daily arm and 20% in the tofacitinib 10 mg twice daily arm at Month 24.
Mean LDL cholesterol/HDL cholesterol ratios were essentially unchanged in tofacitinib-treated patients.
Apolipoprotein B (ApoB)/ApoA1 ratios were essentially unchanged in tofacitinib-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 population, elevations in the lipid parameters remained consistent with what was seen in the controlled clinical studies.
Serum Creatinine: In the controlled clinical trials, dose-related elevations in serum creatinine were observed with tofacitinib 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 tofacitinib 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.
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