Tofacitinibside effects

The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections Increased Risk of Mortality Malignancy and Lymphoproliferative Disorders Major Adverse Cardiovascular Events Thrombosis Gastrointestinal Perforations Hypersensitivity Reactions Laboratory Abnormalities Most common adverse reactions are: RA, PsA, and AS: Reported in ≥2% of adult patients treated with tofacitinib tablets monotherapy or in combination with DMARDs: upper respiratory tract infection (URI), nasopharyngitis, diarrhea, and headache. To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA Inc. at 855-664-7744 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical

Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. The clinical studies described in this subsection were conducted using XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling). Adverse Reactions in Adults with Rheumatoid Arthritis In RA Safety Study 1, 1,455 adults were treated with tofacitinib 5 mg twice daily, 1,456 adults were treated with 10 mg twice daily, and 1,451 adults were treated with a TNF blocker for a median of 4 years. A dosage of tofacitinib 10 mg twice daily is not recommended for the treatment of RA because of increased risks. For the treatment of adults with moderately to severely active RA, the recommended dosage of tofacitinib is 5 mg twice daily and the recommended dosage for tofacitinib extended-release tablets is 11 mg once daily. The safety of tofacitinib was also evaluated in two Phase 2 and five Phase 3 double-blind, placebo-controlled, multicenter trials in patients with RA. In these trials, adults were randomized to receive: Tofacitinib (monotherapy) 5 mg twice daily (292 patients) or 10 mg twice daily (306 patients), In combination with DMARDs (including methotrexate), tofacitinib 5 mg twice daily (1,044 patients) or 10 mg twice daily (1,043 patients) and Placebo (809 patients). All seven trials included provisions for patients taking placebo to receive treatment with tofacitinib at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore, some analyses that follow include patients who changed treatment by design or by patient response from placebo to tofacitinib in both the placebo and tofacitinib group of a given interval. Comparisons between placebo and tofacitinib groups were based on the first 3 months of exposure, and comparisons between tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily were based on the first 12 months of exposure. The long-term safety population includes all adults with RA who participated in a double-blind, placebo-controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. The design of the long-term safety studies allowed for modification of tofacitinib doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose. The most common serious adverse reactions were serious infections. The proportion of patients who discontinued treatment due to any adverse reaction during the 0 month to 3 months exposure in the double-blind, placebo-controlled trials was 4% for tofacitinib-treated patients and 3% for placebo-treated patients. Overall Infections In the seven placebo-controlled trials in patients with RA, during the 0 month to 3 months exposure, the overall frequency of infections was 20% and 22% in the tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily groups, respectively, and 18% in the placebo group. The most commonly reported infections with tofacitinib were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).

Serious Infections: In the seven placebo-controlled trials in patients with RA, during the 0 month 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 tofacitinib 5 mg twice daily and 10 mg twice daily group minus placebo. In the seven placebo-controlled trials, during the 0 month to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received tofacitinib 5 mg twice daily and 33 patients (2.7 events per 100 patient-years) who received tofacitinib 10 mg twice daily. 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 tofacitinib 10 mg twice daily minus tofacitinib tablets 5 mg twice daily. The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection.

Tuberculosis: In the seven placebo-controlled trials in patients with RA, during the 0 month to 3 months exposure, tuberculosis (TB) was not reported in patients who received placebo, tofacitinib 5 mg twice daily, or tofacitinib 10 mg twice daily. In the seven placebo-controlled trials, during the 0 month to 12 months exposure, TB was reported in 0 patients who received tofacitinib 5 mg twice daily and 6 patients (0.5 events per 100 patient-years) who received tofacitinib 10 mg twice daily. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was 0.5 events per 100 patient-years for tofacitinib 10 mg twice daily minus tofacitinib 5 mg twice daily. Cases of disseminated TB were also reported. The median XELJANZ exposure prior to diagnosis of TB was 10 months (range from 152 days to 960 days). Opportunistic Infections (excluding tuberculosis): In the seven placebo-controlled trials in patients with RA, during the 0 month to 3 months exposure, opportunistic infections were not reported in patients who received placebo, tofacitinib 5 mg twice daily, or tofacitinib 10 mg twice daily. In the seven placebo-controlled trials, during the 0 month to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received tofacitinib 5 mg twice daily and 4 patients (0.3 events per 100 patient-years) who received tofacitinib 10 mg twice daily. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for tofacitinib 10 mg twice daily minus tofacitinib 5 mg twice daily. The median tofacitinib exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 days to 698 days). Malignancies In the seven placebo-controlled trials in patients with RA, during the 0 month 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 tofacitinib 5 mg and 10 mg twice daily group minus placebo. In the seven placebo-controlled trials, during the 0 month to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received tofacitinib 5 mg twice daily and 7 patients (0.6 events per 100 patient-years) who received tofacitinib 10 mg twice daily. 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 tofacitinib 10 mg twice daily minus tofacitinib 5 mg twice daily. One of these malignancies was a case of lymphoma that occurred during the 0-to-12-month period in a patient treated with tofacitinib tablets 10 mg twice daily. The most common types of malignancy, including malignancies observed during the long-term extension in tofacitinib-treated patients, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma.

Laboratory Abnormalities Lymphopenia: In the placebo-controlled clinical trials in patients with RA, confirmed decreases in absolute lymphocyte counts below 500 cells/mm 3 occurred in 0.04% of patients for the tofacitinib 5 mg twice daily and 10 mg twice daily groups combined during the first 3 months of exposure. Confirmed lymphocyte counts less than 500 cells/mm 3 were associated with an increased incidence of treated and serious infections.

Neutropenia: In the placebo-controlled clinical trials in patients with RA, confirmed decreases in ANC below 1,000 cells/mm 3 occurred in 0.07% of patients for the tofacitinib 5 mg twice daily and 10 mg twice daily groups combined during the first 3 months of exposure. There were no confirmed decreases in ANC below 500 cells/mm 3 observed in any treatment group. There was no clear relationship between neutropenia and the occurrence of serious infections. In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the placebo-controlled clinical trials.

Liver Enzyme Elevations: Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were observed in patients with RA treated with tofacitinib. 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 dosage, resulted in decrease or normalization of liver enzymes. In the placebo-controlled monotherapy trials (0 month to 3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and tofacitinib 5 mg, and 10 mg twice daily groups. In the placebo-controlled background DMARD trials (0 month to 3 months), ALT elevations greater than 3x ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, tofacitinib 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3x ULN were observed in 0.6%, 0.5% and 0.4% of patients who received placebo, tofacitinib 5 mg, and 10 mg twice daily, respectively. One case of drug-induced liver injury was reported in a patient treated with tofacitinib 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and a liver biopsy.

Lipid Elevations: In the placebo-controlled clinical trials in patients with RA, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the placebo-controlled clinical trials are summarized below: Mean LDL cholesterol increased by 15% in the tofacitinib 5 mg twice daily arm and 19% in the tofacitinib 10 mg twice daily arm. Mean HDL cholesterol increased by 10% in the tofacitinib 5 mg twice daily arm and 12% in the tofacitinib 10 mg twice daily arm. Mean LDL/HDL ratios were essentially unchanged in tofacitinib-treated patients. In a placebo-controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy. In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the placebo-controlled clinical trials.

Serum Creatinine Elevations: In the placebo-controlled clinical trials in patients with RA, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from 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. Common Adverse Reactions Table 5 displays adverse reactions that occurred in 2% or more of patients on tofacitinib 5 mg or 10 mg twice daily and at least 1% greater than in tofacitinib -treated patients that observed in placebo-treated patients with or without DMARD in the RA trials.

Table 5: Common Adverse Reactions* in Clinical Trials of XELJANZ for the Treatment of Rheumatoid Arthritis in Adults With or Without Concomitant DMARDs (0 Month to 3 Months) N reflects randomized and treated patients from the seven placebo-controlled clinical trials. * reported in ≥2% of patients treated with either dose of XELJANZ and ≥1% greater than that reported for placebo. ** The recommended dose of XELJANZ for the treatment of RA is 5 mg twice daily. Preferred Term Placebo XELJANZ 5 mg Twice Daily XELJANZ 10 mg Twice Daily** N = 809 (%) N = 1,336 (%) N = 1,349 (%) Upper respiratory tract infection 3 4 4 Nasopharyngitis 3 4 3 Diarrhea 2 4 3 Headache 2 4 3 Hypertension 1 2 2 Other adverse reactions that occurred in placebo-controlled and open-label extension studies in patients with RA included: Blood and lymphatic system disorders: Anemia Infections and infestations: Diverticulitis Metabolism and nutrition disorders: Dehydration Psychiatric disorders: Insomnia Nervous system disorders: Paresthesia Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with RA and some were fatal) Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea Hepatobiliary disorders: Hepatic steatosis Skin and subcutaneous tissue disorders: Rash, erythema, pruritus Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancers General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema Clinical Experience in Methotrexate-Naïve Patients Study RA-VI was an active-controlled clinical trial in methotrexate-naïve patients. The safety experience in these patients was consistent with Studies RA-I through V. Adverse Reactions in Adults with Psoriatic Arthritis The safety of tofacitinib was evaluated in 2 double-blind Phase 3 clinical trials in adults with active psoriatic arthritis (PsA): Study PsA-I (NCT01877668) had a duration of 12 months and enrolled adults who had an inadequate response to a nonbiologic DMARD and who were naïve to treatment with a TNF blocker. Study PsA-I included a 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months. Study PsA-II (NCT01882439) had a duration of 6 months and enrolled adults who had an inadequate response to at least one approved TNF blocker. This clinical trial included a 3-month placebo-controlled period. In these combined Phase 3 clinical trials, 238 patients were randomized and treated with tofacitinib 5 mg twice daily and 236 patients were randomized and treated with tofacitinib 10 mg twice daily. A dosage of tofacitinib tablets 10 mg twice daily is not recommended for the treatment of PsA. For the treatment of adults with active PsA, the recommended dosage of tofacitinib is 5 mg twice daily and the recommended dosage for tofacitinib extended-release tablets is 11 mg once daily. All patients in the clinical trials in patients with PsA were required to receive treatment with a stable dose of a nonbiologic DMARD [the majority (79%) received methotrexate]. The study population randomized and treated with tofacitinib (474 patients) included 45 (10%) patients aged 65 years or older and 66 (14%) patients with diabetes at baseline. During the 2 PsA controlled clinical trials, there were: 3 malignancies (excluding NMSC) in 474 patients who received tofacitinib plus non-biologic DMARD (6 months to 12 months exposure) 0 malignancies in 236 patients who received placebo plus non-biologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in patients who received adalimumab plus non-biologic DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also been observed in the long-term extension study in patients with PsA treated with tofacitinib. The safety profile observed in adults with active PsA treated with tofacitinib was consistent with the safety profile observed in adults with RA. Adverse Reactions in Adults with Ankylosing Spondylitis The safety of tofacitinib was evaluated in adults with active ankylosing spondylitis (AS) in a double-blind placebo-controlled Phase 3 clinical trial (Study AS-I) and in a dose-ranging Phase 2 clinical trial (Study AS-II). Study AS-I (NCT03502616) had a duration of 48 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. Study AS-I included a 16-week double-blind period in which patients received tofacitinib 5 mg or placebo twice daily and a 32-week open-label treatment period in which all patients received tofacitinib 5 mg twice daily. Study AS-II (NCT01786668) had a duration of 16 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. This clinical trial included a 12-week treatment period in which patients received either tofacitinib 2 mg (40% of the recommended dose), 5 mg, 10 mg, or placebo twice daily. A dosage of tofacitinib 10 mg twice daily is not recommended for the treatment of AS. For the treatment of adults with active AS, the recommended dosage of tofacitinib is 5 mg twice daily and the recommended dosage for tofacitinib extended-release is 11 mg once daily. In the combined Phase 2 and Phase 3 clinical trials, a total of 420 patients were treated with either tofacitinib 2 mg, 5 mg, or 10 mg twice daily. Of these, 316 patients were treated with tofacitinib 5 mg twice daily for up to 48 weeks. In the combined double-blind period, 185 patients were randomized to and treated with tofacitinib 5 mg twice daily and 187 to placebo for up to 16 weeks. Concomitant treatment with stable doses of nonbiologic DMARDs, NSAIDs, or corticosteroids (≤10 mg/day) was permitted. The study population randomized and treated with tofacitinib included 13 (3.1%) patients aged 65 years or older and 18 (4.3%) patients with diabetes at baseline. The safety profile observed in adults with AS treated with tofacitinib was consistent with the safety profile observed in adults with RA and PsA.

6.2 Postmarketing

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

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