tofacitinib

1 INDICATIONS AND USAGE Tofacitinib tablets are Janus kinase (JAK) inhibitors. Tofacitinib tablets are indicated for the treatment of adult patients with: Moderately to severely active rheumatoid arthritis (RA), who have had an inadequate response or intolerance to one or more TNF blockers. Active psoriatic arthritis (PsA), who have had an inadequate response or intolerance to one or more TNF blockers. Active ankylosing spondylitis (AS), who have had an inadequate response or intolerance to one or more TNF blockers. Moderately to severely active ulcerative colitis (UC), who have had an inadequate response or intolerance to one or more TNF blockers. Tofacitinib tablets are indicated for the treatment of pediatric patients 2 years of age and older with: Active PsA, who have had an inadequate response or intolerance to one or more TNF blockers. Active polyarticular course juvenile idiopathic arthritis (pcJIA), who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use : Use of tofacitinib tablets for RA, AS, PsA, or pcJIA in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. ( 1.1 , 1.2 , 1.3 , 1.4 ) Use of tofacitinib tablets for UC in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. ( 1.5 ) 1.1 Rheumatoid Arthritis Tofacitinib tablets are indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA), who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use Use of tofacitinib tablets in combination with biologic disease-modifying antirheumatic drugs (DMARDs) or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. 1.2 Psoriatic Arthritis Tofacitinib tablets are indicated for the treatment of adult and pediatric patients 2 years of age and older with active psoriatic arthritis (PsA), who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use Use of tofacitinib tablets in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. 1.3 Ankylosing Spondylitis Tofacitinib tablets are indicated for the treatment of adult patients with active ankylosing spondylitis (AS), who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use Use of tofacitinib tablets in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. 1.4 Polyarticular Course Juvenile Idiopathic Arthritis Tofacitinib tablets are indicated for the treatment of pediatric patients 2 years of age and older with of active polyarticular course juvenile idiopathic arthritis (pcJIA), who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use Use of tofacitinib tablets in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. 1.5 Ulcerative Colitis Tofacitinib tablets are indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC), who have an inadequate response or intolerance to one or more TNF blockers. Limitations of Use Use of tofacitinib tablets in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

2 DOSAGE AND ADMINISTRATION Recommended Evaluations and Immunization Prior to Treatment Initiation Prior to initiating tofacitinib tablets, consider performing an active and latent TB evaluation, viral hepatitis screening, a complete blood count, and updating immunizations. Avoid tofacitinib tablets initiation if absolute lymphocyte count < 500 cells/mm 3 , an absolute neutrophil count (ANC) < 1,000 cells/mm 3 or hemoglobin < 9 g/dL. ( 2.1 ) Important Administration Instructions Tofacitinib extended-release tablets is not substitutable with tofacitinib tablets and tofacitinib oral solution. ( 2.2 ) Switching between tofacitinib tablets and tofacitinib extended-release tablets should be made by the healthcare provider. ( 2.2 ) Recommended Dosage Adult Patients with RA, PsA or AS Tofacitinib tablets 5 mg twice daily. ( 2.3 ) Pediatric Patients 2 Years of Age and Older with PsA or pcJIA Who Weigh At Least 10 kg Tofacitinib (tablets or oral solution) 5 mg twice daily for those ≥ 40 kg or weight-based equivalent twice daily for those < 40 kg. ( 2.4 ) Adult Patients with UC Induction: Tofacitinib tablets 10 mg twice daily for 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed, continue tofacitinib tablets 10 mg twice daily for a maximum of 16 weeks. Discontinue tofacitinib tablets 10 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. ( 2.5 ) Maintenance: Tofacitinib tablets 5 mg twice daily. For patients with loss of response during maintenance treatment, tofacitinib tablets 10 mg twice daily may be considered and limited to the shortest duration, with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dose needed to maintain response. ( 2.5 ) Dosage in Patients with Renal Impairment or Hepatic Impairment Use of tofacitinib tablets in patients with severe HI is not recommended. ( 2.3 , 2.4 , 2.5 , 8.7 ) See full prescribing information (FPI) for recommended dosage in patients with moderate or severe RI or moderate HI. ( 2.3 , 2.4 , 2.5 , 8.6 , 8.7 ) Dosage Modification See the full prescribing information for dosage modification by indication for patients who concomitantly use CYP2C19 and/or CYP3A4 inhibitors and patients with lymphopenia, neutropenia, or anemia. ( 2.3 , 2.4 , 2.5 , 7 ) 2.1 Recommended Evaluations and Immunization Prior to Treatment Initiation Prior to initiating tofacitinib tablets, consider performing the following: Active and latent tuberculosis (TB) infection evaluation: If the patient has latent TB, treat for TB prior to tofacitinib tablets treatment [see Warnings and Precautions ( 5.1 )]. Viral hepatitis screening in accordance with clinical guidelines [see Warnings and Precautions ( 5.1 )]. A complete blood count: Avoid initiation of tofacitinib tablets treatment in patients with a lymphocyte count less than 500 cells/mm 3 , absolute neutrophil count less than 1,000 cells/mm 3 , or hemoglobin level less than 9 g/dL [see Warnings and Precautions ( 5.8 )]. Baseline hepatic function evaluation: tofacitinib tablets is not recommended for patients with severe hepatic impairment [see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )]. Update immunizations according to current immunization guidelines. The interval between live vaccinations and initiation of tofacitinib tablets should be in accordance with current vaccination guidelines regarding immunosuppressive agents [see Warnings and Precautions ( 5.9 )]. 2.2 Important Administration Instructions Tofacitinib extended-release tablets is not substitutable with tofacitinib tablets and tofacitinib oral solution. Switching between tofacitinib tablets and tofacitinib extended-release tablets should be made by the healthcare provider. Dose interruption is recommended for management of lymphopenia, neutropenia, and anemia [see Warnings and Precautions ( 5.8 ) and Adverse Reactions ( 6.1 )] . Interrupt use of tofac…

5 WARNINGS AND PRECAUTIONS Serious Infections : Avoid use of tofacitinib tablets during an active serious infection, including localized infections. ( 5.1 ) Gastrointestinal Perforations : Promptly evaluate patients at increased risk for gastrointestinal perforation who present with new onset abdominal symptoms. ( 5.6 ) Laboratory Monitoring : Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. ( 5.8 ) Vaccinations : Avoid use of live vaccines concurrently with tofacitinib tablets. ( 5.9 ) 5.1 Serious Infections Serious and sometimes fatal infections may occur with tofacitinib tablets. Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. The most common serious infections reported with tofacitinib included pneumonia, urinary tract infection, cellulitis, herpes zoster, bronchitis, septic shock, diverticulitis, gastroenteritis, appendicitis, and sepsis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multi−dermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with tofacitinib. Some patients have presented with disseminated rather than localized disease and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids. In the UC population, treatment with tofacitinib tablets 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily. Additionally, opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with tofacitinib tablets 10 mg twice daily. Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis). Avoid use of tofacitinib tablets in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating tofacitinib tablets in patients: with chronic or recurrent infection who have been exposed to tuberculosis with a history of a serious or an opportunistic infection who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or with underlying conditions that may predispose them to infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with tofacitinib tablets. Interrupt tofacitinib tablets if a patient develops a serious infection, an opportunistic infection, or sepsis. In patients who develop a new infection during treatment with tofacitinib tablets, promptly complete diagnostic testing appropriate for an immunocompromised patient; initiate appropriate antimicrobial therapy, and monitor the patients closely. 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 infections. 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. Discontinuation and monitoring criteria for lymphopenia are recommended [see Dosage and Administration ( 2.3 , 2.4 , 2.5 )]. Tuberculosis Evaluate and test patients for latent or active tuberculosis (TB) infection prior to and per applicable guidelines during administration of tofacitinib tablets. Consider anti-TB therapy prior to administration of tofacitinib tablets in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Consultation with a physician with expertise in the treatment of TB is recommended to …

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS Table 7 includes drugs with clinically significant drug interactions when concomitantly used with tofacitinib tablets and instructions for preventing or managing them. Table 7 Clinically Significant Interactions Affecting Tofacitinib Tablets When Concomitantly Used with Other Drugs Strong CYP3A4 Inhibitors (e.g., ketoconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage modification of tofacitinib tablets is recommended [see Dosage and Administration ( 2 ), Clinical Pharmacology, Figure 3 ( 12.3 )] Moderate CYP3A4 Inhibitors Concomitantly Used with Strong CYP2C19 Inhibitors (e.g., fluconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage modification of tofacitinib tablets is recommended [see Dosage and Administration ( 2 ), Clinical Pharmacology, Figure 3 ( 12.3 )] Strong CYP3A4 Inducers (e.g., rifampin) Clinical Impact Decreased exposure to tofacitinib and may result in loss of or reduced clinical response Intervention Concomitant use with tofacitinib tablets is not recommended [see Clinical Pharmacology, Figure 3 ( 12.3 )] Immunosuppressive Drugs (e.g., azathioprine, tacrolimus, cyclosporine) Clinical Impact Risk of added immunosuppression; concomitant use of tofacitinib tablets with biologic DMARDs or potent immunosuppressants has not been studied in patients with RA, PsA, AS, UC, or pcJIA. Intervention Concomitant use with tofacitinib tablets is not recommended [see Indications and Usage ( 1 ), Clinical Pharmacology, Figure 3 ( 12.3 )] See FPI for clinically significant drug interactions. ( 2 , 7 )

8.1 Pregnancy Risk Summary The available data with tofacitinib tablets from a pregnancy exposure registry that enrolled 11 exposed pregnant females, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with RA and UC in pregnancy (see Clinical Considerations) . In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively. Further, in a peri- and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dosage of 5 mg twice daily and approximately 36 times the maximum recommended dosage of 10 mg twice daily, respectively (see Data) . The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with RA or UC. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 grams) infants, and small for gestational age at birth. Data Animal Data: In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the recommended dose of 5 mg twice daily, and approximately 73 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the recommended dose of 5 mg twice daily, and approximately 29 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats). In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the recommended dose of 5 mg twice daily, and approximately 6.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the recommended dose of 5 mg twice daily, and approximately 1.5 times the maximum recommended dose of 10 mg twice daily (on an AU…

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections [see Warnings and Precautions ( 5.1 )] Increased Risk of Mortality [see Warnings and Precautions ( 5.2 )] Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions ( 5.3 )] Major Adverse Cardiovascular Events [see Warnings and Precautions ( 5.4 )] Thrombosis [see Warnings and Precautions ( 5.5 )] Gastrointestinal Perforations [see Warnings and Precautions ( 5.6 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] Laboratory Abnormalities [see Warnings and Precautions ( 5.8 )] 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. ( 6.1 ) PcJIA : Consistent with common adverse reactions reported in adult patients with RA. ( 6.1 ) UC : Reported in ≥ 5% of adult patients treated with either tofacitinib tablets and ≥ 1% greater than reported in patients treated with placebo: nasopharyngitis, elevated cholesterol levels, headache, URI, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 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 tofacitinib tablets (referred to as "tofacitinib" 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 [see Clinical Studies ( 14.6 )] . A dosage of tofacitinib 10 mg twice daily is not recommended for the treatment of RA because of increased risks [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5 )]. For the treatment of adults with moderately to severely active RA [see Indications and Usage ( 1.1 )] , the recommended dosage of tofacitinib is 5 mg twice 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 …