Tofacitinib

1 INDICATIONS AND USAGE Tofacitinib extended-release tablets are Janus kinase (JAK) inhibitors. Tofacitinib extended-release 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. Limitations of Use: Use of tofacitinib extended-release tablets for RA, AS, or PsA, in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. ( 1.1 , 1.2 , 1.3 ) 1.1 Rheumatoid Arthritis Tofacitinib extended-release 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 extended-release 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 extended -release tablets are indicated for the treatment of adults with active PsA who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use: Use of tofacitinib extended-release tablets in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. 1.3 Ankylosing Spondylitis Tofacitinib extended-release 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 extended-release tablets in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

12.1 Mechanism of Action Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC 50 of 406 nM, 56 nM, and 1,377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.

2 DOSAGE AND ADMINISTRATION Recommended Evaluations and Immunization Prior to Treatment Initiation Prior to initiating tofacitinib extended-release tablets, consider performing an active and latent TB evaluation, viral hepatitis screening, a complete blood count, and updating immunizations. Avoid tofacitinib extended-release 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 are not substitutable with XELJANZ (tablets and 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 extended-release tablets 11 mg once daily. ( 2.3 ) Dosage in Patients with Renal Impairment or Hepatic Impairment Use of tofacitinib extended-release tablets in patients with severe HI is not recommended. ( 2.3 , 8.7 ) See full prescribing information (FPI) for recommended dosage in patients with moderate or severe RI or moderate HI. ( 2.3 , 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 , 7 ) 2.1 Recommended Evaluations and Immunization Prior to Treatment Initiation Prior to initiating tofacitinib extended-release tablets, consider performing the following: Active and latent tuberculosis (TB) infection evaluation: If the patient has latent TB, treat for TB prior to tofacitinib extended-release 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 extended-release 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 extended-release tablets are 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 extended-release tablets should be in accordance with current vaccination guidelines regarding immunosuppressive agents [see Warnings and Precautions ( 5.9 )]. 2.2 Important Administration Instruction Tofacitinib extended-release tablets is not substitutable with XELJANZ (tablets and oral solution). Switching between XELJANZ 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 tofacitinib extended-release tablets if a patient develops a serious infection until the infection is controlled [see Warnings and Precautions ( 5.1 )]. Take tofacitinib extended-release tablets with or without food [see Clinical Pharmacology ( 12.3 )]. Swallow tofacitinib extended-release tablets whole and intact. Do not crush, split, or chew the extended-release tablets [see Clinical Pharmacology ( 12.3 )]. 2.3 Recommended Dosage in Adults with Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis Table 1 displays the recommended dosage of tofacitinib extended-release tablets for adults with RA, PsA, and AS [see Indication and Usage ( 1.1 , 1.2 , 1.3 )] with and without renal impairment (including those who are undergoing hemodialysis) or hepatic impairment [see Use in Specific Populations ( 8.6 , 8.7 )] . The table also displays the recommended dosage modifications for p

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 ) 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 [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 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 [see Warnings and Precautions ( 5.1 )]. The proportion of pa

5 WARNINGS AND PRECAUTIONS Serious Infections: Avoid use of tofacitinib extended-release 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 extended-release tablets ( 5.9 ) 5.1 Serious Infections Serious and sometimes fatal infections may occur with tofacitinib extended-release 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, multidermatomal 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. Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis). Avoid use of tofacitinib extended-release tablets in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating tofacitinib extended-release 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 extended-release tablets. Interrupt tofacitinib extended-release tablets if a patient develops a serious infection, an opportunistic infection, or sepsis. In patients who develop a new infection during treatment with tofacitinib extended-release 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 )]. Tuberculosis Evaluate and test patients for latent or active tuberculosis (TB) infection prior to and per applicable guidelines during administration of tofacitinib extended-release tablets. Consider anti-TB therapy prior to administration of tofacitinib extended-release 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 aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient. Monitor patients closely for the development of signs and symptoms of TB, including patients who tested negative for

4 CONTRAINDICATIONS None. None ( 4 )

10 OVERDOSAGE There is no specific antidote for overdose with tofacitinib extended-release tablets. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. In a study in patients with end-stage renal disease (ESRD) undergoing hemodialysis, plasma tofacitinib concentrations declined more rapidly during the period of hemodialysis and dialyzer efficiency, calculated as dialyzer clearance/blood flow entering the dialyzer, was high [mean (SD) = 0.73 (0.15)]. However, due to the significant non-renal clearance of tofacitinib, the fraction of total elimination occurring by hemodialysis was small, and thus, limits the value of hemodialysis for treatment of overdose with tofacitinib. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.