tofacitinib

RECENT MAJOR CHANGES Boxed Warning 10/2025 Indications and Usage, Psoriatic Arthritis ( 1.2 ) 10/2025 Dosage and Administration, Recommended Dosage in Pediatric Patients 2 Years of Age and Older with Psoriatic Arthritis or Polyarticular Course Juvenile Idiopathic Arthritis ( 2.4 ) 10/2025 Warnings and Precautions, Serious Infections ( 5.1 ) 03/2026 Warnings and Precautions, Hypoglycemia in Patients with Diabetes ( 5.8 ) 06/2026

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 50 and ≤80 mL/min) 5 mg twice daily Moderate RI (CLcr ≥30 and ≤50 mL/min) 5 mg once daily Severe RI (CLcr 80 mL/min (normal renal function); >50 and ≤80 mL/min (mild renal impairment); ≥30 and ≤50 mL/min (moderate renal impairment); 80 mL/min (normal renal function); CLcr >50 and ≤80 mL/min (mild renal impairment); ≥30 and ≤50 mL/min (moderate renal impairment); 50 and ≤80 mL/min) Same as patients with normal renal function. Moderate RI (CLcr ≥30 and ≤50 mL/min) Induction: 5 mg twice daily for at least 8 weeks [see Clinical Studies (14.5) ] ; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 5 mg twice daily for a maximum of 16 weeks. Discontinue 5 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. Maintenance: 5 mg once daily. For patients with loss of response during maintenance treatment, may consider a dosage of 5 mg twice daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dosage needed to maintain response . For patients undergoing hemodialysis, administer the dose after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended after dialysis. Severe RI (CLcr <30 mL/min) Recommended Dosage in Patients with Hepatic Impairment (HI) Mild HI (Child-Pugh A) Same as patients with normal hepatic function. Moderate HI (Child-Pugh B) Induction: 5 mg twice daily for at least 8 weeks [see Clinical Studies (14.5) ] ; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 5 mg twice daily for a maximum of 16 weeks. Discontinue 5 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. Maintenance: 5 mg once daily. For patients with loss of response during maintenance treatment, may consider a dosage of 5 mg twice daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dosage needed to maintain response . Severe HI (Child-Pugh C) Use of tofacitinib tablets are not recommended. Table 4: Dosage Modifications of Tofacitinib Tablets Due to Drug Interactions and for Lymphopenia, Neutropenia or Anemia in Adults with Ulcerative Colitis Adults Tofacitinib Tablets Dosage Modifications with Concomitant Use of CYP3A4 and/or CYP2C19 Inhibitor(s) Strong CYP2C19 inhibitor(s) No dosage modification is recommended. Moderate CYP2C19 inhibitor(s) Moderate CYP3A4 inhibitor(s) Moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) Induction: 5 mg twice daily for at least 8 weeks [see Clinical Studies (14.5) ] ; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 5 mg twice daily for a maximum of 16 weeks. Discontinue 5 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. Maintenance: 5 mg once daily. For patients with loss of response during maintenance treatment, may consider a dosage of 5 mg twice daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dosage needed to maintain response . Strong CYP3A4 inhibitor(s) Dosage Modifications for Lymphopenia, Neutropenia, or Anemia Lymphocyte count less than 500 cells/mm 3 , confirmed by repeat testing Discontinue dosing. ANC less than 500 cells/mm 3 Discontinue dosing. ANC 500 to 1000 cells/mm 3 If taking: 10 mg twice daily, reduce to 5 mg twice daily. Whe …

3 DOSAGE FORMS AND STRENGTHS Tofacitinib tablets, 5 mg (equivalent to 8.08 mg tofacitinib citrate) are white to off white colored, round, film-coated tablets, debossed with "1243" on one side and plain on the other side. Tofacitinib tablets, 10 mg (equivalent to 16.15 mg tofacitinib citrate) are light green to green colored, round shaped, film coated tablets debossed with "1589" on one side and plain on the other side. Tofacitinib tablets: 5 mg, 10 mg ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

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 tabletsmonotherapy 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 tofacitinib tabletsand ≥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 AvKARE at 1-855-361-3993 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 and/or XELJANZ oral solution. Adverse Reactions in Adults with Rheumatoid Arthritis In RA Safety Study 1, 1,455 adults were treated with tofacitinib tablets 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 tablets 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 tablets is 5 mg twice daily. The safety of tofacitinib tablets 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 tablets (monotherapy) 5 mg twice daily (292 patients) or 10 mg twice daily (306 patients), In combination with DMARDs (including methotrexate), tofacitinib tablets 5 mg twice daily (1044 patients) or 10 mg twice daily (1043 patients) and Placebo (809 patients). All seven trials included provisions for patients taking placebo to receive treatment with tofacitinib tablets 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 tablets in both the placebo and tofacitinib tablets group of a given interval. Comparisons between placebo and tofacitinib tablets groups were based on the first 3 months of exposure, and comparisons between tofacitinib tablets 5 mg twice daily and tofacitinib tablets 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 …

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 are 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 are 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 are 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 are not recommended [see Indications and Usage ( 1 ), Clinical Pharmacology, Figure 3 ( 12.3 )] See FPI for clinically significant drug interactions. ( 2 , 7 )

8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) 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 approxi …

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, 56, and 1,377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.

11 DESCRIPTION Tofacitinib tablets are formulated with the citrate salt of tofacitinib, a JAK inhibitor. Tofacitinib citrate is a white to off-white powder with the following chemical name: (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino)-ß-oxo-1-piperidinepropanenitrile, 2-hydroxy-1,2,3-propanetricarboxylate (1:1). Tofacitinib citrate is sparingly soluble in 20% aqueous acetic acid, slightly soluble in methanol, water and insoluble in dichloromethane. Tofacitinib citrate has a molecular weight of 504.5 Daltons (or 312.4 Daltons as the tofacitinib free base) and a molecular formula of C 16 H 20 N 6 O•C 6 H 8 O 7 . The chemical structure of tofacitinib citrate is: Tofacitinib tablets are supplied for oral administration as a: 5 mg white to off white colored, round shaped, biconvex, immediate-release film-coated tablet. Each tablet of tofacitinib contains 5 mg tofacitinib (equivalent to 8.08 mg tofacitinib citrate) and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose,hypromellose, titanium dioxide, polyethylene glycol and triacetin. 10 mg blue colored, round shaped, biconvex, immediate-release film-coated tablet. Each tablet of tofacitinib contains 10 mg tofacitinib (equivalent to 16.16 mg tofacitinib citrate) and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, hypromellose, titanium dioxide, polyethylene glycol, triacetin, FD&C Blue No.2 and FD&C Blue No.1. tafacitinib-structure

10 OVERDOSAGE There is no specific antidote for overdose with tofacitinib 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 tablets. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING Tofacitinib tablets, 5 mg (equivalent to 8.08 mg tofacitinib citrate) are white to off white colored, round, film-coated tablets, debossed with "1243" on one side and plain on the other side and supplied as follows: NDC 70710-1243-6 in bottle of 60 tablets with child-resistant closure. NDC 70710-1243-8 in bottle of 180 tablets with child-resistant closure. Tofacitinib tablets, 10 mg (equivalent to 16.15 mg tofacitinib citrate) are light green to green colored, round shaped, film coated tablets debossed with "1589" on one side and plain on the other side and supplied as follows: NDC 70710-1589-7 in bottle of 28 tablets with child-resistant closure. NDC 70710-1589-6 in bottle of 60 tablets with child-resistant closure. NDC 70710-1589-8 in bottle of 180 tablets with child-resistant closure. Store tofacitinib tablets at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (between 59°F and 86°F) [see USP Controlled Room Temperature]. Do not repackage.