tofacitinib

RECENT MAJOR CHANGES Summary of Heart Protection Study Results Boxed Warning 10/2025 Indications and Usage, Psoriatic Arthritis ( 1.2 ) 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 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. Moderately to severely active ulcerative colitis (UC), 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 ) Use of tofacitinib extended-release 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 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 adult 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 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. 1.5 Ulcerative Colitis Tofacitinib extended-release 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 extended-release 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 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 80 mL/min (normal renal function); > 50 and ≤ 80 mL/min (mild renal impairment); ≥ 30 and ≤ 50 mL/min (moderate renal impairment); 50 and ≤ 80 mL/min) 11 mg once daily Moderate RI (CLcr ≥ 30 and ≤ 50 mL/min) Tofacitinib tablets 5 mg once daily Severe RI (CLcr 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: 11 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 11 mg once daily for a maximum of 16 weeks. Discontinue 11 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Maintenance: Tofacitinib extended-release tablets are not recommended. 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: 11 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 11 mg once daily for a maximum of 16 weeks. Discontinue 11 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Maintenance: Tofacitinib extended-release tablets are not recommended. Severe HI (Child-Pugh C) Use of tofacitinib extended-release tablets is not recommended. Table 4 Dosage Modifications of Tofacitinib extended-release tablets Due to Drug Interactions and for Lymphopenia, Neutropenia or Anemia in Adults with Ulcerative Colitis Adults Tofacitinib extended-release 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: 11 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 11 mg once daily for a maximum of 16 weeks. Discontinue 11 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Strong CYP3A4 inhibitor(s) Maintenance: Tofacitinib extended-release tablets are not recommended. 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 1,000 cells/mm 3 If taking: ●22 mg once daily, reduce to 11 mg once daily. When ANC is greater than 1,000, increase to 22 mg once daily based on clinical response. ●11 mg once daily, interrupt dosing. When ANC is greater than 1000, resume 11 mg once daily. Hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL Interrupt dosing until hemoglobin values have normalized. Switching from Tofacitinib tablets to Tofacitinib Extended-Release Tablets Patients treated with tofacitinib tablets : 5 mg twice daily may be switched to tofacitinib extended-release tablets 11 mg once daily the day following the last dose of tofacitinib tablets 5 mg. 10 mg twice daily may be switched to tofacitinib extended-release tablets 22 mg once daily the day following the last dose of tofacitinib exte …

3 DOSAGE FORMS AND STRENGTHS Tofacitinib extended-release tablets, 11 mg (equivalent to 17.77 mg tofacitinib citrate) are light pink to pink, oval shaped, film-coated tablets, imprinted with '1353' in black ink on one side and plain on other side. Tofacitinib extended-release tablets, 22 mg (equivalent to 35.53 mg tofacitinib citrate) are white to off-white, oval shaped, film-coated tablets imprinted with "1727" in black ink on one side and plain on other side. Tofacitinib Extended-Release Tablets: 11 mg, 22 mg tofacitinib ( 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 XELJANZ tablets monotherapy or in combination with DMARDs: upper respiratory tract infection (URI), nasopharyngitis, diarrhea, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or drugsafety@avkare.com 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 XELJANZ 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 XELJANZ 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 XELJANZ is 5 mg twice daily and the recommended dosage for tofacitinib extended-release tablets are 11 mg once daily. The safety of XELJANZ 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: XELJANZ (monotherapy) 5 mg twice daily (292 patients) or 10 mg twice daily (306 patients), In combination with DMARDs (including methotrexate), XELJANZ 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 XELJANZ 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 XELJANZ in both the placebo and XELJANZ group of a given interval. Comparisons between placebo and XELJANZ groups were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 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 XELJANZ 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 patients who discontinued treatment due to any adverse rea …

7 DRUG INTERACTIONS Table 7 includes drugs with clinically significant drug interactions when concomitantly used with tofacitinib extended-release tablets and instructions for preventing or managing them. Table 7: Clinically Significant Interactions Affecting Tofacitinib Extended-Release Tablets When Concomitantly Used with Other Drugs Strong CYP3A4 Inhibitors (e.g., ketoconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage modification of tofacitinib extended-release 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 extended-release 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 extended-release 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 extended-release tablets with biologic DMARDs or potent immunosuppressants has not been studied in patients with RA, PsA or AS. Intervention Concomitant use with tofacitinib extended-release 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 extended-release tablets from a pregnancy exposure registry that enrolled 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 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. 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 approxim …

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 extended-release 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). The solubility of tofacitinib citrate in water is 2.9 mg/mL. 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 extended-release tablets are supplied for oral administration as a: 11 mg yellow, cylindrical, extended-release film-coated tablets imprinted with “OPT1” in black color. Each 11 mg tablet contains 11 mg tofacitinib (equivalent to 17.77 mg tofacitinib citrate) and the following inactive ingredients: fructose, corn starch, cellulose acetate, hydroxyethylcellulose, magnesium stearate, hydroxypropyl cellulose, hypromellose 2910/5, ferric oxide, polyvinyl alcohol, talc, titanium dioxide, glyceryl mono and dicaprylocaprate, sodium lauryl sulfate, yellow iron oxide and red iron oxide. Printing ink contains black iron oxide, propylene glycol, and shellac glaze. Structure.

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 extended-release 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 extended-release tablets, 11 mg (equivalent to 17.77 mg tofacitinib citrate) are light pink to pink, oval shaped, film-coated tablets, imprinted with '1353' in black ink on one side and plain on other side and are supplied as follows: NDC 70710-1353-3 in bottle of 30 tablets with child-resistant closure. NDC 70710-1353-9 in bottle of 90 tablets with child-resistant closure. Tofacitinib extended-release tablets, 22 mg (equivalent to 35.53 mg tofacitinib citrate) are white to off-white, oval shaped, film-coated tablets imprinted with "1727" in black ink on one side and plain on other side and are supplied as follows: NDC 70710-1727-3 in bottle of 30 tablets with child-resistant closure. NDC 70710-1727-9 in bottle of 90 tablets with child-resistant closure. Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Tofacitinib extended-release tablets Do not repackage.