TRIJAN

Tofacitinib extended-release tablets are formulated with the citrate salt of tofacitinib, a JAK inhibitor.

Tofacitinib citrate is a white to off-white powder and soluble in dimethylsulfoxide and insoluble in water 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: Each 11 mg and 22 mg film-coated extended-release tablet contains tofacitinib equivalent to 17.77 mg and 35.53 mg of tofacitinib citrate respectively for oral administration and contains following inactive ingredients: ethyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sodium lauryl sulfate and titanium dioxide.

Additionally each 11 mg tablet contains D&C red #27 Aluminum Lake, FD&C blue #2 Aluminum Lake, and iron oxide red.

The tablet is imprinted with black ink and contains following inactive ingredients: black iron oxide, propylene glycol and shellac.

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.

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.

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. 1.1 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.

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.

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.

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.

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.

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 of 406, 56, and 1377 nM, respectively.

However, the relevance of specific JAK combinations to therapeutic effectiveness is not known. 12.2 Pharmacodynamics Treatment with tofacitinib was associated with dose-dependent reductions of circulating CD16/56+ natural killer cells, with estimated maximum reductions occurring at approximately 8 weeks to 10 weeks after initiation of therapy.

These changes generally resolved within 2 weeks to 6 weeks after discontinuation of treatment.

Treatment with tofacitinib was associated with dose-dependent increases in B cell counts.

Changes in circulating T-lymphocyte counts and

T-lymphocyte subsets (CD3+, CD4+ and CD8+) were small and inconsistent.

The clinical significance of these changes is unknown.

Total serum

IgG, IgM, and IgA levels after 6-month dosing in patients with rheumatoid arthritis (RA) were lower than in patients who received placebo; however, changes were small and not dose-dependent.

After treatment with tofacitinib in patients with RA, rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout dosing.

Changes in

CRP observed with tofacitinib treatment do not reverse fully within 2 weeks after discontinuation, indicating a longer duration of pharmacodynamic activity compared to the pharmacokinetic half-life.

Similar changes in

T cells, B cells, and serum CRP have been observed in patients with active psoriatic arthritis (PsA) although reversibility was not assessed.

Total serum immunoglobulins were not assessed in patients with active PsA. 12.3 Pharmacokinetics Following oral administration of tofacitinib extended-release tablets, peak plasma concentrations were reached at 4 hours and half-life was about to 8 hours.

Steady state concentrations were achieved within 48 hours with negligible accumulation after once daily administration.

Table 8 describes the pharmacokinetic parameters of tofacitinib extended-release tablets.

Table 8 Pharmacokinetic Parameters of Tofacitinib extended-release tablets Following Multiple Oral Dosing Abbreviations: AUC 24 = area under the concentration time profile from time to 24 hours; C max = maximum plasma concentration; C min = minimum plasma concentration; T max = time to C max; CV = Coefficient of variation. a Values represent the geometric mean, except T max, for which is the median (range) is shown.

PK Parameters a (CV%) Tofacitinib extended-release tablets Dosing Regimen 11 mg Once Daily 22 mg Once Daily AUC 24 (ng.hr/mL) 269 596.6 C max (ng/mL) 38.2 83.8 C min (ng/mL) 1.07 3.11 T max (hours) 4 (3 to 4) 4 (2 to 4) Absorption Coadministration of tofacitinib extended-release tablets and 22 mg with a high-fat meal resulted in no changes in AUC while C max was increased by 27% and 19% respectively.

T max was extended by approximately 1 hour for both tofacitinib extended-release tablets and 22 mg. Distribution After intravenous administration, the volume of distribution was 87 L. The protein binding of tofacitinib is approximately 40%.

Tofacitinib binds predominantly to albumin and does not appear to bind to α1-acid glycoprotein.

Tofacitinib distributes equally between red blood cells and plasma.

Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug.

The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19.

In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity.

The pharmacologic activity of tofacitinib is attributed to the parent molecule.

Pharmacokinetics in Patients with

RA, PsA, AS, and UC Population pharmacokinetic (PK) analyses indicated that PK characteristics were similar between patients with RA, PsA, ankylosing spondylitis, and UC.

The coefficient of variation (%) in AUC of tofacitinib were generally similar across different disease patients, ranging from 22% to 34% (Table 9).

Table 9 Tofacitinib Exposure in Patients with RA, PsA, AS, and UC After Administration of Tofacitinib tablets 5 mg Twice Daily or 10 mg Twice Daily Abbreviations: AUC 0-24,ss = area under the plasma concentration-time curve over 24 hours at steady state; CV = coefficient of variation. a Pharmacokinetic parameters estimated based on population pharmacokinetic analysis.

Mean (CV%) Tofacitinib tablets 5 mg Twice Daily Tofacitinib tablets 10 mg Twice Daily Rheumatoid Arthritis Psoriatic Arthritis Ankylosing Spondylitis Ulcerative Colitis Ulcerative Colitis AUC 0-24,ss (ngꞏh/mL) 504 (22%) 419 (34.1%) 381 (25.4%) 423 (22.6%) 807 (24.6%) Specific Populations Covariate evaluation as part of population PK analyses in adult patient populations indicated no clinically relevant change in tofacitinib exposure, after accounting for differences in renal function (i.e., creatinine clearance) between patients, based on age, weight, biological sex and race (Figure 1).

An approximately linear relationship between body weight and volume of distribution was observed, resulting in higher peak (C max ) and lower trough (C min ) concentrations in lighter patients.

However, this difference is not considered to be clinically relevant.

The effect of renal and hepatic impairment and other intrinsic factors on the PK of tofacitinib is shown in Figure 1.

Figure 1: Impact of Intrinsic Factors on Tofacitinib Pharmacokinetics Note: Reference values for weight, age, biological sex, and race comparisons are 70 kg, 55 years, male, and white, respectively; reference groups for renal and hepatic impairment data are patients with normal renal and hepatic function.

Renal function was estimated using creatinine clearance by Cockcroft-Gault method and hepatic function was estimated using Child-Pugh scoring method.

In patients with end-stage renal disease maintained on hemodialysis, mean AUC was approximately 40% higher compared with historical healthy subject data, consistent with approximately 30% contribution of renal clearance to the total clearance of tofacitinib.

Drug Interaction Studies Potential for

Tofacitinib extended-release tablets to Influence the PK of Other Drugs In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the major human drug-metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations corresponding to the steady state C max of a 10 mg twice daily dose.

These in vitro results were confirmed by a human drug interaction study showing no changes in the pharmacokinetics of midazolam, a highly sensitive CYP3A4 substrate, when concomitantly administered with tofacitinib.

In vitro studies indicate that tofacitinib does not significantly inhibit the activity of the major human drug-metabolizing uridine 5'-diphospho-glucuronosyltransferases (UGTs) [UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7] at concentrations exceeding 250 times the steady state C max of a 10 mg twice daily dose.

In patients with

RA, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in patients with RA.

Therefore, concomitant use with tofacitinib extended-release tablets is not expected to result in clinically relevant increases in the metabolism of CYP substrates in patients with RA.

In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, organic anionic or cationic transporters at therapeutic concentrations is low.

The impact of tofacitinib on the

PK of other drugs for the concomitant drugs are shown in Figure 2.

Figure 2: Impact of Tofacitinib on the Pharmacokinetics of Other Drugs Note: Reference group is administration of concomitant medication alone; OCT = Organic Cationic Transporter; MATE = Multidrug and Toxic Compound Extrusion.

Potential for Other Drugs to Influence the Pharmacokinetics of Tofacitinib Since tofacitinib is metabolized by CYP3A4, interaction with drugs that inhibit or induce CYP3A4 is likely.

Inhibitors of

CYP2C19 alone or P-glycoprotein are unlikely to substantially alter the pharmacokinetics of tofacitinib.

Figure 3: Impact of Other Drugs on the Pharmacokinetics of Tofacitinib Note: Reference group is administration of tofacitinib alone.

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 extended-release tablets monotherapy or in combination with DMARDs: upper respiratory tract infection (URI), nasopharyngitis, diarrhea, and headache.

UC: Reported in ≥ 5% of adult patients treated with either tofacitinib extended-release 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.

To report SUSPECTED ADVERSE

REACTIONS, contact Zydus Pharmaceuticals (USA) Inc.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.

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 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.

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).

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 5 mg twice daily.

The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection.

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 tofacitinib exposure prior to diagnosis of TB was 10 months (range from 152 days to 960 days) .

Infections (excluding tuberculosis): In the seven placebo-controlled trials in patients with RA, during the 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.

• month to 12-month period in a patient treated with tofacitinib 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.

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 were associated with an increased incidence of treated and serious infections.

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.

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 dose, 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%, 1.3% and 1.2% of patients who received 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.

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.

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 or a medical toxicologist for additional overdose management recommendations.

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/mm3, an absolute neutrophil count (ANC) < 1,000 cells/mm3 or hemoglobin < 9 g/dL.

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.

Recommended Dosage Adult Patients with

RA, PsA or AS Tofacitinib extended-release tablets 11 mg ones daily.

Tofacitinib extended-release tablets 22 mg once daily for 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response.

If needed, continue tofacitinib extended-release tablets 22 mg once daily for a maximum of 16 weeks.

Discontinue tofacitinib extended-release tablets 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved.

Tofacitinib extended-release tablets 11 mg once daily.

For patients with loss of response during maintenance treatment, tofacitinib extended-release tablets 22 mg once 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.

Dosage in Patients with Renal Impairment or Hepatic Impairment Use of tofacitinib extended-release tablets in patients with severe HI is not recommended.

See full prescribing information (FPI) for recommended dosage in patients with moderate or severe RI or moderate HI.

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. 2.1 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.

Viral hepatitis screening in accordance with clinical guidelines.

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.

Baseline hepatic function evaluation: tofacitinib extended-release tablets is not recommended for patients with severe hepatic impairment.

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. 2.2 Important Administration Instructions Tofacitinib extended-release tablets is not substitutable with tofacitinib tablets and tofacitinib oral solution.

Dose interruption is recommended for management of lymphopenia, neutropenia, and anemia.

Interrupt use of tofacitinib extended-release tablets if a patient develops a serious infection until the infection is controlled.

Take tofacitinib extended-release tablets with or without food.

Swallow tofacitinib extended-release tablets whole and intact.

Do not crush, split, or chew the extended-release tablets. 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 with and without renal impairment (including those who are undergoing hemodialysis) or hepatic impairment.

The table also displays the recommended dosage modifications for patients concomitantly using CYP2C19 and/or CYP3A4 inhibitors, and patients with lymphopenia, neutropenia, or anemia.

Table 1 Recommended Dosage of Tofacitinib extended-release tablets in Adults with Rheumatoid Arthritis, Psoriatic Arthritis, or Ankylosing Spondylitis a Excludes patients who concomitantly use tofacitinib extended-release tablets with strong CYP3A4 inhibitor(s) or moderate CYP3A4 inhibitor(s) and strong CYP2C19 inhibitor(s), as well as patients with lymphocyte count less than 500 cells/mm 3, ANC < 1,000 cells/mm 3, or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL. b Tofacitinib PK was evaluated in subjects with varying degrees of renal impairment, where the severity of renal impairment was defined based on creatinine clearance (CLcr) estimated using the Cockcroft-Gault equation: CLcr > 80 mL/min (normal renal function); > 50 and ≤ 80 mL/min (mild renal impairment); ≥ 30 and ≤ 50 mL/min (moderate renal impairment); < 30 mL/min (severe renal impairment).

Adults Tofacitinib extended-release tablets Patients with Normal Renal and Hepatic Function a 11 mg once daily Recommended Dosage in Patients with Renal Impairment (RI) b Mild RI (CLcr > 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 < 30 mL/min) Tofacitinib tablets 5 mg once daily 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.

Impairment (HI) Mild HI (Child-Pugh A) 11 mg once daily Moderate HI (Child-Pugh B) Tofacitinib tablets 5 mg once daily Severe HI (Child-Pugh C) Use of tofacitinib extended-release tablets is not recommended.

Dosage Modifications with Concomitant Use of

CYP3A4 and/or CYP2C19 Inhibitor(s) Strong CYP2C19 inhibitor(s) 11 mg once daily Moderate CYP2C19 inhibitor(s) Moderate CYP3A4 inhibitor(s) Moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) Tofacitinib tablets 5 mg once daily Strong CYP3A4 inhibitor(s) Dosage Modifications for Lymphopenia, Neutropenia, or Anemia Patients with lymphocyte count less than 500 cells/mm 3, confirmed by repeat testing Discontinue dosing.

Patients with

ANC less than 500 cells/mm 3 Discontinue dosing.

ANC 500 cells/mm to 1,000 cells/mm 3 Interrupt dosing.

ANC is greater than 1000, resume 11 mg once daily.

Patients with 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. 2.5 Recommended Dosage in Adults with Ulcerative Colitis Table 3 displays the recommended dosage of tofacitinib extended-release tablets in adult patients with ulcerative colitis (UC) with and without renal impairment (including those who are undergoing hemodialysis) or hepatic impairment.

Table 4 displays the recommended dosage modification for patients concomitantly using CYP2C19 and/or CYP3A4 inhibitors, and patients with lymphopenia, neutropenia, or anemia.

Table 3 Recommended Dosage of tofacitinib extended-release tablets in Adults with Ulcerative Colitis With and Without Renal Impairment or Hepatic Impairment a Excludes patients who concomitantly use tofacitinib extended-release tablets with strong CYP3A4 inhibitor(s) or moderate CYP3A4 inhibitor(s) and strong CYP2C19 inhibitor(s), as well as patients with lymphocyte count less than 500 cells/mm 3, ANC < 1,000 cells/mm 3, or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL. b Tofacitinib PK was evaluated in subjects with varying degrees of renal impairment, where the severity of renal impairment was defined based on creatinine clearance (CLcr) estimated using the Cockcroft-Gault equation: CLcr > 80 mL/min (normal renal function); CLcr > 50 and ≤ 80 mL/min (mild renal impairment); ≥ 30 and ≤ 50 mL/min (moderate renal impairment); < 30 mL/min (severe renal impairment).

Adults Tofacitinib extended-release tablets Patients with Normal Renal and Hepatic Function a Induction: 22 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response.

If needed continue 22 mg once daily for a maximum of 16 weeks.

Discontinue 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved.

Maintenance: 11 mg once daily.

For patients with loss of response during maintenance treatment, may consider a dosage of 22 mg once daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient.

Impairment (RI) b Mild RI (CLcr > 50 and ≤ 80 mL/min) Same as patients with normal renal function.

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.

Tofacitinib extended-release tablets are not recommended.

For patients undergoing hemodialysis, administer the dose after the dialysis session on dialysis days.

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.

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.

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.

CYP2C19 inhibitor(s) Moderate CYP3A4 inhibitor(s) Moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) Induction: 1.

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.

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) .

Tofacitinib extended-release tablets

Do not repackage.

The available data with tofacitinib extended-release tablet 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.

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.

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.

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 2,500 grams) infants, and small for gestational age at birth.

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 AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits).

In a peri.

• and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the recommended dose of 5 mg twice daily, and approximately 36 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats).

There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the recommended dose of 5 mg twice daily, and approximately 8.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats).

The safety and effectiveness of tofacitinib extended-release tablets in pediatric patients for indications, other than in patients with PsA, have not been established.

The safety and effectiveness of tofacitinib extended-release tablets in pediatric patients have not been established.

Of the 3,315 adults who were enrolled in clinical trials with RA (Studies RA-I to V), a total of 505 patients were 65 years of age and older, including 71 patients 75 years and older.

The frequency of serious infection among tofacitinib tablets -treated patients 65 years of age and older was higher than among those adults under the age of 65.

Of the 1,156 tofacitinib tablet-treated patients in clinical trials of patients with UC, a total of 77 patients (7%) were 65 years of age or older.

Clinical studies of tofacitinib in patients with UC did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger adult patients.

Of the 783 tofacitinib tablet-treated patients in clinical trials of patients with PsA, a total of 72 (9.2%) patients were 65 years of age and older, including 2 (0.3%) patients 75 years and older.

These clinical studies did not include sufficient numbers of patients aged 65 years and older with PsA to determine if they respond differently from younger adult patients.

Of the 420 tofacitinib tablet-treated patients in clinical trials of patients with AS, a total of 12 (2.9%) patients were 65 years of age and older, including 1 (0.2%) patient 75 years and older.

These clinical studies did not include sufficient numbers of patients aged 65 years and older with AS to determine if they respond differently from younger adult patients.