The safety and effectiveness of XELJANZ (tablets and oral solution) in pediatric patients for indications, other than in patients with active pcJIA and PsA, have not been established.

The safety and effectiveness of XELJANZ have not been established in pediatric patients less than 2 years of age.

The safety and effectiveness of XELJANZ XR (extended-release tablets) in pediatric patients have not been established.

Polyarticular Course Juvenile Idiopathic Arthritis (pcJIA)

The safety and effectiveness of XELJANZ (tablets and oral solution) for the treatment of active pcJIA have been established in pediatric patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers.

Use of XELJANZ for this indication is supported by evidence from adequate and well-controlled studies of XELJANZ tablets in adults with RA, pharmacokinetic (PK) data from adult patients with RA, and with additional safety, efficacy, and PK data from a clinical trial of XELJANZ in pediatric patients 2 years and older with active pcJIA (Study pcJIA-I)

[see

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) and/or XELJANZ oral solution.

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

[seeClinical Studies (14.6)]

. A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of RA because of increased risks

[seeDosage and Administration (2.3)andWarnings and Precautions (5)]

. For the treatment of adults with moderately to severely active RA

[seeIndications and Usage (1.1)]

, the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 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 (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 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

[seeWarnings and Precautions (5.1)]

The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for XELJANZ-treated patients and 3% for placebo-treated patients.

Overall Infections

In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily groups, respectively, and 18% in the placebo group.

The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).

Serious Infections:

In the seven placebo-controlled trials in patients with RA, during the 0 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 XELJANZ 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 XELJANZ 5 mg twice daily and 10 mg twice daily group minus placebo.

In the seven placebo-controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received XELJANZ 5 mg twice daily and 33 patients (2.7 events per 100 patient-years) who received XELJANZ 10 mg twice daily. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for XELJANZ 10 mg twice daily minus XELJANZ 5 mg twice daily.

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

[seeWarnings and Precautions (5.1)]

Tuberculosis:

In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, tuberculosis (TB) was not reported in patients who received placebo, XELJANZ 5 mg twice daily, or XELJANZ 10 mg twice daily.

In the seven placebo-controlled trials, during the 0 to 12 months exposure, TB was reported in 0 patients who received XELJANZ 5 mg twice daily and 6 patients (0.5 events per 100 patient-years) who received XELJANZ 10 mg twice daily. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for XELJANZ 10 mg twice daily minus XELJANZ 5 mg twice daily.

Cases of disseminated TB were also reported. The median XELJANZ exposure prior to diagnosis of TB was 10 months (range from 152 to 960 days)

[seeWarnings and Precautions (5.1)].

Opportunistic Infections (excluding tuberculosis):

In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, XELJANZ 5 mg twice daily, or XELJANZ 10 mg twice daily.

In the seven placebo-controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received XELJANZ 5 mg twice daily and 4 patients (0.3 events per 100 patient-years) who received XELJANZ 10 mg twice daily. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for XELJANZ 10 mg twice daily minus XELJANZ 5 mg twice daily.

The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days)

[seeWarnings and Precautions (5.1)].

Malignancies

In the seven placebo-controlled trials in patients with RA, during the 0 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 XELJANZ 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 XELJANZ 5 mg and 10 mg twice daily group minus placebo.

In the seven placebo-controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received XELJANZ 5 mg twice daily and 7 patients (0.6 events per 100 patient-years) who received XELJANZ 10 mg twice daily. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for XELJANZ 10 mg twice daily minus XELJANZ 5 mg twice daily. One of these malignancies was a case of lymphoma that occurred during the 0-to-12-month period in a patient treated with XELJANZ 10 mg twice daily.

The most common types of malignancy, including malignancies observed during the long-term extension in XELJANZ-treated patients, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma

[seeWarnings and Precautions (5.3)].

Laboratory Abnormalities

Lymphopenia:

In the placebo-controlled clinical trials in patients with RA, confirmed decreases in absolute lymphocyte counts below 500 cells/mm³occurred in 0.04% of patients for the XELJANZ 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/mm³were associated with an increased incidence of treated and serious infections

[seeWarnings and Precautions (5.8)].

Neutropenia:

In the placebo-controlled clinical trials in patients with RA, confirmed decreases in ANC below 1,000 cells/mm³occurred in 0.07% of patients for the XELJANZ 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/mm³observed 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

[seeWarnings and Precautions (5.8)].

Liver Enzyme Elevations:

Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3× ULN) were observed in patients with RA treated with XELJANZ. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dosage, resulted in decrease or normalization of liver enzymes.

In the placebo-controlled monotherapy trials (0–3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg twice daily groups.

In the placebo-controlled background DMARD trials (0–3 months), ALT elevations greater than 3× ULN were observed in 1.0%, 1.3% and 1.2% of patients who received placebo, XELJANZ 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3× ULN were observed in 0.6%, 0.5% and 0.4% of patients who received placebo, XELJANZ 5 mg, and 10 mg twice daily, respectively.

One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3× ULN and bilirubin elevations greater than 2× ULN, which required hospitalizations and a liver biopsy.

Lipid Elevations:

In the placebo-controlled clinical trials in patients with RA, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the placebo-controlled clinical trials are summarized below:

•Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.
•Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.
•Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.

In a placebo-controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.

In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the placebo-controlled clinical trials.

Serum Creatinine Elevations:

In the placebo-controlled clinical trials in patients with RA, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however, with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.

Common Adverse Reactions

Table 5 displays adverse reactions that occurred in 2% or more of patients on XELJANZ 5 mg or 10 mg twice daily and at least 1% greater than in XELJANZ-treated patients that observed in placebo-treated patients with or without DMARD in the RA trials.

Table 5: Common Adverse Reactionsreported in ≥2% of patients treated with either dose of XELJANZ and ≥1% greater than that reported for placebo.in Clinical Trials of XELJANZ for the Treatment of Rheumatoid Arthritis in Adults With or Without Concomitant DMARDs (0–3 Months)
Preferred Term	Placebo	XELJANZ 5 mg Twice Daily	XELJANZ 10 mg Twice Daily The recommended dose of XELJANZ for the treatment of RA is 5 mg twice daily [seeDosage and Administration (2)] .
Preferred Term	N = 809 (%)	N = 1336 (%)	N = 1349 (%)
N reflects randomized and treated patients from the seven placebo-controlled clinical trials.
Upper respiratory tract infection	3	4	4
Nasopharyngitis	3	4	3
Diarrhea	2	4	3
Headache	2	4	3
Hypertension	1	2	2

Other adverse reactions that occurred in placebo-controlled and open-label extension studies in patients with RA included:

Blood and lymphatic system disorders:

Anemia

Infections and infestations:

Diverticulitis

Metabolism and nutrition disorders:

Dehydration

Psychiatric disorders:

Insomnia

Nervous system disorders:

Paresthesia

Respiratory, thoracic and mediastinal disorders:

Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with RA and some were fatal)

Gastrointestinal disorders:

Abdominal pain, dyspepsia, vomiting, gastritis, nausea

Hepatobiliary disorders:

Hepatic steatosis

Skin and subcutaneous tissue disorders:

Rash, erythema, pruritus

Musculoskeletal, connective tissue and bone disorders:

Musculoskeletal pain, arthralgia, tendonitis, joint swelling

Neoplasms benign, malignant and unspecified (including cysts and polyps):

Non-melanoma skin cancers

General disorders and administration site conditions:

Pyrexia, fatigue, peripheral edema

Clinical Experience in Methotrexate-Naïve Patients

Study RA-VI was an active-controlled clinical trial in methotrexate-naïve patients

[seeClinical Studies (14)]

. The safety experience in these patients was consistent with Studies RA-I through V.

Adverse Reactions in Adults with Psoriatic Arthritis

The safety of XELJANZ was evaluated in 2 double-blind Phase 3 clinical trials in adults with active psoriatic arthritis (PsA):

•Study PsA-I (NCT01877668) had a duration of 12 months and enrolled adults who had an inadequate response to a nonbiologic DMARD and who were naïve to treatment with a TNF blocker. Study PsA-I included a 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months.
•Study PsA-II (NCT01882439) had a duration of 6 months and enrolled adults who had an inadequate response to at least one approved TNF blocker. This clinical trial included a 3-month placebo-controlled period.

In these combined Phase 3 clinical trials, 238 patients were randomized and treated with XELJANZ 5 mg twice daily and 236 patients were randomized and treated with XELJANZ 10 mg twice daily. A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of PsA. For the treatment of adults with active PsA

[seeIndications and Usage (1.2)]

, the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily

[seeDosage and Administration (2.3)].

All patients in the clinical trials in patients with PsA were required to receive treatment with a stable dose of a nonbiologic DMARD [the majority (79%) received methotrexate]. The study population randomized and treated with XELJANZ (474 patients) included 45 (10%) patients aged 65 years or older and 66 (14%) patients with diabetes at baseline.

During the 2 PsA controlled clinical trials, there were:

•3 malignancies (excluding NMSC) in 474 patients who received XELJANZ plus non-biologic DMARD (6 to 12 months exposure)
•0 malignancies in 236 patients who received placebo plus non-biologic DMARD group (3 months exposure) and
•0 malignancies in 106 patients in patients who received adalimumab plus non-biologic DMARD group (12 months exposure).

No lymphomas were reported. Malignancies have also been observed in the long-term extension study in patients with PsA treated with XELJANZ.

The safety profile observed in adults with active PsA treated with XELJANZ was consistent with the safety profile observed in adults with RA.

Adverse Reactions in Adults with Ankylosing Spondylitis

The safety of XELJANZ was evaluated in adults with active ankylosing spondylitis (AS) in a double-blind placebo-controlled Phase 3 clinical trial (Study AS-I) and in a dose-ranging Phase 2 clinical trial (Study AS-II).

•Study AS-I (NCT03502616) had a duration of 48 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. Study AS-I included a 16-week double-blind period in which patients received XELJANZ 5 mg or placebo twice daily and a 32-week open-label treatment period in which all patients received XELJANZ 5 mg twice daily.
•Study AS-II (NCT01786668) had a duration of 16 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. This clinical trial included a 12-week treatment period in which patients received either XELJANZ 2 mg (40% of the recommended dose), 5 mg, 10 mg, or placebo twice daily. A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of AS. For the treatment of adults with active AS
[seeIndications and Usage (1.3)]
, the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily
[seeDosage and Administration (2.3)]
.

In the combined Phase 2 and Phase 3 clinical trials, a total of 420 patients were treated with either XELJANZ 2 mg, 5 mg, or 10 mg twice daily. Of these, 316 patients were treated with XELJANZ 5 mg twice daily for up to 48 weeks. In the combined double-blind period, 185 patients were randomized to and treated with XELJANZ 5 mg twice daily and 187 to placebo for up to 16 weeks. Concomitant treatment with stable doses of nonbiologic DMARDs, NSAIDs, or corticosteroids (≤10 mg/day) was permitted. The study population randomized and treated with XELJANZ included 13 (3%) patients aged 65 years or older and 18 (4%) patients with diabetes at baseline.

The safety profile observed in adults with AS treated with XELJANZ was consistent with the safety profile observed in adults with RA and PsA.

Adverse Reactions in Pediatric Patients 2 Years of Age and Older with Polyarticular Course Juvenile Idiopathic Arthritis

XELJANZ tablets and XELJANZ oral solution 5 mg twice daily or weight-based equivalent twice daily was studied in 225 pediatric patients from 2 years to 17 years of age in Study pcJIA-I

[seeClinical Studies (14.4)]

and one open-label extension study (Study A3921145). The total patient exposure (defined as patients who received at least one dose of XELJANZ tablets or XELJANZ oral solution) was 105.6 patient-years in Study pcJIA-I and 777.5 patient-years in Study A3921145.

In general, the types of adverse reactions in pediatric patients 2 years of age and older with pcJIA, were consistent with those seen in adults with RA and PsA

(seeAdverse Reactions in Adults with Rheumatoid ArthritisandAdverse Reactions in Adults with Psoriatic Arthritis)

Adverse Reactions in Adults with Ulcerative Colitis

The safety of XELJANZ has been evaluated in adults with moderately to severely active UC in 4 randomized, double-blind, placebo-controlled trials (UC-I, UC-II, UC-III, and dose-ranging UC-V) and an open-label long-term extension study (UC-IV)

[seeClinical Studies (14.5)]

Adverse reactions reported in ≥5% of patients treated with either XELJANZ 5 mg or 10 mg twice daily and ≥1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials of patients with UC were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.

Induction Trials in Adults with UC

Common adverse reactions reported in ≥2% of patients treated with XELJANZ 10 mg twice daily and ≥1% greater in XELJANZ-treated patients than placebo-treated patients in the 3 induction trials of patients with UC (Studies UC-I, UC-II, and UC-V) were: headache, nasopharyngitis, elevated cholesterol levels, acne, increased blood creatine phosphokinase, and pyrexia.

Maintenance Trial in Adults with UC

Common adverse reactions reported in ≥4% of patients treated with either dosage of XELJANZ and ≥1% greater than reported in patients treated with placebo in the maintenance trial of patients with UC (Study UC-III) are shown in Table 6.

Table 6: Common Adverse ReactionsReported in ≥4% of patients treated with either XELJANZ dosage and ≥1% greater in XELJANZ-treated patients than placebo-treated patients.in Adults with UC During the 52-Week Maintenance Trial (Study UC-III)
Preferred Term	Placebo	XELJANZ 5 mg Twice Daily	XELJANZ 10 mg Twice Daily
Preferred Term	N = 198 (%)	N = 198 (%)	N = 196 (%)
Nasopharyngitis	6	10	14
Elevated cholesterol levelsIncludes hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low-density lipoprotein increased, low-density lipoprotein abnormal, or lipids increased.	1	5	9
Headache	6	9	3
Upper respiratory tract infection	4	7	6
Increased blood creatine phosphokinase	2	3	7
Rash	4	3	6
Diarrhea	3	2	5
Herpes zoster	1	1	5
Gastroenteritis	3	3	4
Anemia	2	4	2
Nausea	3	1	4

Dose-dependent adverse reactions seen in patients treated with XELJANZ 10 mg twice daily, in comparison to 5 mg twice daily, include the following: herpes zoster infections, serious infections, and NMSC

[seeWarnings and Precautions (5.1,5.3)]

During the UC controlled clinical studies (8-week induction and 52-week maintenance studies), which included 1,220 patients, 0 cases of solid cancer or lymphoma were observed in XELJANZ-treated patients.

In the long-term extension study, malignancies (including solid cancers, lymphomas and NMSC) were observed in patients treated with XELJANZ 5 mg and 10 mg twice daily

[seeWarnings and Precautions (5.3)]

. Five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one fatality in a patient with advanced cancer

[seeWarnings and Precautions (5.5)]

12.3 Pharmacokinetics

Following oral administration of XELJANZ (tablets and oral solution), peak plasma concentrations were reached within 0.5 hour - 1 hour, elimination half-life was about 3 hours and a dose-proportional increase in systemic exposure was observed in the therapeutic dosage range. Steady state concentrations were achieved in 24-48 hours with negligible accumulation after twice daily administration.

Following oral administration of XELJANZ XR (extended-release tablets), peak plasma concentrations were reached at 4 hours and half-life was about 6 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 XELJANZ and XELJANZ XR.

Table 8: Pharmacokinetic Parameters of XELJANZ/XELJANZ XR Following Multiple Oral Dosing
PK Parameters Values represent the geometric mean, except T_max, for which is the median (range) is shown. (CV%)	XELJANZ		XELJANZ XR
Dosing Regimen	5 mg Twice Daily	10 mg Twice Daily	11 mg Once Daily	22 mg Once Daily
Abbreviations: AUC₂₄= area under the concentration time profile from time 0 to 24 hours; C_max= maximum plasma concentration; C_min= minimum plasma concentration; T_max= time to C_max; CV = Coefficient of variation.
AUC₂₄(ng.hr/mL)	263.4 (15)	539.6 (22)	269.0 (18)	596.6 (19)
C_max(ng/mL)	42.7 (26)	84.7 (18)	38.2 (15)	83.8 (25)
C_min(ng/mL)	1.41 (40)	3.10 (54)	1.07 (69)	3.11 (43)
T_max(hours)	1.0 (0.5 to14.0Values beyond 12 hours were after the evening dose which was administered 12 hours after the morning dose of twice-daily XELJANZ.)	0.8 (0.5 to 14.0 )	4.0 (3.0 to 4.0)	4.0 (2.0 to 4.0)

Absorption

XELJANZ

The absolute oral bioavailability of XELJANZ is 74%. Coadministration of XELJANZ with a high-fat meal resulted in no changes in AUC while C_maxwas reduced by 32%. In clinical trials, XELJANZ was administered without regard to meals

[see

Dosage and Administration (2.2)

]

XELJANZ XR

Coadministration of XELJANZ XR 11 and 22 mg with a high-fat meal resulted in no changes in AUC while C_maxwas increased by 27% and 19% respectively. T_maxwas extended by approximately 1 hour for both XELJANZ XR 11 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.

Metabolism and Excretion

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 XELJANZ 5 mg Twice Daily or 10 mg Twice Daily
Pharmacokinetic Parameters Pharmacokinetic parameters estimated based on population pharmacokinetic analysis. Geometric Mean (CV%)	XELJANZ 5 mg Twice Daily				XELJANZ 10 mg Twice Daily
	Rheumatoid Arthritis	Psoriatic Arthritis	Ankylosing Spondylitis	Ulcerative Colitis	Ulcerative Colitis
Abbreviations: AUC_0–24,ss= area under the plasma concentration-time curve over 24 hours at steady state; CV = coefficient of variation.
AUC_0–24,_ss (ng∙h/mL)	504 (22.0%)	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.

Covariate evaluation as part of population PK analyses in pediatric patients with pcJIA, including PsA, identified body weight significantly impacting tofacitinib exposure, which supports weight-based dosing in this population. There were no identified clinically significant differences in tofacitinib exposure with different age, biological sex, racial, or pcJIA or PsA disease severity groups.

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

[seeDosage and Administration (2.3,2.4,

2.5)

andUse in Specific Populations (8.6)]

Figure 1

Drug Interaction Studies

Potential for XELJANZ/XELJANZ XR 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_maxof 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 XELJANZ.

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_maxof 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 XELJANZ/XELJANZ XR 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.

Figure 2

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 (seeFigure 3).

Figure 3: Impact of Other Drugs on the Pharmacokinetics of Tofacitinib

Note: Reference group is administration of XELJANZ alone.

Figure 3

, and

14.1 Clinical Studies in Rheumatoid Arthritis

The rheumatoid arthritis (RA) clinical development program with XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling) included six randomized controlled trials in adults with moderate to severe active RA.

Trial Design

•Study RA-I (NCT00814307) was a 6-month monotherapy trial in which 610 patients with moderate to severe active RA who had an inadequate response to a DMARD (nonbiologic or biologic) received XELJANZ 5 mg or 10 mg twice daily or placebo added to their background DMARD. At the Month 3 visit, all patients randomized to placebo treatment were switched in a blinded fashion to a second predetermined treatment of XELJANZ 5 mg or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, changes in Health Assessment Questionnaire – Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) less than 2.6.
•Study RA-II (NCT00856544) was a 12-month trial in which 792 patients with moderate to severe active RA who had an inadequate response to a nonbiologic DMARD received XELJANZ 5 mg or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppressive treatments such as azathioprine or cyclosporine). At the Month 3 visit, nonresponding patients were switched in a blinded fashion to a second predetermined treatment of XELJANZ 5 mg or 10 mg twice daily. At the end of Month 6, all patients treated with placebo were switched to their second predetermined XELJANZ treatment in a blinded fashion. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, changes in HAQ-DI at Month 3, and rates of DAS28-4(ESR) less than 2.6 at Month 6.
•Study RA-III (NCT00853385) was a 12-month trial in 717 patients with moderate to severe active RA who had an inadequate response to methotrexate (MTX). Patients received XELJANZ 5 mg or 10 mg orally twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX. Patients treated with placebo were switched as in Study RA-II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
•Study RA-IV (NCT00847613) was a 2-year trial with a planned analysis at 1 year in which 797 patients with moderate to severe active RA who had an inadequate response to MTX received XELJANZ 5 mg or 10 mg twice daily or placebo added to background MTX. Patients treated with placebo were switched as in Study RA-II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, mean change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
•Study RA-V (NCT00960440) was a 6-month trial in which 399 patients with moderate to severe active RA who had an inadequate response to at least one approved TNF blocking biological product received XELJANZ 5 mg or 10 mg twice daily or placebo added to background MTX. At the Month 3 visit, all patients randomized to placebo treatment were switched in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, HAQ-DI, and DAS28-4(ESR) less than 2.6.
•Study RA-VI (NCT01039688) was a 2-year monotherapy trial with a planned analysis at 1 year in which 952 MTX-naïve patients with moderate to severe active RA received XELJANZ 5 or 10 mg twice daily or MTX dose-titrated over 8 weeks to 20 mg weekly. The primary endpoints were mean change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at Month 6 and the proportion of patients who achieved an ACR70 response at Month 6.

Although other dosages have been studied, the recommended dosage of XELJANZ is 5 mg twice daily. XELJANZ 10 mg twice daily is not recommended for the treatment of RA

[seeDosage and Administration (2.3)]

Clinical Response

The percentages of XELJANZ-treated patients who achieved ACR20, ACR50, and ACR70 responses in Studies RA-I, IV, and V are shown in Table 10. Similar results were observed with Studies RA-II and III. In trials RA-I through V, patients treated with 5 mg twice daily XELJANZ had higher ACR20, ACR50, and ACR70 response rates versus patients treated with placebo, with or without background DMARD treatment, at Month 3 and Month 6. Higher ACR20 response rates were observed within 2 weeks compared to placebo. In the 12-month trials, ACR response rates in XELJANZ-treated patients were consistent at 6 and 12 months.

Table 10: Proportion of Adults with Moderate to Severe Active RA with an ACR Response at Months 3 and 6 in Studies RA-I, IV, and V
	Monotherapy in Nonbiologic or Biologic DMARD Inadequate Responders Inadequate response to at least one DMARD (biologic or nonbiologic) due to lack of efficacy or toxicity.		MTX Inadequate Responders Inadequate response to MTX defined as the presence of sufficient residual disease activity to meet the entry criteria.		TNF Blocker Inadequate Responders Inadequate response to a least one TNF blocker due to lack of efficacy and/or intolerance.
	Study RA-I		Study RA-IV		Study RA-V
NN is number of randomized and treated patients.	Placebo + background DMARD	XELJANZ 5 mg Twice Daily + background DMARD	Placebo + background MTX	XELJANZ 5 mg Twice Daily + background MTX	Placebo + background MTX	XELJANZ 5 mg Twice Daily + background MTX
	122	243	160	321	132	133
ACR20 Month 3 Month 6	26% NANA (not applicable), as data for placebo treatment is not available beyond 3 months in Studies RA-I and RA-V due to placebo advancement.	59% 69%	27% 25%	55% 50%	24% NA	41% 51%
ACR50 Month 3 Month 6	12% NA	31% 42%	8% 9%	29% 32%	8% NA	26% 37%
ACR70 Month 3 Month 6	6% NA	15% 22%	3% 1%	11% 14%	2% NA	14% 16%

In Study RA-IV, a greater proportion of patients treated with XELJANZ 5 mg twice daily plus MTX achieved a low level of disease activity as measured by a DAS28-4(ESR) less than 2.6 at 6 months compared to those treated with MTX alone (Table 11).

Table 11: Proportion and Numbers of Adults with Moderate to Severe Active RA with DAS28-4(ESR) Less Than 2.6 with Number of Residual Active Joints at Month 6 in Study RA-IV
	Study RA-IV
DAS28-4(ESR) Less Than 2.6	Placebo + MTX 160	XELJANZ 5 mg Twice Daily + MTX 321
Proportion of responders at Month 6 (n)	1% (2)	6% (19)
Of responders, proportion with 0 active joints (n)	50% (1)	42% (8)
Of responders, proportion with 1 active joint (n)	0	5% (1)
Of responders, proportion with 2 active joints (n)	0	32% (6)
Of responders, proportion with 3 or more active joints (n)	50% (1)	21% (4)

The results of the components of the ACR response criteria for Study RA-IV are shown in Table 12. Similar results were observed for XELJANZ in Studies RA-I, II, III, V, and VI.

Table 12: Components of ACR Response in Adults with Moderate to Severe Active RA at Baseline and Month 3 in Study RA-IV
	Study RA-IV
	Placebo + MTX N=160		XELJANZ 5 mg Twice Daily + MTX N=321
Component (mean)Data shown is mean (Standard Deviation) at Month 3.	Baseline	Month 3	Baseline	Month 3
Number of tender joints (0-68)	23 (13)	18 (14)	24 (14)	13 (14)
Number of swollen joints (0-66)	14 (9)	10 (9)	14 (8)	6 (8)
PainVisual analog scale: 0 = best, 100 = worst.	55 (24)	47 (24)	58 (23)	34 (23)
Patient global assessment	54 (23)	47 (24)	58 (24)	35 (23)
Disability index (HAQ-DI)Health Assessment Questionnaire Disability Index: 0 = best, 3 = worst; 20 questions; categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.	1.32 (0.67)	1.19 (0.68)	1.41 (0.68)	0.99 (0.65)
Physician global assessment	56 (18)	43 (22)	59 (16)	30 (19)
CRP (mg/L)	13.7 (14.9)	14.6 (18.7)	15.3 (19.0)	7.1 (19.1)

The percent of ACR20 responders by visit for Study RA-IV is shown in Figure 4. Similar responses were observed for XELJANZ in Studies RA-I, II, III, V, and VI.

Figure 4: Percentage of ACR20 Responders by Visit Through Month 6 in Study RA-IV

Radiographic Response

Two studies were conducted to evaluate the effect of XELJANZ on structural joint damage. In Study RA-IV and Study RA-VI, progression of structural joint damage was assessed radiographically and expressed as change from baseline in mTSS and its components, the erosion score and joint space narrowing score, at Months 6 and 12. The proportion of patients with no radiographic progression (mTSS change less than or equal to 0) was also assessed.

In Study RA-IV, XELJANZ 5 mg twice daily reduced the mean progression of structural damage (not statistically significant) as shown in Table 13. Analyses of erosion and joint space narrowing scores were consistent with the overall results.

In the placebo plus MTX group, 74% of patients experienced no radiographic progression at Month 6 compared to 84% of patients treated with XELJANZ plus MTX 5 mg twice daily.

In Study RA-VI, XELJANZ monotherapy inhibited the progression of structural damage compared to MTX at Months 6 and 12 as shown in Table 13. Analyses of erosion and joint space narrowing scores were consistent with the overall results.

In the MTX group, 55% of patients experienced no radiographic progression at Month 6 compared to 73% of patients treated with XELJANZ 5 mg twice daily.

Table 13: Radiographic Changes in Adults with Moderate to Severe Active RA at Months 6 and 12 in Studies RA-IV and VI
	Study RA-IV
	Placebo N=139 Mean (SD) SD = Standard Deviation	XELJANZ 5 mg Twice Daily N=277 Mean (SD)	XELJANZ 5 mg Twice Daily Mean Difference from Placebo Difference between least squares means XELJANZ minus placebo or MTX (95% CI = 95% confidence interval) (CI)
mTSSMonth 6 and Month 12 data are mean change from baseline.
Baseline	33 (42)	31 (48)	-
Month 6	0.5 (2.0)	0.1 (1.7)	-0.3 (-0.7, 0.0)
	Study RA-VI
	MTX N=166 Mean (SD)	XELJANZ 5 mg Twice Daily N=346 Mean (SD)	XELJANZ 5 mg Twice Daily Mean Difference from MTX (CI)
mTSS
Baseline	17 (29)	20 (40)	-
Month 6	0.8 (2.7)	0.2 (2.3)	-0.7 (-1.0, -0.3)
Month 12	1.3 (3.7)	0.4 (3.0)	-0.9 (-1.4, -0.4)

Physical Function Response

Improvement in physical functioning was measured by the HAQ-DI. Patients who received XELJANZ 5 mg twice daily demonstrated greater improvement from baseline in physical functioning compared to patients who received placebo at Month 3.

The mean (95% CI) difference from placebo in HAQ-DI improvement from baseline at Month 3 in Study RA-III was -0.22 (-0.35, -0.10) in patients who received 5 mg XELJANZ twice daily. Similar results were obtained in Studies RA-I, II, IV and V. In the 12-month trials, HAQ-DI results in XELJANZ-treated patients were consistent at 6 and 12 months.

Other Health-Related Outcomes

General health status was assessed by the Short Form health survey (SF-36). In Studies RA-I, IV, and V, patients who received XELJANZ 5 mg twice daily demonstrated greater improvement from baseline compared to placebo in physical component summary (PCS), mental component summary (MCS) scores and in all 8 domains of the SF-36 at Month 3.

Figure 4

14.4 Clinical Studies in Polyarticular Course Juvenile Idiopathic Arthritis

The efficacy of XELJANZ (tablets and oral solution) for pcJIA was assessed in Study pcJIA-I (NCT02592434). This was a 44-week, two-part study (that consisted of an 18-week, open-label, run-in phase, followed by a 26-week double-blind, placebo-controlled, randomized withdrawal phase) in pediatric patients 2 years to 17 years of age with active rheumatoid factor (RF) negative polyarthritis, RF positive polyarthritis, extended oligoarthritis, and systemic JIA without systemic manifestations who had an inadequate response or intolerance to at least one DMARD which could have included MTX or biologic agents. This study also included patients ages 2 years to 17 years of age with active juvenile psoriatic arthritis (jPsA) and enthesitis-related arthritis (ERA) who had an inadequate response to NSAIDs. Although the clinical studies included some patients who are TNF blocker-naïve, XELJANZ is not approved for use in TNF blocker-naïve patients

[seeIndications and Usage (1.4)]

Patients received XELJANZ (dosed at 5 mg twice daily or body weight-based equivalent twice daily) for 18 weeks (run-in phase) followed by randomization to either XELJANZ (dosed at 5 mg twice daily or body weight-based equivalent twice daily) or placebo for 26 weeks (double blind phase). Only patients who achieved at least a JIA ACR30 response at the end of the run-in phase were randomized (1:1) to the double-blind phase. Treatment with a stable dose of MTX was permitted but was not required during the study. Concurrent use of biologics or DMARDs other than MTX was not permitted in the study.

Baseline Disease Characteristics

A total of 225 pediatric patients with JIA (56 male and 169 female) with active polyarthritis were enrolled in the run-in phase including RF negative (104), RF positive (39), extended oligoarthritis (28), systemic JIA without systemic manifestations (13), jPsA (20), and ERA (21). Patients had a mean (SD) disease duration of 3.8 ± 3.5 years, and a mean (SD) number of active joints of 12.2 ± 8.1.

Efficacy Results

Of the 225 patients, 173 (77%) patients achieved JIA ACR30 response at Week 18 and were randomized into the double-blind phase to either XELJANZ (n=88) or placebo (n=85). At the conclusion of the 18-week, open-label, run-in phase, pediatric ACR 30/50/70 responses were 77%, 70%, and 49%, respectively.

In both the run-in and double-blind phases, approximately one-third of the patients were taking concomitant oral corticosteroids, and approximately two-thirds were taking concomitant MTX.

The primary endpoint was the occurrence of disease flare at Week 44 relative to the double-blind phase baseline at Week 18. Disease flare was defined (according to Pediatric Rheumatology Collaborative Study Group (PRCSG)/Pediatric Rheumatology International Trials Organization (PRINTO) Disease Flare criteria) as worsening of ≥30% in 3 or more of the 6 JIA core response variables with no more than 1 of the remaining JIA core response variables improving by ≥30%.

XELJANZ-treated patients experienced significantly fewer disease flares at Week 44 compared to placebo-treated patients (31% [27/88] vs. 55% [47/85]; difference in proportions -25% [95% CI: -39%, -10%]; p=0.0007). The occurrence of disease flare by visit in Study pcJIA-I is shown in Figure 7.

Figure 7: Occurrence of Disease Flare in Pediatric Patients 2 Years of Age and Older with JIA by Visit from Week 18 to Week 44 in the Double-Blind Phase in Study pcJIA-I
BID = twice daily; SE = standard error; N = total number of patients.
The 26-week double-blind phase is from Week 18 through Week 44 on and after randomization day.

Figure 7

]

Adverse reactions observed in pediatric patients with pcJIA who received XELJANZ were consistent with those reported in adults with RA

[see

6.1 Clinical Trials Experience

The clinical studies described in this subsection were conducted using XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling) and/or XELJANZ oral solution.

Adverse Reactions in Adults with Rheumatoid Arthritis

[seeClinical Studies (14.6)]

. A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of RA because of increased risks

[seeDosage and Administration (2.3)andWarnings and Precautions (5)]

. For the treatment of adults with moderately to severely active RA

[seeIndications and Usage (1.1)]

, the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 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 (1044 patients) or 10 mg twice daily (1043 patients and
•Placebo (809 patients).

The most common serious adverse reactions were serious infections

[seeWarnings and Precautions (5.1)]

Overall Infections

The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).

Serious Infections:

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

[seeWarnings and Precautions (5.1)]

Tuberculosis:

Cases of disseminated TB were also reported. The median XELJANZ exposure prior to diagnosis of TB was 10 months (range from 152 to 960 days)

[seeWarnings and Precautions (5.1)].

Opportunistic Infections (excluding tuberculosis):

The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days)

[seeWarnings and Precautions (5.1)].

Malignancies

[seeWarnings and Precautions (5.3)].

Laboratory Abnormalities

Lymphopenia:

Confirmed lymphocyte counts less than 500 cells/mm³were associated with an increased incidence of treated and serious infections

[seeWarnings and Precautions (5.8)].

Neutropenia:

There were no confirmed decreases in ANC below 500 cells/mm³observed 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

[seeWarnings and Precautions (5.8)].

Liver Enzyme Elevations:

Lipid Elevations:

•Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.
•Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.
•Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.

In a placebo-controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.

In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the placebo-controlled clinical trials.

Serum Creatinine Elevations:

Common Adverse Reactions

Table 5: Common Adverse Reactionsreported in ≥2% of patients treated with either dose of XELJANZ and ≥1% greater than that reported for placebo.in Clinical Trials of XELJANZ for the Treatment of Rheumatoid Arthritis in Adults With or Without Concomitant DMARDs (0–3 Months)
Preferred Term	Placebo	XELJANZ 5 mg Twice Daily	XELJANZ 10 mg Twice Daily The recommended dose of XELJANZ for the treatment of RA is 5 mg twice daily [seeDosage and Administration (2)] .
Preferred Term	N = 809 (%)	N = 1336 (%)	N = 1349 (%)
N reflects randomized and treated patients from the seven placebo-controlled clinical trials.
Upper respiratory tract infection	3	4	4
Nasopharyngitis	3	4	3
Diarrhea	2	4	3
Headache	2	4	3
Hypertension	1	2	2

Other adverse reactions that occurred in placebo-controlled and open-label extension studies in patients with RA included:

Blood and lymphatic system disorders:

Anemia

Infections and infestations:

Diverticulitis

Metabolism and nutrition disorders:

Dehydration

Psychiatric disorders:

Insomnia

Nervous system disorders:

Paresthesia

Respiratory, thoracic and mediastinal disorders:

Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with RA and some were fatal)

Gastrointestinal disorders:

Abdominal pain, dyspepsia, vomiting, gastritis, nausea

Hepatobiliary disorders:

Hepatic steatosis

Skin and subcutaneous tissue disorders:

Rash, erythema, pruritus

Musculoskeletal, connective tissue and bone disorders:

Musculoskeletal pain, arthralgia, tendonitis, joint swelling

Neoplasms benign, malignant and unspecified (including cysts and polyps):

Non-melanoma skin cancers

General disorders and administration site conditions:

Pyrexia, fatigue, peripheral edema

Clinical Experience in Methotrexate-Naïve Patients

Study RA-VI was an active-controlled clinical trial in methotrexate-naïve patients

[seeClinical Studies (14)]

. The safety experience in these patients was consistent with Studies RA-I through V.

Adverse Reactions in Adults with Psoriatic Arthritis

The safety of XELJANZ was evaluated in 2 double-blind Phase 3 clinical trials in adults with active psoriatic arthritis (PsA):

•Study PsA-I (NCT01877668) had a duration of 12 months and enrolled adults who had an inadequate response to a nonbiologic DMARD and who were naïve to treatment with a TNF blocker. Study PsA-I included a 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months.
•Study PsA-II (NCT01882439) had a duration of 6 months and enrolled adults who had an inadequate response to at least one approved TNF blocker. This clinical trial included a 3-month placebo-controlled period.

[seeIndications and Usage (1.2)]

, the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily

[seeDosage and Administration (2.3)].

During the 2 PsA controlled clinical trials, there were:

•3 malignancies (excluding NMSC) in 474 patients who received XELJANZ plus non-biologic DMARD (6 to 12 months exposure)
•0 malignancies in 236 patients who received placebo plus non-biologic DMARD group (3 months exposure) and
•0 malignancies in 106 patients in patients who received adalimumab plus non-biologic DMARD group (12 months exposure).

No lymphomas were reported. Malignancies have also been observed in the long-term extension study in patients with PsA treated with XELJANZ.

The safety profile observed in adults with active PsA treated with XELJANZ was consistent with the safety profile observed in adults with RA.

Adverse Reactions in Adults with Ankylosing Spondylitis

•Study AS-I (NCT03502616) had a duration of 48 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. Study AS-I included a 16-week double-blind period in which patients received XELJANZ 5 mg or placebo twice daily and a 32-week open-label treatment period in which all patients received XELJANZ 5 mg twice daily.
•Study AS-II (NCT01786668) had a duration of 16 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. This clinical trial included a 12-week treatment period in which patients received either XELJANZ 2 mg (40% of the recommended dose), 5 mg, 10 mg, or placebo twice daily. A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of AS. For the treatment of adults with active AS
[seeIndications and Usage (1.3)]
, the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily
[seeDosage and Administration (2.3)]
.

The safety profile observed in adults with AS treated with XELJANZ was consistent with the safety profile observed in adults with RA and PsA.

Adverse Reactions in Pediatric Patients 2 Years of Age and Older with Polyarticular Course Juvenile Idiopathic Arthritis

XELJANZ tablets and XELJANZ oral solution 5 mg twice daily or weight-based equivalent twice daily was studied in 225 pediatric patients from 2 years to 17 years of age in Study pcJIA-I

[seeClinical Studies (14.4)]

In general, the types of adverse reactions in pediatric patients 2 years of age and older with pcJIA, were consistent with those seen in adults with RA and PsA

(seeAdverse Reactions in Adults with Rheumatoid ArthritisandAdverse Reactions in Adults with Psoriatic Arthritis)

Adverse Reactions in Adults with Ulcerative Colitis

[seeClinical Studies (14.5)]

Induction Trials in Adults with UC

Maintenance Trial in Adults with UC

Table 6: Common Adverse ReactionsReported in ≥4% of patients treated with either XELJANZ dosage and ≥1% greater in XELJANZ-treated patients than placebo-treated patients.in Adults with UC During the 52-Week Maintenance Trial (Study UC-III)
Preferred Term	Placebo	XELJANZ 5 mg Twice Daily	XELJANZ 10 mg Twice Daily
Preferred Term	N = 198 (%)	N = 198 (%)	N = 196 (%)
Nasopharyngitis	6	10	14
Elevated cholesterol levelsIncludes hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low-density lipoprotein increased, low-density lipoprotein abnormal, or lipids increased.	1	5	9
Headache	6	9	3
Upper respiratory tract infection	4	7	6
Increased blood creatine phosphokinase	2	3	7
Rash	4	3	6
Diarrhea	3	2	5
Herpes zoster	1	1	5
Gastroenteritis	3	3	4
Anemia	2	4	2
Nausea	3	1	4

[seeWarnings and Precautions (5.1,5.3)]

In the long-term extension study, malignancies (including solid cancers, lymphomas and NMSC) were observed in patients treated with XELJANZ 5 mg and 10 mg twice daily

[seeWarnings and Precautions (5.3)]

. Five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one fatality in a patient with advanced cancer

[seeWarnings and Precautions (5.5)]

]

Psoriatic Arthritis

The safety and effectiveness of XELJANZ (tablets and oral solution) for the treatment of active PsA have been established in pediatric patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers.

Use of XELJANZ for this indication is supported by evidence from well-controlled studies of XELJANZ tablets in adults with PsA, PK data from adults with PsA, and PK data from a clinical trial of XELJANZ in 225 pediatric patients with JIA, and safety data from 280 pediatric patients 2 years of age and older with JIA

[see

6.1 Clinical Trials Experience

The clinical studies described in this subsection were conducted using XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling) and/or XELJANZ oral solution.

Adverse Reactions in Adults with Rheumatoid Arthritis

[seeClinical Studies (14.6)]

. A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of RA because of increased risks

[seeDosage and Administration (2.3)andWarnings and Precautions (5)]

. For the treatment of adults with moderately to severely active RA

[seeIndications and Usage (1.1)]

, the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 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 (1044 patients) or 10 mg twice daily (1043 patients and
•Placebo (809 patients).

The most common serious adverse reactions were serious infections

[seeWarnings and Precautions (5.1)]

Overall Infections

The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).

Serious Infections:

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

[seeWarnings and Precautions (5.1)]

Tuberculosis:

Cases of disseminated TB were also reported. The median XELJANZ exposure prior to diagnosis of TB was 10 months (range from 152 to 960 days)

[seeWarnings and Precautions (5.1)].

Opportunistic Infections (excluding tuberculosis):

The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days)

[seeWarnings and Precautions (5.1)].

Malignancies

[seeWarnings and Precautions (5.3)].

Laboratory Abnormalities

Lymphopenia:

Confirmed lymphocyte counts less than 500 cells/mm³were associated with an increased incidence of treated and serious infections

[seeWarnings and Precautions (5.8)].

Neutropenia:

There were no confirmed decreases in ANC below 500 cells/mm³observed 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

[seeWarnings and Precautions (5.8)].

Liver Enzyme Elevations:

Lipid Elevations:

•Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.
•Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.
•Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.

In a placebo-controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.

In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the placebo-controlled clinical trials.

Serum Creatinine Elevations:

Common Adverse Reactions

Table 5: Common Adverse Reactionsreported in ≥2% of patients treated with either dose of XELJANZ and ≥1% greater than that reported for placebo.in Clinical Trials of XELJANZ for the Treatment of Rheumatoid Arthritis in Adults With or Without Concomitant DMARDs (0–3 Months)
Preferred Term	Placebo	XELJANZ 5 mg Twice Daily	XELJANZ 10 mg Twice Daily The recommended dose of XELJANZ for the treatment of RA is 5 mg twice daily [seeDosage and Administration (2)] .
Preferred Term	N = 809 (%)	N = 1336 (%)	N = 1349 (%)
N reflects randomized and treated patients from the seven placebo-controlled clinical trials.
Upper respiratory tract infection	3	4	4
Nasopharyngitis	3	4	3
Diarrhea	2	4	3
Headache	2	4	3
Hypertension	1	2	2

Other adverse reactions that occurred in placebo-controlled and open-label extension studies in patients with RA included:

Blood and lymphatic system disorders:

Anemia

Infections and infestations:

Diverticulitis

Metabolism and nutrition disorders:

Dehydration

Psychiatric disorders:

Insomnia

Nervous system disorders:

Paresthesia

Respiratory, thoracic and mediastinal disorders:

Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with RA and some were fatal)

Gastrointestinal disorders:

Abdominal pain, dyspepsia, vomiting, gastritis, nausea

Hepatobiliary disorders:

Hepatic steatosis

Skin and subcutaneous tissue disorders:

Rash, erythema, pruritus

Musculoskeletal, connective tissue and bone disorders:

Musculoskeletal pain, arthralgia, tendonitis, joint swelling

Neoplasms benign, malignant and unspecified (including cysts and polyps):

Non-melanoma skin cancers

General disorders and administration site conditions:

Pyrexia, fatigue, peripheral edema

Clinical Experience in Methotrexate-Naïve Patients

Study RA-VI was an active-controlled clinical trial in methotrexate-naïve patients

[seeClinical Studies (14)]

. The safety experience in these patients was consistent with Studies RA-I through V.

Adverse Reactions in Adults with Psoriatic Arthritis

The safety of XELJANZ was evaluated in 2 double-blind Phase 3 clinical trials in adults with active psoriatic arthritis (PsA):

•Study PsA-I (NCT01877668) had a duration of 12 months and enrolled adults who had an inadequate response to a nonbiologic DMARD and who were naïve to treatment with a TNF blocker. Study PsA-I included a 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months.
•Study PsA-II (NCT01882439) had a duration of 6 months and enrolled adults who had an inadequate response to at least one approved TNF blocker. This clinical trial included a 3-month placebo-controlled period.

[seeIndications and Usage (1.2)]

, the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily

[seeDosage and Administration (2.3)].

During the 2 PsA controlled clinical trials, there were:

•3 malignancies (excluding NMSC) in 474 patients who received XELJANZ plus non-biologic DMARD (6 to 12 months exposure)
•0 malignancies in 236 patients who received placebo plus non-biologic DMARD group (3 months exposure) and
•0 malignancies in 106 patients in patients who received adalimumab plus non-biologic DMARD group (12 months exposure).

No lymphomas were reported. Malignancies have also been observed in the long-term extension study in patients with PsA treated with XELJANZ.

The safety profile observed in adults with active PsA treated with XELJANZ was consistent with the safety profile observed in adults with RA.

Adverse Reactions in Adults with Ankylosing Spondylitis

•Study AS-I (NCT03502616) had a duration of 48 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. Study AS-I included a 16-week double-blind period in which patients received XELJANZ 5 mg or placebo twice daily and a 32-week open-label treatment period in which all patients received XELJANZ 5 mg twice daily.
•Study AS-II (NCT01786668) had a duration of 16 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. This clinical trial included a 12-week treatment period in which patients received either XELJANZ 2 mg (40% of the recommended dose), 5 mg, 10 mg, or placebo twice daily. A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of AS. For the treatment of adults with active AS
[seeIndications and Usage (1.3)]
, the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily
[seeDosage and Administration (2.3)]
.

The safety profile observed in adults with AS treated with XELJANZ was consistent with the safety profile observed in adults with RA and PsA.

Adverse Reactions in Pediatric Patients 2 Years of Age and Older with Polyarticular Course Juvenile Idiopathic Arthritis

XELJANZ tablets and XELJANZ oral solution 5 mg twice daily or weight-based equivalent twice daily was studied in 225 pediatric patients from 2 years to 17 years of age in Study pcJIA-I

[seeClinical Studies (14.4)]

In general, the types of adverse reactions in pediatric patients 2 years of age and older with pcJIA, were consistent with those seen in adults with RA and PsA

(seeAdverse Reactions in Adults with Rheumatoid ArthritisandAdverse Reactions in Adults with Psoriatic Arthritis)

Adverse Reactions in Adults with Ulcerative Colitis

[seeClinical Studies (14.5)]

Induction Trials in Adults with UC

Maintenance Trial in Adults with UC

Table 6: Common Adverse ReactionsReported in ≥4% of patients treated with either XELJANZ dosage and ≥1% greater in XELJANZ-treated patients than placebo-treated patients.in Adults with UC During the 52-Week Maintenance Trial (Study UC-III)
Preferred Term	Placebo	XELJANZ 5 mg Twice Daily	XELJANZ 10 mg Twice Daily
Preferred Term	N = 198 (%)	N = 198 (%)	N = 196 (%)
Nasopharyngitis	6	10	14
Elevated cholesterol levelsIncludes hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low-density lipoprotein increased, low-density lipoprotein abnormal, or lipids increased.	1	5	9
Headache	6	9	3
Upper respiratory tract infection	4	7	6
Increased blood creatine phosphokinase	2	3	7
Rash	4	3	6
Diarrhea	3	2	5
Herpes zoster	1	1	5
Gastroenteritis	3	3	4
Anemia	2	4	2
Nausea	3	1	4

[seeWarnings and Precautions (5.1,5.3)]

In the long-term extension study, malignancies (including solid cancers, lymphomas and NMSC) were observed in patients treated with XELJANZ 5 mg and 10 mg twice daily

[seeWarnings and Precautions (5.3)]

. Five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one fatality in a patient with advanced cancer

[seeWarnings and Precautions (5.5)]

12.3 Pharmacokinetics

Table 8 describes the pharmacokinetic parameters of XELJANZ and XELJANZ XR.

Table 8: Pharmacokinetic Parameters of XELJANZ/XELJANZ XR Following Multiple Oral Dosing
PK Parameters Values represent the geometric mean, except T_max, for which is the median (range) is shown. (CV%)	XELJANZ		XELJANZ XR
Dosing Regimen	5 mg Twice Daily	10 mg Twice Daily	11 mg Once Daily	22 mg Once Daily
Abbreviations: AUC₂₄= area under the concentration time profile from time 0 to 24 hours; C_max= maximum plasma concentration; C_min= minimum plasma concentration; T_max= time to C_max; CV = Coefficient of variation.
AUC₂₄(ng.hr/mL)	263.4 (15)	539.6 (22)	269.0 (18)	596.6 (19)
C_max(ng/mL)	42.7 (26)	84.7 (18)	38.2 (15)	83.8 (25)
C_min(ng/mL)	1.41 (40)	3.10 (54)	1.07 (69)	3.11 (43)
T_max(hours)	1.0 (0.5 to14.0Values beyond 12 hours were after the evening dose which was administered 12 hours after the morning dose of twice-daily XELJANZ.)	0.8 (0.5 to 14.0 )	4.0 (3.0 to 4.0)	4.0 (2.0 to 4.0)

Absorption

XELJANZ

[see

Dosage and Administration (2.2)

]

XELJANZ XR

Distribution

Metabolism and Excretion

Pharmacokinetics in Patients with RA, PsA, AS, and UC

Table 9: Tofacitinib Exposure in Patients with RA, PsA, AS, and UC After Administration of XELJANZ 5 mg Twice Daily or 10 mg Twice Daily
Pharmacokinetic Parameters Pharmacokinetic parameters estimated based on population pharmacokinetic analysis. Geometric Mean (CV%)	XELJANZ 5 mg Twice Daily				XELJANZ 10 mg Twice Daily
	Rheumatoid Arthritis	Psoriatic Arthritis	Ankylosing Spondylitis	Ulcerative Colitis	Ulcerative Colitis
Abbreviations: AUC_0–24,ss= area under the plasma concentration-time curve over 24 hours at steady state; CV = coefficient of variation.
AUC_0–24,_ss (ng∙h/mL)	504 (22.0%)	419 (34.1%)	381 (25.4%)	423 (22.6%)	807 (24.6%)

Specific Populations

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

[seeDosage and Administration (2.3,2.4,

2.5)

andUse in Specific Populations (8.6)]

Figure 1

Drug Interaction Studies

Potential for XELJANZ/XELJANZ XR to Influence the PK of Other Drugs

In vitro

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 XELJANZ.

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.

Figure 2

Potential for Other Drugs to Influence the Pharmacokinetics of Tofacitinib

Figure 3: Impact of Other Drugs on the Pharmacokinetics of Tofacitinib

Note: Reference group is administration of XELJANZ alone.

Figure 3

, and

14.2 Clinical Studies in Psoriatic Arthritis

The psoriatic arthritis (PsA) clinical development program with XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling) included 2 multicenter, randomized, double-blind, placebo-controlled trials in 816 adults with active PsA (Studies PsA-I and PsA-II).

Trial Designs and Population

All patients had active PsA for at least 6 months based upon the Classification Criteria for Psoriatic Arthritis (CASPAR), at least 3 tender/painful joints and at least 3 swollen joints, and active plaque psoriasis. Patients randomized and treated across the 2 clinical trials represented different PsA subtypes at screening, including <5 joints or asymmetric involvement (21%), ≥5 joints involved (90%), distal interphalangeal (DIP) joint involvement (61%), arthritis mutilans (8%), and spondylitis (19%). Patients in these clinical trials had a diagnosis of PsA for a mean (SD) of 7.7 (7.2) years. At baseline, 80% and 53% of patients had enthesitis and dactylitis, respectively. At baseline, all patients were required to receive treatment with a stable dose of a nonbiologic DMARD (79% received methotrexate, 13% received sulfasalazine, 7% received leflunomide, 1% received other nonbiologic DMARDs). In both clinical trials, the primary endpoints were the ACR20 response and the change from baseline in HAQ-DI at Month 3.

•Study PsA-I was a 12-month clinical trial in 422 patients who had an inadequate response to a nonbiologic DMARD (67% and 33% were inadequate responders to 1 nonbiologic DMARD and ≥2 nonbiologic DMARDs, respectively) and who were naïve to treatment with a TNF blocker. Although Study PsA-1 included patients who are TNF blocker-naïve, XELJANZ and XELJANZ XR are not approved for use in TNF blocker-naïve patients
[seeIndications and Usage (1.2)]
. Patients were randomized in a 2:2:2:1:1 ratio to receive XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, adalimumab 40 mg subcutaneously once every 2 weeks, placebo to XELJANZ 5 mg twice daily treatment sequence, or placebo to XELJANZ 10 mg twice daily treatment sequence, respectively; study drug was added to background nonbiologic DMARD treatment. At the Month 3 visit, all patients randomized to placebo treatment were switched in a blinded fashion to a predetermined XELJANZ dosage of 5 mg or 10 mg twice daily. Study PsA-I was not designed to demonstrate noninferiority or superiority to adalimumab.
•Study PsA-II was a 6-month clinical trial in 394 patients who had an inadequate response to at least 1 approved TNF blocker (66%, 19%, and 15% were inadequate responders to 1 TNF blocker, 2 TNF blockers and ≥3 TNF blockers, respectively). Patients were randomized in a 2:2:1:1 ratio to receive XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, placebo to XELJANZ 5 mg twice daily treatment sequence, or placebo to XELJANZ 10 mg twice daily treatment sequence, respectively; study drug was added to background nonbiologic DMARD treatment. At the Month 3 visit, placebo patients were switched in a blinded fashion to a predetermined XELJANZ dosage of 5 mg or 10 mg twice daily as in Study PsA-I.

Although other dosages have been studied, the recommended dosage of XELJANZ is 5 mg twice daily. XELJANZ 10 mg twice daily is not recommended for treatment of PsA

[seeDosage and Administration (2.3)]

Clinical Response

At Month 3, patients treated with XELJANZ 5 mg twice daily had higher (p≤0.05) response rates versus placebo for ACR20, ACR50, and ACR70 in Study PsA-I and for ACR20 and ACR50 in Study PsA-II; ACR70 response rates were also higher for XELJANZ 5 mg twice daily versus placebo in Study PsA-II, although the differences versus placebo were not statistically significant (p>0.05) (Tables 14 and 15).

Table 14: Proportion of Adults with Active PsA with an ACR Response at Month 3 in Study PsA-IPatients received one concomitant nonbiologic DMARD.[Nonbiologic DMARD Inadequate Responders (TNF Blocker-Naïve)]XELJANZ and XELJANZ XR are not approved for use in TNF blocker-naïve patients
[seeIndications and Usage (1.2)]
.
Treatment Group	Placebo	XELJANZ 5 mg Twice Daily + Background Nonbiologic DMARD
Patients with missing data were treated as non-responders.
NN is number of randomized and treated patients.	105	107
	Response Rate	Response Rate	Difference (%) 95% CI from Placebo
Month 3
ACR20	33%	50%	17.1 (4.1, 30.2)
ACR50	10%	28%	18.5 (8.3, 28.7)
ACR70	5%	17%	12.1 (3.9, 20.2)

Table 15: Proportion of Adults with Active PsA with an ACR Response at Month 3 in Study PsA-IIPatients received one concomitant nonbiologic DMARD.(TNF Blocker Inadequate Responders)
Treatment Group	Placebo	XELJANZ 5 mg Twice Daily
Patients with missing data were treated as non-responders.
NN is number of randomized and treated patients.	131	131
	Response Rate	Response Rate	Difference (%) 95% CI from Placebo
Month 3
ACR20	24%	50%	26.0 (14.7, 37.2)
ACR50	15%	30%	15.3 (5.4, 25.2)
ACR70	10%	17%	6.9 (-1.3, 15.1)

Improvements from baseline in the ACR response criteria components for both studies are shown in Table 16.

Table 16: Components of ACR Response in Adults with Active PsA at Baseline and Month 3 in Studies PsA-I and PsA-II
	Nonbiologic DMARD Inadequate Responders (TNF Blocker-Naïve)		TNF Blocker Inadequate Responders
	Study PsA-I Patients received one concomitant nonbiologic DMARD.^,XELJANZ and XELJANZ XR are not approved for use in TNF blocker-naïve patients [seeIndications and Usage (1.2)] .		Study PsA-II
Treatment Group	Placebo	XELJANZ 5 mg Twice Daily	Placebo	XELJANZ 5 mg Twice Daily
N at Baseline	105	107	131	131
ACR ComponentData shown are mean value at baseline and at Month 3.
Number of tender/painful joints (0–68)
Baseline	20.6	20.5	19.8	20.5
Month 3	14.6	12.2	15.1	11.5
Number of swollen joints (0–66)
Baseline	11.5	12.9	10.5	12.1
Month 3	7.1	6.3	7.7	4.8
Patient assessment of arthritis painVisual analog scale (VAS): 0 = best, 100 = worst.
Baseline	53.2	55.7	54.9	56.4
Month 3	44.7	34.7	48.0	36.1
Patient global assessment of arthritis
Baseline	53.9	54.7	55.8	57.4
Month 3	44.4	35.5	49.2	36.9
HAQ-DIHAQ-DI = Health Assessment Questionnaire – Disability Index: 0 = best, 3 = worst; 20 questions; categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
Baseline	1.11	1.16	1.25	1.26
Month 3	0.95	0.81	1.09	0.88
Physician's Global Assessment of Arthritis
Baseline	53.8	54.6	53.7	53.5
Month 3	35.4	29.5	36.4	27.0
CRP (mg/L)
Baseline	10.4	10.5	12.1	13.8
Month 3	8.6	4.0	11.4	7.7

The percentage of ACR20 responders by visit for Study PsA-I is shown in Figure 5. Similar responses were observed in Study PsA-II. In both studies, improvement in ACR20 response on XELJANZ was observed at the first visit after baseline (Week 2).

Figure 5: Percentage of ACR20 Responders by Visit Through Month 3 in Study PsA-ISubjects received one concomitant nonbiologic DMARD.XELJANZ and XELJANZ XR are not approved for use in TNF blocker-naïve patients
[seeIndications and Usage (1.2)]
.
BID = twice daily; SE = standard error.
Patients with missing data were treated as non-responders.

Figure 5

In patients with active PsA evidence of benefit in enthesitis and dactylitis was observed with XELJANZ treatment.

Physical Function

Improvement in physical functioning was measured by the HAQ-DI. Patients receiving XELJANZ 5 mg twice daily demonstrated significantly greater improvement (p ≤0.05) from baseline in physical functioning compared to placebo at Month 3 (Table 17).

Table 17: Change from Baseline in HAQ-DI in Adults with Active PsA at Month 3 Studies PsA-I and PsA-II
	Least Squares Mean Change from Baseline In HAQ-DI at Month 3
	Nonbiologic DMARD Inadequate Responders Inadequate response to at least one nonbiologic DMARD due to lack of efficacy and/or intolerability. (TNF Blocker-Naïve)		TNF Blocker Inadequate Responders Inadequate response to at least one TNF blocker due to lack of efficacy and/or intolerability.
	Study PsA-I Patients received one concomitant nonbiologic DMARD. ^, XELJANZ and XELJANZ XR are not approved for use in TNF blocker-naïve patients [seeIndications and Usage (1.2)] .		Study PsA-II
Treatment Group	Placebo	XELJANZ 5 mg Twice Daily	Placebo	XELJANZ 5 mg Twice Daily
NN is the total number of patients in the statistical analysis.	104	107	131	129
LSM Change from Baseline	-0.18	-0.35	-0.14	-0.39
Difference from Placebo (95% CI)	-	-0.17 (-0.29, -0.05)	-	-0.25 (-0.38, -0.13)

In Study PsA-I, the HAQ-DI responder rate (response defined as having improvement from baseline of ≥0.35) at Month 3 was 53% in patients receiving XELJANZ 5 mg twice daily and 31% in patients receiving placebo. Similar responses were observed in Study PsA-II.

Other Health-Related Outcomes

General health status was assessed by the Short Form health survey (SF-36). In Studies PsA-I and PsA-II, patients receiving XELJANZ 5 mg twice daily had greater improvement from baseline compared to placebo in Physical Component Summary (PCS) score, but not in Mental Component Summary (MCS) score at Month 3. Patients receiving XELJANZ 5 mg twice daily reported consistently greater improvement relative to placebo in the domains of Physical Functioning, Bodily Pain, Vitality, and Social Functioning, but not in Role-Physical, General Health, Role-Emotional, or Mental Health.

Radiographic Response

Treatment effect on inhibition of radiographic progression in PsA could not be established from the results of Study PsA-I.

]

. Following administration of the recommended XELJANZ dosage in pediatric patients 2 years of age and older with PsA, tofacitinib plasma exposures are predicted to be comparable to those observed in adults with PsA based on population PK modeling and simulation

[see

12.3 Pharmacokinetics

Table 8 describes the pharmacokinetic parameters of XELJANZ and XELJANZ XR.

Table 8: Pharmacokinetic Parameters of XELJANZ/XELJANZ XR Following Multiple Oral Dosing
PK Parameters Values represent the geometric mean, except T_max, for which is the median (range) is shown. (CV%)	XELJANZ		XELJANZ XR
Dosing Regimen	5 mg Twice Daily	10 mg Twice Daily	11 mg Once Daily	22 mg Once Daily
Abbreviations: AUC₂₄= area under the concentration time profile from time 0 to 24 hours; C_max= maximum plasma concentration; C_min= minimum plasma concentration; T_max= time to C_max; CV = Coefficient of variation.
AUC₂₄(ng.hr/mL)	263.4 (15)	539.6 (22)	269.0 (18)	596.6 (19)
C_max(ng/mL)	42.7 (26)	84.7 (18)	38.2 (15)	83.8 (25)
C_min(ng/mL)	1.41 (40)	3.10 (54)	1.07 (69)	3.11 (43)
T_max(hours)	1.0 (0.5 to14.0Values beyond 12 hours were after the evening dose which was administered 12 hours after the morning dose of twice-daily XELJANZ.)	0.8 (0.5 to 14.0 )	4.0 (3.0 to 4.0)	4.0 (2.0 to 4.0)

Absorption

XELJANZ

[see

Dosage and Administration (2.2)

]

XELJANZ XR

Distribution

Metabolism and Excretion

Pharmacokinetics in Patients with RA, PsA, AS, and UC

Table 9: Tofacitinib Exposure in Patients with RA, PsA, AS, and UC After Administration of XELJANZ 5 mg Twice Daily or 10 mg Twice Daily
Pharmacokinetic Parameters Pharmacokinetic parameters estimated based on population pharmacokinetic analysis. Geometric Mean (CV%)	XELJANZ 5 mg Twice Daily				XELJANZ 10 mg Twice Daily
	Rheumatoid Arthritis	Psoriatic Arthritis	Ankylosing Spondylitis	Ulcerative Colitis	Ulcerative Colitis
Abbreviations: AUC_0–24,ss= area under the plasma concentration-time curve over 24 hours at steady state; CV = coefficient of variation.
AUC_0–24,_ss (ng∙h/mL)	504 (22.0%)	419 (34.1%)	381 (25.4%)	423 (22.6%)	807 (24.6%)

Specific Populations

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

[seeDosage and Administration (2.3,2.4,

2.5)

andUse in Specific Populations (8.6)]

Figure 1

Drug Interaction Studies

Potential for XELJANZ/XELJANZ XR to Influence the PK of Other Drugs

In vitro

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 XELJANZ.

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.

Figure 2

Potential for Other Drugs to Influence the Pharmacokinetics of Tofacitinib

Figure 3: Impact of Other Drugs on the Pharmacokinetics of Tofacitinib

Note: Reference group is administration of XELJANZ alone.

Figure 3

]

Systemic Juvenile Idiopathic Arthritis

The safety and effectiveness of XELJANZ for the treatment of pediatric patients with systemic juvenile idiopathic arthritis (sJIA) have not been established.

The results from a two-part study (an open-label, run-in phase, followed by a double-blind, placebo-controlled, randomized event-driven withdrawal phase) in 100 patients 2 years to 17 years of age with sJIA with active systemic features did not demonstrate that XELJANZ (dosed at 5 mg twice daily or body weight-based equivalent twice daily) was efficacious in the treatment of sJIA with active systemic features.

Of the 100 patients enrolled in the open-label run-in phase, 59 (59%) patients achieved a clinical response and were eligible for the double-blind withdrawal phase. There were 28 patients randomized to XELJANZ and 31 patients to placebo. The study data were insufficient to demonstrate efficacy and, therefore, XELJANZ is not recommended for the treatment of sJIA.

Adverse reactions observed in pediatric patients with sJIA receiving XELJANZ/XELJANZ oral solution were consistent with those reported in pcJIA and RA patients

[see

6.1 Clinical Trials Experience

The clinical studies described in this subsection were conducted using XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling) and/or XELJANZ oral solution.

Adverse Reactions in Adults with Rheumatoid Arthritis

[seeClinical Studies (14.6)]

. A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of RA because of increased risks

[seeDosage and Administration (2.3)andWarnings and Precautions (5)]

. For the treatment of adults with moderately to severely active RA

[seeIndications and Usage (1.1)]

, the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 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 (1044 patients) or 10 mg twice daily (1043 patients and
•Placebo (809 patients).

The most common serious adverse reactions were serious infections

[seeWarnings and Precautions (5.1)]

Overall Infections

The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).

Serious Infections:

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

[seeWarnings and Precautions (5.1)]

Tuberculosis:

Cases of disseminated TB were also reported. The median XELJANZ exposure prior to diagnosis of TB was 10 months (range from 152 to 960 days)

[seeWarnings and Precautions (5.1)].

Opportunistic Infections (excluding tuberculosis):

The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days)

[seeWarnings and Precautions (5.1)].

Malignancies

[seeWarnings and Precautions (5.3)].

Laboratory Abnormalities

Lymphopenia:

Confirmed lymphocyte counts less than 500 cells/mm³were associated with an increased incidence of treated and serious infections

[seeWarnings and Precautions (5.8)].

Neutropenia:

There were no confirmed decreases in ANC below 500 cells/mm³observed 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

[seeWarnings and Precautions (5.8)].

Liver Enzyme Elevations:

Lipid Elevations:

•Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.
•Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.
•Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.

In a placebo-controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.

In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the placebo-controlled clinical trials.

Serum Creatinine Elevations:

Common Adverse Reactions

Table 5: Common Adverse Reactionsreported in ≥2% of patients treated with either dose of XELJANZ and ≥1% greater than that reported for placebo.in Clinical Trials of XELJANZ for the Treatment of Rheumatoid Arthritis in Adults With or Without Concomitant DMARDs (0–3 Months)
Preferred Term	Placebo	XELJANZ 5 mg Twice Daily	XELJANZ 10 mg Twice Daily The recommended dose of XELJANZ for the treatment of RA is 5 mg twice daily [seeDosage and Administration (2)] .
Preferred Term	N = 809 (%)	N = 1336 (%)	N = 1349 (%)
N reflects randomized and treated patients from the seven placebo-controlled clinical trials.
Upper respiratory tract infection	3	4	4
Nasopharyngitis	3	4	3
Diarrhea	2	4	3
Headache	2	4	3
Hypertension	1	2	2

Other adverse reactions that occurred in placebo-controlled and open-label extension studies in patients with RA included:

Blood and lymphatic system disorders:

Anemia

Infections and infestations:

Diverticulitis

Metabolism and nutrition disorders:

Dehydration

Psychiatric disorders:

Insomnia

Nervous system disorders:

Paresthesia

Respiratory, thoracic and mediastinal disorders:

Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with RA and some were fatal)

Gastrointestinal disorders:

Abdominal pain, dyspepsia, vomiting, gastritis, nausea

Hepatobiliary disorders:

Hepatic steatosis

Skin and subcutaneous tissue disorders:

Rash, erythema, pruritus

Musculoskeletal, connective tissue and bone disorders:

Musculoskeletal pain, arthralgia, tendonitis, joint swelling

Neoplasms benign, malignant and unspecified (including cysts and polyps):

Non-melanoma skin cancers

General disorders and administration site conditions:

Pyrexia, fatigue, peripheral edema

Clinical Experience in Methotrexate-Naïve Patients

Study RA-VI was an active-controlled clinical trial in methotrexate-naïve patients

[seeClinical Studies (14)]

. The safety experience in these patients was consistent with Studies RA-I through V.

Adverse Reactions in Adults with Psoriatic Arthritis

The safety of XELJANZ was evaluated in 2 double-blind Phase 3 clinical trials in adults with active psoriatic arthritis (PsA):

•Study PsA-I (NCT01877668) had a duration of 12 months and enrolled adults who had an inadequate response to a nonbiologic DMARD and who were naïve to treatment with a TNF blocker. Study PsA-I included a 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months.
•Study PsA-II (NCT01882439) had a duration of 6 months and enrolled adults who had an inadequate response to at least one approved TNF blocker. This clinical trial included a 3-month placebo-controlled period.

[seeIndications and Usage (1.2)]

, the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily

[seeDosage and Administration (2.3)].

During the 2 PsA controlled clinical trials, there were:

•3 malignancies (excluding NMSC) in 474 patients who received XELJANZ plus non-biologic DMARD (6 to 12 months exposure)
•0 malignancies in 236 patients who received placebo plus non-biologic DMARD group (3 months exposure) and
•0 malignancies in 106 patients in patients who received adalimumab plus non-biologic DMARD group (12 months exposure).

No lymphomas were reported. Malignancies have also been observed in the long-term extension study in patients with PsA treated with XELJANZ.

The safety profile observed in adults with active PsA treated with XELJANZ was consistent with the safety profile observed in adults with RA.

Adverse Reactions in Adults with Ankylosing Spondylitis

•Study AS-I (NCT03502616) had a duration of 48 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. Study AS-I included a 16-week double-blind period in which patients received XELJANZ 5 mg or placebo twice daily and a 32-week open-label treatment period in which all patients received XELJANZ 5 mg twice daily.
•Study AS-II (NCT01786668) had a duration of 16 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. This clinical trial included a 12-week treatment period in which patients received either XELJANZ 2 mg (40% of the recommended dose), 5 mg, 10 mg, or placebo twice daily. A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of AS. For the treatment of adults with active AS
[seeIndications and Usage (1.3)]
, the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily
[seeDosage and Administration (2.3)]
.

The safety profile observed in adults with AS treated with XELJANZ was consistent with the safety profile observed in adults with RA and PsA.

Adverse Reactions in Pediatric Patients 2 Years of Age and Older with Polyarticular Course Juvenile Idiopathic Arthritis

XELJANZ tablets and XELJANZ oral solution 5 mg twice daily or weight-based equivalent twice daily was studied in 225 pediatric patients from 2 years to 17 years of age in Study pcJIA-I

[seeClinical Studies (14.4)]

In general, the types of adverse reactions in pediatric patients 2 years of age and older with pcJIA, were consistent with those seen in adults with RA and PsA

(seeAdverse Reactions in Adults with Rheumatoid ArthritisandAdverse Reactions in Adults with Psoriatic Arthritis)

Adverse Reactions in Adults with Ulcerative Colitis

[seeClinical Studies (14.5)]

Induction Trials in Adults with UC

Maintenance Trial in Adults with UC

Table 6: Common Adverse ReactionsReported in ≥4% of patients treated with either XELJANZ dosage and ≥1% greater in XELJANZ-treated patients than placebo-treated patients.in Adults with UC During the 52-Week Maintenance Trial (Study UC-III)
Preferred Term	Placebo	XELJANZ 5 mg Twice Daily	XELJANZ 10 mg Twice Daily
Preferred Term	N = 198 (%)	N = 198 (%)	N = 196 (%)
Nasopharyngitis	6	10	14
Elevated cholesterol levelsIncludes hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low-density lipoprotein increased, low-density lipoprotein abnormal, or lipids increased.	1	5	9
Headache	6	9	3
Upper respiratory tract infection	4	7	6
Increased blood creatine phosphokinase	2	3	7
Rash	4	3	6
Diarrhea	3	2	5
Herpes zoster	1	1	5
Gastroenteritis	3	3	4
Anemia	2	4	2
Nausea	3	1	4

[seeWarnings and Precautions (5.1,5.3)]

In the long-term extension study, malignancies (including solid cancers, lymphomas and NMSC) were observed in patients treated with XELJANZ 5 mg and 10 mg twice daily

[seeWarnings and Precautions (5.3)]

. Five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one fatality in a patient with advanced cancer

[seeWarnings and Precautions (5.5)]

]

Coverage for Xeljanz