Tofacitinib Solution
FDA Label NDC 70095-008

SERIOUS INFECTIONS

Patients treated with tofacitinib oral solution are at increased risk for developing serious bacterial, fungal, viral, and opportunistic infections, including tuberculosis (TB), that may lead to hospitalization or death [ see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Reported infections included:

• Active TB, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent TB before tofacitinib oral solution use and during therapy. Treatment for latent infection should be initiated prior to tofacitinib oral solution use.
• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

The risks and benefits of tofacitinib oral solution treatment should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after tofacitinib oral solution treatment, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. If a serious infection develops, interrupt tofacitinib oral solution until the infection is controlled [see Warnings and Precautions (5.1)] .

MORTALITY

In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular (CV) risk factor comparing XELJANZ tablets 5 mg or 10 mg twice a day to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden CV death, was observed with XELJANZ tablets 5 mg or 10 mg twice a day [see Warnings and Precautions (5.2)] . A tofacitinib oral solution 10 mg twice daily dosage is not recommended for the treatment of psoriatic arthritis (PsA), or polyarticular course juvenile idiopathic arthritis (pcJIA) [see Dosage and Administration (2.4)] .

MALIGNANCIES

Malignancies, including lymphomas and solid tumors, have occurred in patients treated with XELJANZ tablets and other Janus kinase inhibitors used to treat inflammatory conditions.

In RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with XELJANZ tablets 5 mg or 10 mg twice a day compared with TNF blockers [see Warnings and Precautions (5.3)] .

Lymphomas and lung cancers were observed at a higher rate in patients treated with XELJANZ tablets 5 mg or 10 mg twice a day in RA patients compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.

MAJOR ADVERSE CARDIOVASCULAR EVENTS

RA patients 50 years of age and older with at least one cardiovascular risk factor, treated with XELJANZ tablets 5 mg or 10 mg twice daily, had a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke), compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue tofacitinib oral solution in patients that have experienced a myocardial infarction or stroke [see Warnings and Precautions (5.4)] .

THROMBOSIS

Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis have occurred in patients treated with XELJANZ tablets and other Janus kinase inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death. RA patients 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ tablets 5 mg or 10 mg twice daily compared to TNF blockers had an observed increase in incidence of these events. Avoid tofacitinib oral solution in patients at risk. Discontinue tofacitinib oral solution and promptly evaluate patients with symptoms of thrombosis [see Warnings and Precautions (5.5)] .

Tofacitinib oral solution is indicated for the treatment of pediatric patients 2 years of age and older with active psoriatic arthritis (PsA), who have had an inadequate response or intolerance to one or more TNF blockers.

Limitations of Use

Use of tofacitinib oral solution in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Tofacitinib oral solution is indicated for the treatment of pediatric patients 2 years of age and older with of active polyarticular course juvenile idiopathic arthritis (pcJIA), who have had an inadequate response or intolerance to one or more TNF blockers.

Limitations of Use

Use of tofacitinib oral solution in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Prior to initiating tofacitinib oral solution, consider performing the following:

• Active and latent tuberculosis (TB) infection evaluation: If the patient has latent TB, treat for TB prior to tofacitinib treatment [see Warnings and Precautions (5.1)].
• Viral hepatitis screening in accordance with clinical guidelines [see Warnings and Precautions (5.1)].
• A complete blood count: Avoid initiation of tofacitinib treatment in patients with a lymphocyte count less than 500 cells/mm ³, absolute neutrophil count less than 1,000 cells/mm ³, or hemoglobin level less than 9 g/dL [see Warnings and Precautions (5.8)].
• Baseline hepatic function evaluation: tofacitinib is not recommended for patients with severe hepatic impairment [see Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)].
• Update immunizations according to current immunization guidelines. The interval between live vaccinations and initiation of tofacitinib should be in accordance with current vaccination guidelines regarding immunosuppressive agents [see Warnings and Precautions (5.9)].

• XELJANZ XR (extended-release tablets) is not substitutable with tofacitinib oral solution. Switching between tofacitinib oral solution and XELJANZ XR should be made by the healthcare provider.
• Dose interruption is recommended for management of lymphopenia, neutropenia, and anemia [see Warnings and Precautions (5.8)and Adverse Reactions (6.1)] .
• Interrupt use of tofacitinib if a patient develops a serious infection until the infection is controlled [see Warnings and Precautions (5.1)] .
• Take tofacitinib oral solution with or without food [see Clinical Pharmacology (12.3)] .

Table 2 displays the recommended body weight-based dosages for XELJANZ tablets and tofacitinib oral solution in pediatric patients 2 years of age and older with PsA or pcJIA [see Indication and Usage (1.2, 1.4)] with and without renal impairment (including those who are undergoing hemodialysis) or hepatic impairment [see Use in Specific Populations (8.6, 8.7)]. The table also includes recommended dosage modification for pediatric patients concomitantly using CYP2C19 and/or CYP3A4 inhibitors [see Drug Interactions (7)and Clinical Pharmacology (12.3)] , and pediatric patients with lymphopenia, neutropenia, or anemia.

Administer tofacitinib oral solution using the included press-in bottle adapter and oral dosing syringe [see Instructions for Use] .

Table 2: Recommended Dosage of XELJANZ Tablets and Tofacitinib Oral Solution in Pediatric Patients 2 Years of Age and Older with PsA or pcJIA

^a Excludes patients who concomitantly use XELJANZ tablets and tofacitinib oral solution with strong CYP3A4 inhibitor(s) or moderate CYP3A4 inhibitor(s) and strong CYP2C19 inhibitor(s), as well as patients with lymphocyte count less than 500 cells/mm ³, ANC <1,000 cells/mm ³, or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL.

^b Patients treated with tofacitinib oral solution 5 mL may be switched to XELJANZ tablets 5 mg.

Tofacitinib oral solution:

1 mg/mL of tofacitinib: Clear, colorless oral solution.

None.

Serious and sometimes fatal infections may occur with tofacitinib oral solution. Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. The most common serious infections reported with tofacitinib included pneumonia, urinary tract infection, cellulitis, herpes zoster, bronchitis, septic shock, diverticulitis, gastroenteritis, appendicitis, and sepsis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multi−dermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with tofacitinib. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids.

Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis).

Avoid use of tofacitinib oral solution in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating tofacitinib oral solution in patients:

• with chronic or recurrent infection
• who have been exposed to tuberculosis
• with a history of a serious or an opportunistic infection
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
• with underlying conditions that may predispose them to infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with tofacitinib oral solution. Interrupt tofacitinib oral solution if a patient develops a serious infection, an opportunistic infection, or sepsis. In patients who develop a new infection during treatment with tofacitinib oral solution, promptly complete diagnostic testing appropriate for an immunocompromised patient; initiate appropriate antimicrobial therapy, and monitor the patients closely.

Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections.

Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Discontinuation and monitoring criteria for lymphopenia are recommended [see Dosage and Administration (2.4)].

Tuberculosis

Evaluate and test patients for latent or active tuberculosis (TB) infection prior to and per applicable guidelines during administration of tofacitinib oral solution.

Consider anti-TB therapy prior to administration of tofacitinib oral solution in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection.

Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient.

Monitor patients closely for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy.

Treat patients with latent TB with standard antimycobacterial therapy before administering tofacitinib oral solution.

Viral Reactivation

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with tofacitinib. Postmarketing cases of hepatitis B reactivation have been reported in patients treated with tofacitinib. The impact of tofacitinib oral solution on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Perform screening for viral hepatitis in accordance with clinical guidelines before starting therapy with tofacitinib oral solution. The risk of herpes zoster is increased in patients treated with tofacitinib oral solution and appears to be higher in patients treated with tofacitinib in Japan and Korea.

Increased risk of mortality may occur with tofacitinib oral solution. Adult patients with rheumatoid arthritis (RA), 50 years of age and older, with at least one cardiovascular risk factor treated with XELJANZ tablets 5 mg or 10 mg twice a day had a higher observed rate of all-cause mortality, including sudden cardiovascular death, compared to those treated with TNF blockers in a large, randomized, postmarketing safety study (RA Safety Study 1). The incidence rate of all-cause mortality per 100 patient-years was 1.23 for XELJANZ tablets 10 mg twice a day, 0.88 for XELJANZ tablets 5 mg twice a day, and 0.69 for TNF blockers [see Clinical Studies (14.6)] . Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with tofacitinib oral solution.

A tofacitinib oral solution 10 mg twice daily dosage is not recommended for the treatment of PsA or pcJIA [see Dosage and Administration (2.4)] .

Malignancies and lymphoproliferative disorders may occur with tofacitinib oral solution. Malignancies, including lymphomas and solid cancers, were observed in clinical studies of tofacitinib [see Adverse Reactions (6.1)].

Other malignancies were observed in tofacitinib clinical studies and the postmarketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer.

In RA Safety Study 1, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with XELJANZ tablets 5 mg or 10 mg twice a day compared with TNF blockers. The incidence rate of malignancies (excluding NMSC) per 100 patient-years was 1.13 for XELJANZ tablets 10 mg twice a day, 1.13 for XELJANZ tablets 5 mg twice a day, and 0.77 for TNF blockers. Patients who are current or past smokers are at additional increased risk [see Clinical Studies (14.6)].

Lymphomas and lung cancers, which are a subset of all malignancies in RA Safety Study 1, were observed at a higher rate in patients treated with XELJANZ tablets 5 mg twice a day and XELJANZ tablets 10 mg twice a day compared to those treated with TNF blockers. The incidence rate of lymphomas per 100 patient-years was 0.11 for XELJANZ tablets 10 mg twice a day, 0.07 for XELJANZ tablets 5 mg twice a day, and 0.02 for TNF blockers. The incidence rate of lung cancers per 100 patient-years among current and past smokers was 0.59 for XELJANZ tablets 10 mg twice a day, 0.48 for XELJANZ tablets 5 mg twice a day, and 0.27 for TNF blockers [see Clinical Studies (14.6)] .

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with tofacitinib oral solution, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy while on treatment, and patients who are current or past smokers. A tofacitinib oral solution 10 mg twice daily dosage is not recommended for the treatment of PsA or pcJIA [see Dosage and Administration (2.4)] .

Non-Melanoma Skin Cancer

Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ tablets. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Major adverse cardiovascular events may occur with tofacitinib oral solution. In RA Safety Study 1, patients with RA who were 50 years of age and older with at least one cardiovascular risk factor and treated with XELJANZ tablets 5 mg or 10 mg twice daily had a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke, compared to those treated with TNF blockers. The incidence rate of MACE per 100 patient-years was 1.11 for XELJANZ tablets 10 mg twice a day, 0.91 for XELJANZ tablets 5 mg twice a day, and 0.79 for TNF blockers. The incidence rate of fatal or non-fatal myocardial infarction per 100 patient-years was 0.39 for XELJANZ tablets 10 mg twice a day, 0.36 for XELJANZ tablets 5 mg twice a day, and 0.2 for TNF blockers [see Clinical Studies (14.6)] . Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with tofacitinib oral solution, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Inform patients about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue tofacitinib oral solution in patients that have experienced a MI or stroke. A tofacitinib oral solution 10 mg twice daily dosage is not recommended for the treatment of PsA or pcJIA [see Dosage and Administration (2.4)] .

Thrombosis may occur with tofacitinib oral solution. Thrombosis, including pulmonary embolism (PE), deep venous thrombosis (DVT), and arterial thrombosis, have occurred in patients treated with tofacitinib and other Janus kinase (JAK) inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death [see Warnings and Precautions (5.2)] .

Patients with RA 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ tablets 5 mg or 10 mg twice daily compared to TNF blockers in RA Safety Study 1 had an observed increase in incidence of these thrombotic events. The incidence rate of DVT per 100 patient-years was 0.28 for XELJANZ tablets 10 mg twice a day, 0.22 for XELJANZ tablets 5 mg twice a day, and 0.16 for TNF blockers. The incidence rate of PE per 100 patient-years was 0.49 for XELJANZ tablets 10 mg twice a day, 0.18 for XELJANZ tablets 5 mg twice a day, and 0.05 for TNF blockers [see Clinical Studies (14.6)] .

A tofacitinib oral solution 10 mg twice daily dosage is not recommended for the treatment of PsA or pcJIA [see Dosage and Administration (2.4)] .

Promptly evaluate patients with symptoms of thrombosis and discontinue tofacitinib oral solution in patients with symptoms of thrombosis.

Avoid tofacitinib oral solution in patients that may be at increased risk of thrombosis.

Gastrointestinal perforations may occur with tofacitinib oral solution. Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ tablets, although the role of JAK inhibition in these events is not known. In these studies, many patients with RA received background therapy with nonsteroidal anti-inflammatory drugs (NSAIDs).

There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ tablets treatment groups in clinical trials of patients with UC, and many of them were receiving background corticosteroids.

Promptly evaluate patients treated with tofacitinib oral solution who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs) and who present with new onset abdominal symptoms for early identification of gastrointestinal perforation [see Adverse Reactions (6.1)] .

Hypersensitivity reactions may occur with tofacitinib oral solution. Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving tofacitinib oral solution. Some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib oral solution while evaluating the potential cause or causes of the reaction [see Adverse Reactions (6.2)] .

Laboratory abnormalities may occur with tofacitinib oral solution.

Lymphocyte Abnormalities

Treatment with XELJANZ tablets was associated with initial lymphocytosis at one month of XELJANZ tablets treatment followed by a gradual decrease in mean absolute lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm ³ in these patients were associated with an increased incidence of treated and serious infections.

• Monitor lymphocyte counts at baseline and every 3 months thereafter.
• Avoid initiation of tofacitinib oral solution treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm ³). In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm ³, treatment with tofacitinib oral solution is not recommended.

Neutropenia

Treatment with XELJANZ tablets was associated with an increased incidence of neutropenia (less than 2,000 cells/mm ³) compared to treatment with placebo.

• Monitor neutrophil counts at baseline and after 4 to 8 weeks of treatment and every 3 months thereafter.
• Avoid initiation of tofacitinib oral solution treatment in patients with a low neutrophil count (i.e., ANC less than 1,000 cells/mm ³). For patients who develop a persistent ANC of 500 to 1,000 cells/mm ³, interrupt dosing until ANC is greater than or equal to 1,000 cells/mm ³. In patients who develop an ANC less than 500 cells/mm ³, treatment with tofacitinib oral solution is not recommended.

Anemia

• Monitor hemoglobin at baseline and after 4 to 8 weeks of treatment and every 3 months thereafter.
• Avoid initiation of tofacitinib oral solution treatment in patients with a low hemoglobin level (i.e., less than 9 g/dL). Interrupt treatment with tofacitinib oral solution in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment until hemoglobin values have normalized.

Liver Enzyme Elevations

Treatment with XELJANZ tablets was associated with an increased incidence of liver enzyme elevation compared to treatment with placebo. Most of these abnormalities occurred in studies with background DMARD therapy (primarily methotrexate).

• Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury.
• If drug-induced liver injury is suspected, interrupt the administration of tofacitinib oral solution until this diagnosis has been excluded.

Lipid Elevations

Treatment with XELJANZ tablets was associated with dose-dependent increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum changes in these lipid parameters were generally observed within 6 weeks. There were no clinically relevant changes in LDL/HDL cholesterol ratios. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

• Perform assessment of lipid parameters approximately 4 to 8 weeks following initiation of tofacitinib oral solution therapy.
• Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.

Avoid use of live vaccines concurrently with tofacitinib oral solution. Prior to initiating tofacitinib oral solution therapy, update immunizations in agreement with current immunization guidelines. The interval between live vaccinations and initiation of tofacitinib oral solution therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Serious Infections [see Warnings and Precautions (5.1)]
• Increased Risk of Mortality [see Warnings and Precautions (5.2)]
• Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions (5.3)]
• Major Adverse Cardiovascular Events [see Warnings and Precautions (5.4)]
• Thrombosis [see Warnings and Precautions (5.5)]
• Gastrointestinal Perforations [see Warnings and Precautions (5.6)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.7)]
• Laboratory Abnormalities [see Warnings and Precautions (5.8)]

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 tablets” in this subsection of labeling) and/or tofacitinib oral solution.

Adverse Reactions in Adults with Rheumatoid Arthritis

In RA Safety Study 1, 1,455 adults were treated with XELJANZ tablets 5 mg twice daily, 1,456 adults were treated with 10 mg twice daily, and 1,451 adults were treated with a TNF blocker for a median of 4 years [see Clinical Studies (14.6)] .

The safety of XELJANZ tablets was also evaluated in two Phase 2 and five Phase 3 double-blind, placebo-controlled, multicenter trials in patients with RA. In these trials, adults were randomized to receive:

• XELJANZ tablets (monotherapy) 5 mg twice daily (292 patients) or 10 mg twice daily (306 patients),
• In combination with DMARDs (including methotrexate), XELJANZ tablets 5 mg twice daily (1,044 patients) or 10 mg twice daily (1,043 patients and
• Placebo (809 patients).

All seven trials included provisions for patients taking placebo to receive treatment with XELJANZ tablets at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore, some analyses that follow include patients who changed treatment by design or by patient response from placebo to XELJANZ tablets in both the placebo and XELJANZ tablets group of a given interval. Comparisons between placebo and XELJANZ tablets groups were based on the first 3 months of exposure, and comparisons between XELJANZ tablets 5 mg twice daily and XELJANZ tablets 10 mg twice daily were based on the first 12 months of exposure.

The long-term safety population includes all adults with RA who participated in a double-blind, placebo-controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. The design of the long-term safety studies allowed for modification of XELJANZ tablets doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose.

The most common serious adverse reactions were serious infections [see Warnings and Precautions (5.1)] .

The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for XELJANZ tablets-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 tablets 5 mg twice daily and XELJANZ tablets 10 mg twice daily groups, respectively, and 18% in the placebo group.

The most commonly reported infections with XELJANZ tablets 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 tablets 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 tablets 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 tablets 5 mg twice daily and 33 patients (2.7 events per 100 patient-years) who received XELJANZ tablets 10 mg twice daily. The rate difference between XELJANZ tablets doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for XELJANZ tablets 10 mg twice daily minus XELJANZ tablets 5 mg twice daily.

The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection [see Warnings 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 tablets 5 mg twice daily, or XELJANZ tablets 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 tablets 5 mg twice daily and 6 patients (0.5 events per 100 patient-years) who received XELJANZ tablets 10 mg twice daily. The rate difference between XELJANZ tablets doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for XELJANZ tablets 10 mg twice daily minus XELJANZ tablets 5 mg twice daily.

Cases of disseminated TB were also reported. The median XELJANZ tablets exposure prior to diagnosis of TB was 10 months (range from 152 to 960 days) [see Warnings 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 tablets 5 mg twice daily, or XELJANZ tablets 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 tablets 5 mg twice daily and 4 patients (0.3 events per 100 patient-years) who received XELJANZ tablets 10 mg twice daily. The rate difference between XELJANZ tablets doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for XELJANZ tablets 10 mg twice daily minus XELJANZ tablets 5 mg twice daily.

The median XELJANZ tablets exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days) [see Warnings 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 tablets 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 tablets 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 tablets 5 mg twice daily and 7 patients (0.6 events per 100 patient-years) who received XELJANZ tablets 10 mg twice daily. The rate difference between XELJANZ tablets doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for XELJANZ tablets 10 mg twice daily minus XELJANZ tablets 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 tablets 10 mg twice daily.

The most common types of malignancy, including malignancies observed during the long-term extension in XELJANZ tablets-treated patients, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma [see Warnings 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/mm ³ occurred in 0.04% of patients for the XELJANZ tablets 5 mg twice daily and 10 mg twice daily groups combined during the first 3 months of exposure.

Confirmed lymphocyte counts less than 500 cells/mm ³ were associated with an increased incidence of treated and serious infections [see Warnings and Precautions (5.8)].

Neutropenia: In the placebo-controlled clinical trials in patients with RA, confirmed decreases in ANC below 1,000 cells/mm ³ occurred in 0.07% of patients for the XELJANZ tablets 5 mg twice daily and 10 mg twice daily groups combined during the first 3 months of exposure.

There were no confirmed decreases in ANC below 500 cells/mm ³ observed in any treatment group. There was no clear relationship between neutropenia and the occurrence of serious infections.

In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the placebo-controlled clinical trials [see Warnings and Precautions (5.8)].

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

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

In the placebo-controlled background DMARD trials (0 to 3 months), ALT elevations greater than 3x ULN were observed in 1%, 1.3% and 1.2% of patients who received placebo, XELJANZ tablets 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3x ULN were observed in 0.6%, 0.5% and 0.4% of patients who received placebo, XELJANZ tablets 5 mg, and 10 mg twice daily, respectively.

One case of drug-induced liver injury was reported in a patient treated with XELJANZ tablets 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x 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 tablets 5 mg twice daily arm and 19% in the XELJANZ tablets 10 mg twice daily arm.
• Mean HDL cholesterol increased by 10% in the XELJANZ tablets 5 mg twice daily arm and 12% in the XELJANZ tablets 10 mg twice daily arm.
• Mean LDL/HDL ratios were essentially unchanged in XELJANZ tablets -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 tablets 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 tablets 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 tablets 5 mg or 10 mg twice daily and at least 1% greater than in XELJANZ tablets -treated patients that observed in placebo-treated patients with or without DMARD in the RA trials.

Table 5: Common Adverse Reactions ^*in Clinical Trials of XELJANZ tablets for the Treatment of Rheumatoid Arthritis in Adults With or Without Concomitant DMARDs (0 to 3 Months)

Preferred Term	Placebo	XELJANZ Tablets 5 mg Twice Daily	XELJANZ Tablets 10 mg Twice Daily **
	N = 809 (%)	N = 1,336 (%)	N = 1,349 (%)
Upper respiratory tract infection	3	4	4
Nasopharyngitis	3	4	3
Diarrhea	2	4	3
Headache	2	4	3
Hypertension	1	2	2

N reflects randomized and treated patients from the seven placebo-controlled clinical trials.

^*reported in ≥ 2% of patients treated with either dose of XELJANZ tablets and ≥ 1% greater than that reported for placebo.

^**The recommended dose of XELJANZ tablets for the treatment of RA is 5 mg twice daily [see Dosage and Administration (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

Adverse Reactions in Adults with Psoriatic Arthritis

The safety of XELJANZ tablets 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 tablets 5 mg twice daily and 236 patients were randomized and treated with XELJANZ tablets 10 mg twice daily. A dosage of XELJANZ tablets 10 mg twice daily is not recommended for the treatment of PsA.

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 tablets (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 tablets 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 tablets.

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

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

XELJANZ tablets or tofacitinib 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 [see Clinical 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 tofacitinib 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 (see Adverse Reactions in Adults with Rheumatoid Arthritis and Adverse Reactions in Adults with Psoriatic Arthritis).

The following adverse reactions have been identified during post-approval use of XELJANZ tablets/tofacitinib oral solution and XELJANZ XR (extended-release tablets). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders:Drug hypersensitivity (events such as angioedema and urticaria have been observed)

Skin and subcutaneous tissue disorders:Acne

Table 7 includes drugs with clinically significant drug interactions when concomitantly used with tofacitinib oral solution and instructions for preventing or managing them.

Table 7: Clinically Significant Interactions Affecting Tofacitinib Oral Solution When Concomitantly Used with Other Drugs

Risk Summary

The available data with XELJANZ Tablets/tofacitinib oral solution and XELJANZ XR (extended-release tablets) from a pregnancy exposure registry that enrolled 11 exposed pregnant females, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with RA and UC in pregnancy (see Clinical Considerations). In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively. Further, in a peri- and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dosage of 5 mg twice daily and approximately 36 times the maximum recommended dosage of 10 mg twice daily, respectively (see Data).

The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk: Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with RA or UC. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 grams) infants, and small for gestational age at birth.

Data

Animal In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the recommended dose of 5 mg twice daily, and approximately 73 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the recommended dose of 5 mg twice daily, and approximately 29 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats).

In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the recommended dose of 5 mg twice daily, and approximately 6.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the recommended dose of 5 mg twice daily, and approximately 1.5 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits).

In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the recommended dose of 5 mg twice daily, and approximately 36 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the recommended dose of 5 mg twice daily, and approximately 8.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats).

Risk Summary

Based on published data, tofacitinib is present in human milk. Data on the effects of tofacitinib on the breastfed infant is limited to a small number of cases with no reported adverse effects. There are no data on the effects on milk production. Given the serious adverse reactions seen in patients treated with tofacitinib oral solution, such as increased risk of serious infections, advise patients that breastfeeding is not recommended during treatment and for at least 18 hours after the last dose of tofacitinib oral solution.

Data

Following administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum and were approximately 2 times higher in milk relative to maternal serum at all time points measured.

Contraception

Females

In an animal reproduction study, tofacitinib at AUC multiples of 13 times the recommended dosage of 5 mg twice daily and 6.3 times the maximum recommended dosage of 10 mg twice daily demonstrated adverse embryo-fetal findings [see Use in Specific Populations (8.1)] . However, there is uncertainty as to how these animal findings relate to females of reproductive potential treated with the recommended clinical dosage. Consider pregnancy planning and prevention for females of reproductive potential.

Infertility

Females

Based on findings in rats, treatment with tofacitinib oral solution may result in reduced fertility in females of reproductive potential. It is not known if this effect is reversible [see Nonclinical Toxicology (13.1)] .

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

Polyarticular Course Juvenile Idiopathic Arthritis (pcJIA)

The safety and effectiveness of tofacitinib 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 tofacitinib oral solution 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 tofacitinib in pediatric patients 2 years and older with active pcJIA (Study pcJIA-I) [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.4)] .

Adverse reactions observed in pediatric patients with pcJIA who received tofacitinib were consistent with those reported in adults with RA [see Adverse Reactions (6.1)] .

Psoriatic Arthritis

The safety and effectiveness of tofacitinib 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 tofacitinib for this indication is supported by evidence from well-controlled studies of tofacitinib tablets in adults with PsA, PK data from adults with PsA, and PK data from a clinical trial of tofacitinib in 225 pediatric patients with JIA, and safety data from 280 pediatric patients 2 years of age and older with JIA [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. Following administration of the recommended tofacitinib 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 Clinical Pharmacology (12.3)].

Systemic Juvenile Idiopathic Arthritis

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

Additional pediatric information describing a clinical study in which efficacy was not demonstrated is approved for Pfizer Inc.’s Xeljanz (tofacitinib) oral solution. However, due to Pfizer Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

Of the 3,315 adults who were enrolled in clinical trials with RA, a total of 505 patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among XELJANZ tablets-treated patients 65 years of age and older was higher than among those adults under the age of 65.

Of the 783 XELJANZ tablet-treated patients in clinical trials of patients with PsA, a total of 72 (9.2%) patients were 65 years of age and older, including 2 (0.3%) patients 75 years and older. These clinical studies did not include sufficient numbers of patients aged 65 years and older with PsA to determine if they respond differently from younger adult patients.

Moderate and Severe Renal Impairment

Tofacitinib-treated patients with moderate renal impairment (RI) (CLcr ≥ 30 and ≤ 50 mL/minute) or severe RI (< 30 mL/minute) had greater tofacitinib blood concentrations than tofacitinib-treated patients with normal renal function (CLcr > 80 mL/minute). The recommended dosage of tofacitinib oral solution in patients with moderate or severe RI (including those with severe RI who are undergoing hemodialysis) is lower than the recommended dosage in patients with normal renal function [see Dosage and Administration (2.4)] .

Mild Renal Impairment

The recommended dosage in patients with mild RI (CLcr > 50 and ≤ 80 mL/minute) is the same as patients with normal renal function.

Severe Hepatic Impairment

Tofacitinib oral solution has not been studied in patients with severe hepatic impairment (HI) (Child-Pugh C); therefore, use of tofacitinib in patients with severe HI is not recommended.

Moderate Hepatic Impairment

Tofacitinib-treated patients with moderate hepatic impairment (Child-Pugh B) had greater tofacitinib blood concentration than tofacitinib-treated patients with normal hepatic function [see Clinical Pharmacology (12.3)] . Higher blood concentrations may increase the risk of some adverse reactions. The recommended tofacitinib oral solution dosage in patients with moderate HI is lower than the recommended dosage in patients with normal hepatic function [see Dosage and Administration (2.4)] .

Mild Hepatic Impairment

The recommended dosage of tofacitinib in patients with mild hepatic impairment (Child-Pugh A) is the same as patients with normal hepatic function.

Hepatitis B or C Serology

The safety and efficacy of tofacitinib have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.

There is no specific antidote for overdose with tofacitinib oral solution. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions.

In a study in patients with end-stage renal disease (ESRD) undergoing hemodialysis, plasma tofacitinib concentrations declined more rapidly during the period of hemodialysis and dialyzer efficiency, calculated as dialyzer clearance/blood flow entering the dialyzer, was high [mean (SD) = 0.73 (0.15)]. However, due to the significant non-renal clearance of tofacitinib, the fraction of total elimination occurring by hemodialysis was small, and thus, limits the value of hemodialysis for treatment of overdose with tofacitinib.

Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

Tofacitinib oral solution is formulated with the citrate salt of tofacitinib, a JAK inhibitor.

Tofacitinib citrate is a white to off-white powder with the following chemical name: (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin-4-yl)amino)-ß-oxo-1­ piperidinepropanenitrile, 2-hydroxy-1,2,3-propanetricarboxylate (1:1).

The solubility of tofacitinib citrate in water is 2.38 mg/mL.

Tofacitinib citrate has a molecular weight of 504.5 Daltons (or 312.4 Daltons as the tofacitinib free base) and a molecular formula of C ₁₆H ₂₀N ₆O•C ₆H ₈O ₇. The chemical structure of tofacitinib citrate is:

Tofacitinib oral solution is supplied for oral administration as a 1 mg/mL clear, colorless solution. Each 1 mL of tofacitinib oral solution contains 1 mg of tofacitinib (equivalent to 1.62 mg of tofacitinib citrate) and the following inactive ingredients: grape flavor (natural), hydrochloric acid, L-lactic acid, purified water, sodium benzoate, sodium hydroxide, sucralose, and xylitol. Grape flavor (natural) contains propylene glycol and natural flavor.

Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitroactivities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.

Treatment with tofacitinib was associated with dose-dependent reductions of circulating CD16/56+ natural killer cells, with estimated maximum reductions occurring at approximately 8 to 10 weeks after initiation of therapy. These changes generally resolved within 2 to 6 weeks after discontinuation of treatment. Treatment with tofacitinib was associated with dose-dependent increases in B cell counts. Changes in circulating T-lymphocyte counts and T-lymphocyte subsets (CD3+, CD4+ and CD8+) were small and inconsistent. The clinical significance of these changes is unknown.

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

After treatment with tofacitinib in patients with RA, rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout dosing. Changes in CRP observed with tofacitinib treatment do not reverse fully within 2 weeks after discontinuation, indicating a longer duration of pharmacodynamic activity compared to the pharmacokinetic half-life.

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

Following oral administration of XELJANZ tablets and tofacitinib oral solution, peak plasma concentrations were reached within 0.5 hour to 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 to 48 hours with negligible accumulation after twice daily administration.

Absorption

TofacitinibThe absolute oral bioavailability of tofacitinib is 74%. Coadministration of tofacitinib with a high-fat meal resulted in no changes in AUC while C _max was reduced by 32%. In clinical trials, tofacitinib was administered without regard to meals [see Dosage and Administration (2.2)] .

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 a1-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%.

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 [see Dosage and Administration (2.4)and Use in Specific Populations (8.6)] .

Drug Interaction Studies

Potential for Tofacitinib to Influence the PK of Other Drugs

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

In vitrostudies 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 tofacitinib is not expected to result in clinically relevant increases in the metabolism of CYP substrates in patients with RA.

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

The impact of tofacitinib on the PK of other drugs for the concomitant drugs are shown in Figure 2.

Figure 2: Impact of Tofacitinib on the Pharmacokinetics of Other Drugs

Note: Reference group is administration of concomitant medication alone; OCT = Organic Cationic Transporter; MATE = Multidrug and Toxic Compound Extrusion.

Potential for Other Drugs to Influence the Pharmacokinetics of Tofacitinib

Since tofacitinib is metabolized by CYP3A4, interaction with drugs that inhibit or induce CYP3A4 is likely. Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to substantially alter the pharmacokinetics of tofacitinib (see Figure 3).

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

Note: Reference group is administration of tofacitinib alone.

In a 39-week toxicology study in monkeys, tofacitinib at exposure levels approximately 6 times the recommended dose of 5 mg twice daily, and approximately 3 times the 10 mg twice daily dose (on an AUC basis at oral doses of 5 mg/kg twice daily) produced lymphomas. No lymphomas were observed in this study at exposure levels 1 times the recommended dose of 5 mg twice daily, and approximately 0.5 times the 10 mg twice daily dose (on an AUC basis at oral doses of 1 mg/kg twice daily).

The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib, at exposure levels approximately 34 times the recommended dose of 5 mg twice daily, and approximately 17 times the 10 mg twice daily dose (on an AUC basis at oral doses of 200 mg/kg/day) was not carcinogenic in mice.

In the 24-month oral carcinogenicity study in Sprague-Dawley rats, tofacitinib caused benign Leydig cell tumors, hibernomas (malignancy of brown adipose tissue), and benign thymomas at doses greater than or equal to 30 mg/kg/day (approximately 42 times the exposure levels at the recommended dose of 5 mg twice daily, and approximately 21 times the 10 mg twice daily dose on an AUC basis). The relevance of benign Leydig cell tumors to human risk is not known.

Tofacitinib was not mutagenic in the bacterial reverse mutation assay. It was positive for clastogenicity in the in vitro chromosome aberration assay with human lymphocytes in the presence of metabolic enzymes, but negative in the absence of metabolic enzymes. Tofacitinib was negative in the in vivorat micronucleus assay and in the in vitro CHO-HGPRT assay and the in vivo rat hepatocyte unscheduled DNA synthesis assay.

In rats, tofacitinib at exposure levels approximately 17 times the recommended dose of 5 mg twice daily, and approximately 8.3 times the 10 mg twice daily dose (on an AUC basis at oral doses of 10 mg/kg/day) reduced female fertility due to increased post-implantation loss. There was no impairment of female rat fertility at exposure levels of tofacitinib equal to the recommended dose of 5 mg twice daily, and approximately 0.5 times the 10 mg twice daily dose (on an AUC basis at oral doses of 1 mg/kg/day). Tofacitinib exposure levels at approximately 133 times the recommended dose of 5 mg twice daily, and approximately 67 times the 10 mg twice daily dose (on an AUC basis at oral doses of 100 mg/kg/day) had no effect on male fertility, sperm motility, or sperm concentration.

The psoriatic arthritis (PsA) clinical development program with XELJANZ tablets (referred to as “XELJANZ tablets” 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, tofacitinib oral solution is not approved for use in TNF blocker-naïve patients [see Indications and Usage (1.2)]. Patients were randomized in a 2:2:2:1:1 ratio to receive XELJANZ tablets 5 mg twice daily, XELJANZ tablets 10 mg twice daily, adalimumab 40 mg subcutaneously once every 2 weeks, placebo to XELJANZ tablets 5 mg twice daily treatment sequence, or placebo to XELJANZ tablets 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 tablets dosage of 5 mg or 10 mg twice daily. Study PsA-I was not designed to demonstrate non-inferiority 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 tablets 5 mg twice daily, XELJANZ tablets 10 mg twice daily, placebo to XELJANZ tablets 5 mg twice daily treatment sequence, or placebo to XELJANZ tablets 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 tablets dosage of 5 mg or 10 mg twice daily as in Study PsA-I.

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

Clinical Response

At Month 3, patients treated with XELJANZ tablets 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 tablets 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-I ^*[Nonbiologic DMARD Inadequate Responders (TNF Blocker-Naïve)] ^**

Treatment Group	Placebo	XELJANZ Tablets 5 mg Twice Daily + Background Nonbiologic DMARD
N a	105	107
	Response Rate	Response Rate	Difference (%) 95% CI from Placebo
Month 3 ACR20 ACR50 ACR70	33% 10% 5%	50% 28% 17%	17.1 (4.1, 30.2) 18.5 (8.3, 28.7) 12.1 (3.9, 20.2)

Patients with missing data were treated as non-responders.

* Patients received one concomitant nonbiologic DMARD.

^**XELJANZ is not approved for use in TNF blocker-naïve patients [see Indications and Usage (1.2)].

^a N is number of randomized and treated patients.

Table 15: Proportion of Adults with Active PsA with an ACR Response at Month 3 in Study PsA-II ^*(TNF Blocker Inadequate Responders)

Treatment Group	Placebo	XELJANZ 5 mg Twice Daily
N a	131	131
	Response Rate	Response Rate	Difference (%) 95% CI from Placebo
Month 3 ACR20 ACR50 ACR70	24% 15% 10%	50% 30% 17%	26 (14.7, 37.2) 15.3 (5.4, 25.2) 6.9 (-1.3, 15.1)

Patients with missing data were treated as non-responders.

* Patients received one concomitant nonbiologic DMARD.

^a N is number of randomized and treated patients.

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 ***		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 Component a
Number of tender/painful joints (0 to 68) Baseline Month 3	20.6 14.6	20.5 12.2	19.8 15.1	20.5 11.5
Number of swollen joints (0 to 66) Baseline Month 3	11.5 7.1	12.9 6.3	10.5 7.7	12.1 4.8
Patient assessment of arthritis pain b Baseline Month 3	53.2 44.7	55.7 34.7	54.9 48	56.4 36.1
Patient global assessment of arthritis b Baseline Month 3	53.9 44.4	54.7 35.5	55.8 49.2	57.4 36.9
HAQ-DI c Baseline Month 3	1.11 0.95	1.16 0.81	1.25 1.09	1.26 0.88
Physician’s Global Assessment of Arthritis b Baseline Month 3	53.8 35.4	54.6 29.5	53.7 36.4	53.5 27
CRP (mg/L) Baseline Month 3	10.4 8.6	10.5 4	12.1 11.4	13.8 7.7

* Patients received one concomitant nonbiologic DMARD.

^**XELJANZ is not approved for use in TNF blocker-naïve patients [see Indications and Usage (1.2)].

^a Data shown are mean value at baseline and at Month 3.

^b Visual analog scale (VAS): 0 = best, 100 = worst.

c 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.

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 tablets was observed at the first visit after baseline (Week 2).

Figure 5: Percentage of ACR20 Responders by Visit Through Month 3 in Study PsA-I ^*,**

BID = twice daily; SE = standard error.

Patients with missing data were treated as non-responders.

* Subjects received one concomitant nonbiologic DMARD.

^**XELJANZ is not approved for use in TNF blocker-naïve patients [see Indications and Usage (1.2)].

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

Physical Function

Improvement in physical functioning was measured by the HAQ-DI. Patients receiving XELJANZ tablets 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 b (TNF Blocker-Naïve)		TNF Blocker Inadequate Responders c
	Study PsA-I ***		Study PsA-II *
Treatment Group	Placebo	XELJANZ 5 mg Twice Daily	Placebo	XELJANZ 5 mg Twice Daily
N a	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)

* Patients received one concomitant nonbiologic DMARD.

^**XELJANZ is not approved for use in TNF blocker-naïve patients [see Indications and Usage (1.2)].

a N is the total number of patients in the statistical analysis.

^b Inadequate response to at least one nonbiologic DMARD due to lack of efficacy and/or intolerability.

c Inadequate response to at least one TNF blocker due to lack of efficacy and/or intolerability.

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 tablets 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 tablets 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 tablets 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.

The efficacy of XELJANZ 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, tofacitinib is not approved for use in TNF blocker-naïve patients [see Indications and Usage (1.4)] .

Patients received tofacitinib (dosed at 5 mg twice daily or body weight-based equivalent twice daily) for 18 weeks (run-in phase) followed by randomization to either tofacitinib (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 tofacitinib (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%.

Tofacitinib-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.

A randomized open-label trial (RA Safety Study 1; NCT02092467) was conducted to evaluate safety with XELJANZ tablets (referred to as “XELJANZ tablets” in this subsection of labeling) at two doses, 5 mg twice daily (N=1,455) and 10 mg twice daily (N=1,456), versus the TNF-blocker control (N=1,451) in RA patients 50 years of age and older with at least one cardiovascular risk factor. The co-primary endpoints were adjudicated MACE (defined as cardiovascular death, non-fatal MI, and non-fatal stroke) and adjudicated malignancy (excluding non-melanoma skin cancer). The study was designed to exclude a prespecified risk margin of 1.8 for the hazard ratio of combined XELJANZ tablets regimens versus the TNF-blocker control for each co-primary endpoint. An independent committee conducted a blinded evaluation of the co-primary endpoints according to predefined criteria (adjudication). The study was event-driven and patients were followed until a sufficient number of primary outcome events accrued. Other endpoints included mortality, serious infections, and thromboembolic events. The median on-study follow-up time was 4 years.

The mean age of the population was 61 years (range: 50 to 88 years). Most patients were female (78%) and Caucasian (77%). Patients had a diagnosis of RA for a mean of 10 years, and a median swollen and tender joint count of 11 and 15 respectively. Cardiovascular risk factors included cigarette smoking (current or past) (48%), hypertension (66%), high density lipoprotein <40 mg/dL (12%), diabetes mellitus (17%), family history of premature coronary heart disease (15%), extra-articular disease associated with RA (37%), and history of coronary artery disease (11%).

The non-inferiority criterion was not met for the primary comparison of the combined XELJANZ tablets dosages to TNF blockers since the upper limit of the 95% CI exceeded the pre-specified non-inferiority criterion of 1.8 (for MACE, the upper limit of the 95% CI was 1.94; for malignancies excluding NMSC, the upper limit of the 95% CI was 2.09).

Table 22 shows the study results for each of the co-primary endpoints, and other endpoints. There was an increased risk of death, MACE, malignancies, serious infections, thromboembolic events, and fractures associated with both dosages of XELJANZ tablets.

Table 22: Results of RA Safety Study 1 in Adults with Rheumatoid Arthritis 50 years of Age and Older with at Least One Cardiovascular Risk Factor

Note: XELJANZ tablets 10 mg twice daily was discontinued by the Data Monitoring Committee due to safety concerns, and ongoing patients switched from XELJANZ tablets 10 mg to XELJANZ tablets 5 mg. The column “XELJANZ tablets 10 mg Twice Daily” includes all events and follow-up for patients randomized to XELJANZ tablets 10 mg twice daily. A tofacitinib oral solution 10 mg twice daily dosage is not recommended for the treatment of PsA or pcJIA.

N indicates number of patients; n indicates number of patients with events.

IR indicates incidence rate per 100 person-year (PY).

^†MI and Stroke include fatal and non-fatal events.

^††Data and analyses for Malignancies excluding NMSC for current and ex-smokers are included. There were 720 current and ex-smokers randomized to XELJANZ tablets 5 mg, 704 to XELJANZ tablets 10 mg, and 679 to TNF blockers.

*HR (95%) CI for XELJANZ tablets vs. TNF Blocker (Univariate Cox Proportional Hazard Model).

NMSC: Non-melanoma Skin Cancer; MACE: Major Adverse Cardiac Events; HR: Hazard Ratio; DVT: Deep Vein Thrombosis;

PE: Pulmonary Embolism; VTE: Venous Thromboembolism, first occurrence of a VTE, defined as the composite of adjudicated DVT and adjudicated PE; ATE: Arterial Thromboembolism; TE: Thromboembolism, first occurrence of a TE, defined as the composite of adjudicated VTE and unadjudicated ATE.

Lymphomas and lung cancers, which are a subset of all malignancies in RA Safety Study 1, were observed at a higher rate in patients treated with XELJANZ tablets 5 mg twice a day and XELJANZ tablets 10 mg twice a day compared to those treated with TNF blockers. Lymphoma was reported for 4 patients who received XELJANZ tablets 5 mg twice a day, 6 patients who received XELJANZ tablets 10 mg twice a day, and 1 patient who received TNF blockers (Incidence Rate [IR] of 0.07, 0.11, and 0.02 per 100 patient-years, respectively). Among current and past smokers, lung cancer was reported for 13 patients who received XELJANZ tablets 5 mg twice a day, 15 patients who received XELJANZ tablets 10 mg twice a day, and 7 patients who received TNF blockers (IR of 0.48, 0.59, and 0.27 per 100 patient-years, respectively).

Given these increased risks, a tofacitinib oral solution 10 mg twice daily dosage is not recommended for the treatment of PsA or pcJIA [see Dosage and Administration (2.4)] .

The overall fractures and osteoporotic fractures were observed at a higher rate in both XELJANZ tablets treatment groups compared to the TNF blocker treatment group. The observed incidence rate of osteoporotic fractures was higher in women than men, and was highest in women on XELJANZ tablets 10 mg twice daily (1.56 per 100 patient-years), followed by XELJANZ tablets 5 mg twice daily (1.26 per 100 patient-years), and TNF blockers (1.01 per 100 patient-years).

How supplied information for tofacitinib oral solution is shown in Table 23.

Table 23: How Supplied Information for Tofacitinib Oral Solution

Tofacitinib oral solution

Tofacitinib oral solution 1 mg/ mL is a clear, colorless solution that contains 1 mg of tofacitinib. It is packaged in HDPE bottles as follows:

Each bottle is packaged with one press-in bottle adapter and one 5 mL oral dosing syringe with 3.2 mL, 4 mL, and 5 mL gradations. The press-in bottle adapter and oral dosing syringe are not made with natural rubber latex.

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

Store in the original bottle and carton to protect from light.

Use contents of bottle within 60 days of opening.

Discard unused oral solution after 60 days.

Advise patients to read the FDA-approved patient labeling ( Medication Guide and Instructions for Use).

Serious Infections

Inform patients that tofacitinib oral solution may lower the ability of their immune system to fight infections. Advise patients not to start taking tofacitinib if they have an active infection. Instruct patients to contact their healthcare provider immediately during treatment if symptoms suggesting infection appear to ensure rapid evaluation and appropriate treatment [see Warnings and Precautions (5.1)] .

Advise patients that the risk of herpes zoster, some cases of which can be serious, is increased in patients treated with tofacitinib [see Warnings and Precautions (5.1)] .

Malignancies and Lymphoproliferative Disorders

Inform patients that tofacitinib may increase their risk of certain cancers, and that lymphoma and other cancers have been observed in patients taking tofacitinib. Instruct patients to inform their healthcare provider if they have ever had any type of cancer [see Warnings and Precautions (5.3)] .

Major Adverse Cardiovascular Events

Inform patients that tofacitinib may increase their risk of major adverse cardiovascular events (MACE) defined as myocardial infarction, stroke, and cardiovascular death. Instruct all patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events [see Warnings and Precautions (5.4)] .

Thrombosis

Advise patients to stop taking tofacitinib and to call their healthcare provider right away if they experience any symptoms of thrombosis (sudden shortness of breath, chest pain worsened with breathing, swelling of leg or arm, leg pain or tenderness, red or discolored skin in the affected leg or arm) [see Warnings and Precautions (5.5)] .

Hypersensitivity

Advise patients to stop taking tofacitinib and to call their healthcare provider right away if they experience any symptoms of allergic reactions while taking tofacitinib [see Warnings and Precautions (5.7)] .

Important Information on Laboratory Abnormalities

Inform patients that tofacitinib may affect certain lab test results, and that blood tests are required before and during tofacitinib treatment [see Warnings and Precautions (5.8)] .

Pregnancy

Advise pregnant females and females of reproductive potential of the potential risk to a fetus. Advise females to inform their prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise women not to breastfeed during treatment with tofacitinib and for at least 18 hours after the last dose of tofacitinib [see Use in Specific Populations (8.2)].

Infertility

Advise females of reproductive potential that tofacitinib may impair fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)] . It is not known if this effect is reversible.

Manufactured by:

Ohm Laboratories Inc.

New Brunswick, NJ 08901

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

All trademarks are the property of their respective owners.

XELJANZ/XELJANZ XR is a registered trademark of Pfizer Inc.

Revised: 05/2026

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: May 2026

INSTRUCTIONS FOR USE

Tofacitinib (toe-fa-sye-ti-nib) Oral Solution

Read this Instructions for Use before you start taking tofacitinib oral solution and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment.

Important information about measuring tofacitinib oral solution:

Always use the oral dosing syringe that comes with tofacitinib oral solution to measure and take your prescribed dose. Ask your healthcare provider or pharmacist to show you how to measure your prescribed dose if you are not sure.

How should I store tofacitinib oral solution?

• Store tofacitinib oral solution at room temperature, 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
• Always store tofacitinib oral solution in the original bottle and carton to protect from light.

Keep tofacitinib and all medicines out of the reach of children.

Use tofacitinib oral solution within 60 days of opening the bottle. Throw away (discard) remaining tofacitinib oral solution after 60 days.

To help you remember when to throw away your bottle of tofacitinib oral solution, you can write the date when you first start to use it on the carton and below:

Date of first use ____ / ____ / ____.

Before each use:

Wash your hands with soap and water and place the items from the carton on a clean, flat surface.

Each carton of tofacitinib oral solution contains:

• 1 press-in bottle adapter
• 1 bottle of tofacitinib oral solution
• 1 oral dosing syringe

Step 1. Remove bottle from carton

Open the carton and remove the bottle of tofacitinib oral solution.

Step 2. Open bottle

Open the bottle by pushing down on the child-resistant cap and turning it to the left (counter-clockwise) as shown.

Remove the seal off the top of the bottle (first time only).

Do not throw away the child-resistant cap.

Note:The bottle does not need to be shaken before use.

Step 3. Insert press-in bottle adapter (first time only)

Remove the press-in bottle adapter and oral dosing syringe from the plastic overwrap. With the bottle on a flat surface, push the ribbed end of the press-in bottle adapter all the way into the neck of the bottle with your thumbs while holding the bottle firmly.

Note: Do not remove the press-in bottle adapter from the bottle after it is inserted.

Step 4. Remove air from oral dosing syringe

Push the oral dosing syringe plunger all the way down to the tip of the syringe barrel to remove excess air.

Step 5. Insert the oral dosing syringe

Insert the oral dosing syringe tip into the upright bottle through the opening of the press-in bottle adapter until it is firmly in place.

Step 6. Withdraw dose from bottle

With the oral dosing syringe in place, turn the bottle upside down. Pull down on the plunger until the bottom of the plunger is even with the markings on the oral dosing syringe for your prescribed dose of oral solution.

If you see air bubbles in the oral dosing syringe, fully push the plunger in so that the oral solution flows back into the bottle. Then withdraw your prescribed dose of oral solution.

Step 7. Remove oral dosing syringe

Turn the bottle upright and place the bottle on a flat surface. Remove the oral dosing syringe from the press-in bottle adapter and bottle by pulling straight up on the oral dosing syringe barrel.

Step 8. Check the dose

Check that the correct dose was drawn up into the oral dosing syringe.

If the dose is not correct, insert the oral dosing syringe tip firmly into the press-in bottle adapter. Fully push in the plunger so that the oral solution flows back into the bottle. Repeat Step 6 and Step 7.

Step 9. Take the dose of tofacitinib oral solution

Place the tip of the oral dosing syringe into the inside of the cheek.

Slowly push the plunger all the way down to give all of the medicine in the oral dosing syringe. Make sure there is time to swallow the medicine.

Step 10. Close the bottle



Ifu11 (Ifu11)

Close the bottle tightly by turning the child-resistant cap to the right (clockwise), leaving the press-in bottle adapter in place.

Place the bottle back into the carton.

Close the carton to protect tofacitinib oral solution from light.

Step 11. Clean oral dosing syringe

Remove the plunger from the barrel by pulling the plunger and the barrel away from each other.

Rinse both with water after each use.

Allow to air dry. When the barrel and plunger are dry, put the oral dosing syringe back together by inserting the plunger into the barrel.

Store the oral dosing syringe with the tofacitinib oral solution.

Do not throw away the oral dosing syringe.

Manufactured by:

Ohm Laboratories Inc.

New Brunswick, NJ 08901

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Revised: February 2026

NDC 70095-008-01

Tofacitinib Oral Solution

1 mg/mL

Rx only

NDC 70095-008-02

Tofacitinib Oral Solution

1 mg/mL

Rx only