Tofacitinib Tablet, Extended Release
FDA Label NDC 27241-270

SERIOUS INFECTIONS
Patients treated with tofacitinib extended-release tablets are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt tofacitinib extended-release tablets until the infection is controlled.

Reported infections include:

• Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before tofacitinib extended-release tablets use and during therapy. Treatment for latent infection should be initiated prior to tofacitinib extended-release tablets 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 treatment with tofacitinib extended-release tablets 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 treatment with tofacitinib extended-release tablets, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [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 risk factor comparing tofacitinib tablets 5 mg twice a day or tofacitinib tablets 10 mg twice a day to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with tofacitinib tablets 5 mg twice a day or tofacitinib tablets 10 mg twice a day [see Warnings and Precautions (5.2)]. A tofacitinib tablets 10 mg twice daily (or a tofacitinib extended-release tablets 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].

MALIGNANCIES
Malignancies, including lymphomas and solid tumors, have occurred in patients treated with tofacitinib and other Janus kinase inhibitors used to treat inflammatory conditions. In RA patients, a higher rate of malignancies (excluding NMSC) was observed in patients treated with tofacitinib tablets 5 mg twice a day or tofacitinib tablets 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 tofacitinib tablets 5 mg twice a day or tofacitinib tablets 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.

Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with tofacitinib and concomitant immunosuppressive medications [see Warnings and Precautions (5.3)].

MAJOR ADVERSE CARDIOVASCULAR EVENTS
RA patients 50 years of age and older with at least one cardiovascular risk factor, treated with tofacitinib tablets 5 mg twice daily or tofacitinib tablets 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 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 tofacitinib 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 tofacitinib tablets 5 mg twice daily or tofacitinib tablets 10 mg twice daily compared to TNF blockers had an observed increase in incidence of these events. Avoid tofacitinib in patients at risk. Discontinue tofacitinib and promptly evaluate patients with symptoms of thrombosis [see Warnings and Precautions (5.5)].

Tofacitinib extended-release tablets are indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more TNF blockers. 

• Limitations of Use: Use of tofacitinib extended-release tablets in combination with biologic disease-modifying antirheumatic drugs (DMARDs) or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Tofacitinib extended-release tablets are indicated for the treatment of adult patients with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to one or more TNF blockers.

•  Limitations of Use: Use of tofacitinib extended-release tablets in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Tofacitinib extended-release tablets are indicated for the treatment of adult patients with active ankylosing spondylitis (AS) who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: Use of tofacitinib extended-release tablets in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

• Tofacitinib extended-release tablets are not interchangeable or substitutable with tofacitinib oral solution.

• Changes between tofacitinib tablets and tofacitinib extended-release tablets should be made by the healthcare provider [see Dosage and Administration (2.2)].

• Do not initiate tofacitinib extended-release tablets in patients with an absolute lymphocyte count less than 500 cells/mm³, an absolute neutrophil count (ANC) less than 1,000 cells/mm³ or who have hemoglobin levels less than 9 g/dL.

• Dose interruption is recommended for management of lymphopenia, neutropenia, and anemia [see Warnings and Precautions (5.8), Adverse Reactions (6.1)].

• Interrupt use of tofacitinib extended-release tablets if a patient develops a serious infection until the infection is controlled [see Warnings and Precautions (5.1)].

• Take tofacitinib extended-release tablets with or without food [see Clinical Pharmacology (12.3)].

• Swallow tofacitinib extended-release tablets whole and intact. Do not crush, split, or chew.

Table 1 displays the recommended adult daily dosage of tofacitinib extended-release tablets and dosage adjustments for patients receiving CYP2C19 and/or CYP3A4 inhibitors, in patients with moderate or severe renal impairment (including but not limited to those with severe insufficiency who are undergoing hemodialysis) or moderate hepatic impairment, with lymphopenia, neutropenia, or anemia.

Switching from Tofacitinib Tablets to Tofacitinib Extended-Release Tablets

 Patients treated with tofacitinib tablets 5 mg twice daily may be switched to tofacitinib extended-release tablets 11 mg once daily the day following the last dose of tofacitinib tablets 5 mg.

Tofacitinib Extended-Release Tablets:

• 11 mg tofacitinib: Pink colored, oval-shaped, film-coated, extended-release tablets, debossed with "TF" on one side and plain on other side.

None.

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, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal 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 extended-release tablets in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating tofacitinib extended-release tablets 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.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tofacitinib extended-release tablets. Tofacitinib extended-release tablets should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with tofacitinib extended-release tablets should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.




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 (2.2)].




Tuberculosis

Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of tofacitinib extended-release tablets.




Anti-tuberculosis therapy should also be considered prior to administration of tofacitinib extended-release tablets in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.




Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.




Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering tofacitinib extended-release tablets.




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

Rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular risk factor treated with tofacitinib 5 mg twice a day or tofacitinib 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 0.88 for tofacitinib 5 mg twice a day, 1.23 for tofacitinib 10 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 extended-release tablets.

 A tofacitinib tablets 10 mg twice daily (or a tofacitinib extended-release tablets 22 mg once daily) dosage is not recommended for the treatment of RA, PsA, or AS [see Dosage and Administration (2.2)].

Malignancies, including lymphomas and solid cancers, were observed in clinical studies of tofacitinib [see Adverse Reactions (6.1)].

In RA Safety Study 1, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with tofacitinib 5 mg twice a day or tofacitinib 10 mg twice a day as compared with TNF blockers. The incidence rate of malignancies (excluding NMSC) per 100 patient-years was 1.13 for tofacitinib 5 mg twice a day, 1.13 for tofacitinib 10 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 tofacitinib 5 mg twice a day and tofacitinib 10 mg twice a day compared to those treated with TNF blockers. The incidence rate of lymphomas per 100 patient-years was 0.07 for tofacitinib 5 mg twice a day, 0.11 for tofacitinib 10 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 0.48 for tofacitinib 5 mg twice a day, 0.59 for tofacitinib 10 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 extended-release tablets, 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 tablets 10 mg twice daily (or a tofacitinib extended-release tablets 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].

In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with tofacitinib (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

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

Non-Melanoma Skin Cancer

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

In RA Safety Study 1, RA patients who were 50 years of age and older with at least one cardiovascular risk factor treated with tofacitinib 5 mg twice daily or tofacitinib 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 0.91 for tofacitinib 5 mg twice a day, 1.11 for tofacitinib 10 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 0.36 for tofacitinib 5 mg twice a day, 0.39 for tofacitinib 10 mg twice a day, and 0.20 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 extended-release tablets, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue tofacitinib extended-release tablets in patients that have experienced a myocardial infarction or stroke. A tofacitinib 10 mg twice daily (or a tofacitinib extended-release tablets 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].

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

A tofacitinib tablets 10 mg twice daily (or a tofacitinib extended-release tablets 22 mg once daily) dosage is not recommended for the treatment of RA, PsA, or AS [see Dosage and Administration (2.2)].

Promptly evaluate patients with symptoms of thrombosis and discontinue tofacitinib extended- release tablets in patients with symptoms of thrombosis.

Avoid tofacitinib extended-release tablets in patients that may be at increased risk of thrombosis.

Events of gastrointestinal perforation have been reported in clinical studies with tofacitinib, although the role of JAK inhibition in these events is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).

Tofacitinib extended-release tablets should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation [see Adverse Reactions (6.1)].

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

Lymphocyte Abnormalities

Treatment with tofacitinib was associated with initial lymphocytosis at one month of exposure 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/mm³ were associated with an increased incidence of treated and serious infections.

Avoid initiation of tofacitinib extended-release tablets treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm³). In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm³, treatment with tofacitinib extended-release tablets is not recommended.

Monitor lymphocyte counts at baseline and every 3 months thereafter. For recommended modifications based on lymphocyte counts [see Dosage and Administration (2.2)].

Neutropenia

Treatment with tofacitinib was associated with an increased incidence of neutropenia (less than 2,000 cells/mm³) compared to placebo.

Avoid initiation of tofacitinib extended-release tablets treatment in patients with a low neutrophil count (i.e., ANC less than 1,000 cells/mm³). For patients who develop a persistent ANC of 500 cells/mm³ to 1,000 cells/mm³, interrupt tofacitinib dosing until ANC is greater than or equal to 1,000 cells/mm³. In patients who develop an ANC less than 500 cells/mm³, treatment with tofacitinib extended-release tablets is not recommended.

Monitor neutrophil counts at baseline and after 4 weeks to 8 weeks of treatment and every 3 months thereafter. For recommended modifications based on ANC results [see Dosage and Administration (2.2)].

Anemia

Avoid initiation of tofacitinib extended-release tablets treatment in patients with a low hemoglobin level (i.e., less than 9 g/dL). Treatment with tofacitinib extended-release tablets should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment.

Monitor hemoglobin at baseline and after 4 weeks to 8 weeks of treatment and every 3 months thereafter. For recommended modifications based on hemoglobin results [see Dosage and Administration (2)].

Liver Enzyme Elevations

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

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, the administration of tofacitinib extended-release tablets should be interrupted until this diagnosis has been excluded.

Lipid Elevations

Treatment with tofacitinib was associated with dose-dependent increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects 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.

Assessment of lipid parameters should be performed approximately 4 weeks to 8 weeks following initiation of tofacitinib extended-release tablets 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 extended-release tablets. The interval between live vaccinations and initiation of tofacitinib extended-release  tablets  therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.  

A patient experienced dissemination of the vaccine strain of varicella zoster virus, 16 days after vaccination with live attenuated (Zostavax) virus vaccine and 2 days after treatment start with tofacitinib 5 mg twice daily. The patient was varicella virus naïve, as evidenced by no previous history of varicella infection and no anti-varicella antibodies at baseline. Tofacitinib was discontinued and the patient recovered after treatment with standard doses of antiviral medication.

 Update immunizations in agreement with current immunization guidelines prior to initiating tofacitinib extended-release tablets therapy.

As with any other non-deformable material, caution should be used when administering tofacitinib extended-release tablets to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended-release formulation.

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

• Serious Infections [see Warnings and Precautions (5.1)]

• 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 [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.

Rheumatoid Arthritis

The clinical studies described in the following sections were conducted using tofacitinib. Although other doses of tofacitinib have been studied, the recommended dose of tofacitinib tablets is 5 mg twice daily. The recommended dose for tofacitinib extended-release tablets is 11 mg once daily. A dosage of tofacitinib tablets 10 mg twice daily or tofacitinib extended-release tablets 22 mg once daily is not a recommended regimen for the treatment of rheumatoid arthritis [see Dosage and Administration (2.2)].  In RA Safety Study 1, 1,455 patients were treated with tofacitinib 5 mg twice daily, 1,456 patients were treated with 10 mg twice daily, and 1,451 patients were treated with a TNF blocker for a median of 4.0 years [see Clinical Studies (14.6)].

The following data includes two Phase 2 and five Phase 3 double-blind, placebo-controlled, multicenter trials. In these trials, patients were randomized to doses of tofacitinib 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, tofacitinib 5 mg twice daily (1,044 patients) and 10 mg twice daily (1,043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven placebo-controlled protocols included provisions for patients taking placebo to receive treatment with tofacitinib at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore, some analyses that follow include patients who changed treatment by design or by patient response from placebo to tofacitinib in both the placebo and tofacitinib group of a given interval. Comparisons between placebo and tofacitinib were based on the first 3 months of exposure, and comparisons between tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily were based on the first 12 months of exposure.

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

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

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

Overall Infections

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

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

Serious Infections

In the seven placebo-controlled trials, during the 0 month to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received tofacitinib 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily tofacitinib group minus placebo.

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

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, during the 0 month to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of tofacitinib, or 10 mg twice daily of tofacitinib.

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

Cases of disseminated tuberculosis were also reported. The median tofacitinib exposure prior to diagnosis of tuberculosis was 10 months (range from 152 days to 960 days) [see Warnings and Precautions (5.1)].

Opportunistic Infections (excluding tuberculosis)

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

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

The median tofacitinib exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 days to 698 days) [see Warnings and Precautions (5.1)].

Malignancy

In the seven placebo-controlled trials, during the 0 month to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either tofacitinib 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined 5 mg and 10 mg twice daily tofacitinib group minus placebo.

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

The most common types of malignancy, including malignancies observed during the long-term extension, 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, confirmed decreases in absolute lymphocyte counts below 500 cells/mm³ occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily tofacitinib groups combined during the first 3 months of exposure.

Confirmed lymphocyte counts less than 500 cells/mm³ were associated with an increased incidence of treated and serious infections [see Warnings and Precautions (5.8)].

Neutropenia

In the placebo-controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm³ occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily tofacitinib groups combined during the first 3 months of exposure.

There were no confirmed decreases in ANC below 500 cells/mm³ 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 treated with tofacitinib. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of tofacitinib, or reduction in tofacitinib dose, resulted in decrease or normalization of liver enzymes.

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

In the placebo-controlled background DMARD trials (0 month to 3 months), ALT elevations greater than 3x ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 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 receiving placebo, 5 mg, and 10 mg twice daily, respectively.

One case of drug-induced liver injury was reported in a patient treated with tofacitinib 10 mg twice daily for approximately 2.5 months. 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, 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 tofacitinib 5 mg twice daily arm and 19% in the tofacitinib 10 mg twice daily arm.

• Mean HDL cholesterol increased by 10% in the tofacitinib 5 mg twice daily arm and 12% in the tofacitinib 10 mg twice daily arm.

• Mean LDL/HDL ratios were essentially unchanged in tofacitinib-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, dose-related elevations in serum creatinine were observed with tofacitinib 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 tofacitinib 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.




Other Adverse Reactions

Adverse reactions occurring in 2% or more of patients on 5 mg twice daily or 10 mg twice daily tofacitinib and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in Table 4.  

                                           

Table 4: Common Adverse Reactions* in Clinical Trials of Tofacitinib for the Treatment of Rheumatoid Arthritis With or Without Concomitant DMARDs (0 Month to 3 Months)

N reflects randomized and treated patients from the seven placebo-controlled clinical trials. * reported in ≥2% of patients treated with either dose of tofacitinib and ≥1% greater than that reported for placebo. ** The recommended dose of tofacitinib for the treatment of rheumatoid arthritis is 5 mg twice daily [see Dosage and Administration (2)].
Preferred Term	Tofacitinib  5 mg Twice Daily	Tofacitinib  10 mg Twice Daily**	Placebo
	N = 1,336  (%)	N = 1,349  (%)	N = 809  (%)
Upper respiratory tract infection	4	4	3
Nasopharyngitis	4	3	3
Diarrhea	4	3	2
Headache	4	3	2
Hypertension	2	2	1

Other adverse reactions occurring in placebo-controlled and open-label extension studies 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 rheumatoid arthritis and some were fatal)

Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea

Hepatobiliary disorders: Hepatic steatosis

Skin and subcutaneous tissue disorders: Rash, erythema, pruritus

Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling

Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancers

General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema




Clinical Experience in Methotrexate-Naïve Patients

Study RA-VI was an active-controlled clinical trial in methotrexate-naïve patients [see Clinical Studies (14)]. The safety experience in these patients was consistent with Studies RA-I through V.

Psoriatic Arthritis

Tofacitinib 5 mg twice daily and 10 mg twice daily were studied in 2 double-blind Phase 3 clinical trials in patients with active psoriatic arthritis (PsA). Although other doses of tofacitinib have been studied, the recommended dose of tofacitinib is 5 mg twice daily. The recommended dose for tofacitinib extended-release tablets is 11 mg once daily. A dosage of tofacitinib extended-release tablets 22 mg once daily is not recommended for the treatment of PsA [see Dosage and Administration (2.2)].




Study PsA-I (NCT01877668) had a duration of 12 months and enrolled patients 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 patients 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 tofacitinib 5 mg twice daily and 236 patients were randomized and treated with tofacitinib 10 mg twice daily. All patients in the clinical trials 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 tofacitinib (474 patients) included 45 (9.5%) patients aged 65 years or older and 66 (13.9%) patients with diabetes at baseline.




During the 2 PsA controlled clinical trials, there were 3 malignancies (excluding NMSC) in 474 patients receiving tofacitinib plus non-biologic DMARD (6 months to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus non-biologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in the 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 psoriatic arthritis patients treated with tofacitinib.




The safety profile observed in patients with active psoriatic arthritis treated with tofacitinib was consistent with the safety profile observed in rheumatoid arthritis patients.




Ankylosing Spondylitis

Tofacitinib 5 mg twice daily was studied in patients with active ankylosing spondylitis (AS) in a confirmatory double-blind placebo-controlled Phase 3 clinical trial (Study AS-I) and in a dose-ranging Phase 2 clinical trial (Study AS-II).




Study AS-I (NCT03502616) had a duration of 48 weeks and enrolled patients who had an inadequate response to at least 2 NSAIDs. Study AS-I included a 16-week double-blind period in which patients received tofacitinib 5 mg or placebo twice daily and a 32-week open-label treatment period in which all patients received tofacitinib 5 mg twice daily.

Study AS-II (NCT01786668) had a duration of 16 weeks and enrolled patients who had an inadequate response to at least 2 NSAIDs. This clinical trial included a 12-week treatment period in which patients received either tofacitinib 2 mg, 5 mg, 10 mg, or placebo twice daily.




In the combined Phase 2 and Phase 3 clinical trials, a total of 420 patients were treated with either tofacitinib 2 mg, 5 mg, or 10 mg twice daily. Of these, 316 patients were treated with tofacitinib 5 mg twice daily for up to 48 weeks. In the combined double-blind period, 185 patients were randomized to and treated with tofacitinib 5 mg twice daily and 187 to placebo for up to 16 weeks. Concomitant treatment with stable doses of nonbiologic DMARDs, NSAIDs, or corticosteroids (≤10 mg/day) was permitted. The study population randomized and treated with tofacitinib included 13 (3.1%) patients aged 65 years or older and 18 (4.3%) patients with diabetes at baseline.




The safety profile observed in patients with AS treated with tofacitinib was consistent with the safety profile observed in RA and PsA patients.

The following adverse reactions have been identified during post-approval use of tofacitinib 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 6 includes drugs with clinically important drug interactions when administered concomitantly with tofacitinib and instructions for preventing or managing them.

All information provided in this section is applicable to tofacitinib tablets/tofacitinib extended-release tablets as they contain the same active ingredient (tofacitinib).

Risk Summary

The available data with tofacitinib from a pregnancy exposure registry that enrolled 11 exposed patients, 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 rheumatoid arthritis 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 dose of 5 mg twice daily and approximately 36 times the maximum recommended dose 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 rheumatoid arthritis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 g) infants, and small for gestational age at birth.

Data

Animal Data

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

In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the recommended dose of 5 mg twice daily, and approximately 6.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the recommended dose of 5 mg twice daily, and 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, such as increased risk of serious infections, advise patients that breastfeeding is not recommended during treatment and for at least 36 hours after the last dose of tofacitinib extended-release tablets (approximately 6 elimination half-lives).

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 dose of 5 mg twice daily and 6.3 times the maximum recommended dose 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 dose. Consider pregnancy planning and prevention for females of reproductive potential.

Infertility

Females

 Based on findings in rats, treatment with tofacitinib 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 extended-release tablets in pediatric patients have not been established.

Of the 3,315 patients who enrolled in rheumatoid arthritis Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among tofacitinib-treated subjects 65 years of age and older was higher than among those under the age of 65.

As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly [see Warnings and Precautions (5.1)].

As there is a higher incidence of infection in diabetic population in general, caution should be used when treating patients with diabetes.

Moderate and Severe Impairment

Tofacitinib-treated patients with moderate or severe renal impairment had greater tofacitinib blood concentrations than tofacitinib-treated patients with normal renal function. Therefore, dosage adjustment of tofacitinib is recommended in patients with moderate or severe renal impairment (including but not limited to those with severe insufficiency who are undergoing hemodialysis) [see Dosage and Administration (2.2)].

Mild impairment

 No dosage adjustment is required in patients with mild renal impairment.

Severe Impairment

Tofacitinib has not been studied in patients with severe hepatic impairment; therefore, use of tofacitinib in patients with severe hepatic impairment is not recommended.

Moderate Impairment

Tofacitinib-treated patients with moderate hepatic impairment 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. Therefore, dosage adjustment of tofacitinib is recommended in patients with moderate hepatic impairment [see Dosage and Administration (2.2)].

Mild Impairment

No dosage adjustment of tofacitinib is required in patients with mild hepatic impairment.

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. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions.

 In a study in subjects 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.

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

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

The solubility of tofacitinib citrate in water is 2.9 mg/mL.

Tofacitinib citrate has a molecular weight of 504.5 Daltons (or 312.4 Daltons as the tofacitinib free base) and a molecular formula of C₁₆H₂₀N₆O•C₆H₈O₇. The chemical structure of tofacitinib citrate is:

Structure (Tofacitinib Structure)

Tofacitinib extended-release tablets are supplied for oral administration as a 11 mg pink, oval, extended-release film-coated tablets, debossed with “TF” on one side and plain on other side. Each 11 mg tablet of tofacitinib extended-release  contains 11 mg tofacitinib (equivalent to 17.77 mg of tofacitinib citrate) and the following inactive ingredients: povidone, hypromellose 2208, magnesium stearate, hydrophobic colloidal silica, lactose monohydrate, polyethylene glycol, polyvinyl alcohol, titanium dioxide, talc, red iron oxide, and yellow iron oxide.

Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC₅₀ of 406 nM, 56 nM, and 1,377 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 weeks to 10 weeks after initiation of therapy. These changes generally resolved within 2 weeks to 6 weeks after discontinuation of treatment. Treatment with tofacitinib was associated with dose-dependent increases in B cell counts. Changes in circulating T-lymphocyte counts and T-lymphocyte subsets (CD3+, CD4+ and CD8+) were small and inconsistent. The clinical significance of these changes is unknown.

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

After treatment with tofacitinib in patients with rheumatoid arthritis, 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 although reversibility was not assessed. Total serum immunoglobulins were not assessed in patients with active psoriatic arthritis.

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

Tofacitinib extended-release tablets
Following oral administration of tofacitinib extended-release tablets, peak plasma concentrations are reached at 4 hours and half-life is about 6 hours to 8 hours. Steady state concentrations are achieved within 48 hours with negligible accumulation after once daily administration.

Absorption

Tofacitinib tablets
The absolute oral bioavailability of tofacitinib tablets is 74%. Coadministration of tofacitinib tablets with a high-fat meal resulted in no changes in AUC while C_max was reduced by 32%. In clinical trials, tofacitinib tablets was administered without regard to meals [see Dosage and Administration (2.1)].

Tofacitinib extended-release tablets
Coadministration of tofacitinib extended-release tablets 11 and 22 mg with a high-fat meal resulted in no changes in AUC while C_max was increased by 27% and 19% respectively. T_max was extended by approximately 1 hour for both tofacitinib extended-release tablets 11 and 22 mg.

Distribution

After intravenous administration, the volume of distribution is 87 L. The protein binding of tofacitinib is approximately 40%. Tofacitinib binds predominantly to albumin and does not appear to bind to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.

Metabolism and Excretion

Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule.

Pharmacokinetics in Patient Populations

Population pharmacokinetic analyses indicated that pharmacokinetic characteristics were similar between patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. The coefficient of variation (%) in AUC of tofacitinib were generally similar across different disease patients, ranging from 22% to 34% (Table 8).

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, gender and race (Figure 1). An approximately linear relationship between body weight and volume of distribution was observed, resulting in higher peak (C_max) and lower trough (C_min) concentrations in lighter patients. However, this difference is not considered to be clinically relevant.

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

Figure 1: Impact of Intrinsic Factors on Tofacitinib Pharmacokinetics

Figure1 (Tofacitinib Figure1)

Note: Reference values for weight, age, gender, and race comparisons are 70 kg, 55 years, male, and white, respectively; reference groups for renal and hepatic impairment data are subjects with normal renal and hepatic function.  

^a Refer to Dosage and Administration (2.2)for dosage adjustment in RA, PsA, and AS patients.

In subjects with ESRD 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. Dose adjustment is recommended in RA, PsA, AS patients with ESRD maintained on hemodialysis [see Dosage and Administration (2.2)].

Drug Interaction Studies

Potential for Tofacitinib to Influence the PK of Other Drugs

In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the major human drug-metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations corresponding to the steady state C_max of a 10 mg twice daily dose. These in vitro results were confirmed by a human drug interaction study showing no changes in the pharmacokinetics of midazolam, a highly sensitive CYP3A4 substrate, when coadministered with tofacitinib.

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

In rheumatoid arthritis patients, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in rheumatoid arthritis patients. Therefore, coadministration with tofacitinib tablets/tofacitinib extended-release tablets is not expected to result in clinically relevant increases in the metabolism of CYP substrates in rheumatoid arthritis patients.

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

Dosing recommendations for coadministered drugs following administration with tofacitinib are shown in Figure 2.

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

Figure2 (Tofacitinib Figure2)

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

Figure3 (Tofacitinib Figure3)

Note: Reference group is administration of tofacitinib alone.  

 ^a [see Dosage and Administration (2.2), Drug Interactions (7)]. 

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 vivo rat 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 tofacitinib clinical development program included six confirmatory trials. Although other doses have been studied, the recommended dose of tofacitinib tablets is 5 mg twice daily. Tofacitinib tablets 10 mg twice daily is not recommended for the treatment of rheumatoid arthritis [see Dosage and Administration (2.2)].

Confirmatory Trials

Study RA-I (NCT00814307) was a 6-month monotherapy trial in which 610 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a DMARD (nonbiologic or biologic) received tofacitinib 5 mg or 10 mg twice daily or placebo. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of tofacitinib 5 mg or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, changes in Health Assessment Questionnaire – Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) less than 2.6.

Study RA-II (NCT00856544) was a 12-month trial in which 792 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a nonbiologic DMARD received tofacitinib 5 mg or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppressive treatments such as azathioprine or cyclosporine). At the Month 3 visit, nonresponding patients were advanced in a blinded fashion to a second predetermined treatment of tofacitinib 5 mg or 10 mg twice daily. At the end of Month 6, all placebo patients were advanced to their second predetermined treatment in a blinded fashion. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, changes in HAQ-DI at Month 3, and rates of DAS28-4(ESR) less than 2.6 at Month 6.

Study RA-III (NCT00853385) was a 12-month trial in 717 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX. Patients received tofacitinib 5 mg or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.

Study RA-IV (NCT00847613) was a 2-year trial with a planned analysis at 1 year in which
797 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX received tofacitinib 5 mg or 10 mg twice daily or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, mean change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.

Study RA-V (NCT00960440) was a 6-month trial in which 399 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to at least one approved TNF blocking biologic agent received tofacitinib 5 mg or 10 mg twice daily or placebo added to background MTX. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of tofacitinib 5 mg or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, HAQ-DI, and DAS28-4(ESR) less than 2.6.

Study RA-VI (NCT01039688) was a 2-year monotherapy trial with a planned analysis at 1 year in which 952 MTX-naïve patients with moderate to severe active rheumatoid arthritis received tofacitinib 5 mg or 10 mg twice daily or MTX dose-titrated over 8 weeks to 20 mg weekly. The primary endpoints were mean change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at Month 6 and the proportion of patients who achieved an ACR70 response at Month 6.

Clinical Response

The percentages of tofacitinib-treated patients achieving ACR20, ACR50, and ACR70 responses in Studies RA-I, IV, and V are shown in Table 9. Similar results were observed with Studies RA-II and III. In trials RA-I through V, patients treated with 5 mg twice daily tofacitinib had higher ACR20, ACR50, and ACR70 response rates versus placebo, with or without background DMARD treatment, at Month 3 and Month 6. Higher ACR20 response rates were observed within 2 weeks compared to placebo. In the 12-month trials, ACR response rates in tofacitinib-treated patients were consistent at 6 months and 12 months. 

In Study RA-IV, a greater proportion of patients treated with tofacitinib 5 mg twice daily plus MTX achieved a low level of disease activity as measured by a DAS28-4(ESR) less than 2.6 at 6 months compared to those treated with MTX alone (Table 10).

The results of the components of the ACR response criteria for Study RA-IV are shown in  Table 11. Similar results were observed for tofacitinib in Studies RA-I, II, III, V, and VI.

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

Figure 4: Percentage of ACR20 Responders by Visit for Study RA-IV

Figure4 (Tofacitinib Fig4)

Radiographic Response

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

In Study RA-IV, tofacitinib 5 mg twice daily reduced the mean progression of structural damage (not statistically significant) as shown in Table 12. Analyses of erosion and joint space narrowing scores were consistent with the overall results.

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

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

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

Physical Function Response

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

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

Other Health-Related Outcomes

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

The tofacitinib clinical development program to assess efficacy and safety included 2 multicenter, randomized, double-blind, placebo-controlled confirmatory trials in 816 patients 18 years of age and older (PsA-I and PsA- II). Although other doses have been studied, the recommended dose of tofacitinib is 5 mg twice daily. Tofacitinib 10 mg twice daily is not recommended for the treatment of psoriatic arthritis [see Dosage and Administration (2.2)]. All patients had active psoriatic arthritis 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 psoriatic arthritis 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 psoriatic arthritis 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. Patients were randomized in a 2:2:2:1:1 ratio to receive tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, adalimumab 40 mg subcutaneously once every 2 weeks, placebo to tofacitinib 5 mg twice daily treatment sequence, or placebo to tofacitinib 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 advanced in a blinded fashion to a predetermined tofacitinib dose of 5 mg or 10 mg twice daily. Study PsA-I was not designed to demonstrate noninferiority or superiority to adalimumab.

Study PsA-II was a 6-month clinical trial in 394 patients who had an inadequate response to at least 1 approved TNF blocker (66%, 19%, and 15% were inadequate responders to 1 TNF blocker, 2 TNF blockers and ≥3 TNF blockers, respectively). Patients were randomized in a 2:2:1:1 ratio to receive tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, placebo to tofacitinib 5 mg twice daily treatment sequence, or placebo to tofacitinib 10 mg twice daily treatment sequence, respectively; study drug was added to background nonbiologic DMARD treatment. At the Month 3 visit, placebo patients were advanced in a blinded fashion to a predetermined tofacitinib dose of 5 mg or 10 mg twice daily as in Study PsA-I.

Clinical Response 

At Month 3, patients treated with tofacitinib 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 tofacitinib 5 mg twice daily versus placebo in Study PsA-II, although the differences versus placebo were not statistically significant (p>0.05) (Tables 13 and 14).

Improvements from baseline in the ACR response criteria components for both studies are shown in Table 15.

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 tofacitinib 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*

Figure5 (Tofacitinib Figure5)

BID=twice daily; SE=standard error.

Subjects with missing data were treated as non-responders.

*Subjects received one concomitant nonbiologic DMARD.

In patients with active psoriatic arthritis evidence of benefit in enthesitis and dactylitis was observed with tofacitinib treatment.

Physical Function

Improvement in physical functioning was measured by the HAQ-DI. Patients receiving tofacitinib 5 mg twice daily demonstrated significantly greater improvement (p ≤0.05) from baseline in physical functioning compared to placebo at Month 3 (Table 16).

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 tofacitinib 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 tofacitinib 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 tofacitinib 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 psoriatic arthritis could not be established from the results of Study PsA-I.

The tofacitinib clinical development program to assess the efficacy and safety included one placebo-controlled confirmatory trial (Study AS-I). Patients had active disease as defined by both Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and back pain score (BASDAI question 2) of greater or equal to 4 despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid or disease modifying anti-rheumatic drug (DMARD) therapy.

Confirmatory Trial (Study AS-I)

Study AS-I was a randomized, double-blind, placebo-controlled, 48-week clinical trial in 269 adult patients who had an inadequate response (inadequate clinical response or intolerance) to at least 2 NSAIDs. Patients were randomized and treated with tofacitinib 5 mg twice daily or placebo for 16 weeks of blinded treatment and then all received treatment of tofacitinib 5 mg twice daily for additional 32 weeks. The primary endpoint was to evaluate the proportion of patients who achieved an ASAS20 response at Week 16.

Approximately 7% and 21% of patients used concomitant methotrexate or sulfasalazine, respectively from baseline to Week 16. Twenty-two percent of patients had an inadequate response to 1 or 2 TNF blockers.

Clinical Response

Patients treated with tofacitinib 5 mg twice daily achieved greater improvements in ASAS20 and ASAS40 responses compared to placebo at Week 16 (Table 17). Consistent results were observed in the subgroup of patients who had an inadequate response to TNF blockers for both the ASAS20 (primary endpoint) and ASAS40 (secondary endpoint) at Week 16 (Table 17).

The improvements in the components of the ASAS response and other measures of disease activity were higher in tofacitinib 5 mg twice daily compared to placebo as shown in Table 18.

The percentage of patients achieving ASAS20 response by visit is shown in Figure 6.  

Figure 6: ASAS20 Response Over Time Up to Week 16, Study AS-I

Figure6 (Tofacitinib Figure6)

SE=standard error.

Patients with missing data were treated as non-responders.

Other Health-Related Outcomes

Patients treated with tofacitinib 5 mg twice daily achieved greater improvements from baseline in Ankylosing Spondylitis Quality of Life (ASQoL) (-4.0 vs -2.0) compared to placebo-treated patients at Week 16.

A randomized open-label trial (RA Safety Study 1; NCT02092467) was conducted to evaluate safety with tofacitinib at two doses, 5 mg twice daily (N= l,455) and 10 mg twice daily (N= 1,456), versus the TNF-blocker control (N= 1,45l) 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 tofacitinib 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 4.0 years.

The mean age of the population was 61 years (range: 50 years 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 tofacitinib doses 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 21 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, and thromboembolic events associated with both doses of tofacitinib. 

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 tofacitinib 5 mg twice a day and tofacitinib 10 mg twice a day compared to those treated with TNF blockers. Lymphoma was reported for 4 patients receiving tofacitinib 5 mg twice a day, 6 patients receiving tofacitinib 10 mg twice a day, and 1 patient receiving 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 receiving tofacitinib 5 mg twice a day, 15 patients receiving tofacitinib 10 mg twice a day, and 7 patients receiving TNF blockers (IR of 0.48, 0.59, and 0.27 per 100 patient-years, respectively).

A tofacitinib tablets 10 mg twice daily (or a tofacitinib extended-release tablets 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].

How supplied information for tofacitinib extended-release tablets are shown in Table 22.

Tofacitinib extended-release tablets

Store tofacitinib extended-release tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

 Do not repackage.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Serious Infections

Inform patients that tofacitinib extended-release tablets may lower the ability of their immune system to fight infections. Advise patients not to start taking tofacitinib extended-release tablets if they have an active infection. Instruct patients to contact their healthcare provider immediately during treatment if symptoms suggesting infection appear in order 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 tablets/tofacitinib extended-release tablets [see Warnings and Precautions (5.1)].

Malignancies and Lymphoproliferative Disorders

Inform patients that tofacitinib extended-release tablets may increase their risk of certain cancers, and that lymphoma and other cancers have been observed in patients taking tofacitinib tablets. 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 extended-release tablets 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 extended-release tablets 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 extended-release tablets and to call their healthcare provider right away if they experience any symptoms of allergic reactions while taking tofacitinib extended-release tablets [see Warnings and Precautions (5.7)].

Important Information on Laboratory Abnormalities

Inform patients that tofacitinib extended-release tablets 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 women 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 extended-release tablets and for at least 36 hours after the last dose of tofacitinib extended-release tablets [see Use in Specific Populations (8.2)].

Infertility

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

For medical information about tofacitinib extended-release tablets, please call 855-664-7744.

Product of India

Manufactured by:
Ajanta Pharma Limited, India
Marketed by:

 Ajanta Pharma USA Inc.

Bridgewater, NJ 08807.

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

NDC 27241-270-30

30 Tablets

Tofacitinib Extended-Release Tablets

11 mg

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

Rx Only

ajanta

11mg (Tofacitinib 11mg)