2.1 Important Administration Instructions

•   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 (5.7), 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.

2.2 Recommended Dosage in Rheumatoid Arthritis and Psoriatic Arthritis

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

2.3 Recommended Dosage in Ulcerative Colitis

Table 2 displays the recommended adult daily dosage of tofacitinib extended-release tablets and dosage adjustments for patients receiving CYP2C19 and/or CYP3A4 inhibitors, 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. Patients treated with tofacitinib tablets 10 mg twice daily may be switched to tofacitinib extended-release tablets 22 mg once daily the day following the last dose of tofacitinib tablets 10 mg.

5.1 Serious Infections

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.

In the UC population, tofacitinib treatment with 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily. Additionally, opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with tofacitinib 10 mg twice daily.

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, 2.3)].

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. Postmarketing cases of hepatitis B reactivation have been reported in patients treated with tofacitinib. The impact of tofacitinib extended-release tablets 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 extended-release tablets and appears to be higher in patients treated with tofacitinib in Japan and Korea.

5.2 Mortality

Rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular (CV) risk factor treated with tofacitinib 10 mg twice a day had a higher rate of all-cause mortality, including sudden CV death, compared to those treated with tofacitinib 5 mg given twice daily or TNF blockers in a large, ongoing, postmarketing safety study.

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

For the treatment of UC, use tofacitinib at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response [see Dosage and Administration (2.3)].

5.3 Malignancy and Lymphoproliferative Disorders

Consider the risks and benefits of tofacitinib extended-release tablets treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing tofacitinib extended-release tablets in patients who develop a malignancy. Malignancies were observed in clinical studies of tofacitinib [see Adverse Reactions (6.1)].

In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3,328 patients receiving tofacitinib with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with tofacitinib.

During the 2 PsA controlled clinical studies there were 3 malignancies (excluding NMSC) in 474 patients receiving tofacitinib plus nonbiologic DMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus nonbiologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus nonbiologic 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.

During the UC controlled clinical studies (8-week induction and 52-week maintenance studies), which included 1,220 patients, 0 cases of solid cancer or lymphoma were observed in tofacitinib-treated patients. In the long-term extension study, malignancies (including solid cancers and lymphomas) were observed more often in patients treated with tofacitinib 10 mg twice daily.

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 the UC population, treatment with tofacitinib 10 mg twice daily was associated with greater risk of NMSC.

5.4 Thrombosis

Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, have occurred in patients treated with tofacitinib and other Janus kinase (JAK) inhibitors used to treat inflammatory conditions. Patients with rheumatoid arthritis 50 years of age and older with at least one CV risk factor treated with tofacitinib 10 mg twice daily compared to tofacitinib 5 mg twice daily or TNF blockers in a large, ongoing postmarketing study had an observed increase in incidence of these events. Many of these events were serious and some resulted in death [see Warnings and Precautions (5.2)].

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

In a long-term extension study in patients with UC, four cases of pulmonary embolism were reported in patients taking tofacitinib 10 mg twice daily, including one death in a patient with advanced cancer.

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. For the treatment of UC, use tofacitinib at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response [see Dosage and Administration (2.3)].

5.5 Gastrointestinal Perforations

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).

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

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)].

5.6 Hypersensitivity

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

5.7 Laboratory Abnormalities

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, 2.3)].

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 to 1,000 cells/mm3, interrupt tofacitinib extended-release tablets 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 to 8 weeks of treatment and every 3 months thereafter. For recommended modifications based on ANC results [see Dosage and Administration (2.2, 2.3)].

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 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 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.

5.8 Vaccinations

Avoid use of live vaccines concurrently with tofacitinib extended-release tablets. The interval between live vaccinations and initiation of tofacitinib 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.

5.9 Risk of Gastrointestinal Obstruction with a Non-Deformable Extended-Release Formulation such as Tofacitinib Extended-Release Tablets

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.

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

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 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 a recommended regimen for the treatment of rheumatoid arthritis [see Dosage and Administration (2.2)].

The following data includes two Phase 2 and five Phase 3 double-blind, 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 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, 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 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 controlled trials, during the 0 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 controlled trials, 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 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 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 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 controlled trials, during the 0 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 controlled trials, during the 0 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 to 960 days) [see Warnings and Precautions (5.1)].

Opportunistic Infections (excluding tuberculosis)

In the seven controlled trials, during the 0 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 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 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 to 698 days) [see Warnings and Precautions (5.1)].

Malignancy

In the seven controlled trials, 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 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 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 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 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 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 (5.7)].

Neutropenia

In the controlled clinical trials, confirmed decreases in ANC below 1,000 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 controlled clinical trials [see Warnings and Precautions (5.7)].

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 controlled monotherapy trials (0 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 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 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 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 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 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 controlled clinical trials.

Serum Creatinine Elevations

In the 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 3.

Other adverse reactions occurring in 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.

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

Ulcerative Colitis

Tofacitinib has been studied in patients with moderately to severely active UC in 4 randomized, double-blind, placebo-controlled trials (UC-I, UC-II, UC-III, and dose-ranging UC-V) and an open-label long-term extension study (UC-IV) [see Clinical Studies (14.3)].

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

Induction Trials (Study UC-I, UC-II, and UC-V)

Common adverse reactions reported in ≥2% of patients treated with tofacitinib 10 mg twice daily and ≥1% greater than that reported in patients receiving placebo in the 3 induction trials were: headache, nasopharyngitis, elevated cholesterol levels, acne, increased blood creatine phosphokinase, and pyrexia.

Maintenance Trial (Study UC-III)

Common adverse reactions reported in ≥4% of patients treated with either dose of tofacitinib and ≥1% greater than reported in patients receiving placebo are shown in Table 4.

In the long-term extension study, malignancies (including solid cancers, lymphomas and NMSC) were observed more often in patients treated with tofacitinib 10 mg twice daily [see Warnings and Precautions (5.3)]. Four cases of pulmonary embolism were reported in patients taking tofacitinib 10 mg twice daily, including one fatality in a patient with advanced cancer [see Warnings and Precautions (5.4)].

Dose-dependent adverse reactions seen in patients treated with tofacitinib 10 mg twice daily, in comparison to 5 mg twice daily, include the following: herpes zoster infections, serious infections, and NMSC [see Warnings and Precautions (5.1, 5.3)].

6.2 Postmarketing Experience

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).

8.1 Pregnancy

Risk Summary

Available data with tofacitinib extended-release tablets use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or 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 estimated 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 or ulcerative colitis. 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).

8.2 Lactation

Risk Summary

There are no data on the presence of tofacitinib in human milk, the effects on a breastfed infant, or the effects on milk production. Tofacitinib is present in the milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Given the serious adverse reactions seen in adults treated with tofacitinib extended-release tablets, 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.

8.3 Females and Males of Reproductive Potential

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 extended-release tablets may result in reduced fertility in females of reproductive potential. It is not known if this effect is reversible [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the 3315 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.

Of the 1,156 tofacitinib-treated patients in the UC program, a total of 77 patients (7%) were 65 years of age or older. The number of patients aged 65 years and older was not sufficient to determine whether they responded differently from younger patients.

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)].

8.6 Use in Diabetics

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

8.7 Renal Impairment

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 extended-release tablet 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, 2.3)].

Mild impairment

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

8.8 Hepatic Impairment

Severe Impairment

Tofacitinib extended-release tablets have not been studied in patients with severe hepatic impairment; therefore, use of tofacitinib extended-release tablets 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 extended-release tablet is recommended in patients with moderate hepatic impairment [see Dosage and Administration (2.2, 2.3)].

Mild Impairment

No dosage adjustment of tofacitinib extended-release tablets are required in patients with mild hepatic impairment.

Hepatitis B or C Serology

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

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Treatment with tofacitinib was associated with dose-dependent reductions of circulating CD16/56+ natural killer cells, with estimated maximum reductions occurring at approximately 8 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 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.

12.3 Pharmacokinetics

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

Coadministration of tofacitinib extended-release tablets 11 mg and 22 mg with a high-fat meal resulted in no changes in AUC while Cmax was increased by 27% and 19% respectively. Tmax was extended by approximately 1 hour for both tofacitinib extended-release tablets 11 mg 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 UC. The coefficient of variation (%) in AUC of tofacitinib were generally similar across different disease patients, ranging from 22% to 34% (Table 7).

Specific Populations

Covariate evaluation as part of population PK analyses in 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 (Cmax) and lower trough (Cmin) 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

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 [see Dosage and Administration (2.2, 2.3)] for dosage adjustment in RA, PsA and UC 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 ESRD patients maintained on hemodialysis ([see Dosage and Administration (2.2, 2.3)] for dosage adjustment in RA, PsA and UC patients).

Drug Interaction Studies

Potential for Tofacitinib Extended-Release Tablets to Influence the PK of Other Drugs

In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the major human drug-metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations corresponding to the steady state Cmax 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 Cmax 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 extended-release tablets are 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 extended-release tablets 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.

a [see Dosage and Administration (2.2, 2.3), Drug Interactions (7)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

14.1 Rheumatoid Arthritis

The tofacitinib clinical development program included two dose-ranging trials and five confirmatory trials. 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 rheumatoid arthritis [see Dosage and Administration (2.2)].

Dose-Ranging Trials

Dose selection for tofacitinib was based on two pivotal dose-ranging trials.

Dose-Ranging Study 1 was a 6 month monotherapy trial in 384 patients with active rheumatoid arthritis who had an inadequate response to a DMARD. Patients who previously received adalimumab therapy were excluded.  Patients were randomized to 1 of 7 monotherapy treatments: tofacitinib 1, 3, 5, 10 or 15 mg twice daily, adalimumab 40 mg subcutaneously every other week for 10 weeks followed by tofacitinib 5 mg twice daily for 3 months, or placebo.

Dose-Ranging Study 2 was a 6 month trial in which 507 patients with active rheumatoid arthritis who had an inadequate response to MTX alone received one of 6 dose regimens of tofacitinib (20 mg once daily; 1, 3, 5, 10 or 15 mg twice daily), or placebo added to background MTX.

The results of tofacitinib-treated patients achieving ACR20 responses in Studies 1 and 2 are shown in Figure 4. Although a dose-response relationship was observed in Study 1, the proportion of patients with an ACR20 response did not clearly differ between the 10 mg and 15 mg doses. In Study 2, a smaller proportion of patients achieved an ACR20 response in the placebo and tofacitinib 1 mg groups compared to patients treated with the other tofacitinib doses. However, there was no difference in the proportion of responders among patients treated with tofacitinib 3, 5, 10, 15 mg twice daily or 20 mg once daily doses.

Figure 4

Proportion of Patients with ACR20 Response at Month 3 in Dose-Ranging Studies 1 and 2

*Tofacitinib twice daily dosing in mg, except for 20 mg which is once daily dosing in mg.

PBO is placebo; ADA is adalimumab 40 mg subcutaneous injection every other week.

Study 1 was a dose-ranging monotherapy trial not designed to provide comparative effectiveness data and should not be interpreted as evidence of superiority to adalimumab.

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 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 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 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 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 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 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 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 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 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 8. 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 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 9).

The results of the components of the ACR response criteria for Study RA-IV are shown in Table 10. 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 5. Similar responses were observed for tofacitinib in Studies RA-I, II, III, V, and VI.

Figure 5

Percentage of ACR20 Responders by Visit for Study RA-IV

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 10. 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 11. 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 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.

14.2 Psoriatic Arthritis

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 12 and 13).

Improvements from baseline in the ACR response criteria components for both studies are shown in Table 14.

The percentage of ACR20 responders by visit for Study PsA-I is shown in Figure 6. 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 6

Percentage of ACR20 Responders by Visit Through Month 3 in Study PsA-I*

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 15).

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.

14.3 Ulcerative Colitis

Induction Trials (Study UC-I [NCT01465763] and Study UC-II [NCT01458951])

In two identical induction trials (UC-I and UC-II), 1,139 patients were randomized (598 and 541 patients, respectively) to tofacitinib 10 mg twice daily or placebo with a 4:1 treatment allocation ratio. These trials included adult patients with moderately to severely active UC (total Mayo score of 6 to 12, with an endoscopy subscore of at least 2, and rectal bleeding subscore of at least 1) and who had failed or were intolerant to at least 1 of the following treatments: oral or intravenous corticosteroids, azathioprine, 6-MP or TNF blocker. Tofacitinib is indicated for patients who have an inadequate response or who are intolerant to TNF blockers [see Indications and Usage (1)].

The disease activity was assessed by Mayo scoring index (0 to 12) which consists of four subscores (0 to 3 for each subscore): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment. An endoscopy subscore of 2 was defined by marked erythema, absent vascular pattern, any friability, and erosions; an endoscopy subscore of 3 was defined by spontaneous bleeding and ulceration.

Patients were permitted to use stable doses of oral aminosalicylates and corticosteroids (prednisone daily dose up to 25 mg equivalent). Concomitant immunosuppressants (oral immunomodulators or biologic therapies) were not permitted for UC patients during these studies.

A total of 52%, 73% and 72% of patients had previously failed or were intolerant to TNF blockers (51% in Study UC-1 and 52% in Study UC-II), corticosteroids (75% in Study UC-I and 71% in Study UC-II), and/or immunosuppressants (74% in Study UC-I and 70% in Study UC-II), respectively.

Oral corticosteroids were received as concomitant treatment for UC by 47% of patients (45% in Study UC-I and 48% in Study UC-II) and 71% were receiving concomitant aminosalicylates as treatment for UC (71% in Study UC-I, and 72% in Study UC-II). The baseline clinical characteristics were generally similar between the tofacitinib treated patients and patients receiving placebo.

The primary endpoint of Study UC-I and Study UC-II was the proportion of patients in remission at Week 8, and the key secondary endpoint was the proportion of patients with improvement of endoscopic appearance of the mucosa at Week 8.

The efficacy results of Study UC-I and Study UC-II based on the centrally read endoscopy results are shown in Table 16.

Clinical Response at Week 8

Clinical response was defined as a decrease from baseline in Mayo score of ≥3 points and ≥30%, with an accompanying decrease in the subscore for rectal bleeding of ≥1 point or absolute subscore for rectal bleeding of 0 or 1.

Clinical response was observed in 60% of patients treated with tofacitinib 10 mg twice daily compared to 33% of placebo patients in Study UC-I and 55% compared to 29% in Study UC-II.

Normalization of the Endoscopic Appearance of the Mucosa at Week 8

Normalization of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of 0 and was observed in 7% of patients treated with tofacitinib 10 mg twice daily compared to 2% of placebo patients in both Studies UC-I and UC-II.

Rectal Bleeding and Stool Frequency

Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 in patients treated with tofacitinib.

Maintenance Trial (Study UC-III [NCT01458574])

A total of 593 patients who completed the induction trials (UC-I or UC-II) and achieved clinical response were re-randomized with 1:1:1 treatment allocation ratio to tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or placebo for 52 weeks in Study UC-III. Tofacitinib 5 mg twice daily is the recommended dosage for maintenance therapy; limit use of tofacitinib 10 mg twice daily beyond induction to those with loss of response and should be used for the shortest duration [see Dosage and Administration (2.3)]. As in the induction trials, patients were permitted to use stable doses of oral aminosalicylates; however, corticosteroid tapering was required upon entrance into this study for patients who were receiving corticosteroids at baseline. Concomitant immunosuppressants (oral immunomodulators or biologic therapies) were not permitted.

At baseline of Study UC-III:

• 179 (30%) patients were in remission
• 289 (49%) patients were receiving oral corticosteroids
• 265 (45%), 445 (75%), and 413 (70%) patients had previously failed or were intolerant to TNF blocker therapy, corticosteroids, and immunosuppressants, respectively.

The primary endpoint was the proportion of patients in remission at Week 52. There were 2 key secondary endpoints: the proportion of patients with improvement of endoscopic appearance at Week 52, and the proportion of patients with sustained corticosteroid-free remission at both Week 24 and Week 52 among patients in remission at baseline of Study UC-III.

The efficacy results of Study UC-III based on the centrally read endoscopy results are summarized in Table 17.

Maintenance of Clinical Response

Maintenance of clinical response was defined as the proportion of patients who met the definition of clinical response (defined as a decrease from the induction study (UC-I, UCII) baseline Mayo score of ≥3 points and ≥30%, with an accompanying decrease in the rectal bleeding subscore of ≥1 point or rectal bleeding subscore of 0 or 1) at both Baseline and Week 52 of Study UC-III.

Maintenance of clinical response was observed in 52% in the tofacitinib 5 mg twice daily group and 62% in the tofacitinib 10 mg twice daily group compared to 20% of placebo patients.

Maintenance of Remission (Among Patients in Remission at Baseline)

In the 179 patients who were in remission at baseline of Study UC-III (N = 59 for placebo, N = 65 for tofacitinib 5 mg twice daily, N = 55 for tofacitinib 10 mg twice daily), 46% in the tofacitinib 5 mg twice daily group and 56% in the tofacitinib 10 mg twice daily group maintained remission at Week 52 compared to 10% of placebo patients.

Normalization of the Endoscopic Appearance of the Mucosa

Normalization of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of 0 and was observed at Week 52 in 15% of patients in the tofacitinib 5 mg twice daily group and 17% of patients in the tofacitinib 10 mg twice daily group compared to 4% of placebo patients.

Open-label Extension Study (Study UC-IV [NCT01470612])

In Study UC-IV, 914 patients were treated of which 156 received 5 mg twice daily and 758 received 10 mg twice daily.

Of the 905 patients who were assigned to tofacitinib 10 mg twice daily in the 8-week induction studies (Study UC-I or Study UC-II), 322 patients completed the induction studies but did not achieve clinical response. Of these 322 patients, 291 continued to receive tofacitinib 10 mg twice daily (unblinded) and had available data after an additional 8 weeks in Study UC-IV. After 8 additional weeks (a total of 16 weeks treatment), 148 patients achieved clinical response, and 25 patients achieved remission (based on central endoscopy read). Among those 143 patients who achieved clinical response by 16 weeks and had available data at Week 52, 66 patients achieved remission (based on local endoscopy read) after continued treatment with tofacitinib 10 mg twice daily for 52 weeks.