Tofacitinib extended-release tablets are Janus kinase (JAK) inhibitors. Tofacitinib extended-release tablets are indicated for the treatment of adult patients with: Moderately to severely active rheumatoid arthritis (RA), who have had an inadequate response or intolerance to one or more TNF blockers. Active psoriatic arthritis (PsA), who have had an inadequate response or intolerance to one or more TNF blockers. Active ankylosing spondylitis (AS), who have had an inadequate response or intolerance to one or more TNF blockers.
Limitations of Use : Use of tofacitinib extended-release tablets for RA, AS, or PsA in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. ( 1.1 , 1.2 , 1.3 )
1.1Rheumatoid Arthritis
Tofacitinib extended-release tablets are indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA), who have had an inadequate response or intolerance to one or more TNF blockers. 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.
1.2Psoriatic Arthritis
Tofacitinib extended-release tablets are indicated for the treatment of adults with active PsA who have had an inadequate response or intolerance to one or more TNF blockers. Limitations o f Use Use of tofacitinib extended-release tablets in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
1.3Ankylosing Spondylitis
Tofacitinib extended-release tablets are indicated for the treatment of adult patients with active ankylosing spondylitis (AS), who have had an inadequate response or intolerance to one or more TNF blockers. 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.
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Serious Infections : Avoid use of tofacitinib extended-release tablets during an active serious infection, including localized infections. ( 5.1 ) Gastrointestinal Perforations : Promptly evaluate patients at increased risk for gastrointestinal perforation who present with new onset abdominal symptoms. ( 5.6 ) Laboratory Monitoring : Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids.
( 5.8 ) Vaccinations : Avoid use of live vaccines concurrently with tofacitinib extended-release tablets. ( 5.9 )
5.1Serious Infections Serious
and sometimes fatal infections may occur with tofacitinib extended-release tablets. Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. The most common serious infections reported with tofacitinib included pneumonia, urinary tract infection, cellulitis, herpes zoster, bronchitis, septic shock, diverticulitis, gastroenteritis, appendicitis, and sepsis.
Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multi-dermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with tofacitinib. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids.
Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis). Avoid use of tofacitinib 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.
Closely monitor patients for the development of signs and symptoms of infection during and after treatment with tofacitinib extended-release tablets. Interrupt tofacitinib extended-release tablets if a patient develops a serious infection, an opportunistic infection, or sepsis. In patients who develop a new infection during treatment with tofacitinib extended-release tablets, promptly complete diagnostic testing appropriate for an immunocompromised patient; initiate appropriate antimicrobial therapy, and monitor the patients closely.
Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections. Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Discontinuation and monitoring criteria for lymphopenia are recommended [see Dosage and Administration (2.3) ].
Tuberculosis Evaluate and test patients for latent or active tuberculosis (TB) infection prior to and per applicable guidelines during administration of tofacitinib extended-release tablets. Consider anti-TB therapy prior to administration of tofacitinib extended-release tablets in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection.
Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient. Monitor patients closely for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy. Treat patients with latent TB with standard antimycobacterial therapy before administering tofacitinib 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.
Perform screening for viral hepatitis 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.
5.2Increased Risk of Mortality
Increased risk of mortality may occur with tofacitinib extended-release tablets. Adult patients with rheumatoid arthritis (RA), 50 years of age and older, with at least one cardiovascular risk factor treated with tofacitinib tablets 5 mg or 10 mg twice a day had a higher observed rate of all-cause mortality, including sudden cardiovascular death, compared to those treated with TNF blockers in a large, randomized, postmarketing safety study (RA Safety Study 1).
The incidence rate of all-cause mortality per 100 patient-years was 1.23 for tofacitinib tablets 10 mg twice a day, 0.88 for tofacitinib tablets 5 mg twice a day, and 0.69 for TNF blockers [see Clinical Studies (14.6) ] . Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with tofacitinib extended-release tablets. Tofacitinib tablets 10 mg twice daily (or tofacitinib extended-release tablets 22 mg once daily) dosages are not recommended for the treatment of RA, PsA, or AS [see Dosage and Administration (2.3) ] .
5.3Malignancy and Lymphoproliferative Disorders Malignancies
and lymphoproliferative disorders may occur with tofacitinib extended-release tablets. Malignancies, including lymphomas and solid cancers, were observed in clinical studies of tofacitinib [see Adverse Reactions (6.1) ]. Other malignancies were observed in tofacitinib clinical studies and the postmarketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer.
In RA Safety Study 1, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with tofacitinib tablets 5 mg or 10 mg twice a day compared with TNF blockers. The incidence rate of malignancies (excluding NMSC) per 100 patient-years was 1.13 for tofacitinib tablets 10 mg twice a day, 1.13 for tofacitinib tablets 5 mg twice a day, and 0.77 for TNF blockers. Patients who are current or past smokers are at additional increased risk [see Clinical Studies (14.6) ].
Lymphomas and lung cancers, which are a subset of all malignancies in RA Safety Study 1, were observed at a higher rate in patients treated with tofacitinib tablets 5 mg twice a day and tofacitinib tablets 10 mg twice a day compared to those treated with TNF blockers. The incidence rate of lymphomas per 100 patient-years was 0.11 for tofacitinib tablets 10 mg twice a day, 0.07 for tofacitinib tablets 5 mg twice a day, and 0.02 for TNF blockers.
The incidence rate of lung cancers per 100 patient-years among current and past smokers was 0.59 for tofacitinib tablets 10 mg twice a day, 0.48 for tofacitinib tablets 5 mg twice a day, and 0.27 for TNF blockers [see Clinical Studies (14.6) ] . Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with tofacitinib extended-release tablets, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy whi
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Interactions
Table 7 includes drugs with clinically significant drug interactions when concomitantly used with tofacitinib extended-release tablets and instructions for preventing or managing them. Table 7: Clinically Significant Interactions Affecting Tofacitinib Extended-Release Tablets When Concomitantly Used with Other Drugs Strong CYP3A4 Inhibitors (e.g., ketoconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage modification of tofacitinib extended-release tablets is recommended [see Dosage and Administration (2) , Clinical Pharmacology, Figure 3 (12.3) ] Moderate CYP3A4 Inhibitors Concomitantly Used with Strong CYP2C19 Inhibitors (e.g., fluconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage modification of tofacitinib extended-release tablets is recommended [see Dosage and Administration (2) , Clinical Pharmacology, Figure 3 (12.3) ] Strong CYP3A4 Inducers (e.g., rifampin) Clinical Impact Decreased exposure to tofacitinib and may result in loss of or reduced clinical response Intervention Concomitant use with tofacitinib extended-release tablets is not recommended [see Clinical Pharmacology, Figure 3 (12.3) ] Immunosuppressive Drugs (e.g., azathioprine, tacrolimus, cyclosporine) Clinical Impact Risk of added immunosuppression; concomitant use of tofacitinib extended-release tablets with biologic DMARDs or potent immunosuppressants has not been studied in patients with RA, PsA, or AS.
Intervention Concomitant use with tofacitinib extended-release tablets is not recommended [see Indications and Usage (1) , Clinical Pharmacology, Figure 3 (12.3) ] See FPI for clinically significant drug interactions. ( 2 , 7 )
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
The available data with tofacitinib extended-release tablets from a pregnancy exposure registry that enrolled 11 exposed pregnant females, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with RA in pregnancy (see Clinical Considerations) .
In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively. Further, in a peri- and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dosage of 5 mg twice daily and approximately 36 times the maximum recommended dosage of 10 mg twice daily, respectively (see Data) .
The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with RA.
Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 grams) 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).
Adverse reactions
The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections [see Warnings and Precautions (5.1) ] Increased Risk of Mortality [see Warnings and Precautions (5.2) ] Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions (5.3) ] Major Adverse Cardiovascular Events [see Warnings and Precautions (5.4) ] Thrombosis [see Warnings and Precautions (5.5) ] Gastrointestinal Perforations [see Warnings and Precautions (5.6) ] Hypersensitivity Reactions [see Warnings and Precautions (5.7) ] Laboratory Abnormalities [see Warnings and Precautions (5.8) ] Most common adverse reactions are: RA , PsA, and AS : Reported in ≥2% of adult patients treated with tofacitinib tablets monotherapy or in combination with DMARDs: upper respiratory tract infection (URI), nasopharyngitis, diarrhea, and headache.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. The clinical studies described in this subsection were conducted using tofacitinib tablets and/or tofacitinib oral solution.
Adverse Reactions in Adults with Rheumatoid Arthritis In RA Safety Study 1, 1,455 adults were treated with tofacitinib 5 mg twice daily, 1,456 adults were treated with 10 mg twice daily, and 1,451 adults were treated with a TNF blocker for a median of 4 years [see Clinical Studies (14.6) ] . A dosage of tofacitinib 10 mg twice daily is not recommended for the treatment of RA because of increased risks [see Dosage and Administration (2.3) and Warnings and Precautions (5) ].
For the treatment of adults with moderately to severely active RA [see Indications and Usage (1.1) ] , the recommended dosage of tofacitinib is 5 mg twice daily and the recommended dosage for tofacitinib extended-release tablets is 11 mg once daily. The safety of tofacitinib was also evaluated in two Phase 2 and five Phase 3 double-blind, placebo-controlled, multicenter trials in patients with RA. In these trials, adults were randomized to receive: Tofacitinib (monotherapy) 5 mg twice daily (292 patients) or 10 mg twice daily (306 patients), In combination with DMARDs (including methotrexate), tofacitinib 5 mg twice daily (1044 patients) or 10 mg twice daily (1043 patients) and Placebo (809 patients).
All seven trials included provisions for patients taking placebo to receive treatment with tofacitinib at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore, some analyses that follow include patients who changed treatment by design or by patient response from placebo to tofacitinib in both the placebo and tofacitinib group of a given interval.
Comparisons between placebo and tofacitinib groups were based on the first 3 months of exposure, and comparisons between tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily were based on the first 12 months of exposure. The long-term safety population includes all adults with RA who participated in a double-blind, placebo-controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies.
The design of the long-term safety studies allowed for modification of tofacitinib doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose. The most common serious adverse reactions were serious infections [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 tofacitinib-treated patients and 3% for placebo-treated patients.
Overall Infections In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily groups, respectively, and 18% in the placebo group. The most commonly reported infections with tofacitinib were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).
Serious Infections : In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received tofacitinib 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined tofacitinib 5 mg twice daily and 10 mg twice daily group minus placebo.
In the seven placebo-controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received tofacitinib 5 mg twice daily and 33 patients (2.7 events per 100 patient-years) who received tofacitinib 10 mg twice daily. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for tofacitinib 10 mg twice daily minus tofacitinib 5 mg twice daily.
The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection [see Warnings and Precautions (5.1) ] . Tuberculosis: In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, tuberculosis (TB) was not reported in patients who received placebo, tofacitinib 5 mg twice daily, or tofacitinib 10 mg twice daily. In the seven placebo-controlled trials, during the 0 to 12 months exposure, TB was reported in 0 patients who received tofacitinib 5 mg twice daily and 6 patients (0.5 events per 100 patient-years) who received tofacitinib 10 mg twice daily.
The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for tofacitinib 10 mg twice daily minus tofacitinib 5 mg twice daily. Cases of disseminated TB were also reported. The median tofacitinib exposure prior to diagnosis of TB was 10 months (range from 152 to 960 days) [see Warnings and Precautions (5.1) ]. Opportunistic Infections (excluding tuberculosis): In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, tofacitinib 5 mg twice daily, or tofacitinib 10 mg twice daily.
In the seven placebo-controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received tofacitinib 5 mg twice daily and 4 patients (0.3 events per 100 patient-years) who received tofacitinib 10 mg twice daily. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for tofacitinib 10 mg twice daily minus tofacitinib 5 mg twice daily.
The median tofacitinib exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days) [see Warnings and Precautions (5.1) ]. Malignancies In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either tofacitinib 5 mg or 10 mg t
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Composition
Active ingredients
TOFACITINIB CITRATE EQ 11MG BASE
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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