Tofacitinib is a Janus kinase (JAK) inhibitor indicated for: Rheumatoid Arthritis: Tofacitinib extended-release tablets are indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis 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.
( 1.1 ) Psoriatic Arthritis: Tofacitinib extended-release tablets are indicated for the treatment of adult patients with active psoriatic arthritis 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. ( 1.2 ) Ankylosing Spondylitis: Tofacitinib extended-release tablets are indicated for the treatment of adult patients with active ankylosing spondylitis 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. ( 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 adult patients with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use: Use of tofacitinib extended-release tablets in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
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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.
Contraindications
None. None ( 4 )
Warnings and precautions
Serious Infections: Avoid use of tofacitinib extended-release tablets during an active serious infection, including localized infections. ( 5.1 ) Gastrointestinal Perforations: Use with caution in patients that may be at increased risk. ( 5.6 ) Laboratory Monitoring: Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. ( 5.8 ) Immunizations: Live vaccines: Avoid use with tofacitinib extended-release tablets ( 5.9 )
5.1Serious 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. Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis). Avoid use of tofacitinib extended-release tablets in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating tofacitinib extended-release tablets in patients: with chronic or recurrent infection who have been exposed to tuberculosis with a history of a serious or an opportunistic infection who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or with underlying conditions that may predispose them to infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tofacitinib extended-release tablets. Tofacitinib extended-release tablets should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with tofacitinib extended-release tablets should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.
Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections. Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Discontinuation and monitoring criteria for lymphopenia are recommended [see Dosage and Administration ( 2.2 )].
Tuberculosis Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of tofacitinib extended-release tablets. Anti-tuberculosis therapy should also be considered prior to administration of tofacitinib extended-release tablets in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection.
Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering tofacitinib extended-release tablets.
Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with tofacitinib tablets. Postmarketing cases of hepatitis B reactivation have been reported in patients treated with tofacitinib tablets. The impact of tofacitinib on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials.
Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with tofacitinib extended-release tablets. The risk of herpes zoster is increased in patients treated with tofacitinib and appears to be higher in patients treated with tofacitinib tablets in Japan and Korea.
5.2Mortality
Rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular risk factor treated with tofacitinib 5 mg twice a day or tofacitinib 10 mg twice a day had a higher observed rate of all-cause mortality, including sudden cardiovascular death, compared to those treated with TNF blockers in a large, randomized, postmarketing safety study (RA Safety Study 1). The incidence rate of all-cause mortality per 100 patient-years was 0.88 for tofacitinib 5 mg twice a day, 1.23 for tofacitinib 10 mg twice a day, and 0.69 for TNF blockers [see Clinical Studies ( 14.6 )] .
Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with tofacitinib extended-release tablets. A tofacitinib tablets 10 mg twice daily (or a tofacitinib extended-release tablets 22 mg once daily) dosage is not recommended for the treatment of RA, PsA, or AS [see Dosage and Administration ( 2.2 )].
5.3Malignancy and Lymphoproliferative Disorders
Malignancies, including lymphomas and solid cancers, were observed in clinical studies of tofacitinib [see Adverse Reactions ( 6.1 )]. In RA Safety Study 1, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with tofacitinib 5 mg twice a day or tofacitinib 10 mg twice a day as compared with TNF blockers. The incidence rate of malignancies (excluding NMSC) per 100 patient-years was 1.13 for tofacitinib 5 mg twice a day, 1.13 for tofacitinib 10 mg twice a day, and 0.77 for TNF blockers.
Patients who are current or past smokers are at additional increased risk [see Clinical Studies ( 14.6 )]. Lymphomas and lung cancers, which are a subset of all malignancies in RA Safety Study 1, were observed at a higher rate in patients treated with tofacitinib 5 mg twice a day and tofacitinib 10 mg twice a day compared to those treated with TNF blockers. The incidence rate of lymphomas per 100 patient-years was 0.07 for tofacitinib 5 mg twice a day, 0.11 for tofacitinib 10 mg twice a day, and 0.02 for TNF blockers.
The incidence rate of lung cancers per 100 patient-years among current and past smokers was 0.48 for tofacitinib 5 mg twice a day, 0.59 for tofacitinib 10 mg twice a day, and 0.27 for TNF blockers [see Clinical Studies ( 14.6 )]. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with tofacitinib extended-release tablets, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy while on treatment, and patients who are current or past smokers.
A tofacitinib tablets 10 mg twice daily (or a tofacitinib extended-release tablets 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration ( 2.2 )]. In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoprol
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Interactions
Table 6 includes drugs with clinically important drug interactions when administered concomitantly with tofacitinib and instructions for preventing or managing them. Table 6: Clinically Relevant Interactions Affecting Tofacitinib When Coadministered with Other Drugs Strong CP3A4 Inhibitors (e.g., ketoconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage adjustment of tofacitinib is recommended [see Dosage and Administration ( 2 ), Clinical Pharmacology, Figure 3 ( 12.3 )] Moderate CYP3A4 Inhibitors Coadministered with Strong CYP2C19 Inhibitors (e.g., fluconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage adjustment of tofacitinib 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 Coadministration with tofacitinib is not recommended [see Clinical Pharmacology, Figure 3 ( 12.3 )] Immunosuppressive Drugs (e.g., azathioprine, tacrolimus, cyclosporine) Clinical Impact Risk of added immunosuppression; coadministration with biologic DMARDs or potent immunosuppressants has not been studied in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.
Intervention Coadministration with tofacitinib is not recommended [see Indications and Usage ( 1 ), Clinical Pharmacology, Figure 3 ( 12.3 )] See full prescribing information for clinically relevant drug interactions. ( 2 , 7 )
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
The available data with tofacitinib from a pregnancy exposure registry that enrolled 11 exposed patients, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with rheumatoid arthritis and UC in pregnancy (see Clinical Considerations).
In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively. Further, in a peri- and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dose of 5 mg twice daily and approximately 36 times the maximum recommended dose of 10 mg twice daily, respectively (see Data).
The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis.
Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 g) infants, and small for gestational age at birth. Data Animal Data In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the recommended dose of 5 mg twice daily, and approximately 73 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats).
Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses.
Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the recommended dose of 5 mg twice daily, and approximately 29 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats). In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the recommended dose of 5 mg twice daily, and approximately 6.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity.
Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the recommended dose of 5 mg twice daily, and approximately 1.5 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits).
In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the recommended dose of 5 mg twice daily, and approximately 36 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats).
There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the recommended dose of 5 mg twice daily, and approximately 8.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats).
Adverse reactions
The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections [see Warnings and Precautions ( 5.1 )] Mortality [see Warnings and Precautions ( 5.2 )] Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions ( 5.3 )] Major Adverse Cardiovascular Events [see Warnings and Precautions ( 5.4 )] Thrombosis [see Warnings and Precautions ( 5.5 )] Gastrointestinal Perforations [see Warnings and Precautions ( 5.6 )] Hypersensitivity [see Warnings and Precautions ( 5.7 )] Laboratory Abnormalities [see Warnings and Precautions ( 5.8 )] Most common adverse reactions are: Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis : Reported during the first 3 months in rheumatoid arthritis placebo-controlled clinical trials and occurring in ≥2% of patients treated with tofacitinib monotherapy or in combination with DMARDs: upper respiratory tract infection, nasopharyngitis, diarrhea, and headache.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA Inc. at 855-664-7744 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. Rheumatoid Arthritis The clinical studies described in the following sections were conducted using tofacitinib. Although other doses of tofacitinib have been studied, the recommended dose of tofacitinib tablets is 5 mg twice daily.
The recommended dose for tofacitinib extended-release tablets is 11 mg once daily. A dosage of tofacitinib tablets 10 mg twice daily or tofacitinib extended-release tablets 22 mg once daily is not a recommended regimen for the treatment of rheumatoid arthritis [see Dosage and Administration ( 2.2 )]. In RA Safety Study 1, 1,455 patients were treated with tofacitinib 5 mg twice daily, 1,456 patients were treated with 10 mg twice daily, and 1,451 patients were treated with a TNF blocker for a median of 4.0 years [see Clinical Studies ( 14.6 )].
The following data includes two Phase 2 and five Phase 3 double-blind, placebo-controlled, multicenter trials. In these trials, patients were randomized to doses of tofacitinib 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, tofacitinib 5 mg twice daily (1,044 patients) and 10 mg twice daily (1,043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients).
All seven placebo-controlled protocols included provisions for patients taking placebo to receive treatment with tofacitinib at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore, some analyses that follow include patients who changed treatment by design or by patient response from placebo to tofacitinib in both the placebo and tofacitinib group of a given interval.
Comparisons between placebo and tofacitinib were based on the first 3 months of exposure, and comparisons between tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily were based on the first 12 months of exposure. The long-term safety population includes all patients who participated in a double-blind, placebo-controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies.
The design of the long-term safety studies allowed for modification of tofacitinib doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose. The most common serious adverse reactions were serious infections [see Warnings and Precautions ( 5.1 )]. The proportion of patients who discontinued treatment due to any adverse reaction during the 0 month to 3 months exposure in the double-blind, placebo-controlled trials was 4% for patients taking tofacitinib and 3% for placebo-treated patients.
Overall Infections In the seven placebo-controlled trials, during the 0 month to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group. The most commonly reported infections with tofacitinib were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).
Serious Infections In the seven placebo-controlled trials, during the 0 month to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received tofacitinib 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily tofacitinib group minus placebo.
In the seven placebo-controlled trials, during the 0 month to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received 5 mg twice daily of tofacitinib and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib.
The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection [see Warnings and Precautions ( 5.1 )]. Tuberculosis In the seven placebo-controlled trials, during the 0 month to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of tofacitinib, or 10 mg twice daily of tofacitinib. In the seven placebo-controlled trials, during the 0 month to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of tofacitinib and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily of tofacitinib.
The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib. Cases of disseminated tuberculosis were also reported. The median tofacitinib exposure prior to diagnosis of tuberculosis was 10 months (range from 152 days to 960 days) [see Warnings and Precautions ( 5.1 )].
Opportunistic Infections (excluding tuberculosis) In the seven placebo-controlled trials, during the 0 month to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of tofacitinib, or 10 mg twice daily of tofacitinib. In the seven placebo-controlled trials, during the 0 month to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of tofacitinib and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of tofacitinib.
The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib. The median tofacitinib exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 days to 698 days) [see Warnings and Precautions ( 5.1 )]. Malignancy In the seven placebo-controlled trials, during the 0 month to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either tofacitinib 5 mg or 10 mg twic
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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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