Xeljanz

Tofacitinib citrate.

Each 5 mg film-coated tablet contains 8.078 mg of tofacitinib citrate equivalent to 5 mg of tofacitinib free base active pharmaceutical ingredient.
Tofacitinib citrate (CP-690,550-10) has a molecular weight of 504.5 Daltons, or 312.4 Daltons, for tofacitinib free base (CP 690,550). The molecular formula of tofacitinib citrate is C₁₆H₂₀N₆O•C₆H₈O₇.
Excipients with known effect: Each 5 mg tablet also contains 62.567 mg lactose monohydrate.
Excipients/Inactive Ingredients: Microcrystalline cellulose, Lactose monohydrate, Croscarmellose sodium, Magnesium stearate.
Film Coat for 5 mg tablets: Opadry II White (33G28523) containing: HPMC 2910/Hypromellose 6cP, Titanium dioxide, Lactose monohydrate, Macrogol/PEG3350, Triacetin (glycerol triacetate).

Pharmacology: Pharmacodynamics: Mechanism of Action: Tofacitinib is a potent, selective inhibitor of the JAK family of kinases with a high degree of selectivity against other kinases in the human genome. In kinase assays, tofacitinib inhibits JAK1, JAK2, JAK3, and to a lesser extent TyK2. In cellular settings where JAK kinases signal in pairs, tofacitinib preferentially inhibits signaling by heterodimeric receptors associated with JAK3 and/or JAK1 with functional selectivity over receptors that signal via pairs of JAK2. Inhibition of JAK1 and JAK3 by tofacitinib blocks signaling through the common gamma chain-containing receptors for several cytokines, including IL-2, -4, -7, -9, -15, and -21. These cytokines are integral to lymphocyte activation, proliferation, and function and inhibition of their signaling may thus result in modulation of multiple aspects of the immune response. In addition, inhibition of JAK1 will result in attenuation of signaling by additional pro-inflammatory cytokines, such as IL-6 and Type I interferons. At higher exposures, inhibition of erythropoietin signaling could occur via inhibition of JAK2 signaling.
Pharmacodynamic Effect: Treatment up to 6 months with XELJANZ was associated with dose-dependent reductions of circulating CD16/56+ natural killer (NK) cells, with estimated maximum reductions occurring at approximately 8-10 weeks after initiation of therapy. These changes generally resolved within 2-6 weeks after discontinuation of treatment. Treatment with XELJANZ 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.
Following long-term treatment (median duration of XELJANZ treatment of approximately 5 years), CD4+ and CD8+ counts showed median reductions of 28% and 27%, respectively, from baseline. In contrast to the observed decrease after short-term dosing, CD16/56+ natural killer cell counts showed a median increase of 73% from baseline. CD19+ B cell counts showed no further increases after long-term XELJANZ treatment. These changes returned toward baseline after temporary discontinuation of treatment. There was no evidence of an increased risk of serious or opportunistic infections or herpes zoster at low values of CD4+, CD8+ or NK cell counts or high B cell counts.
Changes in total serum IgG, IgM, and IgA levels over 6-month XELJANZ dosing in patients with rheumatoid arthritis were small, not dose-dependent and similar to those seen on placebo.
After treatment with XELJANZ in patients with rheumatoid arthritis, rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout dosing. Changes in CRP observed with XELJANZ treatment do not reverse fully within 2 weeks after discontinuation, indicating a longer duration of pharmacodynamic activity compared to the half-life.
Clinical Safety: Mortality: In one large ongoing randomized post authorization safety surveillance (PASS) study in RA patients who were 50 years or older with at least one cardiovascular risk factor, patients treated with XELJANZ 10 mg twice a day had a higher incidence rate of all-cause mortality compared to those treated with XELJANZ 5 mg given twice daily or TNF inhibitors.
Clinical Efficacy: The efficacy and safety of XELJANZ were assessed in five randomized, double-blind, placebo-controlled multicenter studies in patients >18 years with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 6 tender and 6 swollen joints at randomization (4 swollen and tender joints for Study II). XELJANZ, 5 or 10 mg twice daily, was given as monotherapy (Study I) and in combination with DMARDs (Study II) in patients with an inadequate response to those drugs, and in combination with methotrexate in patients with either an inadequate response to MTX (Studies III and Study IV) or inadequate efficacy or lack of tolerance to at least one approved TNF-inhibiting biologic agent (Study V).
Study I was a 6-month monotherapy study in which 610 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a DMARD (non-biologic or biologic) received XELJANZ 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 XELJANZ 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) <2.6.
Study II was a 12-month study in which 792 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a non-biologic DMARD received XELJANZ 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, non-responding patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 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) <2.6 at Month 6.
Study III was a 12-month study in which 717 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX. Patients received XELJANZ 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 III was not designed as a head-to-head comparison between XELJANZ and adalimumab.
Study IV was a 2-year study 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 XELJANZ 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 V was a 6-month study in which 399 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to at least one approved TNF-inhibiting biologic agent received XELJANZ 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 XELJANZ 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) <2.6.
Clinical Response: ACR response: The percentages of XELJANZ-treated patients achieving ACR20, ACR50, and ACR70 responses in Studies I, II, IV, and V are shown in Table 1. In all studies, patients treated with either 5 or 10 mg twice daily XELJANZ had statistically significant ACR20, ACR50, and ACR70 response rates at Month 3 and Month 6 vs. placebo treated patients.
In Study IV, ACR20/50/70 response rates at Month 12 were maintained through Month 24.
In Studies I, II, and V, improvement in ACR20 response rate vs. placebo was observed within 2 weeks.
During the 3 month (Studies I and V) and 6 month (Studies II, III, and IV) controlled portions of the studies, patients treated with XELJANZ at a dose of 10 mg twice daily generally had higher response rates compared to patients treated with XELJANZ 5 mg twice daily. In Study III, the primary endpoints were the proportion achieving an ACR20 response at Month 6; change in HAQ-DI at Month 3, and DAS28-4(ESR) <2.6 at Month 6. The data for these primary outcomes were 51.5, 52.6, 47.2 and 28.3%; -0.55, -0.61, -0.49 and -0.24; and 6.2%, 12.5%, 6.7% and 1.1% for the 5 mg twice daily XELJANZ, 10 mg twice daily XELJANZ, adalimumab 40 mg subcutaneously every other week and placebo groups, respectively. For a pre-specified secondary endpoint, the ACR70 response rates at Month 6 for the 5 mg twice daily and 10 mg twice daily XELJANZ groups were significantly greater than adalimumab 19.9%, 21.9% and 9.1%, respectively.
The treatment effect was similar in patients independent of rheumatoid factor status, age, gender, race, or disease status. Time to onset was rapid (as early as Week 2 in Studies I, II and V) and the magnitude of response continued to improve with duration of treatment. As with the overall ACR response in patients treated with 5 mg or 10 mg twice daily XELJANZ, each of the components of the ACR response was consistently improved from baseline including: tender and swollen joint counts; patient and physician global assessment; disability index scores; pain assessment and CRP compared to patients receiving placebo plus MTX or other DMARDs in all studies.
DAS28-4(ESR) response: Patients in the Phase 3 studies had a mean Disease Activity Score (DAS28-4[ESR]) of 6.1-6.7 at baseline. Significant reductions in DAS28-4(ESR) from baseline (mean improvement) of 1.8-2.0 and 1.9-2.2 were observed in 5 mg and 10 mg XELJANZ-treated patients, respectively, compared to placebo-treated patients (0.7-1.1) at 3 months. The proportion of patients achieving a DAS28 clinical remission (DAS28-4(ESR) <2.6) in Studies II, III and IV was significantly higher in patients receiving 5 mg or 10 mg XELJANZ (6-9% and 13-16%, respectively) compared to 1-3% of placebo patients at 6 months. In Study III, the percentages of patients achieving DAS28-4(ESR) <2.6 observed for XELJANZ 5 mg twice daily, 10 mg twice daily, and adalimumab at Month 6 were 6.2%, 12.5%, and 6.7%, respectively.
In a pooled analysis of the Phase 3 studies, the 10 mg twice daily dose provided increased benefit over the 5 mg twice daily dose in multiple measures of signs and symptoms: improvement from baseline (ACR20, ACR50, and ACR70 response rates), and achievement of targeted disease activity state (either DAS28-4(ESR) <2.6 or ≤3.2). Greater benefits of 10 mg versus 5 mg were shown in the more stringent measures (i.e., ACR70 and DAS28-4(ESR) <2.6 response rates). (See Table 1.)

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The results of the proportion of patients with an ACR Response for Studies I, II, IV, and V are shown in Table 1. Similar results were observed in Study III.
The results of the components of the ACR response criteria for Study IV and V are shown in Table 2. Similar results were observed for XELJANZ in Studies I, II, III. (See Table 2.)

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The percent of ACR20 responders by visit for Study IV is shown in Figure 1. Similar responses were observed for XELJANZ in Studies I, II, III and V. (See Figure 1.)

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Physical Function Response and Health Related Outcomes: Improvement in physical functioning was measured by the HAQ-DI. Patients receiving XELJANZ 5 and 10 mg twice daily demonstrated significantly greater improvement from baseline in physical functioning compared to placebo at Month 3 (Studies I, II, III, and V) and Month 6 (Studies II and III). XELJANZ 5 or 10 mg twice daily-treated patients exhibited significantly greater improved physical functioning compared to placebo as early as Week 2 in Studies I and II. In Study III, mean HAQ-DI improvements were maintained to 12 months in XELJANZ-treated patients. Mean HAQ-DI improvements were maintained for 36 months in the ongoing open-label extension studies. Compared with adalimumab-treated patients, at Month 3, patients in the XELJANZ 5 mg twice daily had similar decreases from baseline in HAQ-DI values and patients in 10 mg twice daily group had significantly greater decreases in HAQ-DI. The mean change in HAQ-DI from baseline to Month 3 in Studies I to V are shown in Table 3. (See Table 3.)

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Other Health-related Outcomes: Health-related quality of life was assessed by the Short Form Health Survey (SF-36) in all 5 studies. In these studies, patients receiving XELJANZ 10 mg twice daily demonstrated significantly 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. Both XELJANZ-treated groups exhibited significantly greater improvement from baseline compared to placebo in all 8 domains as well as PCS and MCS at Month 3 in Studies I, IV, and V. In Studies III and IV, mean SF-36 improvements were maintained to 12 months in XELJANZ-treated patients.
Improvement in fatigue was evaluated by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale at Month 3 in all studies. Patients receiving XELJANZ 5 or 10 mg twice daily demonstrated significantly greater improvement from baseline in fatigue compared to placebo in all 5 studies. In Studies III and IV, mean FACIT-F improvements were maintained to 12 months in XELJANZ-treated patients.
Improvement in sleep was assessed using the Sleep Problems Index I and II summary scales of the Medical Outcomes Study Sleep (MOS-Sleep) measure at Month 3 in all studies. Patients receiving XELJANZ 5 or 10 mg twice daily demonstrated significantly greater improvement from baseline in both scales compared to placebo in Studies II, III, and IV. In Studies III and IV, mean improvements in both scales were maintained to 12 months in XELJANZ-treated patients.
Improvement in productivity was evaluated using the Work Limitations Questionnaire (WLQ) scale at Month 3 in all studies. Patients receiving XELJANZ 10 mg twice daily demonstrated significantly greater improvement from baseline in the Overall Output Summary Scale compared to placebo in Studies III, IV, and V. In Studies III and IV, mean Overall Output improvements were maintained to 12 months in XELJANZ 10 mg twice daily-treated patients.
Durability of Clinical Responses: Durability of effect was assessed by ACR20, ACR50, ACR70 response rates, mean HAQ-DI, and mean DAS28-4(ESR) in the three Phase 3 DMARD IR studies with duration of at least one year. Efficacy was maintained in all tofacitinib treatment groups through to the end of the studies. Evidence of persistence of efficacy with tofacitinib treatment for up to 7 years is also provided from data in the one ongoing and one completed open-label, long-term follow-up studies.
Pharmacokinetics: The PK profile of tofacitinib is characterized by rapid absorption (peak plasma concentrations are reached within 0.5-1 hour), rapid elimination (half-life of ~3 hours) and dose-proportional increases in systemic exposure. Steady-state concentrations are achieved in 24-48 hours with negligible accumulation after twice daily administration.
Absorption and Distribution: Tofacitinib is well-absorbed, with an oral bioavailability of 74%. Co-administration of XELJANZ with a high-fat meal resulted in no changes in AUC while C_max was reduced by 32%. In clinical trials, tofacitinib was administered without regard to meal.
After intravenous administration, the volume of distribution is 87 L. Approximately 40% of circulating tofacitinib is bound to proteins. 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 Elimination: 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 drug, 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. In vitro, tofacitinib is a substrate for multidrug resistance (MDR) 1, but not for breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1/1B3, or organic cationic transporter (OCT) 1/2, and is not an inhibitor of MDR1, OAT P1B1/1B3, OCT2, organic anion transporter (OAT) 1/3, or multidrug resistance associated protein (MRP) at clinically meaningful concentrations.
Pharmacokinetic data and dosing recommendations for special populations and drug interactions are provided in Figure 2.
Pharmacokinetics in RA Patients: Population PK analysis in rheumatoid arthritis patients indicated that systemic exposure (AUC) of tofacitinib in the extremes of body weight (40 kg, 140 kg) were similar to that of a 70 kg patient. Elderly patients 80 years of age were estimated to have <5% higher AUC relative to the mean age of 55 years. Women were estimated to have 7% lower AUC compared to men. The available data have also shown that there are no major differences in tofacitinib AUC between White, Black and Asian patients. An approximate linear relationship between body weight and volume of distribution was observed, resulting in higher peak (C_max) and lower trough (C_min) concentrations in lighter patients. However, this difference is not considered to be clinically relevant. The between-subject variability (percentage coefficient of variation) in AUC of XELJANZ is estimated to be approximately 27%.
Renal Impairment: Patients with mild, moderate and severe renal impairment had 37%, 43% and 123% higher AUC, respectively, compared with healthy patients (see Dosage & Administration). In patients with end-stage renal disease, the contribution of dialysis to the total clearance of tofacitinib was relatively small.
Hepatic Impairment: Patients with mild and moderate hepatic impairment had 3%, and 65% higher AUC, respectively, compared with healthy patients. Patients with severe hepatic impairment were not studied (see Dosage & Administration).
Pediatric Population: The pharmacokinetics, safety and efficacy of tofacitinib in pediatric patients have not been established. (See Figure 2.)

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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 or hepatic function.
Toxicology: Non-clinical safety data: In nonclinical studies, effects were observed on the immune and hematopoietic systems that were attributed to the pharmacological properties (JAK inhibition) of tofacitinib. Secondary effects from immunosuppression, such as bacterial and viral infections and lymphoma were observed at clinically relevant doses. Other findings at doses well above human exposures included effects on the liver, lung and gastrointestinal systems.
Lymphoma was observed in 3 of 8 adult and 0 of 14 juvenile monkeys dosed with tofacitinib at 5 mg/kg twice daily. The no observed adverse effect level (NOAEL) for the lymphomas was 1 mg/kg twice daily. The unbound AUC at 1 mg/kg twice daily was 341 ng•h/mL, which is approximately half of the unbound AUC at 10 mg twice daily and similar to the unbound AUC at 5 mg twice daily in humans.
Tofacitinib is not mutagenic or genotoxic based on the results of a series of in vitro and in vivo tests for gene mutations and chromosomal aberrations.
The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib was not carcinogenic in mice up to a high dose of 200 mg/kg/day (unbound drug AUC of ~19-fold the human AUC at 10 mg twice daily). Benign Leydig cell tumors were observed in rats: benign Leydig cell tumors in rats are not associated with a risk of Leydig cell tumors in humans. Hibernomas (malignancy of brown adipose tissue) were observed in female rats at doses ≥30 mg/kg/day (unbound drug AUC of ~41-fold the human AUC at 10 mg twice daily). Benign thymomas were observed in female rats dosed only at the 100 reduced to 75 mg/kg/day dose (unbound drug AUC of ~94-fold the human AUC at 10 mg twice daily).
Tofacitinib was shown to be teratogenic in rats and rabbits, and have effects in rats on female fertility, parturition, and peri/post-natal development. Tofacitinib had no effects on male fertility, sperm motility, or sperm concentration. Tofacitinib was secreted in milk of lactating rats.

XELJANZ (tofacitinib), in combination with methotrexate (MTX), is indicated for reducing the signs and symptoms of rheumatoid arthritis (RA), in adult patients with moderately to severely active RA who have had an inadequate response to MTX.
In cases of intolerance to MTX, physicians may consider the use of XELJANZ (tofacitinib) as monotherapy.

Posology: The recommended posology is 5 mg administered twice daily in combination with methotrexate.
Monotherapy may be considered in cases of intolerance to methotrexate.
XELJANZ has not been studied and its use should be avoided in combination with biological DMARDs, such as tumor necrosis factor (TNF) antagonists, IL-1R antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators and potent immunosuppressants, such as azathioprine, cyclosporine, and tacrolimus because of the possibility of increased immunosuppression and increased risk of infection.
XELJANZ treatment should be interrupted if a patient develops a serious infection until the infection is controlled.
Method of Administration: XELJANZ is given orally with or without food.
Dose Adjustments Due to Laboratory Abnormalities (see Precautions): Dose adjustment or interruption of dosing may be needed for management of dose-related laboratory abnormalities including lymphopenia, neutropenia and anemia as described in Tables 4, 5 and 6 as follows.
It is recommended that XELJANZ not be initiated in patients with a lymphocyte count less than 500 cells/mm³. (See Table 4.)

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It is recommended that XELJANZ not be initiated in patients with an absolute neutrophil count (ANC) <1000 cells/mm³. (See Table 5.)

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It is recommended that XELJANZ not be initiated in patients with hemoglobin <9 g/dL. (See Table 6.)

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Special Populations: Renal Impairment: No dose adjustment is required in patients with mild renal impairment. XELJANZ dosage should be reduced to 5 mg once daily in patients with moderate or severe renal impairment (including but not limited to those undergoing hemodialysis) (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. XELJANZ should not be used in patients with severe hepatic impairment. XELJANZ dosage should be reduced to 5 mg once daily in patients with moderate hepatic impairment (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Patients Receiving Inhibitors of Cytochrome P450 (CYP3A4) and Cytochrome 2C19 (CYP2C19): XELJANZ dosage should be reduced to 5 mg once daily in patients receiving potent inhibitors of CYP3A4 (e.g., ketoconazole). XELJANZ dosage should be reduced to 5 mg once daily in patients receiving one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole). Co-administration of XELJANZ with potent CYP inducers (e.g., rifampin) may result in loss of or reduced clinical response (see Interactions). Co-administration of potent inducers of CYP3A4 with XELJANZ is not recommended.
Elderly Patients (≥65 years): No dosage adjustment is required in patients 65 years and older.
Pediatric: The safety and efficacy of XELJANZ in children <18 years of age has not yet been established.

There is no experience with overdose of XELJANZ. There is no specific antidote for overdose with XELJANZ. Treatment should be symptomatic and supportive. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment.
Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicates that more than 95% of the administered dose is expected to be eliminated within 24 hours.

None.

Serious Infections: Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving immunomodulatory agents, including biologic DMARDs and XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcus, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infection, BK virus infections, and listeriosis were reported with XELJANZ. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents, such as methotrexate or corticosteroids which, in addition to rheumatoid arthritis may predispose them to infections. Other serious infections that were not reported in clinical studies may also occur (e.g., histoplasmosis and coccidioidomycosis).
XELJANZ should not be initiated in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ in patients with chronic or recurrent infections, or those who have been exposed to tuberculosis, or with a history of a serious or an opportunistic infection, or have resided or travelled in areas of endemic tuberculosis or endemic mycoses; or have 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 XELJANZ. XELJANZ 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 XELJANZ 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.
As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes (see Adverse Reactions). Caution is also recommended in patients with a history of chronic lung disease as they may be more prone to infections. Events of interstitial lung disease (some of which had a fatal outcome) have been reported in patients treated with XELJANZ, a Janus-kinase (JAK) inhibitor, in clinical trials and in the post-marketing setting although the role of JAK inhibition in these events is not known.
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 discussed in Dosage & Administration.
Tuberculosis: Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of XELJANZ.
Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ.
Antituberculosis therapy should also be considered prior to administration of XELJANZ 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 health care professional with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating antituberculosis 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.
Viral Reactivation: Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ. Post-marketing cases of hepatitis B reactivation have been reported in patients treated with XELJANZ. The impact of XELJANZ 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.
The risk of herpes zoster appears to be higher in Japanese and Korean patients treated with XELJANZ.
Venous Thromboembolism: Venous thromboembolism (VTE) has been observed in patients taking XELJANZ in clinical trials and post-marketing reporting. In one large ongoing randomized post authorization safety surveillance (PASS) study in RA patients who were 50 years or older with at least one cardiovascular risk factor, patients were treated with tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily or a TNF inhibitor. A dose dependent increase in pulmonary embolism (PE) events was observed in patients treated with tofacitinib compared to TNF inhibitors (see Adverse Reactions). Many of these PE events were serious and some resulted in death. PE events were reported more frequently in this study in patients taking tofacitinib relative to other studies across the tofacitinib program (see Adverse Reactions).
Deep vein thrombosis (DVT) events were observed in all three treatment groups in this study (see Adverse Reactions).
Assess patients for VTE risk factors before starting treatment and periodically during treatment. Use XELJANZ with caution in patients in whom risk factors are identified (see Dosage & Administration). Urgently evaluate patients with signs and symptoms of VTE. Discontinue tofacitinib while evaluating suspected VTE, regardless of dose or indication.
Malignancy and Lymphoproliferative Disorder (Excluding Non-melanoma Skin Cancer [NMSC]): Consider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients with current or a history of malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy. The possibility exists for XELJANZ to affect host defenses against malignancies.
Lymphomas have been observed in patients treated with XELJANZ. Patients with rheumatoid arthritis, particularly those with highly active disease may be at a higher risk (up to several-fold) than the general population for the development of lymphoma. The role of XELJANZ in the development of lymphoma is uncertain.
Other malignancies were observed in clinical studies and the post-marketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. The role of treatment with XELJANZ on the development and course of malignancies is not known.
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 XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.
In the 5 controlled Phase 3 clinical studies in rheumatoid arthritis patients, 21 malignancies (excluding NMSC) including 2 lymphoma were diagnosed in 21 patients receiving XELJANZ/XELJANZ plus DMARD, compared to 0 malignancies (excluding NMSC) in patients in the placebo/placebo plus DMARD and 2 in 2 patients in the adalimumab group.
3030 patients (2679 patient-years of observation) were treated with XELJANZ for durations up to 2 years while 681 patients (203 patient-years of observation) were treated with placebo for a maximum of 6 months and 204 patients (179 patient-years of observation) were treated with adalimumab for 12 months. The exposure-adjusted incidence rate for malignancies and lymphoma was 0.78 and 0.075 events per 100 patient-years, respectively, in the XELJANZ groups.
In the long-term safety population (4867 patients), in rheumatoid arthritis studies, the rate of malignancies (excluding NMSC) and lymphoma was 0.97 and 0.09 events per 100 patient-years, respectively, consistent with the rate observed in the controlled period.
Non-melanoma Skin Cancer: Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
Gastrointestinal Perforations: Events of gastrointestinal perforation have been reported in clinical trials in rheumatoid arthritis patients, although the role of JAK inhibition in these events is not known. The incidence rate of gastrointestinal perforation across all studies (Phase 1, Phase 2, Phase 3 (excluding A3921069) and long-term extension) for all treatments groups all doses was 0.12 events per 100 patient-years with XELJANZ therapy. Events were primarily reported as diverticular perforation, peritonitis, abdominal abscess and appendicitis. All patients who developed gastrointestinal perforations were taking concomitant non-steroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids. The relative contribution of these concomitant medications vs. XELJANZ to the development of gastrointestinal perforations is not known.
XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.
Hypersensitivity: Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ. Some events were serious. Many of these events occurred in patients that have a history of multiple allergies. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction.
Laboratory Parameters: Lymphocytes: Lymphocyte counts <500 cells/mm³ were associated with an increased incidence of treated and serious infections. It is not recommended to initiate XELJANZ treatment in patients with a low lymphocyte count (i.e., <500 cells/mm³). In patients who develop a confirmed absolute lymphocyte count <500 cells/mm³ treatment with XELJANZ is not recommended. Lymphocytes should be monitored at baseline and every 3 months thereafter. For recommended modifications based on lymphocyte counts, see Dosage & Administration.
Neutrophils: Treatment with XELJANZ was associated with an increased incidence of neutropenia (<2000 cells/mm³) compared to placebo. It is not recommended to initiate XELJANZ treatment in patients with a low neutrophil count (i.e., ANC <1000 cells/mm³). For patients who develop a persistent ANC of 500-1000 cells/mm³, interrupt dosing until ANC is >1000 cells/mm³. In patients who develop a confirmed absolute neutrophil count <500 cells/mm³ treatment with XELJANZ is not recommended. Neutrophils should be monitored at baseline and after 4 to 8 weeks of treatment and every 3 months thereafter (see Dosage & Administration and Adverse Reactions).
Hemoglobin: It is not recommended to initiate XELJANZ treatment in patients with low hemoglobin values (i.e., <9 g/dL). Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels <8 g/dL or whose hemoglobin level drops >2 g/dL on treatment. Hemoglobin should be monitored at baseline and after 4 to 8 weeks of treatment and every 3 months thereafter (see Dosage & Adminsitration and Adverse Reactions).
Liver Enzymes: Treatment with XELJANZ 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 XELJANZ should be interrupted until this diagnosis has been excluded.
Lipids: Treatment with XELJANZ was associated with increases in lipid parameters, such as total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. Assessment of lipid parameters should be performed approximately 4 to 8 weeks following initiation of XELJANZ therapy. Patients should be managed according to clinical guidelines (e.g., National Cholesterol Educational Program) for the management of hyperlipidemia. Increases in total and LDL cholesterol associated with XELJANZ may be decreased to pretreatment levels with statin therapy.
Vaccinations: No data are available on the secondary transmission of infection by live vaccines to patients receiving XELJANZ. It is recommended that live vaccines not be given concurrently with XELJANZ. It is recommended that all patients be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunomodulatory agents. Consistent with these guidelines, if live zoster vaccine is administered, it should only be administered to patients with a known history of chickenpox or those that are seropositive for varicella zoster virus. Vaccination should occur at least 2 weeks but preferably 4 weeks before initiating immunomodulatory agents such as tofacitinib.
In a controlled clinical trial, the humoral response to concurrent vaccination with influenza and pneumococcal polysaccharide vaccines in patients with rheumatoid arthritis initiating tofacitinib 10 mg twice daily or placebo was evaluated. A similar percentage of patients achieved a satisfactory humoral response to influenza vaccine (≥4-fold increase in ≥2 of 3 antigens) in the tofacitinib (57%) and placebo (62%) treatment groups. A modest reduction in the percentage of patients who achieved a satisfactory humoral response to pneumococcal polysaccharide vaccine (≥2-fold increase in ≥6 of 12 serotypes) was observed in patients treated with tofacitinib monotherapy (62%) and methotrexate monotherapy (62%) as compared with placebo (77%), with a greater reduction in the response rate of patients receiving both tofacitinib and methotrexate (32%). The clinical significance of this is unknown.
A separate vaccine study evaluated the humoral response to concurrent vaccination with influenza and pneumococcal polysaccharide vaccines in patients receiving tofacitinib 10 mg twice daily for a median of approximately 22 months. Greater than 60% of patients treated with tofacitinib (with or without methotrexate) had satisfactory responses to influenza and pneumococcal vaccines. Consistent with the controlled trial, patients receiving both tofacitinib and MTX had a lower response rate to pneumococcal polysaccharide vaccine as compared with tofacitinib monotherapy (66% vs. 89%).
A controlled study in patients with rheumatoid arthritis on background methotrexate evaluated the humoral and cell-mediated responses to immunization with a live-attenuated virus vaccine (Zostavax) indicated for prevention of herpes zoster. The immunization occurred 2 to 3 weeks before initiating a 12-week treatment with tofacitinib 5 mg twice daily or placebo. Six weeks after immunization with the zoster vaccine, tofacitinib and placebo recipients exhibited similar humoral and cell-mediated responses (mean fold change of VZV IgG antibodies 2.11 in tofacitinib 5 mg twice daily and 1.74 in placebo twice daily; VZV IgG fold-rise ≥1.5 in 57% of tofacitinib recipients and in 43% of placebo recipients; mean fold change of VZV T-cell ELISPOT Spot Forming Cells 1.5 in tofacitinib 5 mg twice daily and 1.29 in placebo twice daily). These responses were similar to those observed in healthy volunteers aged 50 years and older.
In this study, one patient experienced dissemination of the vaccine strain of varicella zoster virus, 16 days after vaccination. 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 subject recovered after treatment with standard doses of antiviral medication. Subsequent testing showed that this patient made robust anti-varicella T-cell and antibody responses to the vaccine approximately 6 weeks post-vaccination, but not at 2 weeks post-vaccination, as expected for a primary infection.
Patients with Renal Impairment: No dose adjustment is required in patients with mild renal impairment. XELJANZ dose should be reduced to 5 mg once daily in patients with moderate or severe renal impairment (see Dosage & Administration). In clinical trials, XELJANZ was not evaluated in patients with baseline creatinine clearance values (estimated by Cockcroft-Gault equation) <40 mL/min (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Patients with Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. XELJANZ dose should be reduced to 5 mg once daily in patients with moderate hepatic impairment (see Dosage & Administration). XELJANZ should not be used in patients with severe hepatic impairment (see Dosage & Administration). In clinical trials, XELJANZ was not evaluated in patients with severe hepatic impairment, or in patients with positive HBV or HCV serology.
Combination with Other RA Therapies: XELJANZ has not been studied and its use should be avoided in RA patients in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators and potent immunosuppressants, such as azathioprine and cyclosporine because of the possibility of increased immunosuppression and increased risk of infection.
Effects on ability to drive and use machines: No formal studies have been conducted on the effects on the ability to drive and use machines.

There are no adequate and well-controlled studies on the use of XELJANZ in pregnant women. Tofacitinib has been shown to be teratogenic in rats and rabbits, and have effects in rats on female fertility, parturition, and peri/post-natal development (see Pharmacology: Toxicology: Non-clinical safety data under Actions). XELJANZ should not be used during pregnancy unless clearly necessary.
Women of reproductive potential should be advised to use effective contraception during treatment with XELJANZ and for at least 4 weeks after the last dose.
Tofacitinib was secreted in the milk of lactating rats (see Pharmacology: Toxicology: Non-clinical safety data under Actions). It is not known whether tofacitinib is secreted in human milk. Women should not breastfeed while treated with XELJANZ.

The following data includes 5 double-blind, controlled, multicenter studies of varying durations from 6-24 months (Studies I-V, see Pharmacology: Pharmacodynamics under Actions). In these studies, 2430 patients were randomized and treated to doses of XELJANZ 5 mg twice daily (243 patients) or 10 mg twice daily (245 patients) monotherapy and XELJANZ 5 mg twice daily (973 patients) or 10 mg twice daily (969 patients) in combination with DMARDs (including methotrexate).
All patients in these studies had moderate to severe rheumatoid arthritis. The study XELJANZ populations had a mean age of 52.7 years and 84.1% were female.
The long-term safety population includes all patients who participated in a double-blind, controlled study (including earlier development phase studies) and then participated in one of two long-term safety studies.
A total of 5305 patients (Phase 1, 2, 3 (excluding A3921069), and long-term extension studies) were treated with any dose of XELJANZ with a mean duration of 3.16 years, with 16785.8 patient-years of accumulated total drug exposure based on more than 8 years of continuous exposure to XELJANZ.
Safety information from ad hoc interim analyses is also included for one large (N=4362), ongoing randomized post authorization safety surveillance (PASS) study in RA patients who were 50 years or older with at least one cardiovascular risk factor (CV risk factors defined as: current cigarette smoker, diagnosis of hypertension, diabetes mellitus, family history of premature coronary heart disease, history of coronary artery disease including a history of revascularization procedure, coronary artery bypass grafting, myocardial infarction, cardiac arrest, unstable angina, acute coronary syndrome, and presence of extra articular disease associated with RA, e.g. nodules, Sjögren's syndrome, anemia of chronic disease, pulmonary manifestations), and were on a stable background dose of methotrexate.
Patients were randomized to open-label tofacitinib 10 mg twice daily, tofacitinib 5 mg twice daily, or a TNF inhibitor (TNF inhibitor was either etanercept 50 mg once weekly or adalimumab 40 mg every other week) in a 1:1:1 ratio. The co-primary endpoints are adjudicated malignancy (excluding NMSC) and adjudicated major adverse cardiovascular events (MACE); cumulative incidence and statistical assessment of endpoints are blinded. The study is an event-powered study that also requires at least 1500 patients to be followed for 3 years. The study treatment of tofacitinib 10 mg twice daily has been stopped and the patients were switched to 5 mg twice daily because of a dose dependent signal of PE.
Clinical Trials Experience: The most common serious adverse reactions were serious infections (see Precautions).
The most commonly reported adverse reactions during the first 3 months in controlled clinical trials (occurring in ≥2% of patients treated with XELJANZ monotherapy or in combination with DMARDs) were headache, upper respiratory tract infections, nasopharyngitis, hypertension, nausea, and diarrhea.
The proportion of patients who discontinued treatment due to any adverse reactions during first 3 months of the double-blind, placebo controlled studies were 4.2% for patients taking XELJANZ and 3.2% for placebo-treated patients. The most common infections resulting in discontinuation of therapy were herpes zoster and pneumonia.
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 XELJANZ 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 XELJANZ 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 XELJANZ and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.
The most common serious infections included pneumonia, cellulitis, herpes zoster and urinary tract infection (see Precautions).
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 XELJANZ, or 10 mg twice daily of XELJANZ.
In the seven controlled clinical trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of XELJANZ and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily of XELJANZ minus 5 mg twice daily of XELJANZ.
Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days) (see Precautions).
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 XELJANZ, or 10 mg twice daily of XELJANZ.
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 XELJANZ and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.
The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days) (see Precautions).
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 XELJANZ 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 XELJANZ 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 XELJANZ and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with XELJANZ 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 Precautions).
The Adverse Drug Reactions (ADRs) listed as follows are presented by System Organ Class (SOC). Within each SOC, undesirable effects are presented in order of decreasing seriousness. (See Table 7.)

Click on icon to see table/diagram/image

Overall Infections: In the 6-month, controlled Phase 3 clinical study the rates of infections in the 5 mg twice daily (total 243 patients) and 10 mg twice daily (total 245 patients) XELJANZ monotherapy group were 16.5% (40 patients), and 19.2% (47 patients), respectively, compared to 18.9% (23 patients) in the placebo group (total 122 patients). In studies of 6-month, 12-month, or 24-month duration with background DMARDs, the rates of infections in the 5 mg twice daily (total 973 patients) and 10 mg twice daily (total 969 patients) XELJANZ plus DMARD group were 21.3% (207 patients) and 21.8% (211 patients), respectively, compared to 18.4% (103 patients) in the placebo plus DMARD group (total 559 patients).
The most commonly reported infections were upper respiratory tract infections and nasopharyngitis (4.1% and 3.4%, respectively).
The overall rate of infections with XELJANZ in the long-term safety all exposure population (total 4867 patients) was 46.1 patients with events per 100 patient-years (43.8 and 47.2 patients with events for 5 mg and 10 mg twice daily, respectively). For patients (total 1750) on monotherapy, the rates were 48.9 and 41.9 patients with events per 100 patient-years for 5 mg and 10 mg twice daily, respectively. For patients (total 3117) on background DMARDs, the rates were 41.0 and 50.3 patients with events per 100 patient-years for 5 mg and 10 mg twice daily, respectively.
In the 6-month, controlled clinical study, the rate of serious infections in the 5 mg twice daily XELJANZ monotherapy group was 0.85 patients with events per 100 patient-years. In the 10 mg twice daily XELJANZ monotherapy group, the rate was 3.5 patients with events per 100 patient-years, and the rate was 0 events per 100 patient-years for the placebo group.
In studies of 6-, 12-, or 24-months duration, the rates of serious infections in the 5 mg twice daily and 10 mg twice daily XELJANZ plus DMARD groups were 3.6 and 3.4 patients with events per 100 patient-years, respectively, compared to 1.7 patients with events per 100 patient-years in the placebo plus DMARD group.
In the long-term safety all exposure population, the overall rates of serious infections were 2.4 and 3.0 patients with events per 100 patient-years for 5 mg and 10 mg twice daily XELJANZ groups, respectively. The most common serious infections reported with XELJANZ included pneumonia, herpes zoster and urinary tract infection, cellulitis, gastroenteritis and diverculitis. Cases of opportunistic infections have been reported (see Precautions).
Of the 3315 patients who enrolled in 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 XELJANZ-treated patients 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.
Viral Reactivation: In XELJANZ clinical trials, Japanese and Korean patients appear to have a higher rate of herpes zoster than that observed in other populations.
Venous Thromboembolism: Ongoing Randomized Post Authorization Safety Surveillance (PASS) Study in Rheumatoid Arthritis Patients: In this ongoing study of patients who were 50 years or older with at least one cardiovascular risk factor, based on interim data (data cut-off date 22 Feb 2019), the incidence rates (IRs) for (95% CI) for PE for tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors were 0.27 (0.12, 0.52), 0.54 (0.32, 0.87), and 0.09 (0.02, 0.26) patients with events per 100 patient-years (PYs), respectively. Compared with TNF inhibitors, the hazard ratio (HR) (95% CI) for PE with tofacitinib 5 mg twice daily was 2.99 (0.81, 11.06), and for tofacitinib 10 mg twice daily the HR (95% CI) was 5.96 (1.75, 20.33).
The IRs (95% CI) for DVT for tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors were 0.30 (0.14, 0.55), 0.38 (0.20, 0.67), and 0.18 (0.07, 0.39) patients with events per 100 PYs, respectively. Compared with TNF inhibitors, the HR (95% CI) for DVT with tofacitinib 5 mg twice daily was 1.66 (0.60, 4.57), and for tofacitinib 10 mg twice daily the HR (95% CI) was 2.13 (0.80, 5.69).
Completed rheumatoid arthritis studies: In the 4 to 12 week placebo period of randomized controlled studies of 4 weeks to 24 months duration, the IRs (95% CI) for tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and placebo for PE were 0.00 (0.00, 0.57), 0.00 (0.00, 0.77), and 0.40 (0.01, 2.22) patients with events per 100 PYs respectively; the IRs (95% CI) for DVT were 0.00 (0.00, 0.57), 0.21 (0.01, 1.16), and 0.40 (0.01, 2.22) patients with events per 100 PYs respectively.
In the full randomized period of controlled studies of 4 weeks to 24 months duration, the IRs (95% CI) for tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for PE were 0.12 (0.02, 0.34) and 0.15 (0.03, 0.44) patients with events per 100 PYs respectively; the IRs (95% CI) for DVT were 0.15 (0.04, 0.40) and 0.10 (0.01, 0.36) patients with events per 100 PYs respectively.
In the long term safety population that includes exposure during completed randomized controlled studies and open label long-term extension studies, the IRs (95% CI) for tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for PE were 0.12 (0.06, 0.22) and 0.13 (0.08, 0.21) patients with events per 100 PYs respectively; the IRs (95% CI) for DVT were 0.17 (0.09, 0.27) and 0.15 (0.09, 0.22) patients with events per 100 PYs respectively.
Laboratory Tests: Lymphocytes: In the controlled clinical studies, confirmed decreases in lymphocyte counts below 500 cells/mm³ occurred in 0.26% of patients for the 5 mg twice daily and 10 mg twice daily doses combined.
In the long-term safety population, confirmed decreases in lymphocyte counts below 500 cells/mm³ occurred in 1.3% of patients for the 5 mg twice daily and 10 mg twice daily doses combined.
Confirmed lymphocyte counts less than 500 cells/mm³ were associated with an increased incidence of treated and serious infections (see Precautions).
Neutrophils: In the controlled clinical studies confirmed decreases in ANC below 1000 cells/mm³ occurred in 0.08% of patients for the 5 mg twice daily and 10 mg twice daily doses combined. 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 studies (see Precautions).
Liver Enzyme Tests: Confirmed increases in liver enzymes >3 times the upper limit of normal (3x ULN) were uncommonly observed. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalization of liver enzymes.
In the controlled portion of the Phase 3 monotherapy study (0-3 months), (Study I, see Pharmacology: Pharmacodynamics under Actions), ALT elevations >3x ULN were observed in 1.65%, 0.41% and 0% of patients receiving placebo, XELJANZ 5 mg and 10 mg twice daily, respectively. In this study, AST elevations >3x ULN were observed in 1.65%, 0.41% and 0% of patients receiving placebo, XELJANZ 5 mg and 10 mg twice daily, respectively.
In the controlled portion of the Phase 3 studies on background DMARDs (0-3 months), (Studies II-V, see Pharmacology: Pharmacodynamics under Actions), ALT elevations >3x ULN were observed in 0.9%, 1.24% and 1.14% of patients receiving placebo, XELJANZ 5 mg, and 10 mg twice daily, respectively. In these studies, AST elevations >3x ULN were observed in 0.72%, 0.52% and 0.31% of patients receiving placebo, XELJANZ 5 mg and 10 mg twice daily, respectively.
Lipids: Elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were first assessed at one month following initiation of XELJANZ in the controlled double-blind clinical trials. Increases were observed at this time point and remained stable thereafter.
Changes in lipid parameters from baseline through the end of the study (6-24 months) in the controlled clinical studies are summarized as follows: Mean LDL cholesterol increased by 14% in the XELJANZ 5 mg twice daily arm and 20% in the XELJANZ 10 mg twice daily at month 12, and increased by 14% in the XELJANZ 5 mg twice daily arm and 15% in the XELJANZ 10 mg twice daily arm at month 24.
Mean HDL cholesterol increased by 16% in the XELJANZ 5 mg twice daily arm and 18% in the XELJANZ 10 mg twice daily arm at month 12, and increased by 18% in the XELJANZ 5 mg twice daily arm and 20% in the XELJANZ 10 mg twice daily arm at month 24.
Mean LDL cholesterol/HDL cholesterol ratios were essentially unchanged in XELJANZ-treated patients.
Apolipoprotein B (ApoB)/ApoA1 ratios were essentially unchanged in XELJANZ-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 the lipid parameters remained consistent with what was seen in the controlled clinical studies.
Serum Creatinine: In the controlled clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ 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.

Interactions Affecting the Use of XELJANZ: Since tofacitinib is metabolized by CYP3A4, interaction with drugs that inhibit or induce CYP3A4 is likely. Tofacitinib exposure is increased when co-administered with potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole) or when administration of one or more concomitant medications results in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole) (see Dosage & Administration).
Tofacitinib exposure is decreased when co-administered with potent CYP inducers (e.g., rifampin). Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to significantly alter the PK of tofacitinib.
Concomitant administration with methotrexate (15-25 mg MTX once weekly) had no effect on the PK of tofacitinib. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, with a single dose of tofacitinib increased the AUC and C_max by 103% and 16%, respectively. Co-administration of fluconazole, a moderate inhibitor of CYP3A4 and a strong inhibitor of CYP2C19, increased the AUC and C_max of tofacitinib by 79% and 27%, respectively. Co-administration of tacrolimus (Tac), a mild inhibitor of CYP3A4, increased the AUC of tofacitinib by 21% and decreased the C_max of tofacitinib by 9%. Co-administration of cyclosporine (CsA), a moderate inhibitor of CYP3A4, increased the AUC of tofacitinib by 73% and decreased C_max of tofacitinib by 17%. The combined use of multiple-dose tofacitinib with these potent immunosuppressives has not been studied in patients with rheumatoid arthritis. Co-administration of rifampin, a strong CYP3A4 inducer, decreased the AUC and C_max of tofacitinib by 84% and 74%, respectively (see Dosage & Administration).
Potential for XELJANZ 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 exceeding 160 and 268 times the respective steady-state total and free C_max of a 5 mg twice daily doses in rheumatoid arthritis patients. These in vitro results were confirmed by a human drug interaction study showing no changes in the PK of midazolam, a highly sensitive CYP3A4 substrate, when co-administered 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 535 and 893 times the steady state total and free C_max of a 5 mg twice daily dose in rheumatoid arthritis patients.
In vitro data indicate that the potential for tofacitinib to inhibit transporters, such as P-glycoprotein, organic anion transporting polypeptide, organic anionic or cationic transporters at therapeutic concentrations is also low.
Co-administration of tofacitinib did not have an effect on the PK of oral contraceptives, levonorgestrel and ethinyl estradiol, in healthy female volunteers.
Co-administration of tofacitinib with methotrexate 15-25 mg once weekly decreased the AUC and C_max of methotrexate by 10% and 13% respectively. The extent of decrease in methotrexate exposure does not warrant modifications to the individualized dosing of methotrexate.
Co-administration of XELJANZ did not have an effect on the PK of metformin, indicating that tofacitinib does not interfere with the organic cationic transporter (OCT2) in healthy volunteers.
In rheumatoid arthritis patients, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in RA patients. Therefore, co-administration with tofacitinib is not expected to result in clinically relevant increases in the metabolism of CYP substrates in RA patients.
Pediatric Population: Studies have only been performed in adults.

Special precautions for disposal and other handling: No special requirements.
Incompatibilities: Not applicable.

Store below 30°C. Store in the original package as the tablet may be sensitive to moisture.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs) / Immunosuppressants

L04AA29 - tofacitinib ; Belongs to the class of selective immunosuppressive agents. Used to induce immunosuppression.

POM

FC tab 5 mg (white, round, immediate-release) x 56's.