Xeljanz

Tofacitinib citrate.

Each film-coated tablet contains tofacitinib citrate 8.078 mg equivalent to tofacitinib 5 mg. It also contains the following excipients: Microcrystalline cellulose, lactose monohydrate 62.567 mg, croscarmellose sodium, magnesium citrate. Film Coat: Opadry II White (33G28523): HPMC 2910/hypromellose 6cP, titanium dioxide, lactose monohydrate, macrogol/PEG3350 triacetin (glycerol triacetate).
Tofacitinib citrate is C₁₆H₂₀N₆O·C₆H₈O₇. 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).

Pharmacology: Pharmacodynamics: Mechanism of Action: Tofacitinib is a potent, selective inhibitor of the Janus-associated kinase (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 (γ) chain-containing receptors for several cytokines, including interleukin (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 eg, IL-6 and type I interferons. At higher exposures, inhibition of erythropoietin signaling could occur via inhibition of JAK2 signaling.
Pharmacodynamic Effects: Treatment with Xeljanz was associated with dose-dependent reductions of circulating CD16/56+ natural killer 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. The clinical significance of these changes is unknown.
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 (t_½).
Clinical Efficacy: The efficacy and safety of Xeljanz were assessed in 5 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 disease-modifying antirheumatic drugs (DMARDs) (study II) in patients with an inadequate response to those drugs, and in combination with methotrexate (MTX) in patients with either an inadequate response to MTX (studies III and IV) or inadequate efficacy or lack of tolerance to at least 1 approved tumor necrosis factor (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 (nonbiologic 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 2nd 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 (DAS)28-4(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 nonbiologic DMARD received Xeljanz 5 or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppressive treatments eg, azathioprine or cyclosporine). At the month 3 visit, nonresponding patients randomized to placebo treatment were advanced in a blinded fashion to a 2nd predetermined treatment of Xeljanz 5 or 10 mg twice daily. At the end of month 6, all placebo patients were advanced to their 2nd 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 SC 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) <2.6 at month 6.
Study IV is an ongoing 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) <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 2nd 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: The percentages of Xeljanz-treated patients achieving ACR20, ACR50 and ACR70 responses in studies I, IV and V are shown in Table 1. In all studies, patients treated with either Xeljanz 5 or 10 mg twice daily had statistically significant ACR 20, ACR50 and ACR70 response rates at month 3 and month 6 versus placebo-treated patients.
In studies I, II and V, improvement in ACR20 response rate versus placebo was observed within 2 weeks. In studies II, III and IV, ACR response rates were maintained to 12 months in Xeljanz-treated patients. ACR response was maintained for 3 years in the ongoing open-label extension studies.
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 Xeljanz 5 mg twice daily, Xeljanz 10 mg twice daily, adalimumab 40 mg SC every other week and placebo groups, respectively. For a pre-specified secondary endpoint, the ACR70 response rates at month 6 for the Xeljanz 5 mg twice daily and 10 mg twice daily 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 Xeljanz 5 or 10 mg twice daily, 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.
Patients in the phase 3 studies had a mean DAS28-4(ESR) of 6.1-6.7 at baseline. Significant reductions in DAS28-4(ESR) from baseline (mean improvement) of 1.8-2 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 Xeljanz 5 mg or 10 mg (6-9% and 13-16%, respectively) compared to 1-3% of placebo patients at 6 months. In study III, similar percentages of patients achieving DAS28-4(ESR) <2.6 were observed for adalimumab and Xeljanz 5 mg twice daily or 10 mg twice daily at month 6.
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 [ie, ACR70 and DAS28-4(ESR) <2.6 response rates].

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The results of the components of the ACR response criteria for studies IV and V are shown in Table 2. Similar results were observed in studies I, II and III.

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The percent of ACR20 responders by visit for study IV is shown in Figure 1. Similar responses were observed in studies I, II, III and V.

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Radiographic Response: In study IV, structural joint damage was assessed radiographically and expressed as change in mTSS score and its components, the erosion score and joint space narrowing (JSN) score. The results from baseline to month 6 are shown in Table 3.
Xeljanz, 10 mg twice daily, inhibited the progression of structural damage compared to placebo plus MTX at 6 and 12 months. When given at a dose of 5 mg twice daily, Xeljanz exhibited similar effects on mean progression of structural damage at 6 and 12 months (not statistically significant). The proportion of patients with no radiographic progression (defined as ≤0.5 unit increase from baseline in mTSS) at months 6 and 12 was significantly greater in both the Xeljanz 5 mg and 10 mg twice daily groups compared with placebo.

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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 or 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 the 10 mg twice daily group had significantly greater decreases in HAQ-DI.
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 all 8 domains of the SF-36 as well as the physical component summary (PCS) and the mental component summary (MCS) 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.
Pharmacokinetics: The pharmacokinetic profile of tofacitinib is characterized by rapid absorption [peak plasma concentrations (C_max) are reached within 0.5-1 hr], rapid elimination (t_½ of approximately 3 hrs) and dose-proportional increases in systemic exposure. Steady-state concentrations are achieved in 24-48 hrs 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 area under the concentration-time curve (AUC) while C_max was reduced by 32%. In clinical trials, tofacitinib was administered without regard to meal.
After IV administration, the volume of distribution is 87 L. The protein-binding of tofacitinib is approximately 40%. Tofacitinib binds predominantly to albumin and does not appear to bind to α₁-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.
Metabolism and 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, >65% of the total circulating radioactivity was accounted for by unchanged drug, with the remaining 35% attributed to 8 metabolites, each accounting for <8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule.
Pharmacokinetic data and dosing recommendations for special populations and drug interactions are provided in Figure 2.
Pharmacokinetics in Rheumatoid Arthritis Patients: Population pharmacokinetic 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 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: Subjects with mild, moderate and severe renal impairment had 37%, 43% and 123% higher AUC, respectively, compared with healthy subjects (see Dosage & Administration). In subjects with end-stage renal disease, the contribution of dialysis to the total clearance of tofacitinib was relatively small.
Hepatic Impairment: Subjects with mild and moderate hepatic impairment had 3% and 65% higher AUC, respectively, compared with healthy subjects. Subjects 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.

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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, respectively; reference group for drug interaction and food effect studies is administration of Xeljanz alone: Mod=moderate; Sev=severe; Imp=impairment.
Toxicology: Preclinical 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 eg, bacterial and viral infections and lymphoma were observed at clinically relevant doses. Other findings at doses well above human exposures included effects on the hepatic 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·hr/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 approximately 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 (unbound drug AUC of approximately 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 approximately 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/postnatal development. Tofacitinib had no effects on male fertility, sperm motility or sperm concentration. Tofacitinib was secreted in milk of lactating rats.

Treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.

Recommended Dose: 5 mg administered twice daily. Xeljanz may be used as monotherapy or in combination with methotrexate (MTX) or other nonbiologic DMARDs.
Xeljanz has not been studied and its use should be avoided in combination with biological DMARDs eg, TNF antagonists, IL-1R antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators and potent immunosuppressants eg, 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.
Dose Adjustments Due to Laboratory Abnormalities: 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. (See Tables 4, 5 and 6.)
It is recommended that Xeljanz not be initiated in patients with a lymphocyte count <500 cells/mm³.

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It is recommended that Xeljanz not be initiated in patients with an absolute neutrophil count (ANC) <1,000 cells/mm³.

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It is recommended that Xeljanz not be initiated in patients with hemoglobin <9 g/dL.

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Elderly (≥65 years): No dosage adjustment is required in patients ≥65 years.
Renal Impairment: No dose adjustment is required in patients with mild renal impairment. Xeljanz dosage should be adjusted to be 5 mg once daily in patients with moderate to severe renal impairment (see Pharmacology: Pharmacokinetics under Actions and Precautions).
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 adjusted to be 5 mg once daily in patients with moderate hepatic impairment (see Pharmacology: Pharmacokinetics under Actions and Precautions).
Patients Receiving Inhibitors of Cytochrome P450 (CYP3A4) and Cytochrome 2C19 (CYP2C19): Xeljanz dosage should not exceed 5 mg twice daily in patients receiving potent inhibitors of CYP3A4 (eg, ketoconazole). Xeljanz dosage should not exceed 5 mg twice daily in patients receiving ≥1 concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (eg, fluconazole). Co-administration of Xeljanz with potent CYP inducers (eg, rifampin) may result in loss of or reduced clinical response (see Interactions).
Administration: Xeljanz is given orally with or without food.

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 >95% of the administered dose is expected to be eliminated within 24 hrs.

Hypersensitivity to tofacitinib or to any of the excipients of Xeljanz. Patients with serious infection and hepatic disease.

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 and urinary tract infection. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcus, esophageal candidiasis, multidermatomal herpes zoster, cytomegalovirus and BK virus were reported with Xeljanz. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents eg, 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 (eg, histoplasmosis, coccidioidomycosis and listeriosis).
Xeljanz should not be initiated in patients with an active infection, including localized infections (see Dosage & Administration). 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 population in general, caution should be used when treating the elderly (see Adverse Reactions).
Tuberculosis: Patients should be evaluated and tested for latent or active infection prior to administration of 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.
The incidence of tuberculosis in Xeljanz worldwide clinical development programs is 0.1-0.2%. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering Xeljanz.
Viral Reactivation: Viral reactivation has been reported with DMARD treatment and cases of herpes virus reactivation (eg, herpes zoster) were observed in clinical studies 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.
Malignancy and Lymphoproliferative Disorder: The possibility exists for Xeljanz to affect host defenses against malignancies. The impact of treatment with Xeljanz on the development and course of malignancies is not known, but malignancies were observed in clinical studies.
In the controlled clinical studies in rheumatoid arthritis patients, 13 malignancies [excluding nonmelanoma skin cancer (NMSC)] were diagnosed in patients receiving Xeljanz/Xeljanz plus DMARD, compared to 0 malignancies (excluding NMSC) in patients in the placebo/placebo plus DMARD group. Over 3,000 patients (2,098 patient-years of observation) were treated with Xeljanz for durations up to 1 year while approximately 680 patients (203 patient-years of observation) were treated with placebo for a maximum of 6 months. The exposure-adjusted incidence rate for malignancies was 0.62 events/100 patient-years in the Xeljanz groups.
Lymphomas have been observed in patients treated with Xeljanz. While patients with rheumatoid arthritis, particularly those with highly active disease, are at a higher risk than the general population (up to several-fold) for the development of lymphoma, the role, if any of JAK inhibition in the development of lymphoma is not known.
In the long-term safety population, the rate of malignancies (excluding NMSC) was 1.12 events/100 patient-years, consistent with the rate observed in the controlled period.
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 2, phase 3 and long-term extension) was 0.177 events/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 nonsteroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids. The relative contribution of these concomitant medications versus 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 (eg, patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.
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 (ie, <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 (<2,000 cells/mm³) compared to placebo. It is not recommended to initiate Xeljanz treatment in patients with a low neutrophil count (ie, ANC <1,000 cells/mm³). For patients who develop a persistent ANC of 500-1,000 cells/mm³, reduce Xeljanz dose or interrupt dosing until ANC is >1,000 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 4-8 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 (ie, <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 4-8 weeks of treatment and every 3 months thereafter (see Dosage & Administration and Adverse Reactions).
Lipids: Treatment with Xeljanz was associated with increases in lipid parameters eg, 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 4-8 weeks following initiation of Xeljanz therapy. Patients should be managed according to clinical guidelines (eg, National Cholesterol Educational Program) for the management of hyperlipidemia. Increases in total and LDL cholesterol associated with Xeljanz may be decreased to pre-treatment levels with statin therapy.
Vaccinations: No data are available on the response to vaccination or 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.
Patients with Renal Impairment: No dose adjustment is required in patients with mild or moderate renal impairment. Xeljanz dose should not exceed 5 mg twice daily in patients with severe renal impairment (see Dosage & Administration). In clinical trials, Xeljanz was not evaluated in patients with baseline creatinine clearance values (estimated by Cockroft-Gault equation) <40 mL/min (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Patients with Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. Xeljanz dose should not exceed 5 mg twice daily in patients with moderate hepatic impairment (see Dosage & Administration). Treatment with Xeljanz is not recommended in patients with severe hepatic impairment (see Adverse Reactions). In clinical trials, Xeljanz was not evaluated in patients with severe hepatic impairment or in patients with positive hepatitis B virus (HBV) or hepatitis C virus (HCV) serology.
Combination with Other Rheumatoid Arthritis Therapies: Xeljanz has not been studied and its use should be avoided in rheumatoid arthritis patients in combination with biological DMARDs eg, TNF antagonists, IL-1R antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators and potent immunosuppressants eg, azathioprine and cyclosporine because of the possibility of increased immunosuppression and increased risk of infection.
Effects on the Ability to Drive or Operate Machinery: No formal studies have been conducted on the effects on the ability to drive and use machines.
Use in Pregnancy & Lactation: 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/postnatal development (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). Xeljanz should not be used during pregnancy unless clearly necessary.
Tofacitinib was secreted in the milk of lactating rats (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). It is not known whether tofacitinib is secreted in human milk. Women should not breastfeed while treated with Xeljanz.
Use in Children: The safety and efficacy of Xeljanz in children aged from neonates to <18 years has not yet been established.

Use in Pregnancy & Lactation: 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/postnatal development (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). Xeljanz should not be used during pregnancy unless clearly necessary.
Tofacitinib was secreted in the milk of lactating rats (see Pharmacology: Toxicology: Preclinical 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. In these studies, 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).
Of the 3,030 patients who received Xeljanz in these 5 clinical studies, including those who advanced from placebo to Xeljanz, 1,871 received treatment for at least 6 months and 580 for at least 1 year.
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 1 of 2 long-term safety studies.
Of the 3,227 patients who received Xeljanz in the long-term studies, 1,689 received open-label treatment for at least 6 months, 970 for at least 1 year, 659 received treatment for at least 2 years and 62 for at least 3 years.
All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 54 years and 84% were female.
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 upper respiratory tract infections, headache, nasopharyngitis 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 was 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.
The adverse drug reactions listed in Table 7 are presented by system organ class (SOC) and frequency categories, defined using the following convention: Very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) or rare (≥1/10,000 to <1/1,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 7.)

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Overall Infections: In the 6-month, controlled clinical study the rates of infections in the 5 mg twice daily and 10 mg twice daily Xeljanz monotherapy group were 16.5% and 19.2%, respectively, compared to 18.9% in the placebo group. In studies of 6- or 12-month duration without background DMARDs, the rates of infections in the 5 mg twice daily and 10 mg twice daily Xeljanz plus DMARD group were 20.9% and 21.7%, respectively, compared to 18.2% in the placebo plus DMARD group.
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 was 41.5 events/100 patient-years (31.5 and 66.9 events for 5 mg and 10 mg twice daily, respectively). For patients on monotherapy, the rates were 35.5 events and 55.8 events/100 patient-years for 5 mg and 10 mg twice daily, respectively. For patients on background DMARDs, the rates were 28.8 events and 78.4 events/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 Xeljanz 5 mg twice daily monotherapy group was 0.85 events/100 patient-years. In the Xeljanz 10 mg twice daily monotherapy group, the rate was 3.5 events/100 patient-years, and the rate was 0 events/100 patient-years for the placebo group.
In studies of 6- or 12-months duration, the rates of serious infections in the Xeljanz 5 mg twice daily and 10 mg twice daily plus DMARD groups were 3.6 events and 2.9 events/100 patient-years, respectively, compared to 1.7 events/100 patient-years in the placebo plus DMARD group.
In the long-term safety all exposure population, the overall rates of serious infections were 2.3 events and 4.9 events/100 patient-years for Xeljanz 5 mg and 10 mg twice daily, respectively. The most common serious infections reported with Xeljanz included pneumonia, herpes zoster and urinary tract infection. Cases of opportunistic infections have been reported (see Precautions).
Of the 3,315 patients who enrolled in studies I-V, a total of 505 rheumatoid arthritis patients were ≥65 years, including 71 patients ≥75 years. The frequency of serious infection among Xeljanz-treated subjects ≥65 years was higher than those <65 years. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.
Laboratory Tests: Lymphocytes: In the controlled clinical studies, confirmed decreases in lymphocyte counts <500 cells/mm³ occurred in 0.21% 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 <500 cells/mm³ occurred in 0.31% of patients for the 5 mg twice daily and 10 mg twice daily doses combined.
Confirmed lymphocyte counts <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 <1,000 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 <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 eg, 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), alanine aminotransferase (ALT) elevations >3x ULN were observed in 1.65%, 0.41% and 0% of patients receiving placebo, 5 mg and 10 mg twice daily, respectively. In this study, aspartate aminotransferase (AST) elevations >3x ULN were observed in 1.65%, 0.41% and 0% of patients receiving placebo, 5 mg and 10 mg twice daily, respectively.
In the controlled portion of the phase 3 studies on background DMARDs (0-3 months), ALT elevations >3x ULN were observed in 0.9%, 1.24% and 1.25% of patients receiving placebo, 5 mg and 10 mg twice daily, respectively. In these studies, AST elevations >3x ULN were observed in 0.72%, 0.5% and 0.42% of patients receiving placebo, 5 mg and 10 mg twice daily, respectively.
Lipids: Elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were first assessed at 1 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 (6-12 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 arm; mean HDL cholesterol increased by 16% in the Xeljanz 5 mg twice daily arm and 18% in the Xeljanz 10 mg twice daily arm; 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 pre-treatment 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.

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 (eg, ketoconazole) or when administration of ≥1 concomitant medications results in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (eg, fluconazole) (see Dosage & Administration).
Tofacitinib exposure is decreased when co-administered with potent CYP inducers (eg, rifampin).
Potent CYP inducers (eg, rifampicin) may result in loss or reduced clinical response.
Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to significantly alter the pharmacokinetics of tofacitinib.
Concomitant administration with methotrexate (MTX 15-25 mg once weekly) had no effect on the pharmacokinetics 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 Pharmacokinetics 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 150 times the steady-state C_max of a 10 mg twice daily dose. These in vitro results were confirmed by a human drug interaction study showing no changes in the pharmacokinetics of midazolam, a highly sensitive CYP3A4 substrate, when co-administered with tofacitinib. In vitro data indicate that the potential for tofacitinib to inhibit transporters eg, P-glycoprotein, organic anionic or cationic transporters at therapeutic concentrations is also low.
Co-administration of tofacitinib did not have an effect on the pharmacokinetics 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 pharmacokinetics of metformin, indicating that tofacitinib does not interfere with the organic cationic transporter (OCT2) in healthy volunteers.
In rheumatoid patients, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in rheumatoid arthritis patients. Therefore, co-administration with tofacitinib is not expected to result in clinically relevant increases in the metabolism of CYP substrates in rheumatoid arthritis patients.
Immunosuppressive Drugs: Use of Xeljanz in combination with biologic DMARDs (eg, abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, tocilizumab) or potent immunosuppressants eg, azathioprine and cyclosporine is not recommended.
Pediatric Population: Studies have only been performed in adults.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

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

S

FC tab 5 mg (white, round immediate-release) x 60's.