XELJANZ 5 MG TABLET

Uses Dosage and Administration Cautions Drug Interactions

Uses

Rheumatoid Arthritis in Adults

Tofacitinib citrate is used for the management of moderately to severely active rheumatoid arthritis in adults who have had an inadequate response or intolerance to methotrexate. Tofacitinib can be used alone or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs; examples include hydroxychloroquine, leflunomide, minocycline, and sulfasalazine). Concomitant use of tofacitinib with biologic DMARDs, such as tumor necrosis factor (TNF) blocking agents (e.g., adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), interleukin-1 (IL-1) receptor antagonists (e.g., anakinra), anti-CD20 monoclonal antibodies (e.g., rituximab), selective costimulation modulators (e.g., abatacept), and anti-interleukin-6-receptor monoclonal antibodies (e.g., tocilizumab), is not recommended. Concomitant use of tofacitinib with potent immunosuppressive agents (e.g., azathioprine, cyclosporine) also is not recommended.

Safety and efficacy of tofacitinib have been evaluated in 5 randomized, double-blind, controlled studies of 6-24 months' duration in adults (18 years of age or older) with moderate to severe active rheumatoid arthritis. In these studies, tofacitinib was administered as monotherapy in patients with an inadequate response to at least one biologic or nonbiologic DMARD, in combination with methotrexate in patients with an inadequate response to methotrexate or at least one TNF blocking agent, or in combination with nonbiologic DMARD(s) in patients with an inadequate response to at least one biologic or nonbiologic DMARD. Patients in these studies generally had 6 or more tender joints and 6 or more swollen joints. Those receiving low stable dosages of corticosteroids (equivalent to 10 mg or less of prednisone daily) and/or stable dosages of nonsteroidal anti-inflammatory agents (NSAIAs) generally could continue such agents. In some studies, patients also were allowed to continue stable dosages of antimalarial agents. Tofacitinib was administered orally at a dosage of 5 or 10 mg twice daily. In all 5 studies, patients randomized to receive placebo were subsequently advanced in a blinded manner to a second predetermined treatment of tofacitinib 5 or 10 mg twice daily. Advancement to tofacitinib therapy occurred at 3 months in clinical studies of 6 months' duration. In studies of at least 12 months' duration, treatment was advanced at 3 months in placebo recipients who were nonresponders and at 6 months in all other placebo recipients.

The principal measures of clinical response in studies evaluating the efficacy of tofacitinib were the American College of Rheumatology criteria for improvement (ACR response) in measures of disease activity, changes in the Health Assessment Questionnaire-Disability Index (HAQ-DI, a measure of physical function and disability), and achievement of a Disease Activity Score (DAS28 [ESR]) of less than 2.6 (i.e., DAS-defined remission) at 3 or 6 months. DAS28 (ESR) is a composite index of 4 weighted variables: swollen and tender counts for 28 joints, patient global assessment, and erythrocyte sedimentation rate (ESR). An ACR 20 response is achieved if the patient experiences a 20% or greater improvement in tender and swollen joint count and a 20% or greater improvement in at least 3 of the following criteria: patient pain assessment, patient global assessment, physician global assessment, patient self-assessed disability, or laboratory measures of disease activity (i.e., ESR or C-reactive protein [CRP] level). An ACR 50 or ACR 70 response is defined using the same criteria but with a level of improvement of 50 or 70%, respectively. Structural damage, as measured by changes in the total modified Sharp/van der Heijde score, a composite measure of radiographically assessed structural damage (i.e., joint erosion and joint space narrowing), also was assessed in the 2-year study.

Clinical evaluations of tofacitinib indicate that, in adults with active rheumatoid arthritis despite therapy with methotrexate or other DMARD(s), administration of tofacitinib (alone or in combination with methotrexate or other nonbiologic DMARDs) at a dosage of 5 or 10 mg twice daily results in higher ACR 20, ACR 50, and ACR 70 response rates at 3 and 6 months compared with placebo. In clinical trials, higher ACR 20 response rates compared with placebo were observed within 2 weeks. In clinical trials with a duration of at least 12 months, ACR response rates and HAQ-DI results were consistent at 6 and 12 months in patients receiving tofacitinib. Across the 5 clinical trials, improvements in HAQ-DI scores for tofacitinib versus placebo were similar.

In a 6-month study evaluating tofacitinib as monotherapy, 610 patients who had an inadequate response to prior DMARD therapy (biologic or nonbiologic) received tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or placebo. An ACR 20 response at 3 months was achieved in 59, 65, or 26% of patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or placebo, respectively. The ACR 20 response rate following 6 months of therapy with tofacitinib 5 or 10 mg twice daily was 69 or 70%, respectively. Patients receiving tofacitinib experienced greater improvements in physical functioning (as measured by change in HAQ-DI score) from baseline to 3 months, but were not substantially more likely to achieve DAS-defined remission at 3 months, compared with patients receiving placebo.

In a 12-month clinical study evaluating concomitant therapy with tofacitinib and methotrexate, 717 patients with an inadequate response to prior methotrexate therapy were randomized to receive tofacitinib 5 or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo, each given in conjunction with a stable dosage of methotrexate. Patients receiving tofacitinib 5 or 10 mg twice daily demonstrated greater improvement from baseline in physical functioning at 3 months compared with patients receiving placebo. The mean difference from placebo in HAQ-DI improvement from baseline was -0.22 or -0.32 in patients receiving tofacitinib 5 or 10 mg twice daily, respectively. At 6 months, an ACR 20 response was achieved in 52, 53, 47, or 28% and DAS-defined remission was achieved in 6, 13, 7, or 1% of patients assigned to receive tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, adalimumab, or placebo, respectively; in these analyses, in order to account for patients who switched from placebo to tofacitinib at 3 months, patients who did not respond by 3 months were considered nonresponders even if they responded after 3 months.

In a 24-month clinical study evaluating concomitant therapy with tofacitinib and methotrexate, 797 patients with an inadequate response to prior methotrexate therapy were randomized to receive tofacitinib 5 or 10 mg twice daily or placebo, each given in conjunction with a stable dosage of methotrexate. Patients receiving tofacitinib 10 mg twice daily, but not those receiving tofacitinib 5 mg twice daily, demonstrated greater improvement from baseline in HAQ-DI scores at 3 months compared with patients receiving placebo. An ACR 20 response at 3 months was achieved in 55, 67, or 27% of patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or placebo, respectively; at 6 months, ACR 20 response rates were 50, 62, and 25%, respectively. DAS-defined remission at 6 months was reported in 6, 13, or 1% of patients assigned to receive tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or placebo, respectively. In these analyses, patients who did not achieve a response by month 3 were considered nonresponders even if they achieved a response after month 3. Although radiographic findings at 6 and 12 months suggested that tofacitinib slows progression of joint damage, interpretation of the results is complicated because the proportion of study patients with radiographic progression of structural damage during this time period was small, approximately one-half of placebo recipients were considered nonresponders at 3 months and were advanced to a tofacitinib regimen, and missing data created problems with analysis. Further study is needed to fully elucidate the drug's effects on progression of structural damage.

Another 6-month clinical study evaluated concomitant therapy with tofacitinib and methotrexate in 399 patients with an inadequate response to prior therapy with at least one TNF blocking agent; patients were randomized to receive tofacitinib 5 or 10 mg twice daily or placebo, each given in conjunction with a stable dosage of methotrexate. An ACR 20 response at 3 months was achieved in 41, 48, or 24% of patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or placebo, respectively. The ACR 20 response rate following 6 months of therapy with tofacitinib 5 or 10 mg twice daily was 51 or 54%, respectively. Patients receiving tofacitinib experienced greater improvements in physical functioning (as measured by change in HAQ-DI score) from baseline to 3 months and were substantially more likely to achieve DAS-defined remission at 3 months compared with patients receiving placebo. DAS-defined remission was reported at 3 months in 7, 9, or 2% of patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or placebo, respectively. The DAS-defined remission rate following 6 months of therapy with tofacitinib 5 or 10 mg twice daily was 8 or 15%, respectively.

In a 12-month study in 792 patients with an inadequate response to at least one biologic or nonbiologic DMARD, tofacitinib 5 or 10 mg twice daily or placebo was added to a stable dosage of a nonbiologic DMARD (excluding potent immunosuppressive agents such as azathioprine or cyclosporine). ACR responses and improvements in physical functioning generally were similar to those observed in other clinical studies evaluating tofacitinib for management of rheumatoid arthritis.

The optimal role of tofacitinib in the management of rheumatoid arthritis has not been established. Some clinicians suggest that, until additional data are available, use of tofacitinib should be reserved for patients with rheumatoid arthritis who have had an inadequate response to treatment with other biologic DMARDs. For further information on the treatment of rheumatoid arthritis,

Dosage and Administration

General

Tofacitinib therapy should not be initiated in patients with a lymphocyte count of less than 500/mm, an absolute neutrophil count (ANC) of less than 1000/mm, or a hemoglobin concentration of less than 9 g/dL.

Methotrexate, other nonbiologic disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory agents (NSAIAs), and corticosteroids may be continued in patients receiving tofacitinib for the management of rheumatoid arthritis.

Concomitant use of tofacitinib with potent inducers of cytochrome P-450 (CYP) isoenzyme 3A4 (e.g., rifampin) may result in loss of or reduced clinical response to tofacitinib.

Administration

Tofacitinib citrate is administered orally without regard to meals.

Dosage

Dosage of tofacitinib citrate is expressed in terms of tofacitinib.

Rheumatoid Arthritis in Adults

For the management of rheumatoid arthritis in adults who have had an inadequate response or intolerance to methotrexate, the recommended dosage of tofacitinib is 5 mg twice daily.

In patients receiving concomitant therapy with potent inhibitors of CYP3A4 (e.g., ketoconazole) and in patients receiving concomitant therapy with one or more drugs that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole), dosage of tofacitinib should be reduced to 5 mg once daily.

Treatment Interruptions for Toxicity

If a serious infection develops, tofacitinib therapy should be interrupted until the infection has been controlled.

Tofacitinib therapy also should be interrupted or discontinued in patients with lymphopenia, neutropenia, or anemia.

Patients with a lymphocyte count of at least 500/mm may continue to receive the recommended dosage of tofacitinib. In patients who develop a lymphocyte count of less than 500/mm (confirmed by repeat testing), tofacitinib should be discontinued.

Patients with an ANC exceeding 1000/mm may continue to receive the recommended dosage of tofacitinib. In patients with a persistent decrease in ANC to 500-1000/mm, tofacitinib therapy should be interrupted until the ANC exceeds 1000/mm; tofacitinib therapy then may be resumed at the usual dosage of 5 mg twice daily. Tofacitinib therapy should be discontinued in patients with an ANC of less than 500/mm (confirmed by repeat testing).

Patients with a decrease in hemoglobin concentration of no more than 2 g/dL when the concentration value does not fall below 9 g/dL may continue to receive the recommended dosage of tofacitinib. In patients with a decrease in hemoglobin concentration of more than 2 g/dL or with a hemoglobin concentration of less than 8 g/dL (confirmed by repeat testing), tofacitinib therapy should be interrupted until the hemoglobin concentration has normalized.

Special Populations

Tofacitinib should not be used in patients with severe hepatic impairment. Dosage of tofacitinib should be reduced to 5 mg once daily in patients with moderate or severe renal impairment and in patients with moderate hepatic impairment. Administration of supplemental doses of tofacitinib following dialysis is not necessary. Dosage adjustment is not necessary in patients with mild renal or hepatic impairment. In addition, dosage adjustments based on body weight, ethnicity, gender, or age are not required.

Cautions

Contraindications

The manufacturer states that there are no known contraindications to the use of tofacitinib.

Warnings/Precautions

Warnings

Infectious Complications

Patients receiving tofacitinib are at increased risk of developing serious infections that may require hospitalization or result in death. Opportunistic infections caused by bacterial, mycobacterial, invasive fungal, viral, or other opportunistic organisms--including cryptococcosis, pneumocystosis, tuberculosis and other mycobacterial infections, esophageal candidiasis, multidermatomal herpes zoster, cytomegalovirus infection, and BK virus infection--have been reported in patients with rheumatoid arthritis receiving tofacitinib. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. Patients should be closely monitored during and after treatment with tofacitinib for the development of signs or symptoms of infection (e.g., fever, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates, serious systemic illness including shock). Most patients who developed serious infections were receiving concomitant therapy with immunosuppressive agents such as methotrexate or corticosteroids.

In controlled clinical trials in patients with rheumatoid arthritis, the overall frequency of infections during the first 3 months of treatment was 20, 22, or 18% in patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or placebo, respectively. Serious infections were reported at a rate of 1.7 events per 100 patient-years in tofacitinib-treated patients and 0.5 events per 100 patient-years in placebo-treated patients during the first 3 months of therapy. The rate of serious infections during the first 12 months of tofacitinib therapy was 2.7 events per 100 patient-years. The most common serious infections reported in patients receiving tofacitinib included pneumonia, cellulitis, herpes zoster, and urinary tract infection. Other serious infections (e.g., histoplasmosis, coccidioidomycosis, listeriosis), although not reported in clinical trials, also may occur in patients receiving tofacitinib.

Tofacitinib therapy should not be initiated in patients with active infections, including localized infections. Tofacitinib should be discontinued in patients who develop a serious infection, opportunistic infection, or sepsis and should not be resumed until the infection is controlled. Clinicians should consider potential risks and benefits of tofacitinib prior to initiating therapy in patients with a history of chronic, recurring, serious, or opportunistic infections; patients with underlying conditions that may predispose them to infections; and patients who have been exposed to tuberculosis or who reside or have traveled in regions where tuberculosis or mycoses are endemic. Any patient who develops a new infection while receiving tofacitinib should undergo a thorough diagnostic evaluation (appropriate for an immunocompromised patient), appropriate anti-infective therapy should be initiated, and the patient should be closely monitored.

Because tuberculosis has been reported in patients receiving tofacitinib, all patients should be evaluated for active or latent tuberculosis and for the presence of risk factors for tuberculosis prior to and periodically during therapy with the drug. When indicated, an appropriate antimycobacterial regimen for the treatment of latent tuberculosis infection should be initiated prior to tofacitinib therapy. Antimycobacterial therapy also should be considered prior to initiation of tofacitinib in individuals with a history of latent or active tuberculosis in whom an adequate course of antimycobacterial therapy cannot be confirmed and in individuals with a negative tuberculin skin test who have risk factors for tuberculosis. Consultation with a tuberculosis specialist is recommended when deciding whether antimycobacterial therapy should be initiated. Patients receiving tofacitinib, including individuals with a negative tuberculin skin test, should be monitored for signs and symptoms of active tuberculosis, which may present with pulmonary or extrapulmonary disease.

Viral reactivation can occur in patients receiving tofacitinib. Herpes zoster reactivation has been reported in patients receiving the drug. The effect of tofacitinib on the risk of reactivation of chronic viral hepatitis is not known; patients with serologic evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection were excluded from clinical trials of tofacitinib.

Malignancies and Lymphoproliferative Disorders

Lymphoma and other malignancies have been observed in patients receiving tofacitinib. In addition, an increased incidence of Epstein Barr virus (EBV)-associated posttransplant lymphoproliferative disorder has been observed in renal allograft recipients receiving tofacitinib concomitantly with immunosuppressive agents.

Among 3328 patients with rheumatoid arthritis receiving tofacitinib with or without other disease-modifying antirheumatic drugs (DMARDs) in clinical trials, 11 solid tumors and one lymphoma were diagnosed during the first 12 months of treatment compared with no cases of solid tumors or lymphoma in 809 patients receiving placebo with or without other DMARDs. Lymphomas and solid tumors also have been observed in long-term extension studies in patients with rheumatoid arthritis receiving tofacitinib.

In controlled clinical trials in patients with rheumatoid arthritis, malignancies (excluding nonmelanoma skin cancer) were reported at a rate of 0.3 events per 100 patient-years in tofacitinib-treated patients and 0 events per 100 patient-years in placebo-treated patients during the first 3 months of treatment. The rate of malignancies (excluding nonmelanoma skin cancer) during the first 12 months of treatment in patients receiving tofacitinib in clinical trials was 0.6 events per 100 patient-years in patients receiving 10 mg twice daily and 0.4 events per 100 patient-years in patients receiving 5 mg twice daily. The most common malignancies reported, including those reported during long-term extension studies, were lung and breast cancer, followed by gastric, colorectal, renal cell, and prostate cancer, lymphoma, and malignant melanoma.

Studies of longer duration are needed to evaluate the risk of malignancy associated with tofacitinib; however, current data suggest that the incidence rates for all malignancies in patients receiving tofacitinib for the treatment of rheumatoid arthritis are consistent with published estimates in patients with rheumatoid arthritis receiving biologic or nonbiologic DMARDs.

EBV-associated posttransplant lymphoproliferative disorder was observed in 5 of 218 patients (2.3%) receiving tofacitinib compared with 0 of 111 patients receiving cyclosporine in dose-ranging trials in de novo renal transplant recipients; all patients had received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolate.

The risks and benefits of tofacitinib should be considered prior to initiating therapy in patients with a known malignancy (other than successfully treated nonmelanoma skin cancer) or when considering whether to continue tofacitinib in patients who develop a malignancy.

Other Warnings/Precautions

GI Perforation

Cases of GI perforation have been reported in patients with rheumatoid arthritis receiving tofacitinib in clinical trials. The role of Janus kinase (JAK) inhibition by tofacitinib in these cases is not known.

Tofacitinib should be used with caution in patients who may be at increased risk for GI perforation (e.g., patients with a history of diverticulitis). Patients with new onset of abdominal symptoms should be evaluated promptly for early identification of GI perforation.

Hematologic Effects

Initial lymphocytosis (e.g., at one month following initiation of treatment) followed by gradual development of lymphopenia, with a decrease from baseline lymphocyte count of about 10% at 12 months, has been observed in patients receiving tofacitinib. Confirmed lymphocyte counts below 500/mm were associated with an increased incidence of treated and serious infections. Initiation of tofacitinib therapy should be avoided in patients with lymphocyte counts of less than 500/mm. Lymphocyte counts should be monitored at baseline and every 3 months during treatment. Tofacitinib therapy should be interrupted or discontinued based on lymphocyte counts (see Treatment Interruptions for Toxicity under Dosage and Administration: Dosage).

Treatment with tofacitinib is associated with an increased incidence of neutropenia (neutrophil count less than 2000/mm) compared with placebo. A clear relationship between neutropenia and the occurrence of serious infection has not been demonstrated. Initiation of tofacitinib therapy should be avoided in patients with an ANC of less than 1000/mm. Neutrophil counts should be monitored at baseline, at 4-8 weeks after initiation of therapy, and every 3 months thereafter. Tofacitinib therapy should be interrupted or discontinued based on ANC measurements (see Treatment Interruptions for Toxicity under Dosage and Administration: Dosage).

Anemia has been reported in patients receiving tofacitinib. Initiation of tofacitinib therapy should be avoided in patients with hemoglobin concentrations of less than 9 g/dL. Hemoglobin concentrations should be monitored at baseline, at 4-8 weeks after initiation of therapy, and every 3 months thereafter. Tofacitinib therapy should be interrupted or discontinued based on hemoglobin concentration (see Treatment Interruptions for Toxicity under Dosage and Administration: Dosage).

Hepatic Effects

Tofacitinib has been associated with an increased incidence of elevated hepatic aminotransferase concentrations compared with placebo. These increases, which included elevations exceeding 3 times the upper limit of normal (ULN), were observed predominately in patients who were receiving concomitant therapy with other DMARDs, primarily methotrexate. Hepatic enzyme elevations were reversible upon modification of the treatment regimen (e.g., dosage reduction of concomitant DMARD or tofacitinib; interruption of tofacitinib therapy). Drug-induced hepatic injury was reported in one patient who received tofacitinib 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT to greater than 3 times the ULN and elevation of bilirubin concentration to greater than 2 times the ULN; hospitalization and liver biopsy were required.

Hepatic aminotransferase concentrations should be routinely monitored in patients receiving tofacitinib. In case of elevations, patients should be evaluated promptly for drug-induced hepatotoxicity. If drug-induced hepatic injury is suspected, tofacitinib therapy should be interrupted until such diagnosis has been excluded.

Metabolic Effects

Dose-related increases in concentrations of total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglycerides have been observed in patients receiving tofacitinib. Increases in these parameters were observed following one month of tofacitinib therapy and remained stable thereafter, with maximum increases generally occurring within the first 6 weeks of therapy. The effect of these increases on cardiovascular morbidity and mortality has not been determined.

In controlled clinical trials, mean concentrations of LDL-cholesterol and HDL-cholesterol increased during the first 3 months of therapy by 15 and 10%, respectively, in patients receiving tofacitinib 5 mg twice daily and by 19 and 12%, respectively, in patients receiving tofacitinib 10 mg twice daily. Mean ratios of LDL-cholesterol to HDL-cholesterol were essentially unchanged. In a controlled clinical trial, elevated concentrations of LDL-cholesterol and apolipoprotein B decreased to pretreatment levels in response to treatment with a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (statin).

Lipid concentrations should be measured approximately 4-8 weeks after initiation of tofacitinib therapy. Hyperlipidemia should be managed according to current standards of care.

Immunizations

Administration of live vaccines should be avoided during therapy with tofacitinib.(See Drug Interactions: Vaccines.) Immunizations should be updated according to current administration guidelines prior to initiation of tofacitinib therapy.

Specific Populations

Pregnancy

Category C. Pregnancy registry at 877-311-8972.

Lactation

Tofacitinib is distributed into milk in rats; it is not known whether the drug is distributed into human milk. A decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Pediatric Use

Safety and efficacy have not been established in children.

Geriatric Use

In controlled trials of tofacitinib in patients with rheumatoid arthritis, 15% of patients were 65 years of age or older, while 2% were 75 years of age and older. In these studies, a higher incidence of serious infections was reported in patients 65 years of age or older compared with younger patients. Tofacitinib should be used with caution in geriatric patients, taking into consideration the higher incidence of infections generally observed in geriatric patients. Age does not substantially alter pharmacokinetics of the drug.

Hepatic Impairment

Use of tofacitinib is not recommended in patients with severe hepatic impairment. Dosage adjustment is recommended in patients with moderate hepatic impairment (see Dosage and Administration: Special Populations). Systemic exposure to tofacitinib is increased by 3 or 65% in patients with mild or moderate hepatic impairment, respectively.

Safety and efficacy of tofacitinib have not been evaluated in patients with serologic evidence of HBV or HCV infection.

Renal Impairment

Safety and efficacy of tofacitinib have not been evaluated in patients with rheumatoid arthritis who have a baseline creatinine clearance of less than 40 mL/minute. Systemic exposure to tofacitinib is increased by 41, 71, or 156% in patients with mild, moderate, or severe renal impairment, respectively. Dosage adjustment is recommended in patients with moderate to severe renal impairment (see Dosage and Administration: Special Populations).

Common Adverse Effects

Adverse effects occurring in 2% or more of patients receiving tofacitinib 5 or 10 mg twice daily and more commonly than in patients receiving placebo include diarrhea, nasopharyngitis, upper respiratory tract infection, headache, and hypertension.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Metabolism of tofacitinib is mediated primarily by cytochrome P-450 (CYP) isoenzyme 3A4, with a minor contribution from CYP2C19. Concomitant administration of tofacitinib with a potent inhibitor of CYP3A4 (e.g., ketoconazole) or with one or more drugs that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole) results in increased tofacitinib exposure; reduction of tofacitinib dosage to 5 mg once daily is recommended when such drugs are used concomitantly.(See Drug Interactions: Antifungal Agents.) Concomitant administration of drugs that inhibit only CYP2C19 is unlikely to substantially alter the pharmacokinetics of tofacitinib.

Concomitant administration of potent inducers of CYP3A4 (e.g., rifampin) results in decreased tofacitinib exposure and may result in decreased efficacy of tofacitinib.(See Drug Interactions: Rifampin.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Tofacitinib does not substantially inhibit or induce the activity of CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro. In addition, tofacitinib does not appear to normalize CYP enzyme activity over time in patients with rheumatoid arthritis. Therefore, tofacitinib is not expected to alter metabolism of CYP substrates.

Drugs Affecting or Affected by Transport Systems

Pharmacokinetic interactions are unlikely with drugs that inhibit the P-glycoprotein transport system.

In vitro studies indicate that tofacitinib is unlikely to inhibit transporter proteins such as P-glycoprotein or organic anionic or cationic transport proteins at clinically relevant concentrations.

Antifungal Agents

In healthy individuals, the potent CYP3A4 inhibitor ketoconazole (400 mg orally once daily for 3 days) increased peak plasma concentrations and area under the concentration-time curve (AUC) of tofacitinib (single oral dose of 10 mg) by 16 and 103%, respectively. Oral administration of fluconazole (a moderate CYP3A4 and potent CYP2C19 inhibitor) under steady-state conditions (400-mg loading dose followed by 200 mg once daily) increased peak plasma concentrations and AUC of tofacitinib (single oral dose of 30 mg) by 27 and 78%, respectively. Reduction of tofacitinib dosage to 5 mg once daily is recommended when ketoconazole or fluconazole is used concomitantly.

Biologic Antirheumatic Agents

Tofacitinib should not be used concomitantly with biologic disease-modifying antirheumatic drugs (DMARDS).(See Uses: Rheumatoid Arthritis in Adults.)

Immunosuppressive Agents

Concomitant use of tofacitinib with potent immunosuppressive agents (e.g., azathioprine, cyclosporine, tacrolimus) increases the risk of immunosuppression and is not recommended. Concomitant use of tofacitinib with such agents in patients with rheumatoid arthritis has not been studied to date.

In healthy individuals, cyclosporine (200 mg orally every 12 hours for 5 days) decreased the clearance of tofacitinib (single oral dose of 10 mg), resulting in a 73% increase in the AUC of tofacitinib, accompanied by a 17% decrease in peak plasma tofacitinib concentrations.

In healthy individuals, tacrolimus (5 mg orally every 12 hours for 7 days) slightly decreased the clearance of tofacitinib (single oral dose of 10 mg), resulting in a 21% increase in the AUC of tofacitinib, accompanied by a 9% decrease in peak plasma tofacitinib concentrations.

Metformin

Metformin (a substrate of organic cationic transporter [OCT] and multidrug and toxic compound extrusion [MATE] proteins) does not substantially alter peak plasma concentrations or AUC of tofacitinib. No dosage adjustment is required when the drugs are used concomitantly.

Methotrexate

Tofacitinib pharmacokinetics were not substantially altered by methotrexate administration in patients with rheumatoid arthritis; tofacitinib decreased peak plasma concentrations and AUC of methotrexate by 13 and 10%, respectively. Dosage adjustments are not necessary when tofacitinib is used concomitantly with methotrexate.

Midazolam

In healthy individuals, tofacitinib (30 mg orally twice daily for 6 days) did not substantially alter peak plasma concentrations or AUC of the CYP3A substrate midazolam (single oral dose of 2 mg). No dosage adjustment is required when the drugs are used concomitantly.

Oral Contraceptives

In healthy women, tofacitinib (30 mg orally twice daily for 9 days) did not substantially alter exposure to a single dose of an oral contraceptive containing ethinyl estradiol 30 mcg and levonorgestrel 0.15 mg. Tofacitinib increased AUCs of ethinyl estradiol and levonorgestrel by 7 and 1%, respectively; decreased peak plasma concentrations of ethinyl estradiol by 10%; and increased peak plasma concentrations of levonorgestrel by 12%. No dosage adjustment is required.

Rifampin

In healthy individuals, the CYP3A inducer rifampin (600 mg orally once daily for 7 days) decreased peak plasma concentrations and AUC of tofacitinib (single oral dose of 30 mg) by 74 and 84%, respectively. Concomitant use of rifampin may decrease efficacy of tofacitinib.

Vaccines

Live vaccines should not be administered to patients receiving tofacitinib. Information is not available regarding immune response to vaccines in patients receiving tofacitinib, nor is information available regarding secondary transmission of infection from individuals receiving live vaccines to patients receiving tofacitinib.

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brand xeljanz 5 mg tablet

Uses

Rheumatoid Arthritis in Adults

Dosage and Administration

General

Administration

Dosage

Rheumatoid Arthritis in Adults

Treatment Interruptions for Toxicity

Special Populations

Cautions

Contraindications

Warnings/Precautions

Warnings

Infectious Complications

Malignancies and Lymphoproliferative Disorders

Other Warnings/Precautions

GI Perforation

Hematologic Effects

Hepatic Effects

Metabolic Effects

Immunizations

Specific Populations

Pregnancy

Lactation

Pediatric Use

Geriatric Use

Hepatic Impairment

Renal Impairment

Common Adverse Effects

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Drugs Metabolized by Hepatic Microsomal Enzymes

Drugs Affecting or Affected by Transport Systems

Antifungal Agents

Biologic Antirheumatic Agents

Immunosuppressive Agents

Metformin

Methotrexate

Midazolam

Oral Contraceptives

Rifampin

Vaccines

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