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  • CLASSES

    Other Specific Antirheumatics

    BOXED WARNING

    Asian patients, corticosteroid therapy, diabetes mellitus, fungal infection, herpes infection, human immunodeficiency virus (HIV) infection, immunosuppression, infection, interstitial lung disease, pulmonary disease, tuberculosis, viral infection

    Avoid use of tofacitinib in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating tofacitinib in patients: 1) with chronic or recurrent infection; 2) who have been exposed to tuberculosis; 3) with a history of a serious or an opportunistic infection; 4) who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or 5) with underlying conditions that may predispose them to infection (e.g., diabetes mellitus, human immunodeficiency virus (HIV) infection, low lymphocyte counts, and pre-existing immunosuppression). Caution is also recommended in patients with a history of chronic pulmonary disease, or in those who develop interstitial lung disease during tofacitinib treatment, as they may be more prone to infections. Serious and sometimes fatal bacterial infection, mycobacterial infection, invasive fungal infection, viral infection, or infections due to other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving tofacitinib. Viral reactivation, including cases of herpes infection reactivation (e.g., herpes zoster), were observed in clinical studies. The risk of herpes zoster is increased in patients treated with tofacitinib and appears to be higher in Asian patients treated with the drug in Japan and Korea. The most common serious infections reported with tofacitinib included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with tofacitinib. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressive agents such as methotrexate or corticosteroid therapy. Other serious infections that were not reported in clinical studies may also occur (e.g., histoplasmosis and coccidioidomycosis). Ask patients if they have lived or have traveled to the Ohio and Mississippi River valleys or the Southwest because of an increased chance of acquiring certain kinds of fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis. Invasive fungal infections such as cryptococcosis and pneumocystosis may present with disseminated disease. Carefully consider the risks and benefits of tofacitinib before starting the drug in patients who have been exposed to tuberculosis. Consider anti-tuberculosis therapy before tofacitinib administration in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tofacitinib. Therapy with tofacitinib should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with tofacitinib 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.

    Lymphoma, neoplastic disease, post-transplant lymphoproliferative disorder (PTLD), secondary malignancy, skin cancer

    Tofacitinib may increase the risk for neoplastic disease or secondary malignancy. Consider the risks and benefits of tofacitinib prior to initiating therapy in patients with a known cancer other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing the drug in patients who develop a malignancy. Epstein Barr virus-associated post-transplant lymphoproliferative disorder (PTLD) has been observed at an increased rate in renal transplant patients treated with tofacitinib and concomitant immunosuppressives. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with tofacitinib. Malignancies were observed in clinical studies and the postmarketing setting, including, but not limited to, lymphoma, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. Non-melanoma skin cancers (NMSCs) have also been reported in patients treated with tofacitinib. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral janus kinase inhibitor that blocks signals arising from cytokine interactions on the cellular membrane
    For adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate
    Serious infections and malignancy may occur

    COMMON BRAND NAMES

    Xeljanz, Xeljanz XR

    HOW SUPPLIED

    Xeljanz Oral Tab: 5mg
    Xeljanz XR Oral Tab ER: 11mg

    DOSAGE & INDICATIONS

    For the treatment of moderately to severely active rheumatoid arthritis in patients who have had an inadequate response to or intolerance to methotrexate.
    Oral dosage (immediate-release tablets)
    Adults

    5 mg PO twice daily with or without methotrexate or other non-biologic disease-modifying antirheumatic drugs (DMARDs). Do not use in combination with biologic DMARDs such as tumor necrosis factor (TNF) modifiers, anakinra, rituximab, tocilizumab, and abatacept or with potent immunosuppressants such as azathioprine and cyclosporine. Use with potent CYP3A4 inducers may result in loss of or reduced clinical response to tofacitinib.

    Adults receiving potent CYP3A4 inhibitors or receiving one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19

    5 mg PO once daily with or without methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). Do not use in combination with biologic DMARDs such as tumor necrosis factor (TNF) modifiers, anakinra, rituximab, tocilizumab, and abatacept or with potent immunosuppressants such as azathioprine and cyclosporine.

    Oral dosage (extended-release tablets)
    Adults

    11 mg PO once daily. Patients treated with tofacitinib 5 mg PO twice daily may be switched to the XR formulation the day following the last dose of the immediate-release tablets. May use with or without methotrexate or other non-biologic disease-modifying antirheumatic drugs (DMARDs). Do not use in combination with biologic DMARDs such as tumor necrosis factor (TNF) modifiers, anakinra, rituximab, tocilizumab, and abatacept or with potent immunosuppressants such as azathioprine and cyclosporine. Also, use with potent inducers of CYP3A4 may result in loss of or reduced clinical response to tofacitinib.

    Adults receiving potent CYP3A4 inhibitors or receiving one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19

    Use the immediate-release tablets at a dose of 5 mg PO once daily. Do not use extended-release tablets as dosage adjustment is not possible. May use with or without methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). Do not use in combination with biologic DMARDs such as tumor necrosis factor (TNF) modifiers, anakinra, rituximab, tocilizumab, and abatacept or with potent immunosuppressants such as azathioprine and cyclosporine.

    MAXIMUM DOSAGE

    Adults

    10 mg/day PO for immediate-release tablets or 11 mg/day PO for extended-release tablets.

    Geriatric

    10 mg/day PO for immediate-release tablets or 11 mg/day PO for extended-release tablets.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild impairment (Child-Pugh class A, total score of 5 or 6): No dosage adjustment required.
    Moderate impairment (Child-Pugh class B, total score of 7 to 9): Reduce dose to 5 mg once daily.
    Severe impairment (Child-Pugh class C, total score greater than 10): Not recommended.

    Renal Impairment

    CrCl 50 to 89 mL/minute (FDA definition of mild renal impairment): No dosage adjustment needed.
    CrCl 30 to 59 mL/minute (FDA definition of moderate renal impairment): Reduce dose to 5 mg once daily.
    CrCl less than 30 mL/minute (FDA definition of severe renal impairment): Reduce dose to 5 mg once daily.
     
    Intermittent hemodialysis
    See dosage for patients with severe renal impairment. Supplemental doses are not necessary in patients after dialysis.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Administer tablets with or without food.
    Extended-release tablet: Administer once daily, at approximately the same time each day. Administer whole and intact. Do not crush, split, or chew.

    STORAGE

    Xeljanz:
    - Store and dispense in original container
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Xeljanz XR:
    - Store and dispense in original container
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Asian patients, corticosteroid therapy, diabetes mellitus, fungal infection, herpes infection, human immunodeficiency virus (HIV) infection, immunosuppression, infection, interstitial lung disease, pulmonary disease, tuberculosis, viral infection

    Avoid use of tofacitinib in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating tofacitinib in patients: 1) with chronic or recurrent infection; 2) who have been exposed to tuberculosis; 3) with a history of a serious or an opportunistic infection; 4) who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or 5) with underlying conditions that may predispose them to infection (e.g., diabetes mellitus, human immunodeficiency virus (HIV) infection, low lymphocyte counts, and pre-existing immunosuppression). Caution is also recommended in patients with a history of chronic pulmonary disease, or in those who develop interstitial lung disease during tofacitinib treatment, as they may be more prone to infections. Serious and sometimes fatal bacterial infection, mycobacterial infection, invasive fungal infection, viral infection, or infections due to other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving tofacitinib. Viral reactivation, including cases of herpes infection reactivation (e.g., herpes zoster), were observed in clinical studies. The risk of herpes zoster is increased in patients treated with tofacitinib and appears to be higher in Asian patients treated with the drug in Japan and Korea. The most common serious infections reported with tofacitinib included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with tofacitinib. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressive agents such as methotrexate or corticosteroid therapy. Other serious infections that were not reported in clinical studies may also occur (e.g., histoplasmosis and coccidioidomycosis). Ask patients if they have lived or have traveled to the Ohio and Mississippi River valleys or the Southwest because of an increased chance of acquiring certain kinds of fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis. Invasive fungal infections such as cryptococcosis and pneumocystosis may present with disseminated disease. Carefully consider the risks and benefits of tofacitinib before starting the drug in patients who have been exposed to tuberculosis. Consider anti-tuberculosis therapy before tofacitinib administration in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tofacitinib. Therapy with tofacitinib should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with tofacitinib 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.

    Hepatic disease, hepatitis

    The impact of tofacitinib on chronic viral hepatitis reactivation is unknown. Other viral reactivation (e.g., herpes zoster) has occurred with tofacitinib. Patients who screened positive for hepatitis B or C were excluded from clinical trials with tofacitinib. Screening for viral hepatitis, especially hepatitis B and C, should be performed in accordance with clinical guidelines before starting therapy with tofacitinib. Use tofacitinib with caution in any other patient with hepatic disease. Treated patients with moderate hepatic impairment had greater tofacitinib levels than patients with normal hepatic function and increased blood levels may increase the risk of some adverse reactions. Tofacitinib is not recommended for patients with severe hepatic impairment (Child Pugh class C), and dose modification is needed for patients with moderate hepatic impairment (Child Pugh Class B). No dose adjustment is needed in patients with mild hepatic impairment. Monitor liver function tests (LFTs) periodically in all patients treated with tofacitinib. Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (ULN) were observed in patients treated with the drug. In patients experiencing liver enzyme elevation, modification of treatment regimen (e.g., reduction in the dose of a concomitant disease modifying anti-rheumatic drug, interruption of treatment or reduction in dose of tofacitinib) resulted in decrease or normalization of liver enzymes. Rare cases of liver injury have been reported.

    Neutropenia

    Determine neutrophil and lymphocyte counts before tofacitinib initiation, and do not start the drug in patients with a lymphocyte count less than 500 cells/mm3 or neutropenia defined as an ANC less than 1000 cells/mm3. Tofacitinib may cause lymphopenia and neutropenia. For patients who have an ANC greater than 1000 cells/mm3, monitor neutrophil counts after 4 to 8 weeks of tofacitinib receipt and every 3 months thereafter. For patients who have a lymphocyte count more than 500 cells/mm3, monitor lymphocyte counts every 3 months. Dose interruption is recommended for management of lymphopenia and neutropenia, since these effects increase the risk for serious infection.

    Anemia

    Determine the hemoglobin concentration before tofacitinib initiation, and do not start the drug in patients with anemia defined as hemoglobin less than 9 grams/dL. Tofacitinib may cause anemia. For patients who have hemoglobin 9 grams/dL or greater, monitor the hemoglobin concentration after 4 to 8 weeks of initiating tofacitinib and every 3 months thereafter. Treatment with tofacitinib should be interrupted in patients who develop hemoglobin levels less than 8 grams/dL or whose hemoglobin level drops by greater than 2 grams/dL on treatment.

    Lymphoma, neoplastic disease, post-transplant lymphoproliferative disorder (PTLD), secondary malignancy, skin cancer

    Tofacitinib may increase the risk for neoplastic disease or secondary malignancy. Consider the risks and benefits of tofacitinib prior to initiating therapy in patients with a known cancer other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing the drug in patients who develop a malignancy. Epstein Barr virus-associated post-transplant lymphoproliferative disorder (PTLD) has been observed at an increased rate in renal transplant patients treated with tofacitinib and concomitant immunosuppressives. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with tofacitinib. Malignancies were observed in clinical studies and the postmarketing setting, including, but not limited to, lymphoma, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. Non-melanoma skin cancers (NMSCs) have also been reported in patients treated with tofacitinib. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

    Renal failure, renal impairment

    Use tofacitinib with caution in patients with renal impairment. Tofacitinib-treated patients with moderate and severe renal impairment had greater tofacitinib blood levels than patients with normal renal function; therefore, a reduced daily dosage is recommended for these patients. Supplemental doses are not necessary in patients with renal failure after dialysis. In clinical trials, the drug was not evaluated in rheumatoid arthritis patients with baseline creatinine clearance (CrCl) less than 40 mL/minute. Patients with mild renal impairment require no dose adjustments.

    Vaccination

    Update immunizations in agreement with current immunization guidelines prior to initiating tofacitinib therapy. People who are taking tofacitinib should not receive vaccination with live vaccines. These patients may receive non-live vaccines. The interval between live vaccinations and the initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

    Diverticulitis, GI obstruction, GI perforation, peptic ulcer disease, ulcerative colitis

    Cautious use of tofacitinib is advised for patients who may be at increased risk for gastrointestinal (GI) perforation such as patients with a history of diverticulitis, peptic ulcer disease, or ulcerative colitis. Gastrointestinal perforation has been noted among tofacitinib recipients. Perforation happens most often in patients who are also taking nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate. Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of GI perforation. Use the extended-release formulation of tofacitinib with caution in patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). The extended-release formulation of tofacitinib utilizes a non-deformable extended release system. There have been rare reports of symptoms of GI obstruction in patients with known GI strictures with the administration of other drugs utilizing a non-deformable extended release formulation.

    Hypercholesterolemia, hyperlipidemia

    Use tofacitinib with caution in patients with hyperlipidemia or hypercholesterolemia. Treatment with tofacitinib was associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined. Assessment of lipid parameters in all patients should be performed approximately 4 to 8 weeks following initiation of tofacitinib therapy. Manage patients according to clinical guidelines such as those of the National Cholesterol Educational Program (NCEP) for the management of hyperlipidemia.

    Geriatric

    Cautious tofacitinib use among geriatric patients may be warranted, as the frequency of serious infection among patients at least 65 years of age was higher than the frequency among those under the age of 65 years.

    Pregnancy

    Tofacitinib use should be avoided during pregnancy. Human pregnancy outcomes data for tofacitinib are sparse and confounded by frequent concomitant methotrexate use. No adequate and well-controlled studies in pregnant women exist. Based on animal studies, tofacitinib has the potential to affect a developing fetus. In the tofacitinib clinical development program in rheumatoid arthritis and other registry monitoring data, birth defects (e.g., pulmonary valve stenosis), and miscarriages were reported. An ongoing prospective pregnancy registry for tofacitinib is being conducted by the Organization of Teratology Information Specialists (OTIS). If a pregnant woman is exposed to tofacitinib, enrollment in the pregnancy registry is encouraged by calling 1-877-311-8972. Fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 146 times and 13 times the human dose of 5 mg twice daily, respectively. Teratogenic effects observed include external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; cranial and skeletal malformations or variations; thoracogastroschisis, omphalocele, and membranous ventricular septal defects. In addition, reductions in live litter size, postnatal survival, and pup body weights occurred with exposure levels approximately 73 times the MRHD. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD.

    Contraception requirements, infertility, reproductive risk

    Counsel female patients about tofacitinib-associated reproductive risk and contraception requirements. Females of reproductive age are advised to use effective contraception during treatment and for at least 4 weeks after the last dose. Fetocidal and teratogenic effects were noted when animals were given tofacitinib during the period of organogenesis and there is potential for fetal harm. Advise females to contact their healthcare provider immediately if the become pregnant or if pregnancy is suspected. The administration of tofacitinib may result in reduced fertility (infertility) in females of reproductive potential based on animal data. Reduced fertility due to increased post-implantation loss was observed in animals exposed to tofacitinib levels approximately 17 times the maximum recommended human dose (MRHD). There was no impairment of female animal fertility at exposure levels of tofacitinib equal to the MRHD. No effect was seen on male fertility, sperm motility, or sperm concentration.

    Breast-feeding

    Discontinue tofacitinib or breast-feeding because of the potential for serious adverse reactions in nursing infants from tofacitinib. It is not known if tofacitinib is excreted in human milk; however, it is was excreted in milk of lactating rats at concentrations higher than in maternal serum. Etanercept and infliximab may be potential alternatives to consider during breast-feeding. However, assess indication and patient specific factors before considering an alternative agent. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    Children, infants

    The safety and efficacy of tofacitinib in infants, children, and adolescents have not been established.

    ADVERSE REACTIONS

    Severe

    post-transplant lymphoproliferative disorder (PTLD) / Delayed / 2.3-2.3
    GI perforation / Delayed / Incidence not known

    Moderate

    hypertension / Early / 1.6-1.6
    elevated hepatic enzymes / Delayed / 0-1.3
    lymphocytosis / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    lymphopenia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    secondary malignancy / Delayed / Incidence not known
    steatosis / Delayed / Incidence not known
    candidiasis / Delayed / Incidence not known
    erythema / Early / Incidence not known
    peripheral edema / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    dehydration / Delayed / Incidence not known
    gastritis / Delayed / Incidence not known
    interstitial lung disease / Delayed / Incidence not known

    Mild

    infection / Delayed / 20.0-22.0
    headache / Early / 4.3-4.3
    diarrhea / Early / 4.0-4.0
    pharyngitis / Delayed / 3.0-3.0
    fatigue / Early / Incidence not known
    rash (unspecified) / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    paresthesias / Delayed / Incidence not known
    insomnia / Early / Incidence not known
    vomiting / Early / Incidence not known
    nausea / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    dyspepsia / Early / Incidence not known
    nasal congestion / Early / Incidence not known
    cough / Delayed / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    arthralgia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abatacept: (Severe) Do not use tofacitinib in combination with biologic disease-modifying antirheumatic drugs (DMARDs) such as tumor necrosis factor (TNF) modifiers, tocilizumab, IL-1R antagonists such as anakinra, anti-CD20 monoclonal antibodies like rituximab and ofatumumab, and selective costimulation modulators such as abatacept because of the possibility of increased immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. Most patients taking tofacitinib who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids.
    Amprenavir: (Major) Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as amprenavir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
    Anakinra: (Severe) Do not use tofacitinib in combination with biologic disease-modifying antirheumatic drugs (DMARDs) such as tumor necrosis factor (TNF) modifiers, tocilizumab, IL-1R antagonists such as anakinra, anti-CD20 monoclonal antibodies like rituximab and ofatumumab, and selective costimulation modulators such as abatacept because of the possibility of increased immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. Most patients taking tofacitinib who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if tofacitinib and aprepitant, fosaprepitant are used concurrently and monitor for an increase in tofacitinib-related adverse effects for several days after administration of a multi-day aprepitant regimen. Tofacitinib is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of tofacitinib. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Azathioprine: (Severe) Do not use tofacitinib in combination with potent immunosuppressants such as azathioprine. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis. Do not use tofacitinib in combination with potent immunosuppressants such as tacrolimus. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
    Bacillus Calmette-Guerin Vaccine, BCG: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Barbiturates: (Major) Barbiturates are CYP3A4 inducers, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Bexarotene: (Major) Bexarotene is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Boceprevir: (Major) Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as boceprevir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
    Bosentan: (Major) Bosentan is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Brigatinib: (Moderate) Monitor for decreased efficacy of tofacitinib if coadministration with brigatinib is necessary. Tofacitinib is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of tofacitinib may decrease.
    Carbamazepine: (Major) Carbamazepine is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Ceritinib: (Moderate) Monitor for tofacitinib-related adverse reactions if concomitant use with ceritinib is necessary. The tofacitinib (regular-release) dose may need to be adjusted to 5 mg once daily, especially if the patient is also receiving a strong inhibitor of CYP2C19; recommendations are not available for the extended-release formulation of tofacitinib. Ceritinib is a CYP3A4 inhibitor and tofacitinib is metabolized by CYP3A4 and CYP2C19. Coadministration with a strong CYP3A4 inhibitor increased the AUC and Cmax of tofacitinib by 103% and 16%, respectively. Coadministration with a moderate inhibitor of CYP3A4 and a strong CYP2C19 inhibitor increased the AUC and Cmax of tofacitinib by 79% and 27%, respectively. The manufacturer of tofacitinib makes recommendations for dosage adjustments as above for patients receiving strong CYP3A4 inhibitors or moderate CYP3A4 inhibitors in combination with strong CYP2C19 inhibitors; the degree of CYP3A4 inhibition with ceritinib is unknown.
    Cyclosporine: (Severe) Do not use tofacitinib in combination with potent immunosuppressants such as cyclosporine. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Cyclosporine is also an inhibitor of CYP3A4, and tofacitinib is a CYP3A4 substrate. Increased systemic exposure of tofacitinib has been noted with concurrent cyclosporine administration. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
    Dalfopristin; Quinupristin: (Major) Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as dalfopristin; quinupristin. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as ritonavir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
    Delavirdine: (Major) Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as delavirdine. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
    Dexamethasone: (Major) Dexamethasone is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Efavirenz: (Major) Efavirenz is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Efavirenz is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Elbasvir; Grazoprevir: (Moderate) Administering tofacitinib with elbasvir; grazoprevir may result in elevated tofacitinib plasma concentrations. Tofacitinib is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Enzalutamide: (Major) Coadministration of tofacitinib with enzalutamide is not recommended due to decreased plasma concentrations of tofacitinib. Tofacitinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tofacitinib exposure by 84%.
    Etravirine: (Major) Etravirine is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Fluconazole: (Major) If used concurrently with fluconazole, the adult dose of tofacitinib must be reduced to 5 mg once daily. Tofacitinib exposure is increased when coadministered with moderate inhibitors of CYP3A4 and potent inhibitors of CYP2C19, such as fluconazole. In one study, the mean AUC and Cmax of tofacitinib were increased by 79% and 27%, respectively, when administered with fluconazole.
    Fosphenytoin: (Major) Phenytoin (or fosphenytoin) is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Grapefruit juice: (Major) Tofacitinib exposure may be increased when coadministered with grapefruit juice, which inhibits CYP3A4. A reduction of the tofacitinib dose to 5 mg once daily is recommended when used with a moderate inhibitor of CYP3A4. However, no recommendations are available for grapefruit juice. As with many similar drugs, it is best to counsel the patient to avoid grapefruit juice during tofacitinib therapy.
    Griseofulvin: (Major) Griseofulvin is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Indinavir: (Major) Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as indinavir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
    Intranasal Influenza Vaccine: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with tofacitinib may result in increased serum concentrations of tofacitinib. Tofacitinib is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH: (Major) Tofacitinib exposure is increased when coadministered with moderate inhibitors of CYP3A4 and potent inhibitors of CYP2C19 such as isoniazid, INH. Reduce the tofacitinib dose to 5 mg once daily when used with a moderate inhibitor of CYP3A4 and a potent inhibitor of CYP2C19.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers such as rifampin. A loss of response or reduced clinical response to tofacitinib may occur. (Major) Tofacitinib exposure is increased when coadministered with moderate inhibitors of CYP3A4 and potent inhibitors of CYP2C19 such as isoniazid, INH. Reduce the tofacitinib dose to 5 mg once daily when used with a moderate inhibitor of CYP3A4 and a potent inhibitor of CYP2C19.
    Isoniazid, INH; Rifampin: (Major) Tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers such as rifampin. A loss of response or reduced clinical response to tofacitinib may occur. (Major) Tofacitinib exposure is increased when coadministered with moderate inhibitors of CYP3A4 and potent inhibitors of CYP2C19 such as isoniazid, INH. Reduce the tofacitinib dose to 5 mg once daily when used with a moderate inhibitor of CYP3A4 and a potent inhibitor of CYP2C19.
    Itraconazole: (Major) Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as itraconazole. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
    Ketoconazole: (Major) Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as ketoconazole. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of tofacitinib; monitor for potential reduction in efficacy. Tofacitinib is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of tofacitinib; monitor for potential reduction in efficacy. Tofacitinib is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Live Vaccines: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Lopinavir; Ritonavir: (Major) Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as ritonavir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
    Lumacaftor; Ivacaftor: (Moderate) Coadministration of tofacitinib and lumacaftor; ivacaftor may result in loss of or reduced clinical response to tofacitinib. Tofacitinib metabolism is primarily mediated by CYP3A4, and lumacaftor is a strong CYP3A inducer.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Measles/Mumps/Rubella Vaccines, MMR: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Mitotane: (Major) Use caution if mitotane and tofacitinib are used concomitantly, and monitor for decreased efficacy of tofacitinib and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and tofacitinib is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of tofacitinib.
    Modafinil: (Major) Modafinil is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Nafcillin: (Major) Nafcillin is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Ofatumumab: (Severe) Do not use tofacitinib in combination with biologic disease-modifying antirheumatic drugs (DMARDs) such as tumor necrosis factor (TNF) modifiers, tocilizumab, IL-1R antagonists such as anakinra, anti-CD20 monoclonal antibodies like rituximab and ofatumumab, and selective costimulation modulators such as abatacept because of the possibility of increased immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. Most patients taking tofacitinib who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as ritonavir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
    Phenytoin: (Major) Phenytoin is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with tofacitinib is necessary, as the systemic exposure of tofacitinib may be increased resulting in an increase in treatment-related adverse reactions; adjust the dose of tofacitinib if necessary. If the patient is also receiving a concomitant medication that results in strong CYP2C19 inhibition along with ribociclib (a moderate CYP3A4 inhibitor), reduce the dose of tofacitinib to 5 mg once daily. Ribociclib is a moderate CYP3A4 inhibitor and tofacitinib is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with tofacitinib is necessary, as the systemic exposure of tofacitinib may be increased resulting in an increase in treatment-related adverse reactions; adjust the dose of tofacitinib if necessary. If the patient is also receiving a concomitant medication that results in strong CYP2C19 inhibition along with ribociclib (a moderate CYP3A4 inhibitor), reduce the dose of tofacitinib to 5 mg once daily. Ribociclib is a moderate CYP3A4 inhibitor and tofacitinib is a CYP3A4 substrate.
    Rifabutin: (Major) Rifabutin is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Rifampin: (Major) Tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers such as rifampin. A loss of response or reduced clinical response to tofacitinib may occur.
    Rifapentine: (Major) Rifapentine is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Ritonavir: (Major) Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as ritonavir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
    Rituximab: (Major) Avoid the concomitant use of rituximab and tofacitinib; coadministration may result in additive immunosuppression and an increased risk of infection.
    Rituximab; Hyaluronidase: (Major) Avoid the concomitant use of rituximab and tofacitinib; coadministration may result in additive immunosuppression and an increased risk of infection.
    Rotavirus Vaccine: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Rubella Virus Vaccine Live: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Smallpox Vaccine, Vaccinia Vaccine: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    St. John's Wort, Hypericum perforatum: (Major) St. John's Wort, Hypericum perforatum is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Streptogramins: (Major) Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as dalfopristin; quinupristin. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
    Tacrolimus: (Severe) Do not use tofacitinib in combination with potent immunosuppressants such as azathioprine. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis. Do not use tofacitinib in combination with potent immunosuppressants such as tacrolimus. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and tofacitinib is necessary, as the systemic exposure of tofacitinib may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of tofacitinib; consider increasing the dose of tofacitinib if necessary. Tofacitinib is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Tipranavir: (Major) Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as tipranavir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
    Tocilizumab: (Major) Avoid using tocilizumab with biological DMARDs because of the possibility of increased immunosuppression and increased risk of infection. The concurrent use of tocilizumab with biological DMARDs such as tofacitinib has not been studied. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives.
    Tumor Necrosis Factor modifiers: (Severe) Do not use tofacitinib in combination with biologic disease-modifying antirheumatic drugs (DMARDs) such as tumor necrosis factor (TNF) modifiers,because of the possibility of increased immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. Most patients taking tofacitinib who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids.
    Typhoid Vaccine: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Varicella-Zoster Virus Vaccine, Live: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Yellow Fever Vaccine, Live: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.

    PREGNANCY AND LACTATION

    Pregnancy

    Tofacitinib use should be avoided during pregnancy. Human pregnancy outcomes data for tofacitinib are sparse and confounded by frequent concomitant methotrexate use. No adequate and well-controlled studies in pregnant women exist. Based on animal studies, tofacitinib has the potential to affect a developing fetus. In the tofacitinib clinical development program in rheumatoid arthritis and other registry monitoring data, birth defects (e.g., pulmonary valve stenosis), and miscarriages were reported. An ongoing prospective pregnancy registry for tofacitinib is being conducted by the Organization of Teratology Information Specialists (OTIS). If a pregnant woman is exposed to tofacitinib, enrollment in the pregnancy registry is encouraged by calling 1-877-311-8972. Fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 146 times and 13 times the human dose of 5 mg twice daily, respectively. Teratogenic effects observed include external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; cranial and skeletal malformations or variations; thoracogastroschisis, omphalocele, and membranous ventricular septal defects. In addition, reductions in live litter size, postnatal survival, and pup body weights occurred with exposure levels approximately 73 times the MRHD. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD.

    Discontinue tofacitinib or breast-feeding because of the potential for serious adverse reactions in nursing infants from tofacitinib. It is not known if tofacitinib is excreted in human milk; however, it is was excreted in milk of lactating rats at concentrations higher than in maternal serum. Etanercept and infliximab may be potential alternatives to consider during breast-feeding. However, assess indication and patient specific factors before considering an alternative agent. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Tofacitinib is an oral janus kinase inhibitor. Janus kinases (JAKs) are intracellular enzymes that transmit signals arising from cytokine or growth factor receptor interactions such as interferons, interleukins, and erythropoetin on the cellular membrane to influence cellular processes of immune cell function and hematopoiesis. Janus kinase-mediated signaling is pivotal in immune activation, as cytokine receptors are expressed on most immune cells. Upon ligand and receptor interaction, JAKs are activated and, thus, phosphorylate their receptors and activate the signal transducers and activators of transcription proteins, which modulate intracellular activity including gene expression. Tofacitinib affects the signaling pathway at the point of JAKs. Janus kinases transmit cytokine signaling through pairing of JAKs such as JAK1/JAK3, JAK1/JAK2, and JAK2/JAK2. Tofacitinib primarily inhibits JAK1 and JAK3 and, to a lesser extent, JAK2. For example, tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. The primary inhibition of JAK1 and JAK3 by tofacitinib is thought to be advantageous in terms of potential hematologic toxicity because hematopoietic cytokine receptors, such as the erythropoietin receptor, associate with JAK2 homodimers. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.

    PHARMACOKINETICS

    Tofacitinib is administered orally. Protein binding is approximately 40%, and it binds predominantly to albumin; it does not appear to bind to alpha-1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma. Metabolism is primarily mediated by CYP3A4 with minor contribution from CYP2C19. Approximately 70% is cleared by hepatic metabolism and 30% is cleared by renal excretion of the parent drug. After oral administration, the elimination half-life is around 3 hours. Rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout the treatment period among patients with rheumatoid arthritis. The observed changes in CRP do not reverse fully within 2 weeks after discontinuation, which indicates a longer duration of activity as compared with the pharmacokinetic half-life. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4 and CYP2C19
    Tofacitinib is a substrate of primarily CYP3A4 with minor contributions from CYP2C19. The potential for tofacitinib to inhibit transporters such as P-glycoprotein (P-gp) and organic anionic or cationic transporters at therapeutic concentrations is low. In vitro, it 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 185 times the steady state Cmax of a 5 mg twice daily dose. In vivo, no changes in the pharmacokinetic parameters of the CYP3A4 substrate midazolam were noted when coadministered. In patients with rheumatoid arthritis, the oral clearance does not vary with time, which indicates that tofacitinib does not normalize CYP enzyme activity in these patients. Thus, it is not expected to result in clinically relevant increases in the metabolism of CYP substrates.[52315]

    Oral Route

    The absolute oral bioavailability of tofacitinib is 74%. In clinical trials, tofacitinib was administered without regard to meals. Coadministration of tofacitinib with a high-fat meal resulted in no changes in systemic exposure, although the maximum serum concentration was reduced by 32%. Peak plasma concentrations of tofacitinib after oral administration were reached within 0.5 to 1 hour, and a dose-proportional increase in systemic exposure was observed in the therapeutic dose range. After twice daily administration, steady state concentrations are achieved in 24 to 48 hours with negligible accumulation. The between-subject variability in tofacitinib systemic exposure is estimated to be approximately 27%.