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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, diverticular infection, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with tofacitinib. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant 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. Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during tofacitinib administration. 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, new primary malignancy, post-transplant lymphoproliferative disorder (PTLD), skin cancer

    Tofacitinib may increase the risk for a new primary 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. During UC controlled studies which included 1220 patients, there were no cases of solid cancer or lymphoma in patients treated with tofacitinib. In the long-term extension study, malignancies (including solid cancers and lymphomas) were observed more often in patients treated with tofacitinib twice daily. 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; in the UC population, treatment with tofacitinib 10 mg twice daily was associated with greater risk of NMSC. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral Janus kinase (JAK) inhibitor
    Used in adults with moderately to severely active rheumatoid arthritis or psoriatic arthritis who have had an inadequate response or intolerance to methotrexate; also used for adults with moderately to severely active ulcerative colitis
    Serious infections and malignancy may occur

    COMMON BRAND NAMES

    Xeljanz, Xeljanz XR

    HOW SUPPLIED

    Xeljanz Oral Tab: 5mg, 10mg
    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. ADJUSTMENTS: Coadministration of certain drugs that inhibit or induce certain CYP isoenzymes may need to be avoided or dosage adjustments may be necessary; review drug interactions. Use with potent CYP3A4 inducers may result in loss of or reduced clinical response to tofacitinib.

    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. ADJUSTMENTS: Coadministration of certain drugs that inhibit or induce certain CYP isoenzymes may need to be avoided or dosage adjustments may be necessary; review drug interactions. Use with potent CYP3A4 inducers may result in loss of or reduced clinical response to tofacitinib.

    For the treatment of psoriatic arthritis (PsA) in patients who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs).
    Oral dosage (immediate release tablets)
    Adults

    5 mg PO twice daily in combination with a non-biologic disease-modifying antirheumatic drug (DMARD). The efficacy of tofacitinib as monotherapy has not been studied. 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. ADJUSTMENTS: Coadministration of certain drugs that inhibit certain CYP isoenzymes may need to be avoided or dosage adjustments may be necessary; review drug interactions. Use with potent CYP3A4 inducers may result in loss of or reduced clinical response to tofacitinib.

    Oral dosage (extended-release tablets)
    Adults

    11 mg PO once daily in combination with a non-biologic disease-modifying antirheumatic drug (DMARD). The efficacy of tofacitinib as monotherapy has not been studied. 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. ADJUSTMENTS: Coadministration of certain drugs that inhibit certain CYP isoenzymes may need to be avoided or dosage adjustments may be necessary; review drug interactions. Use with potent CYP3A4 inducers may result in loss of or reduced clinical response to tofacitinib.

    For the treatment of moderately to severely active ulcerative colitis.
    Oral dosage (immediate-release tablets)
    Adults

    10 mg PO twice daily for at least 8 weeks; followed by 5 mg or 10 mg PO twice daily, depending on therapeutic response. Use the lowest effective dose to maintain response. Discontinue after 16 weeks of treatment with 10 mg twice daily, if adequate therapeutic benefit is not achieved. LIMITATION OF USE: Use of tofacitinib in combination with biologic therapies for ulcerative colitis or with potent immunosuppressants, such as azathioprine and cyclosporine, is not recommended. ADJUSTMENTS: Coadministration of certain drugs that inhibit certain CYP isoenzymes may need to be avoided or dosage adjustments may be necessary; review drug interactions. Use with potent CYP3A4 inducers may result in loss of or reduced clinical response to tofacitinib.

    MAXIMUM DOSAGE

    Adults

    10 mg/day PO for immediate-release tablets or 11 mg/day PO for extended-release tablets for rheumatoid arthritis and psoriatic arthritis; 20 mg/day PO immediate-release tablets for ulcerative colitis.

    Geriatric

    10 mg/day PO for immediate-release tablets or 11 mg/day PO for extended-release tablets for rheumatoid arthritis and psoriatic arthritis; 20 mg/day PO immediate-release tablets for ulcerative colitis.

    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: No dosage adjustment required.
    Moderate impairment: Rheumatoid arthritis and psoriatic arthritis patients receiving the extended-release tablets should switch to the immediate-release tablets and reduce dose to 5 mg once daily. Ulcerative colitis patients who are taking 10 mg twice daily should reduce dose to 5 mg twice daily. Ulcerative colitis patients who are taking 5 mg twice daily should reduce dose to 5 mg once daily.
    Severe impairment: Not recommended.

    Renal Impairment

    Mild renal impairment: No dosage adjustment needed.
    Moderate to severe renal impairment: Rheumatoid arthritis and psoriatic arthritis patients receiving the extended-release tablets should switch to the immediate-release tablets and reduce dose to 5 mg once daily. Ulcerative colitis patients who are taking 10 mg twice daily should reduce dose to 5 mg twice daily. Ulcerative colitis patients who are taking 5 mg twice daily should 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, diverticular infection, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with tofacitinib. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant 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. Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during tofacitinib administration. 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, new primary malignancy, post-transplant lymphoproliferative disorder (PTLD), skin cancer

    Tofacitinib may increase the risk for a new primary 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. During UC controlled studies which included 1220 patients, there were no cases of solid cancer or lymphoma in patients treated with tofacitinib. In the long-term extension study, malignancies (including solid cancers and lymphomas) were observed more often in patients treated with tofacitinib twice daily. 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; in the UC population, treatment with tofacitinib 10 mg twice daily was associated with greater risk of NMSC. 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, although the role of tofacitinib in these events is not known. Perforation happens most often in patients who are also taking nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate. In these studies, many patients with rheumatoid arthritis were receiving background therapy with NSAIDs. There was no discernable difference in frequency of GI perforation between the placebo and the tofacitinib arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids. 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 dose-dependent 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.

    Infertility

    Consider pregnancy planning and prevention for females of reproductive potential. 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. It is not known of this effect is reversible. 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

     Given the serious adverse reactions seen in adults treated with tofacitinib, such as increased risk of serious infections, advise patients that breast-feeding is not recommended during treatment and for at least 18 hours after the last dose of the immediate-release tablet or 36 hours after the last dose of extended-release tablet (approximately 6 elimination half-lives). 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. When a drug is present in animal milk, it is likely that the drug will be present in human milk. 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
    new primary malignancy / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known

    Moderate

    anemia / Delayed / 2.0-4.0
    gastritis / Delayed / 3.0-4.0
    hypertension / Early / 1.6-1.6
    elevated hepatic enzymes / Delayed / 0-1.3
    lymphocytosis / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    lymphopenia / 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
    interstitial lung disease / Delayed / Incidence not known

    Mild

    infection / Delayed / 20.0-22.0
    pharyngitis / Delayed / 3.0-14.0
    headache / Early / 4.3-4.3
    diarrhea / Early / 4.0-4.0
    nausea / Early / 1.0-4.0
    rash / Early / 5.0
    acne vulgaris / Delayed / 2.0
    fatigue / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    insomnia / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    dyspepsia / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    cough / Delayed / Incidence not known
    nasal congestion / Early / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    arthralgia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abatacept: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as abatacept, is not recommended 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.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with clarithromycin. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with clarithromycin. Clarithromycin is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with clarithromycin. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with clarithromycin. Clarithromycin is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Anakinra: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as anakinrat, is not recommended 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.
    Antithymocyte Globulin: (Major) Do not use tofacitinib in combination with potent immunosuppressants such as anti-thymocyte immune globulin. 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.
    Apalutamide: (Major) Coadministration of tofacitinib and apalutamide is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC and Cmax of tofacitinib by 84% and 74%, respectively.
    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.
    Atazanavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with atazanavir. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with atazanavir. Atazanavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Atazanavir; Cobicistat: (Major) A dosage reduction of tofacitinib is necessary if coadministered with atazanavir. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with atazanavir. Atazanavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. (Major) A dosage reduction of tofacitinib is necessary if coadministered with cobicistat. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with cobicistat. Cobicistat is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Coadministration of tofacitinib and phenobarbital is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer.
    Azathioprine: (Major) 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.
    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.
    Baricitinib: (Severe) Concomitant use of baricitinib with tofacitinib is not recommended because of the duplication of the mechanism of action (both are Janus kinase inhibitors, also known as JAK inhibitors) and the possibility of increased immunosuppression and increased infection risk. Both drugs are known to cause elevations in hepatic enzymes and gastrointestinal perforation, and a possibility for increased thrombotic risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Coadministration of tofacitinib and phenobarbital is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer.
    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.
    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.
    Brodalumab: (Major) Do not use tofacitinib in combination with biologic immunosuppressives, such as brodalumab, 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.
    Canakinumab: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as canakinumab, is not recommended 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.
    Carbamazepine: (Major) Coadministration of tofacitinib and carbamazepine is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer.
    Chloramphenicol: (Major) A dosage reduction of tofacitinib is necessary if coadministered with chloramphenicol. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with chloramphenicol. Chloramphenicol is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Clarithromycin: (Major) A dosage reduction of tofacitinib is necessary if coadministered with clarithromycin. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with clarithromycin. Clarithromycin is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Cobicistat: (Major) A dosage reduction of tofacitinib is necessary if coadministered with cobicistat. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with cobicistat. Cobicistat is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) A dosage reduction of tofacitinib is necessary if coadministered with cobicistat. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with cobicistat. Cobicistat is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) A dosage reduction of tofacitinib is necessary if coadministered with cobicistat. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with cobicistat. Cobicistat is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Conivaptan: (Major) A dosage reduction of tofacitinib is necessary if coadministered with conivaptan. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with conivaptan. Conivaptan is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Cyclosporine: (Major) 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.
    Daclizumab: (Major) Do not use tofacitinib in combination with potent immunosuppressants such as daclizumab. 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.
    Dalfopristin; Quinupristin: (Major) A dosage reduction of tofacitinib is necessary if coadministered with dalfopristin; quinupristin. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with dalfopristin; quinupristin. Dalfopristin; quinupristin is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Darunavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with darunavir. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with darunavir. Darunavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Darunavir; Cobicistat: (Major) A dosage reduction of tofacitinib is necessary if coadministered with cobicistat. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with cobicistat. Cobicistat is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. (Major) A dosage reduction of tofacitinib is necessary if coadministered with darunavir. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with darunavir. Darunavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) A dosage reduction of tofacitinib is necessary if coadministered with cobicistat. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with cobicistat. Cobicistat is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. (Major) A dosage reduction of tofacitinib is necessary if coadministered with darunavir. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with darunavir. Darunavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ritonavir. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with ritonavir. Ritonavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Delavirdine: (Major) A dosage reduction of tofacitinib is necessary if coadministered with delavirdine. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with delavirdine. Delavirdine is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    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.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (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.
    Enzalutamide: (Major) Coadministration of tofacitinib and enzalutamide is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer.
    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.
    Everolimus: (Major) Avoid use tofacitinib in combination with potent immunosuppressants such as everolimus. 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.
    Fluconazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with fluconazole. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with fluconazole. Fluconazole is a strong CYP2C19 and moderate CYP3A4 inhibitor; tofacitinib is a CYP3A4/CYP2C19 substrate. Coadministration with fluconazole increased tofacitinib exposure by 1.75-fold.
    Fluvoxamine: (Major) A dosage reduction of tofacitinib is necessary if coadministered with fluvoxamine. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with fluvoxamine. Fluvoxamine is a strong CYP2C19 and moderate CYP3A4 inhibitor; tofacitinib is a CYP3A4/CYP2C19 substrate. Coadministration with another strong CYP2C19 and moderate CYP3A4 inhibitor increased tofacitinib exposure by 1.75-fold.
    Fosamprenavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with fosamprenavir. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with fosamprenavir. Fosamprenavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Fosphenytoin: (Major) Coadministration of tofacitinib and fosphenytoin is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; phenytoin (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer.
    Grapefruit juice: (Major) The exposure to tofacitinib may be significantly increased in patients who regularly consume grapefruit or grapefruit juice, a strong CYP3A4 inhibitor. The manufacturer of tofacitinib recommends a reduced dose of 5 mg once daily or 5 mg twice daily (depending on current dose) when combined with other strong CYP3A4 inhibitors. No specific guidance is provided for grapefruit or grapefruit juice. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold
    Guselkumab: (Major) Do not use tofacitinib in combination with biologic immunosuppressives, such as guselkumab, 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.
    Idelalisib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with idelalisib. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with idelalisib. Idelalisib is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Indinavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with indinavir. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with indinavir. Indinavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    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.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Coadministration of tofacitinib and rifampin is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with rifampin.
    Isoniazid, INH; Rifampin: (Major) Coadministration of tofacitinib and rifampin is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with rifampin.
    Itraconazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with itraconazole. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with itraconazole. Itraconazole is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Ixekizumab: (Major) Do not use tofacitinib in combination with biologic immunosuppressives, such as ixekizumab, 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.
    Ketoconazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ketoconazole. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with ketoconazole. Ketoconazole is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with ketoconazole increased tofacitinib exposure by 2-fold.
    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.
    Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of tofacitinib may occur if given with letermovir. A dosage reduction of tofacitinib is necessary if coadministered with letermovir and cyclosporine because the magnitude of this interaction may be amplified. In patients receiving tofacitinib 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    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) A dosage reduction of tofacitinib is necessary if coadministered with lopinavir; ritonavir. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with lopinavir; ritonavir. Lopinavir; ritonavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. (Major) A dosage reduction of tofacitinib is necessary if coadministered with ritonavir. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with ritonavir. Ritonavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Lumacaftor; Ivacaftor: (Major) Coadministration of tofacitinib and lumacaftor; ivacaftor is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 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.
    Mercaptopurine, 6-MP: (Major) The use of tofacitinib in combination with potent immunosuppressants such as mercaptopurine is not recommended. 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.
    Mifepristone: (Major) A dosage reduction of tofacitinib is necessary if coadministered with chronic mifepristone therapy. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with mifepristone. The clinical significance of this interaction when mifepristone is used for pregnancy termination is unknown. Mifepristone is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Mitotane: (Major) Coadministration of tofacitinib and mitotane is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer.
    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.
    Nefazodone: (Major) A dosage reduction of tofacitinib is necessary if coadministered with nefazodone. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with nefazodone. Nefazodone is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Nelfinavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with nelfinavir. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with nelfinavir. Nelfinavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ritonavir. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with ritonavir. Ritonavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Phenobarbital: (Major) Coadministration of tofacitinib and phenobarbital is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer.
    Phenytoin: (Major) Coadministration of tofacitinib and phenytoin is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer.
    Posaconazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with posaconazole. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with posaconazole. Posaconazole is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Primidone: (Major) Coadministration of tofacitinib and primidone is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer.
    Ribociclib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ribociclib. In patients receiving tofacitinib 5 mg twice daily, reduce to 5 mg once daily; in patients receiving tofacitinib 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving tofacitinib extended-release 11 mg once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Ribociclib; Letrozole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ribociclib. In patients receiving tofacitinib 5 mg twice daily, reduce to 5 mg once daily; in patients receiving tofacitinib 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving tofacitinib extended-release 11 mg once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    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) Coadministration of tofacitinib and rifampin is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with rifampin.
    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) A dosage reduction of tofacitinib is necessary if coadministered with ritonavir. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with ritonavir. Ritonavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Rituximab: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as rituximab, is not recommended 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.
    Rituximab; Hyaluronidase: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as rituximab, is not recommended 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.
    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.
    Saquinavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with saquinavir. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily.
    Sarilumab: (Major) Do not use tofacitinib in combination with biologic disease-modifying antirheumatic drugs (DMARDs), such as sarilumab, 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. Sarilumab has not been studied in combination with janus kinase (JAK) inhibitors such as tofacitinib
    Secukinumab: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as secukinumab, is not recommended 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.
    Sirolimus: (Major) Avoid use of tofacitinib in combination with potent immunosuppressants such as sirolimus. 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.
    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) Coadministration of tofacitinib and St. John's Wort, Hypericum perforatum is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; St. John's Wort, Hypericum perforatum is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer.
    Streptogramins: (Major) A dosage reduction of tofacitinib is necessary if coadministered with dalfopristin; quinupristin. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with dalfopristin; quinupristin. Dalfopristin; quinupristin is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Tacrolimus: (Major) Avoid use of 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.
    Telithromycin: (Major) A dosage reduction of tofacitinib is necessary if coadministered with telithromycin. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with telithromycin. Telithromycin is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    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) A dosage reduction of tofacitinib is necessary if coadministered with tipranavir. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with tipranavir. Tipranavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Tocilizumab: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as tocilizumab, is not recommended 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.
    Tumor Necrosis Factor modifiers: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended 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.
    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.
    Ustekinumab: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as ustekinumab, is not recommended 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.
    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.
    Voriconazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with voriconazole. In patients receiving 5 mg twice daily, reduce to 5 mg once daily; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 11 mg once daily of the extended-release formulation, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with voriconazole. Voriconazole is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    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.

     Given the serious adverse reactions seen in adults treated with tofacitinib, such as increased risk of serious infections, advise patients that breast-feeding is not recommended during treatment and for at least 18 hours after the last dose of the immediate-release tablet or 36 hours after the last dose of extended-release tablet (approximately 6 elimination half-lives). 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. When a drug is present in animal milk, it is likely that the drug will be present in human milk. 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 (JAK) inhibitor. Janus kinases 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. JAK-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. Cytokine signaling is transmitted 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 1,377 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. Patients receiving potent CYP3A4 inhibitors or receiving 1 or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 require tofacitinib dose reductions.[52315] 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, tofacitinib 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%. Patient population pharmacokinetic analyses indicated that pharmacokinetic characteristics were similar between patients with rheumatoid arthritis, psoriatic arthritis, and UC. The coefficient of variation (%) in AUC of tofacitinib were generally similar across different disease patients, ranging from 22% to 34%.