CLASSES

Janus Associated Kinase (JAK) Inhibitors
Other Specific Antirheumatics

BOXED WARNING

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 or acquired immunodeficiency syndrome (AIDS), low lymphocyte counts, and pre-existing immunosuppression). Tofacitinib may induce lymphopenia and risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Discontinuation and monitoring criteria for lymphopenia have been suggested in the product label. 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 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.[52315]

Tofacitinib may increase the risk for a new primary malignancy. Lymphomas and solid cancers have also been observed in clinical safety studies in rheumatoid arthritis patients treated with tofacitinib. A large, randomized, safety clinical trial showed an increased risk of cancer, excluding non-melanoma skin cancer (NMSC), (e.g., lymphoma, lung cancer) with use of tofacitinib 5 mg PO twice daily and tofacitinib 10 mg PO twice daily compared to tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis aged 50 years and older with one or more cardiovascular risk factor. Patients with a history of current or past tobacco smoking were at increased risk of lung cancer and overall cancers. Consider the benefits and risks for the individual patient before initiation or continuation of therapy, particular in those with risk factors such as smoking, those who develop malignancy while on treatment, and those with a known malignancy other than successfully treated NMSC. Reserve tofacitinib for patients who have an inadequate response or intolerance to one or more TNF inhibitors. The tofacitinib 10 mg twice daily dosage is not recommended for the treatment of rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis. Epstein Barr virus-associated post-transplant lymphoproliferative disorder (PTLD) has been observed at an increased rate in kidney transplant patients treated with tofacitinib and concomitant immunosuppressives. In the UC population, treatment with tofacitinib 10 mg twice daily was associated with greater risk of cancer. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Avoid using tofacitinib in patients that may be at increased risk of thrombosis and thromboembolism, including those with thromboembolic disease.[52315] A large randomized safety clinical trial showed an increased risk of all-cause mortality [including sudden cardiovascular death (CV)], major adverse CV events (MACE; defined as CV death, non-fatal myocardial infarction (MI), and non-fatal stroke), thrombosis (including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis) with use of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily compared to tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis aged 50 years and older with one or more CV risk factors. Many of the observed thrombotic events were serious and some resulted in death. Current or past tobacco smokers have an additional increased risk of MACE. Consider the benefits and risks for the individual patient before initiation or continuation of therapy, particular in those with cardiovascular risk factors (e.g., cardiac disease, hypertension, previous myocardial infarction). Reserve tofacitinib for patients who have an inadequate response or intolerance to one or more TNF inhibitors. Advise patients to of the potential increased risk for MACE and to seek emergency medical attention if they experience signs and symptoms of a heart attack, stroke, or blood clot. The tofacitinib 10 mg twice daily dosage is not recommended for the treatment of rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis. In a long-term extension study in patients with ulcerative colitis (UC), there were 5 pulmonary embolism cases, including one death in a patient with cancer. For patients with UC, use tofacitinib at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response. If a patient develops a thromboembolic event, discontinue the drug.[52315]

DEA CLASS

Rx

DESCRIPTION

Oral Janus kinase (JAK) inhibitor, a target-specific DMARD
Used in adults with moderate-to-severe rheumatoid, psoriatic arthritis, or ankylosing spondylitis and pediatric patients with polyarticular juvenile idiopathic arthritis; also used for moderately to severely active ulcerative colitis
Serious infections and malignancy may occur; increased risk of thrombosis, mortality, heart-related problems, and cancers with use of this drug vs. TNF-inhibitors

COMMON BRAND NAMES

Xeljanz, Xeljanz Oral, Xeljanz XR

HOW SUPPLIED

Tofacitinib Oral Sol: 1mg, 1mL
Xeljanz Oral Tab: 5mg, 10mg
Xeljanz XR Oral Tab ER: 11mg, 22mg

DOSAGE & INDICATIONS

†Indicates off-label use

MAXIMUM DOSAGE

10 mg/day PO for immediate-release tablets or 11 mg/day PO for extended-release tablets for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis; 20 mg/day PO for immediate-release tablets or 22 mg/day PO for extended-release tablets for ulcerative colitis; investigational doses of 20 mg/day PO for immediate-release tablets have been used for COVID-19.

10 mg/day PO for immediate-release tablets or 11 mg/day PO for extended-release tablets for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis; 20 mg/day PO for immediate-release tablets or 22 mg/day PO for extended-release tablets for ulcerative colitis; investigational doses of 20 mg/day PO for immediate-release tablets have been used for COVID-19.

Weighing 40 kg or more: 10 mg/day PO immediate-release formulations.
Weighing 20 to 39 kg: 8 mg/day PO immediate-release formulations.

2 to 12 years weighing 40 kg or more: 10 mg/day PO immediate-release formulations.
2 to 12 years weighing 20 to 39 kg: 8 mg/day PO immediate-release formulations.
2 to 12 years weighing 10 to 19 kg: 6.4 mg/day PO immediate-release formulations.
1 year: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Mild impairment: No dosage adjustment is required.
Moderate impairment:
Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS): If the current dose is 5 mg PO twice daily immediate-release, reduce dose to 5 mg PO once daily. If the current dose is 11 mg PO once daily extended-release tablet, reduce to 5 mg PO once daily immediate-release.
Ulcerative colitis (UC): If the current dose is 10 mg PO twice daily immediate-release, reduce dose to 5 mg PO twice daily. If the current dose is 5 mg PO twice daily immediate-release, reduce dose to 5 mg PO once daily. If the current dose is 22 mg PO once daily extended-release tablets, reduce to 11 mg PO once daily extended-release. If the current dose is 11 mg PO once daily extended-release tablet, reduce dose to 5 mg PO once daily immediate-release.
Polyarticular juvenile idiopathic arthritis (pJIA): Reduce to once-daily dosing.
Severe impairment: Use is not recommended.

Mild impairment: No dosage adjustment is required.
Moderate to severe impairment:
Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS): If the current dose is 5 mg PO twice daily immediate-release, reduce to 5 mg PO once daily. If the current dose is 11 mg PO once daily extended-release tablet, reduce to 5 mg PO once daily immediate-release tablet.
Ulcerative colitis (UC): If the current dose is 10 mg PO twice daily immediate-release, reduce dose to 5 mg PO twice daily. If the current dose is 5 mg PO twice daily immediate-release, reduce dose to 5 mg PO once daily. If the current dose is 22 mg PO once daily extended-release tablet, reduce dose to 11 mg PO once daily extended-release. If the current dose is 11 mg PO once daily extended-release tablet, reduce to 5 mg PO once daily immediate-release.
Polyarticular juvenile idiopathic arthritis (pJIA): Reduce to once-daily dosing.
 
Dosage Adjustments for COVID-19 per the National Institutes of Health (NIH) treatment guidelines:
eGFR 60 mL/minute/1.73 m2 or more: No dosage adjustment is needed.
eGFR less than 60 mL/minute/1.73 m2: 5 mg PO twice daily immediate-release tablet.
 
Intermittent hemodialysis
Administer the dose after the dialysis session on dialysis days. Supplemental doses are not recommended after dialysis if the dose was taken before the dialysis procedure.

ADMINISTRATION

Hazardous Drugs Classification
NIOSH 2016 List: Group 2
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.

STORAGE

Xeljanz:
- Store and dispense in original container
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Xeljanz Oral:
- Product should be used within 2 months after opening
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
- Store in the original carton to protect from light
Xeljanz XR:
- Store and dispense in original container
- Store at controlled room temperature (between 68 and 77 degrees F)

CONTRAINDICATIONS / PRECAUTIONS

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 or acquired immunodeficiency syndrome (AIDS), low lymphocyte counts, and pre-existing immunosuppression). Tofacitinib may induce lymphopenia and risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Discontinuation and monitoring criteria for lymphopenia have been suggested in the product label. 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 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.[52315]

Viral infection reactivation has occurred with tofacitinib. Avoid use of tofacitinib in patients with an active, serious infection, including localized infections. While patients who screened positive for hepatitis B or C were excluded from clinical trials with tofacitinib, hepatitis B reactivation has been reported with the postmarketing use of tofacitinib. Reactivation of hepatitis B may lead to hepatitis B exacerbation. The impact of tofacitinib on chronic viral hepatitis reactivation is unknown. Screen patients for viral hepatitis, especially hepatitis B and C, 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 concentrations than patients with normal hepatic function, and increased blood concentrations may increase the risk of some adverse reactions. Tofacitinib is not recommended for patients with severe hepatic impairment, and dose modification is needed for patients with moderate 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.[52315]

Monitor lymphocyte counts at baseline and every 3 months thereafter. Monitor neutrophil counts at baseline, after 4 to 8 weeks of treatment, and every 3 months thereafter. Do not initiate tofacitinib in patients with lymphocytopenia or neutropenia, defined as an absolute lymphocyte count less than 500 cells/mm3 or an absolute neutrophil count (ANC) less than 1,000 cells/mm3, respectively. Discontinue tofacitinib if the lymphocyte count decreases to less than 500 cells/mm3 during therapy, confirmed by repeat testing. If the ANC decreases to 500 to 1,000 cells/mm3, interrupt therapy until the ANC is above 1,000 cells/mm3. For patients with ulcerative colitis taking the higher dose, dose reduce and resume previous dosing when the ANC is greater than 1,000 cells/mm3, based on clinical response. Discontinue tofacitinib if the ANC falls below 500 cells/mm3, regardless of the indication.[52315]

Monitor hemoglobin at baseline, after 4 to 8 weeks of treatment, and every 3 months thereafter. Do not initiate tofacitinib in patients with anemia defined as a hemoglobin less than 9 grams/dL. If the hemoglobin decreases to less than 8 grams/dL or decreases more than 2 grams/dL from baseline, interrupt dosing until hemoglobin values have normalized.[52315]

Tofacitinib may increase the risk for a new primary malignancy. Lymphomas and solid cancers have also been observed in clinical safety studies in rheumatoid arthritis patients treated with tofacitinib. A large, randomized, safety clinical trial showed an increased risk of cancer, excluding non-melanoma skin cancer (NMSC), (e.g., lymphoma, lung cancer) with use of tofacitinib 5 mg PO twice daily and tofacitinib 10 mg PO twice daily compared to tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis aged 50 years and older with one or more cardiovascular risk factor. Patients with a history of current or past tobacco smoking were at increased risk of lung cancer and overall cancers. Consider the benefits and risks for the individual patient before initiation or continuation of therapy, particular in those with risk factors such as smoking, those who develop malignancy while on treatment, and those with a known malignancy other than successfully treated NMSC. Reserve tofacitinib for patients who have an inadequate response or intolerance to one or more TNF inhibitors. The tofacitinib 10 mg twice daily dosage is not recommended for the treatment of rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis. Epstein Barr virus-associated post-transplant lymphoproliferative disorder (PTLD) has been observed at an increased rate in kidney transplant patients treated with tofacitinib and concomitant immunosuppressives. In the UC population, treatment with tofacitinib 10 mg twice daily was associated with greater risk of cancer. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

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 (e.g., those with severe insufficiency, renal failure, and those who are undergoing hemodialysis). Supplemental doses after dialysis are not necessary. 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.[52315]

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.

Cautious use of tofacitinib is advised for patients who may be at increased risk for gastrointestinal (GI) perforation (e.g., patients with a history of diverticulitis or taking NSAIDs). Events of gastrointestinal perforation have been reported in clinical studies with tofacitinib, although the role of Janus kinase (JAK) inhibition in these events is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with NSAIDs. There was no discernable difference in the 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 (tofacitinib XR) with caution in patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). The tofacitinib XR tablets utilize a non-deformable extended-release system. There have been rare reports of symptoms of GI obstruction in patients with known GI stricture with the administration of other drugs utilizing a non-deformable extended-release formulation.[52315]

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.

Avoid using tofacitinib in patients that may be at increased risk of thrombosis and thromboembolism, including those with thromboembolic disease.[52315] A large randomized safety clinical trial showed an increased risk of all-cause mortality [including sudden cardiovascular death (CV)], major adverse CV events (MACE; defined as CV death, non-fatal myocardial infarction (MI), and non-fatal stroke), thrombosis (including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis) with use of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily compared to tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis aged 50 years and older with one or more CV risk factors. Many of the observed thrombotic events were serious and some resulted in death. Current or past tobacco smokers have an additional increased risk of MACE. Consider the benefits and risks for the individual patient before initiation or continuation of therapy, particular in those with cardiovascular risk factors (e.g., cardiac disease, hypertension, previous myocardial infarction). Reserve tofacitinib for patients who have an inadequate response or intolerance to one or more TNF inhibitors. Advise patients to of the potential increased risk for MACE and to seek emergency medical attention if they experience signs and symptoms of a heart attack, stroke, or blood clot. The tofacitinib 10 mg twice daily dosage is not recommended for the treatment of rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis. In a long-term extension study in patients with ulcerative colitis (UC), there were 5 pulmonary embolism cases, including one death in a patient with cancer. For patients with UC, use tofacitinib at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response. If a patient develops a thromboembolic event, discontinue the drug.[52315]

Cautious tofacitinib use among geriatric patients is warranted, as the frequency of serious infection among patients at least 65 years of age was higher than the frequency of serious infection in younger adults during clinical trials. Additionally, a safety trial of rheumatoid arthritis (RA) patients at least 50 years of age with at least one known cardiovascular risk factor for cardiac disease determined that the occurrence of pulmonary embolism and death was higher with tofacitinib 10 mg twice daily compared tofacitinib 5 mg twice daily or the use of a TNF blocker; monitor older patients carefully for symptoms of pulmonary thromboembolism, especially if they are receiving higher doses of tofacitinib.

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). 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. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to tofacitinib; information about the registry can be obtained at mothertobaby.org/ongoing-study/xeljanz or by calling 1-877-311-8972.

Consider pregnancy planning and prevention for females of reproductive potential; inform females of the potential reproductive risk. Fetocidal and teratogenic effects were noted when animals were given tofacitinib during the period of organogenesis, and there is potential for fetal harm. While specific contraception requirements have not been advised in the label, consider the use of adequate contraception in females of reproductive potential. Advise females to contact their healthcare provider immediately if they 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 if this effect is reversible. Reduced fertility due to an 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.[52315] [62380]

Advise lactating females not to breast-feed during tofacitinib therapy. 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 tablets or 36 hours after the last dose of extended-release tablets (approximately 6 elimination half-lives). It is not known if tofacitinib is excreted in human milk; however, it is was excreted in the 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.[52315] [62180] Assess indication and patient-specific factors before considering an alternative agent.[61808] [62180]

ADVERSE REACTIONS

post-transplant lymphoproliferative disorder (PTLD) / Delayed / 2.3-2.3
skin cancer / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known
lymphoma / Delayed / Incidence not known
hepatotoxicity / Delayed / Incidence not known
hepatitis B exacerbation / Delayed / Incidence not known
GI perforation / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
thrombosis / Delayed / Incidence not known
thromboembolism / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
stroke / Early / Incidence not known

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

infection / Delayed / 20.0-22.0
pharyngitis / Delayed / 3.0-14.0
headache / Early / 3.0-9.0
nausea / Early / 1.0-4.0
fever / Early / 2.0
rash / Early / 2.0
acne vulgaris / Delayed / 2.0
diarrhea / Early / 3.0
fatigue / Early / Incidence not known
pruritus / Rapid / Incidence not known
insomnia / Early / Incidence not known
paresthesias / Delayed / Incidence not known
dyspepsia / Early / Incidence not known
abdominal pain / Early / Incidence not known
vomiting / Early / Incidence not known
cough / Delayed / Incidence not known
nasal congestion / Early / Incidence not known
arthralgia / Delayed / Incidence not known
musculoskeletal pain / Early / Incidence not known
urticaria / Rapid / 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 additive immunosuppression and increased infection risk. There is insufficient experience to assess the safety and efficacy of this combination. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Adagrasib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with adagrasib. 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 CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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) Avoid concomitant use of tofacitinib with biologic DMARDs, such as anakinra; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
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.
Atazanavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with atazanavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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.
Azathioprine: (Major) Concomitant use of tofacitinib with azathioprine is not recommended because of the possibility of additive immunosuppression and increased infection risk. There is insufficient experience to assess the safety and efficacy of this combination. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
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: (Major) 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.
Canakinumab: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as canakinumab, is not recommended because of the possibility of additive 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.
Ceritinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ceritinib. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
Chloramphenicol: (Major) A dosage reduction of tofacitinib is necessary if coadministered with chloramphenicol. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clarithromycin: (Major) A dosage reduction of tofacitinib is necessary if coadministered with clarithromycin. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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.
Cyclosporine: (Major) Concomitant use of tofacitinib with cyclosporine is not recommended. 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, and dosage adjustment may be necessary. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Darunavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with darunavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) A dosage reduction of tofacitinib is necessary if coadministered with cobicistat. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) A dosage reduction of tofacitinib is necessary if coadministered with cobicistat. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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.
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.
Everolimus: (Major) Concomitant use of tofacitinib with potent immunosuppressants, such as everolimus, is not recommended; coadministration may result in additive immunosuppression and increased risk of infection. 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 chronically (beyond 1 dosage). In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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.
Fluoxetine: (Moderate) A reduction in tofacitinib dose may be necessary if tofacitinib is coadministered with fluoxetine (a strong CYP2C19 inhibitor) and a medication that is a moderate CYP3A4 inhibitor. Tofacitinib exposure is increased when coadministered with both a strong CYP2C19 and a moderate CYP3A4 inhibitor. Review the patient's other medications for this potential drug interaction and the possible need for tofacitinib dose reduction. Tofacitinib is a CYP3A4 and CYP2C19 substrate. Coadministration of tofacitinib with both a strong CYP2C19 and a moderate CYP3A4 inhibitor 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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) It is best to avoid taking Tofacitinib with grapefruit juice. The exposure to tofacitinib may be significantly increased in patients who regularly consume grapefruit or grapefruit juice, a strong CYP3A4 inhibitor. FDA-approved labeling recommends in patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. No specific guidance is provided for grapefruit or grapefruit juice. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
Idelalisib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with idelalisib. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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) Concomitant use of tofacitinib with biologic immunosuppressants, such as ixekizumab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Ketoconazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ketoconazole. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) A dosage reduction of tofacitinib is necessary if coadministered with clarithromycin. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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.
Letermovir: (Major) 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 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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.
Levoketoconazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ketoconazole. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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.
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.
Lonafarnib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with lonafarnib. 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 and CYP2C19 substrate and lonafarnib is a strong CYP3A4 and moderate CYP2C19 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
Lopinavir; Ritonavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ritonavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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) Concomitant 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with mifepristone. Mifepristone is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. When mifepristone is given chronically, the half-life of the drug is prolonged, and drug-interaction potential is extended. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. The clinical significance of this interaction when mifepristone is used in a regimen for pregnancy termination is unknown.
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.
Nanoparticle Albumin-Bound Sirolimus: (Major) Concomitant use of tofacitinib with potent immunosuppressants, such as sirolimus, is not recommended; coadministration may result in additive immunosuppression and increased risk of infection. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Nefazodone: (Major) A dosage reduction of tofacitinib is necessary if coadministered with nefazodone. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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.
Nirmatrelvir; Ritonavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ritonavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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. (Major) Consider withholding tofacitinib, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the tofacitinib dose. In patients receiving tofacitinib 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Coadministration may increase tofacitinib exposure resulting in increased toxicity. Tofacitinib is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor.
Olanzapine; Fluoxetine: (Moderate) A reduction in tofacitinib dose may be necessary if tofacitinib is coadministered with fluoxetine (a strong CYP2C19 inhibitor) and a medication that is a moderate CYP3A4 inhibitor. Tofacitinib exposure is increased when coadministered with both a strong CYP2C19 and a moderate CYP3A4 inhibitor. Review the patient's other medications for this potential drug interaction and the possible need for tofacitinib dose reduction. Tofacitinib is a CYP3A4 and CYP2C19 substrate. Coadministration of tofacitinib with both a strong CYP2C19 and a moderate CYP3A4 inhibitor increased tofacitinib exposure by 1.75-fold.
Ombitasvir; Paritaprevir; Ritonavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ritonavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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.
Phenobarbital; Hyoscyamine; Atropine; 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.
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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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. Tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. Primidone is metabolized to phenobarbital, a potent CYP3A4 inducer. 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 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR 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 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR 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.
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) Coadministration of tofacitinib and rifapentine is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC and Cmax of tofacitinib by 84% and 74%, respectively.
Ritonavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ritonavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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 additive 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 additive 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 or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with saquinavir. Saquinavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
Sarilumab: (Major) Avoid the concomitant use of sarilumab with other biological DMARDs such as tofacitinib; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Secukinumab: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as secukinumab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Sirolimus: (Major) Concomitant use of tofacitinib with potent immunosuppressants, such as sirolimus, is not recommended; coadministration may result in additive immunosuppression and increased risk of infection. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (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) 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.
Tacrolimus: (Major) Concomitant use of tofacitinib with potent immunosuppressants, such as tacrolimus, is not recommended; coadministration may result in additive immunosuppression and increased risk of infection. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Ticlopidine: (Moderate) A reduction in tofacitinib dose may be necessary if tofacitinib is coadministered with ticlopidine (a strong CYP2C19 inhibitor) and a medication that is a moderate CYP3A4 inhibitor. Tofacitinib exposure is increased when coadministered with both a strong CYP2C19 and a moderate CYP3A4 inhibitor. Review the patient's other medications for this potential drug interaction and the possible need for tofacitinib dose reduction. Tofacitinib is a CYP3A4 and CYP2C19 substrate. Coadministration of tofacitinib with both a strong CYP2C19 and a moderate CYP3A4 inhibitor increased tofacitinib exposure by 1.75-fold.
Tipranavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with tipranavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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) Avoid the concomitant use of tocilizumab with other biological DMARDs such as tofacitinib; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Tucatinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with tucatinib. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
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 additive 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.
Upadacitinib: (Major) Concomitant use of tofacitinib with upadacitinib 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.
Ustekinumab: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as ustekinumab, is not recommended because of the possibility of additive 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.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) A dosage reduction of tofacitinib is necessary if coadministered with clarithromycin. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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.
Voriconazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with voriconazole. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, 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

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). 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. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to tofacitinib; information about the registry can be obtained at mothertobaby.org/ongoing-study/xeljanz or by calling 1-877-311-8972.

Advise lactating females not to breast-feed during tofacitinib therapy. 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 tablets or 36 hours after the last dose of extended-release tablets (approximately 6 elimination half-lives). It is not known if tofacitinib is excreted in human milk; however, it is was excreted in the 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.[52315] [62180] Assess indication and patient-specific factors before considering an alternative agent.[61808] [62180]

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 erythropoietin 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 the pairing of JAKs such as JAK1/JAK3, JAK1/JAK2, JAK/TyK2, 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.[52315]

PHARMACOKINETICS

Tofacitinib is administered orally. Protein binding is approximately 40%, and it binds predominantly to albumin; it does not appear to bind to alpha1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma. A volume of distribution (Vd) of 87 L was found after intravenous administration. Metabolism of tofacitinib is primarily mediated by CYP3A4 with a 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 of the immediate-release and extended-release tablets, the elimination half-life is around 3 hours and 6 to 8 hours, respectively. 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 inactive metabolites, each accounting for less than 8% of total radioactivity. Tofacitinib pharmacokinetics were similar between rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis patients.[52315]
 
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 of tofacitinib. The results indicate a longer duration of activity as compared with the pharmacokinetic half-life.[52315]
 
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 data showed that 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 corresponding to the steady-state Cmax of a 10 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 and indicates that tofacitinib does not normalize CYP enzyme activity. Thus, tofacitinib is not expected to cause clinically relevant increases in the metabolism of CYP substrates.[52315]