In trials with tofacitinib, lymphopenia, lymphocytosis, neutropenia, anemia, and fatigue were noted. Initially, lymphocytosis was noted at 1 month after tofacitinib initiation. A gradual decrease in mean lymphocyte counts of approximately 10% below the baseline was noted during 12 months of therapy. In clinical trials involving tofacitinib 5 mg and 10 mg twice daily dosing, confirmed decreases in lymphocyte counts less than 500 cells/mm³ occurred in 0.04% of all tofacitinib recipients, and the decreases were associated with an increased incidence of treated and serious infections. During the first 3 months of tofacitinib therapy in clinical trials, confirmed decreases in ANC below 1,000 cells/mm³ occurred in 0.07% of tofacitinib recipients; no confirmed decreases in ANC below 500 cells/mm³ were observed, and no clear relationship between neutropenia and the occurrence of serious infections was apparent. However, tofacitinib receipt was associated with an increased incidence of neutropenia (less than 2,000 cells/mm³) as compared with placebo. During the maintenance trial of tofacitinib in patients with ulcerative colitis, anemia was reported in 2% to 4% of tofacitinib patients compared to 2% of placebo patients. Hemoglobin and neutrophil count should be checked prior to initiation of tofacitinib therapy, after 4 to 8 weeks of treatment, and then every 3 months. Lymphocyte count should be checked prior to initiation of tofacitinib therapy, then every 3 months. Interrupt tofacitinib receipt in patients who develop hemoglobin less than 8 grams/dL or whose hemoglobin concentration drops greater than 2 grams/dL on treatment. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm³ or an ANC less than 500 cells/mm³, tofacitinib treatment is not recommended. For patients who develop a persistent ANC of 500 to 1,000 cells/mm³, interrupt tofacitinib receipt until the ANC is greater than 1,000 cells/mm³.[52315]

Tofacitinib may cause a new primary malignancy, including lymphoma, solid cancers, or non-melanoma skin cancer (NMSC), and may be associated with an increased risk of Epstein Barr virus-associated post-transplant lymphoproliferative disorder (PTLD). In a randomized, open-label, safety study in rheumatoid arthritis patients 50 years of age and older with one or more cardiovascular risk factors, a higher rate of malignancies (excluding NMSC) was observed in patients treated with tofacitinib 5 mg twice daily (1.13 events per 100 patient-years) or tofacitinib 10 mg twice daily (1.13 events per 100 patient-years) compared to patients treated with tumor necrosis factor (TNF) inhibitors (0.77 events per 100 patient-years). Patients with a current or past tobacco smoking had an additional increased risk of malignancy, including lung cancer. A higher rate of lymphomas and lung cancers, subsets of all malignancies, were also observed in patients treated with both tofacitinib doses compared to TNF inhibitors. The incidence rates for lymphomas per 100 patient-years were 0.07, 0.11, and 0.02 for tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors, respectively. Among smokers, the incidence rates of lung cancer per 100 patient-years were 0.48 for tofacitinib 5 mg twice daily, 0.59 for tofacitinib 10 mg twice daily, and 0.27 for TNF inhibitors. The tofacitinib 10 mg twice daily dosage is not recommended for the treatment of rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis. Among rheumatoid arthritis patients who were enrolled in 7 clinical trials, malignancies occurred in 5 patients receiving tofacitinib 5 mg twice daily (0.4 events per 100 patient-years) and 7 patients receiving tofacitinib 10 mg twice daily (0.6 events per 100 patient-years) within the first 12 months of treatment; tofacitinib was given with or without disease-modifying antirheumatic drugs (DMARDs). No malignancies were reported with placebo. One of the malignancies reported with tofacitinib 10 mg twice daily was lymphoma. The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma. During the psoriatic arthritis clinical trials, 3 malignancies were reported in adult patients receiving tofacitinib plus a non-biologic DMARD (n = 474) compared to no malignancies reported in the placebo plus non-biologic DMARD group (n = 106). No lymphomas were reported. Malignancies also have been reported in the long-term extension psoriatic arthritis trial. During the ulcerative colitis controlled clinical studies, which included 1,220 patients, there were no cases of solid cancer or lymphoma in patients treated with tofacitinib. In the long-term extension study, malignancies (including solid cancers and lymphomas) were observed more often in patients treated with 10 mg twice daily. In a tofacitinib dose-ranging study involving de novo renal transplant patients who received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid agents, Epstein Barr virus-associated PTLD occurred in 5 tofacitinib patients (2.3%) compared to zero cyclosporine patients. Lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer have been reported with postmarketing use of tofacitinib. NMSCs have been reported with tofacitinib therapy and, among ulcerative colitis patients, the 10 mg twice daily dose was associated with a greater risk of NMSCs. Consider periodic skin examinations for all patients at increased risk for skin cancer. Consider the risks and benefits of tofacitinib prior to initiating or continuing therapy in patients with a known malignancy (excluding NMSC), patients who develop a malignancy while receiving tofacitinib, and patients who are current or past smokers.[52315]

Hepatitis, steatosis, and elevated hepatic enzymes were noted in the clinical trials of tofacitinib. Most of the enzyme abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. For example, no differences in the incidence of ALT or AST elevations were observed between the placebo and tofacitinib 5 mg twice daily groups. However, with concurrent DMARDs, ALT elevations greater than 3 times the upper limit of normal (ULN) were observed in 1% of patients receiving placebo, 1.3% of patients receiving tofacitinib 5 mg twice daily, and 1.2% of patients receiving tofacitinib 10 mg twice daily. AST elevations greater than 3 times the ULN were observed in 0.6% of patients receiving placebo, 0.5% of patients receiving tofacitinib 5 mg twice daily, 0.4% of patients receiving tofacitinib 10 mg twice daily. One patient who received tofacitinib 10 mg twice daily for approximately 2.5 months required hospitalization and liver biopsy after developing drug-induced liver injury, symptomatic elevations of greater than 3 times the ULN in AST and ALT and elevations in bilirubin of greater than 2 times the ULN. Monitor liver function tests routinely during tofacitinib therapy and promptly investigate causes of hepatic enzyme elevations to identify potential cases of drug-induced liver injury. If drug-induced hepatotoxicity is suspected, interrupt tofacitinib receipt until drug-induced liver injury has been excluded. In clinical trials, reduction in the dose of concomitant DMARD, interruption of tofacitinib, or reduction in tofacitinib dose resulted in a decrease or the normalization of liver enzymes. Postmarketing cases of hepatitis B reactivation have been reported in patients treated with tofacitinib, and such reactivation may lead to hepatitis B exacerbation. The safety and efficacy of tofacitinib in patients with positive hepatitis B virus or hepatitis C virus serology are not established.[52315]

A serious and sometimes fatal infection due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens has been reported in rheumatoid arthritis patients who received tofacitinib. In the 7 controlled trials in patients with rheumatoid arthritis (RA), during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group. The most commonly reported infections were upper respiratory tract infections, naso-pharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively). Among RA patients enrolled in 7 clinical trials (1 to 12 months duration), 34 tofacitinib 5 mg twice daily patients (2.7 events per 100 patient-years) and 33 tofacitinib 10 mg twice daily patients (2.7 events per 100 patient-years) developed serious infections. The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection. Opportunistic infections such as cryptococcus, esophageal candidiasis, pneumocystosis, cytomegalovirus, and BK virus were reported in 4 patients who received tofacitinib. The median time of tofacitinib exposure before a diagnosis of an opportunistic infection was 8 months (range, 41 to 698 days). Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids. Six patients (0.5 events per 100 patient-years) who received tofacitinib 10 mg twice daily in RA trials developed tuberculosis compared to zero patients that received tofacitinib 5 mg twice daily. The median time of tofacitinib exposure before a diagnosis of tuberculosis was 10 months (range, 152 to 960 days). In the ulcerative colitis (UC) population, treatment with 10 mg twice daily was associated with a greater risk of serious infections compared to 5 mg twice daily. Additionally, opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with tofacitinib 10 mg twice daily. During the maintenance trial of tofacitinib in patients with UC, naso-pharyngitis was reported in 10% to 14% of patients. Upper respiratory tract infection (6% to 7%), herpes zoster (1% to 5%), and fever (2% or more) were reported in patients receiving tofacitinib for UC. Viral reactivation including cases of herpes virus reactivation (e.g., herpes zoster) were observed; herpes zoster was reported in 1% to 5% of tofacitinib patients. Closely monitor patients for the development of signs and symptoms of infection including tuberculosis during and after treatment with tofacitinib. Monitoring is needed even for patients who tested negative for latent tuberculosis infection before tofacitinib initiation. For any new infection, institute prompt and complete diagnostic testing appropriate for an immunocompromised patient. Also, initiate appropriate antimicrobial therapy and closely monitor the patient. Interrupt tofacitinib if a patient develops a serious or an opportunistic infection until the infection is controlled.[52315]

In rheumatoid arthritis clinical trials, hypertension was reported in 2% of tofacitinib recipients compared to 1% of placebo recipients. Peripheral edema was also noted during clinical trials.[52315]

Of tofacitinib recipients in rheumatoid arthritis clinical trials, 3% to 4% reported headache compared to 2.1% of placebo recipients. Insomnia and paresthesias were also noted in trials. During the maintenance trial of tofacitinib in patients with ulcerative colitis, headache was reported in 3% to 9% of patients compared to 6% of placebo patients.[52315]

Tofacitinib receipt may cause dose-dependent increases in lipid parameters including hypercholesterolemia. During the first 12 weeks of rheumatoid arthritis (RA) trials, the mean LDL cholesterol increased by 15% in the 5 mg twice daily arm and by 19% in the 10 mg twice daily arm. The mean HDL cholesterol increased by 10% in the 5 mg twice daily arm and by 12% in the 10 mg twice daily arm. Of note, the mean LDL/HDL ratios were essentially unchanged among tofacitinib recipients. Dose-related elevations in total cholesterol and triglycerides were also noted. Elevations were observed at one month of exposure and remained stable thereafter. Maximum effects were generally observed within 6 weeks. During the maintenance trial of tofacitinib in patients with ulcerative colitis, elevated cholesterol levels (i.e., hypercholesterolemia, hyperlipidemia, dyslipidemia, hypertriglyceridemia, increased LDL cholesterol, or abnormal LDL cholesterol) were reported in 5% to 9% of patients. The effect of lipid parameter elevations on cardiovascular morbidity and mortality has not been determined; manage patients according to clinical guidelines for the management of hyperlipidemia. In a controlled clinical trial involving RA patients, elevations in LDL cholesterol and ApoB decreased to pretreatment concentrations in response to statin therapy. Assess lipid parameters 4 to 8 weeks after initiation of tofacitinib therapy.[52315]

Of tofacitinib recipients in rheumatoid arthritis (RA) clinical trials, 3 to 4% had diarrhea as compared with 2% of placebo recipients. Abdominal pain, dyspepsia, vomiting, gastritis, dehydration, diverticulitis, and nausea were also during RA trials. During induction trials of tofacitinib in patients with ulcerative colitis (UC), diarrhea was reported in 5% or more of patients. During maintenance UC trials, gastroenteritis (3% to 4%), diarrhea (2% to 5%), and nausea (1% to 4%) were reported with tofacitinib therapy. Serious gastrointestinal (GI) reactions, such as GI perforation, have been noted among tofacitinib recipients, although the role of the drug in these events is unknown. Patients may be at an increased risk of perforation if they have a history of diverticulitis or are taking nonsteroidal antiinflammatory drugs (NSAIDs). In the RA studies, many patients were receiving background therapy with NSAIDs. There was no discernable difference in frequency of GI perforation between the placebo and tofacitinib arms in UC clinical trials and many of the patients were receiving background corticosteroid therapy. Promptly evaluate patients presenting with new-onset abdominal symptoms for early identification of GI perforation. Cautious use of tofacitinib is advised for patients who may be at increased risk for GI perforation, such as those taking NSAID therapy or with a history of diverticulitis.[52315]

In clinical trials of tofacitinib, cough, nasal congestion, dyspnea, and interstitial lung disease (cases were limited to patients with rheumatoid arthritis and some were fatal) were noted.[52315]

In clinical trials of tofacitinib, musculoskeletal pain, arthralgia, tendinitis, and joint swelling were reported. Increased blood creatine phosphokinase (CPK) was reported in 2% to 7% of patients receiving tofacitinib for ulcerative colitis. In trials with tofacitinib, dose-related elevations in serum creatinine (SCr) were observed. The mean increase in SCr was less than 0.1 mg/dL in the 12-month pooled safety analysis; however, up to 2% of patients discontinued tofacitinib in the long-term extensions because of protocol-specified discontinuation criteria for an increase in SCr by more than 50% of baseline. The clinical significance of the SCr elevations is unknown.[52315]

Hypersensitivity reactions, including urticaria and angioedema, have been reported in patients receiving tofacitinib. In rheumatoid arthritis trials with tofacitinib, dermatologic effects, such as erythema, pruritus, and rash were noted. During trials of tofacitinib in patients with ulcerative colitis, rash and acne vulgaris were reported in 2% or more of patients. Acne vulgaris has also been observed during postmarketing use of the drug for various indications. If a serious hypersensitivity reaction occurs, discontinue treatment and evaluate the potential cause or causes of the reaction.[52315]

Thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, has been reported in patients treated with either tofacitinib or other Janus kinase (JAK) inhibitors; many of these events were serious and some resulted in death. In a randomized, open-label, safety study in rheumatoid arthritis patients 50 years of age and older with one or more cardiovascular risk factors, higher rates of thrombosis (including DVT, PE, and arterial thrombosis), all-cause mortality (including sudden cardiac death), and major adverse cardiovascular (CV) events (MACE; defined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) were observed with tofacitinib 5 mg twice daily or tofacitinib 10 mg twice daily compared to tumor necrosis factor (TNF) inhibitors. The incidence rate of DVT per 100 patient-years was 0.22, 0.28, and 0.16 for tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors, respectively. The incidence rates of PE per 100 patient-years were 0.18 for tofacitinib 5 mg twice daily, 0.49 for tofacitinib 10 mg twice daily, and 0.05 for TNF inhibitors. In a long-term extension study of ulcerative colitis patients treated with tofacitinib, there were 5 cases of pulmonary embolism (PE) reported in the group taking 10 mg of the drug twice daily, including one death in a patient with advanced cancer. Tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors had incidence rates of all-cause mortality per 100 patient-years of 0.88, 1.23, and 0.69, respectively. The incidence rate of MACE per 100 patient-years were 0.91 for tofacitinib 5 mg twice daily, 1.11 for tofacitinib 10 mg twice daily, and 0.79 for TNF inhibitors. In addition, the incidence rates of fatal or non-fatal myocardial infarction per 100 patient-years was 0.36 for tofacitinib 5 mg twice daily, 0.39 for tofacitinib 10 mg twice daily, and 0.2 for TNF inhibitors. Patients who are current or past tobacco smokers are at an additional risk of the adverse events. The tofacitinib 10 mg twice daily dosage is not recommended for the treatment of rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis. Avoid tofacitinib therapy in patients at risk of thrombosis. Use the lowest effective dose of tofacitinib for the shortest duration necessary to achieve and maintain therapeutic response. Health care providers should consider the risks and benefits of tofacitinib when deciding to initiate or continue therapy, especially in patients with one or more CV risk factors and patients who are current or past smokers. Advise patients on the potential risks of tofacitinib therapy and to seek immediate medical attention if signs and symptoms of thromboembolism or thrombosis, myocardial infarction, or stroke develop. Discontinue tofacitinib therapy in any patient who develops a thrombosis, thromboembolism, myocardial infarction, or stroke.[52315]

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. Adult 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 elevations, 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/mm^3, 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 g/dL. If the hemoglobin decreases to less than 8 g/dL or decreases more than 2 g/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.[52315] [66958]

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.[52315]

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.[52315]

Avoid using tofacitinib in patients that may be at increased risk of thrombosis and thromboembolism, including those with thromboembolic disease. 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), and 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] [66958]

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.[63972] [52315]

Avoid the use of tofacitinib during pregnancy. Available data from the tofacitinib pregnancy registry (n = 11), pharmacovigilance, and published literature are insufficient to determine the drug-associated risk of major birth defects, miscarriages, or other adverse maternal or fetal outcomes.[52315] [61808] [62180] 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.[62380] Based on animal studies, tofacitinib may cause fetal harm. Fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures of 73-times and 6.3-times the human dose of 10 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 36-times the MRHD of 10 mg twice daily. No developmental toxicity was observed in rabbits at exposure levels approximately 1.5-times the MRHD of 10 mg twice daily.[52315]

Inform tofacitinib recipients of the potential reproductive risk if they are of childbearing reproductive potential; consider pregnancy planning and prevention for these individuals. 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 those of childbearing reproductive potential. Advise these patients to contact their health care 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 8.3-times the maximum recommended human dose (MRHD) of 10 mg twice daily. There was no impairment of female animal fertility at exposure levels of tofacitinib of 0.5-times the MRHD. No effect was seen on male fertility, sperm motility, or sperm concentration.[52315] [62380]

Advise tofacitinib recipients not to breastfeed. Instruct patients to avoid breast-feeding 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). Based on published data, tofacitinib is present in human milk. Data on the effects of the drug on the breastfed infant is limited to a few cases with no reported adverse effects. Additionally, there are no data on the effects of tofacitinib on milk production.[52315] [62180] Assess indication and patient-specific factors before considering an alternative agent.[61808] [62180]

Patients who undergo surgery while taking biologic therapy, such as tofacitinib, may be at greater risk for postoperative infections. For elective surgeries, balance the risk of postoperative infection against the risk of developing a severe or unstable disease by stopping the biologic therapy. The American College of Rheumatology recommends holding tofacitinib for 3 days before undergoing total knee or total hip arthroplasties.[71153]