Interactions between Bedol and Tofacitinib

MONITOR: Grapefruit juice may increase the plasma concentrations of tofacitinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The extent and clinical significance are unknown. Moreover, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability.

MANAGEMENT: Until more information is available, some authorities recommend avoiding consumption of grapefruit juice during tofacitinib therapy (Canada). Patients receiving tofacitinib therapy who ingest grapefruits or grapefruit juice should be monitored for adverse effects and undue fluctuations in plasma drug levels.

Coadministration with grapefruit juice may increase the bioavailability of oral estrogens. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits. In a small, randomized, crossover study, the administration of ethinyl estradiol with grapefruit juice (compared to herbal tea) increased peak plasma drug concentration (Cmax) by 37% and area under the concentration-time curve (AUC) by 28%. Based on these findings, grapefruit juice is unlikely to affect the overall safety profile of ethinyl estradiol. However, as with other drug interactions involving grapefruit juice, the pharmacokinetic alterations are subject to a high degree of interpatient variability. Also, the effect on other estrogens has not been studied.

The use of estrogens is contraindicated in patients with undiagnosed, abnormal vaginal bleeding. Prolonged (greater than 1 year), unopposed estrogen use (i.e. estrogen without concomitant progestin therapy) has been associated with a significant, dose-related risk of endometrial carcinoma. The risk may be offset substantially by the addition of a progestin but may not be completely abolished. Prior to initiating estrogen therapy, appropriate diagnostic tests should be performed in patients with abnormal vaginal bleeding to rule out endometrial malignancy. The same applies if recurrent or persistent bleeding develops during estrogen therapy.

When treated with an estrogen, patients with breast cancer and bone metastases may develop severe hypercalcemia, in which case the drug should be stopped and measures be taken to reduce serum calcium levels.

In a major safety study of a Janus kinase (JAK) inhibitor, tofacitinib, in rheumatoid arthritis patients 50 years and older with at least 1 cardiovascular risk factor, higher rates of all-cause mortality (including sudden cardiovascular death) and major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke) were observed with the JAK inhibitor when compared with tumor necrosis factor (TNF) blockers. Patients who were current or past smokers had an additional increased risk. Based on a shared mechanism of action, this risk should be considered for other JAK inhibitors, including baricitinib, upadacitinib, ruxolitinib, fedratinib, ritlecitinib, deuruxolitinib, and pacritinib. Consider the benefits and risks for each individual patient prior and during treatment with JAK inhibitors, especially in patients with other cardiovascular risk factors, history of cardiovascular events, and patients who are current or past smokers. Patients should be informed about the symptoms of serious cardiovascular events and what to do if they occur.

The use of estrogens is considered by manufacturers and some authorities to be contraindicated in patients with active thrombotic, thromboembolic, or thrombophilic disorders. The use of estrogen-containing oral contraceptives is additionally deemed contraindicated in patients with a history of such disorders and/or current cerebrovascular or coronary artery disease. Females with a history of migraines with aura are at an increased risk for stroke and this stroke risk may be further increased in females who have migraines with aura with use of combination oral contraceptives. Hypercoagulability and changes in various clotting factors and blood components have been observed in women receiving estrogen therapy. Known preexisting risk factors for increased thromboembolic or cardiovascular events include smoking, especially over age of 35; hypertension; hyperlipidemia; obesity; diabetes; age over 40; and lupus. Therapy with estrogens should be administered cautiously in the lowest effective dosage and only after careful consideration of risks and benefits. Estrogens should be avoided in patients with a history of thrombotic and thromboembolic disorders associated with estrogen use, except when used in the treatment of metastatic breast or prostatic malignancy.

The use of estrogens is considered by manufacturers and some authorities to be contraindicated in patients with active thrombotic, thromboembolic, or thrombophilic disorders. The use of estrogen-containing oral contraceptives is additionally deemed contraindicated in patients with a history of such disorders and/or current cerebrovascular or coronary artery disease. Females with a history of migraines with aura are at an increased risk for stroke and this stroke risk may be further increased in females who have migraines with aura with use of combination oral contraceptives. Hypercoagulability and changes in various clotting factors and blood components have been observed in women receiving estrogen therapy. Known preexisting risk factors for increased thromboembolic or cardiovascular events include smoking, especially over age of 35; hypertension; hyperlipidemia; obesity; diabetes; age over 40; and lupus. Therapy with estrogens should be administered cautiously in the lowest effective dosage and only after careful consideration of risks and benefits. Estrogens should be avoided in patients with a history of thrombotic and thromboembolic disorders associated with estrogen use, except when used in the treatment of metastatic breast or prostatic malignancy.

Use of tofacitinib should be avoided in patients with an active, serious infection. Patients should be evaluated and tested for latent or active tuberculosis (TB) infection before and per applicable guidelines during use of tofacitinib. Anti-TB therapy should also be considered before use of tofacitinib in patients with history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient. Patients should be closely monitored for signs/symptoms of TB, including patients who tested negative for latent TB infection before initiating therapy. Patients with latent TB should be treated with standard antimycobacterial therapy before using tofacitinib.

The risk of myocardial infarction and strokes, including those associated with oral contraceptive use and some estrogen use, is increased in patients with hypertension. Moreover, estrogens (and progestogens) may elevate blood pressure and worsen the hypertension, thus compounding the risk. Clinically significant blood pressure increases have been reported during estrogen therapy, particularly in patients receiving high dosages or treated with oral contraceptive combinations having high progestational activity. These effects also increase with duration of therapy and patient age. Therapy with estrogens should be administered cautiously in patients with preexisting hypertension. Some estrogen-based therapies, such as combined hormonal contraceptives, may be contraindicated in patients with uncontrolled hypertension or hypertension with vascular disease. Patients should be monitored for changes in cardiovascular status, and their antihypertensive regimen adjusted or estrogen therapy withdrawn as necessary. In patients requiring contraception, alternative methods should be considered for those who are hypertensive, over age 35, and smoke.

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. Use of tofacitinib should be avoided in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered before starting tofacitinib in patients: with chronic/recurrent infection, who have been exposed to tuberculosis, with history of serious/opportunistic infection, who have resided/traveled in areas of endemic tuberculosis/mycoses, or with underlying conditions that may predispose them to infection. Patients should be closely monitored for signs/symptoms of infection during and after tofacitinib treatment. 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 started, and the patient should be monitored closely. Caution is also recommended in patients with history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections.

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. Use of tofacitinib should be avoided in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered before starting tofacitinib in patients: with chronic/recurrent infection, who have been exposed to tuberculosis, with history of serious/opportunistic infection, who have resided/traveled in areas of endemic tuberculosis/mycoses, or with underlying conditions that may predispose them to infection. Patients should be closely monitored for signs/symptoms of infection during and after tofacitinib treatment. 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 started, and the patient should be monitored closely. Caution is also recommended in patients with history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections.

The use of estrogens is considered by manufacturers and some authorities to be contraindicated in patients with active thrombotic, thromboembolic, or thrombophilic disorders. The use of estrogen-containing oral contraceptives is additionally deemed contraindicated in patients with a history of such disorders and/or current cerebrovascular or coronary artery disease. Females with a history of migraines with aura are at an increased risk for stroke and this stroke risk may be further increased in females who have migraines with aura with use of combination oral contraceptives. Hypercoagulability and changes in various clotting factors and blood components have been observed in women receiving estrogen therapy. Known preexisting risk factors for increased thromboembolic or cardiovascular events include smoking, especially over age of 35; hypertension; hyperlipidemia; obesity; diabetes; age over 40; and lupus. Therapy with estrogens should be administered cautiously in the lowest effective dosage and only after careful consideration of risks and benefits. Estrogens should be avoided in patients with a history of thrombotic and thromboembolic disorders associated with estrogen use, except when used in the treatment of metastatic breast or prostatic malignancy.

The use of estrogens is considered by manufacturers and some authorities to be contraindicated in patients with active thrombotic, thromboembolic, or thrombophilic disorders. The use of estrogen-containing oral contraceptives is additionally deemed contraindicated in patients with a history of such disorders and/or current cerebrovascular or coronary artery disease. Females with a history of migraines with aura are at an increased risk for stroke and this stroke risk may be further increased in females who have migraines with aura with use of combination oral contraceptives. Hypercoagulability and changes in various clotting factors and blood components have been observed in women receiving estrogen therapy. Known preexisting risk factors for increased thromboembolic or cardiovascular events include smoking, especially over age of 35; hypertension; hyperlipidemia; obesity; diabetes; age over 40; and lupus. Therapy with estrogens should be administered cautiously in the lowest effective dosage and only after careful consideration of risks and benefits. Estrogens should be avoided in patients with a history of thrombotic and thromboembolic disorders associated with estrogen use, except when used in the treatment of metastatic breast or prostatic malignancy.

The use of estrogens is generally contraindicated in patients with known or suspected estrogen-dependent neoplasia such as breast and endometrial cancer, since it may stimulate tumor proliferation. High dosages of estrogens may be used for the palliative treatment of inoperable, metastatic breast cancer, but only in appropriately selected men and postmenopausal women.

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. Use of tofacitinib should be avoided in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered before starting tofacitinib in patients: with chronic/recurrent infection, who have been exposed to tuberculosis, with history of serious/opportunistic infection, who have resided/traveled in areas of endemic tuberculosis/mycoses, or with underlying conditions that may predispose them to infection. Patients should be closely monitored for signs/symptoms of infection during and after tofacitinib treatment. 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 started, and the patient should be monitored closely. Caution is also recommended in patients with history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections.

In a major safety study of a Janus kinase (JAK) inhibitor, tofacitinib, in rheumatoid arthritis patients 50 years and older with at least 1 cardiovascular risk factor, higher rates of all-cause mortality (including sudden cardiovascular death) and major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke) were observed with the JAK inhibitor when compared with tumor necrosis factor (TNF) blockers. Patients who were current or past smokers had an additional increased risk. Based on a shared mechanism of action, this risk should be considered for other JAK inhibitors, including baricitinib, upadacitinib, ruxolitinib, fedratinib, ritlecitinib, deuruxolitinib, and pacritinib. Consider the benefits and risks for each individual patient prior and during treatment with JAK inhibitors, especially in patients with other cardiovascular risk factors, history of cardiovascular events, and patients who are current or past smokers. Patients should be informed about the symptoms of serious cardiovascular events and what to do if they occur.

Malignancies (including lymphomas and solid tumors) have been reported in patients treated with tofacitinib, baricitinib, upadacitinib, deuruxolitinib and other Janus kinase (JAK) inhibitors used to treat inflammatory conditions. Patients who are current or past smokers are at additional increased risk of malignancies. Based on a shared mechanism of action, this risk should be considered for other JAK inhibitors, including ruxolitinib, pacritinib, and fedratinib. Before starting or continuing therapy, the benefits and risks for the individual patient should be considered, especially in patients with a known malignancy (other than successfully treated nonmelanoma skin cancer), patients who develop a malignancy during therapy, and patients who are current or past smokers. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Thrombosis (including deep venous thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, and arterial thrombosis) has occurred in patients treated for inflammatory conditions with Janus kinase (JAK) inhibitors, including baricitinib, tofacitinib, deuruxolitinib and upadacitinib. Many of these adverse events were serious and some resulted in death. Based on a shared mechanism of action, this risk should be considered for other JAK inhibitors, including ruxolitinib, fedratinib, and pacritinib. In general, JAK inhibitors should be avoided in patients who may be at increased risk of thrombosis. Tofacitinib should be used at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response when treating ulcerative colitis. If symptoms of thrombosis occur in any patients receiving JAK inhibitors, treatment should be discontinued and patients should be evaluated promptly and treated appropriately.

The use of estrogens is considered by manufacturers and some authorities to be contraindicated in patients with active thrombotic, thromboembolic, or thrombophilic disorders. The use of estrogen-containing oral contraceptives is additionally deemed contraindicated in patients with a history of such disorders and/or current cerebrovascular or coronary artery disease. Females with a history of migraines with aura are at an increased risk for stroke and this stroke risk may be further increased in females who have migraines with aura with use of combination oral contraceptives. Hypercoagulability and changes in various clotting factors and blood components have been observed in women receiving estrogen therapy. Known preexisting risk factors for increased thromboembolic or cardiovascular events include smoking, especially over age of 35; hypertension; hyperlipidemia; obesity; diabetes; age over 40; and lupus. Therapy with estrogens should be administered cautiously in the lowest effective dosage and only after careful consideration of risks and benefits. Estrogens should be avoided in patients with a history of thrombotic and thromboembolic disorders associated with estrogen use, except when used in the treatment of metastatic breast or prostatic malignancy.

Use of tofacitinib should be avoided in patients with an active, serious infection. Patients should be evaluated and tested for latent or active tuberculosis (TB) infection before and per applicable guidelines during use of tofacitinib. Anti-TB therapy should also be considered before use of tofacitinib in patients with history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient. Patients should be closely monitored for signs/symptoms of TB, including patients who tested negative for latent TB infection before initiating therapy. Patients with latent TB should be treated with standard antimycobacterial therapy before using tofacitinib.

Use of tofacitinib should be avoided in patients with an active, serious infection. Patients should be evaluated and tested for latent or active tuberculosis (TB) infection before and per applicable guidelines during use of tofacitinib. Anti-TB therapy should also be considered before use of tofacitinib in patients with history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient. Patients should be closely monitored for signs/symptoms of TB, including patients who tested negative for latent TB infection before initiating therapy. Patients with latent TB should be treated with standard antimycobacterial therapy before using tofacitinib.

The use of exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema. Consider the risk versus benefits of estrogen therapy. Close monitoring is recommended when prescribing these agents to patients predisposed to angioedema.

Estrogens and progestogens may cause fluid retention, particularly when given in high dosages or for prolonged periods. Therapy with these agents should be administered cautiously in patients who have preexisting problems with excess fluid. In addition, patients with conditions that may be adversely affected by fluid accumulation, such as asthma, epilepsy, migraine, and cardiovascular or renal dysfunction, should be observed for exacerbation of their condition during estrogen and/or progestogen therapy.

Estrogens and progestogens may cause fluid retention, particularly when given in high dosages or for prolonged periods. Therapy with these agents should be administered cautiously in patients who have preexisting problems with excess fluid. In addition, patients with conditions that may be adversely affected by fluid accumulation, such as asthma, epilepsy, migraine, and cardiovascular or renal dysfunction, should be observed for exacerbation of their condition during estrogen and/or progestogen therapy.

The use of tofacitinib increases the risk of infections. As there is a higher incidence of infection in diabetic patients in general, caution is recommended when treating patients with diabetes.

Impaired glucose tolerance has been observed in some patients administered oral contraceptives and appears to be related primarily to the estrogen dose. However, progestogens can increase insulin secretion and produce insulin resistance to varying degrees, depending on the agent. Caution and close monitoring are recommended in patients with diabetes mellitus during therapy with estrogens and/or progestogens, and adjustments made accordingly in their antidiabetic regimen.

Estrogens and progestogens may cause fluid retention, particularly when given in high dosages or for prolonged periods. Therapy with these agents should be administered cautiously in patients who have preexisting problems with excess fluid. In addition, patients with conditions that may be adversely affected by fluid accumulation, such as asthma, epilepsy, migraine, and cardiovascular or renal dysfunction, should be observed for exacerbation of their condition during estrogen and/or progestogen therapy.

A two- to four-fold increase in risk of gallbladder disease has been noted in women receiving postmenopausal estrogen therapy. The risk for gallbladder disease may be less for premenopausal women using oral contraceptives containing low-dose estrogens and/or progestins. Therapy with estrogens should be administered cautiously in patients with preexisting gallbladder disease or a history of pregnancy-related cholestasis.

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

As with any other nondeformable material, caution is recommended when administering tofacitinib extended-release tablets to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a nondeformable extended-release formulation.

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

Adverse hematologic effects including neutropenia, lymphocytosis, and anemia have been associated with the use of tofacitinib. It is recommended to avoid starting therapy in patients with absolute lymphocyte counts (ALC) less than 500 cells/mm3, absolute neutrophil counts (ANC) less than 1000 cells/mm3, or hemoglobin levels less than 9 g/dL. For persistent ANC of 500 to 1000 cells/mm3, hemoglobin levels less than 8 g/dL, or a hemoglobin level drop greater than 2 g/dL, therapy should be interrupted until ANC is greater than 1000 cells/mm3 and hemoglobin values have normalized. Treatment with tofacitinib is not recommended in patients who develop a confirmed ALC less than 500 cells/mm3 or an ANC less than 500 cells/mm3. Lymphocyte counts should be monitored at baseline and every 3 months thereafter; neutrophil counts and hemoglobin should be monitored at baseline, after 4 to 8 weeks of therapy, and every 3 months thereafter. Treatment should be modified based on ALC, ANC, and/or hemoglobin levels. Caution is recommended in patients who may be at increased risk.

Treatment with tofacitinib was associated with dose-dependent increases in lipid parameters (including total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol); maximum effects generally occurred within 6 weeks. Lipid parameters should be assessed about 4 to 8 weeks after initiation of therapy. Patients should be managed according to clinical guidelines for the management of hyperlipidemia.

Estrogens may cause adverse lipid changes. Use of estrogens has been associated with elevations in triglyceride levels, particularly in women with pre-existing hypertriglyceridemia. Discontinue therapy if elevated triglycerides lead to pancreatitis. Manage hypercholesterolemia appropriately as indicated.

Estrogens should be used with caution in individuals with severe hypocalcemia or hypoparathyroidism. Estrogen-induced hypocalcemia may occur in patients with hypoparathyroidism; consider whether the benefits of estrogen therapy outweigh the risks.

Viral reactivation (including cases of herpes virus reactivation [e.g., herpes zoster]) was observed in clinical trials with tofacitinib; postmarketing cases of hepatitis B reactivation have been reported with tofacitinib. Patients should be screened for viral hepatitis in accordance with clinical guidelines before starting therapy with tofacitinib. Close monitoring is recommended, and appropriate supportive treatment should be initiated if appropriate.

Treatment with tofacitinib was associated with an increased incidence of liver enzyme elevation compared to placebo. No dose adjustment of tofacitinib is needed in patients with mild liver dysfunction. Tofacitinib-treated patients with moderate liver dysfunction had greater tofacitinib blood levels than those with normal liver function; therefore, dose adjustment of tofacitinib is recommended in these patients. Tofacitinib has not been studied in patients with severe liver dysfunction, and its use is not recommended in these patients. The safety and efficacy of tofacitinib has not been studied in patients with positive hepatitis B virus or hepatitis C virus serology. Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury; if drug-induced liver injury is suspected, therapy should be interrupted until this diagnosis has been excluded.

Estrogens are primarily metabolized by the liver. Use of estrogen therapy is contraindicated in patients with liver dysfunction or disease. Patients with impaired hepatic function may be at increased risk for adverse effects associated with estrogen administration due to decreased drug clearance. Patients with hepatic hemangiomas are at increased risk of exacerbation with use of estrogens. Therapy with estrogens should be administered cautiously in patients with cholestatic jaundice associated with past estrogen use or with pregnancy. In addition, clinicians should be aware that estrogen therapy may affect liver function tests.

Adverse hematologic effects including neutropenia, lymphocytosis, and anemia have been associated with the use of tofacitinib. It is recommended to avoid starting therapy in patients with absolute lymphocyte counts (ALC) less than 500 cells/mm3, absolute neutrophil counts (ANC) less than 1000 cells/mm3, or hemoglobin levels less than 9 g/dL. For persistent ANC of 500 to 1000 cells/mm3, hemoglobin levels less than 8 g/dL, or a hemoglobin level drop greater than 2 g/dL, therapy should be interrupted until ANC is greater than 1000 cells/mm3 and hemoglobin values have normalized. Treatment with tofacitinib is not recommended in patients who develop a confirmed ALC less than 500 cells/mm3 or an ANC less than 500 cells/mm3. Lymphocyte counts should be monitored at baseline and every 3 months thereafter; neutrophil counts and hemoglobin should be monitored at baseline, after 4 to 8 weeks of therapy, and every 3 months thereafter. Treatment should be modified based on ALC, ANC, and/or hemoglobin levels. Caution is recommended in patients who may be at increased risk.

Estrogens and progestogens may cause fluid retention, particularly when given in high dosages or for prolonged periods. Therapy with these agents should be administered cautiously in patients who have preexisting problems with excess fluid. In addition, patients with conditions that may be adversely affected by fluid accumulation, such as asthma, epilepsy, migraine, and cardiovascular or renal dysfunction, should be observed for exacerbation of their condition during estrogen and/or progestogen therapy.

Adverse hematologic effects including neutropenia, lymphocytosis, and anemia have been associated with the use of tofacitinib. It is recommended to avoid starting therapy in patients with absolute lymphocyte counts (ALC) less than 500 cells/mm3, absolute neutrophil counts (ANC) less than 1000 cells/mm3, or hemoglobin levels less than 9 g/dL. For persistent ANC of 500 to 1000 cells/mm3, hemoglobin levels less than 8 g/dL, or a hemoglobin level drop greater than 2 g/dL, therapy should be interrupted until ANC is greater than 1000 cells/mm3 and hemoglobin values have normalized. Treatment with tofacitinib is not recommended in patients who develop a confirmed ALC less than 500 cells/mm3 or an ANC less than 500 cells/mm3. Lymphocyte counts should be monitored at baseline and every 3 months thereafter; neutrophil counts and hemoglobin should be monitored at baseline, after 4 to 8 weeks of therapy, and every 3 months thereafter. Treatment should be modified based on ALC, ANC, and/or hemoglobin levels. Caution is recommended in patients who may be at increased risk.

Estrogens may cause adverse lipid changes. Use of estrogens has been associated with elevations in triglyceride levels, particularly in women with pre-existing hypertriglyceridemia. Discontinue therapy if elevated triglycerides lead to pancreatitis. Manage hypercholesterolemia appropriately as indicated.

No dose adjustment of tofacitinib is needed in patients with mild renal dysfunction. Tofacitinib-treated patients with moderate and severe renal dysfunction had greater tofacitinib blood levels than those with normal renal function; therefore, dose adjustment of tofacitinib is recommended in patients with moderate or severe renal dysfunction (including but not limited to those with severe dysfunction undergoing hemodialysis). Caution should be exercised when using tofacitinib in these patients.

Estrogens and progestogens may cause fluid retention, particularly when given in high dosages or for prolonged periods. Therapy with these agents should be administered cautiously in patients who have preexisting problems with excess fluid. In addition, patients with conditions that may be adversely affected by fluid accumulation, such as asthma, epilepsy, migraine, and cardiovascular or renal dysfunction, should be observed for exacerbation of their condition during estrogen and/or progestogen therapy.

Estrogens and progestogens may cause fluid retention, particularly when given in high dosages or for prolonged periods. Therapy with these agents should be administered cautiously in patients who have preexisting problems with excess fluid. In addition, patients with conditions that may be adversely affected by fluid accumulation, such as asthma, epilepsy, migraine, and cardiovascular or renal dysfunction, should be observed for exacerbation of their condition during estrogen and/or progestogen therapy.

When administering estrogen and/or progestogen therapy in patients with thyroid disorders, clinicians should be aware that these hormones may affect thyroid function tests. Patients on thyroid replacement therapy may require higher doses of thyroid hormone and appropriate monitoring. Changes have mostly been reported with the use of combination oral contraceptives. Specifically, thyroid-binding globulin (TBG) may be increased, resulting in elevated circulating total thyroid hormone, as measured by PBI (protein-bound iodine), T4 by column or radioimmunoassay, or T3 by radioimmunoassay. Free T3 resin uptake may be decreased. On the contrary, a decrease in TBG and, consequently, thyroxine concentration, has been reported by the manufacturers of the progestin-only (norethindrone) oral contraceptives.

Viral reactivation (including cases of herpes virus reactivation [e.g., herpes zoster]) was observed in clinical trials with tofacitinib; postmarketing cases of hepatitis B reactivation have been reported with tofacitinib. Patients should be screened for viral hepatitis in accordance with clinical guidelines before starting therapy with tofacitinib. Close monitoring is recommended, and appropriate supportive treatment should be initiated if appropriate.