Xeljanz XR Disease Interactions

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 are current or past smokers are at 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, and pacritinib. Before starting or continuing therapy, the benefits and risks for the individual patient should be considered, especially in patients with other cardiovascular risk factors 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. Tofacitinib, baricitinib, and upadacitinib are indicated for patients with inadequate response or intolerance to 1 or more TNF blockers, but should be discontinued in patients who have experienced a myocardial infarction or stroke. The dosage recommended for tofacitinib should not be exceeded; for the treatment of ulcerative colitis, tofacitinib should be used at the lowest effective dose and for the shortest duration needed to achieve and/or maintain therapeutic response.

Malignancies (including lymphomas and solid tumors) have been reported in patients treated with tofacitinib and other Janus kinase (JAK) inhibitors used to treat inflammatory conditions; lymphomas and other malignancies have been seen in patients treated with baricitinib or upadacitinib. 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, and arterial thrombosis) has occurred in patients treated for inflammatory conditions with Janus kinase (JAK) inhibitors, including baricitinib, tofacitinib, 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. Baricitinib, pacritinib, tofacitinib, and upadacitinib should be avoided in patients who may be at increased risk of thrombosis; for the treatment of ulcerative colitis, tofacitinib should be used at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response. If symptoms of thrombosis occur, baricitinib, pacritinib, tofacitinib, and upadacitinib should be discontinued and patients should be evaluated promptly and treated appropriately.

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.

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.

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.

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.

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.

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.

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.

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.

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.