TOFACITINIB Drug Interactions: What You Need to Know

INTERACTIONS Table 7 includes drugs with clinically significant drug interactions when concomitantly used with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) and instructions for preventing or managing them.

Table

7: Clinically Significant Interactions Affecting XELJANZ/XELJANZ XR When Concomitantly Used with Other Drugs Strong CYP3A4 Inhibitors (e.g., ketoconazole)

Clinical Impact

Increased exposure to tofacitinib Intervention Dosage modification of XELJANZ/XELJANZ XR is recommended [see Dosage and Administration (2) , Clinical Pharmacology, Figure 3 (12.3) ] Moderate CYP3A4 Inhibitors Concomitantly Used with Strong CYP2C19 Inhibitors (e.g., fluconazole)

Clinical Impact

Increased exposure to tofacitinib Intervention Dosage modification of XELJANZ/XELJANZ XR is recommended [see Dosage and Administration (2) , Clinical Pharmacology, Figure 3 (12.3) ] Strong CYP3A4 Inducers (e.g., rifampin)

Clinical Impact

Decreased exposure to tofacitinib and may result in loss of or reduced clinical response Intervention Concomitant use with XELJANZ/XELJANZ XR is not recommended [see Clinical Pharmacology, Figure 3 (12.3) ]

Immunosuppressive

Drugs (e.g., azathioprine, tacrolimus, cyclosporine)

Clinical Impact

Risk of added immunosuppression; concomitant use of XELJANZ/XELJANZ XR with biologic DMARDs or potent immunosuppressants has not been studied in patients with RA, PsA, AS, UC, or pcJIA.

Intervention

Concomitant use with XELJANZ/XELJANZ XR is not recommended [see Indications and Usage (1) , Clinical Pharmacology, Figure 3 (12.3) ] See FPI for clinically significant drug interactions. ( 2 , 7 )

None. None. ( 4 )

AND PRECAUTIONS

• Serious Infections : Avoid use of XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) during an active serious infection, including localized infections. ( 5.1 )
• Gastrointestinal Perforations : Promptly evaluate patients at increased risk for gastrointestinal perforation who present with new onset abdominal symptoms. ( 5.6 )
• Laboratory Monitoring : Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. ( 5.8 )
• Vaccinations : Avoid use of live vaccines concurrently with XELJANZ or XELJANZ XR. ( 5.9 )

5.1 Serious Infections Serious and sometimes fatal infections may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multi-dermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with XELJANZ. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids. In the UC population, treatment with XELJANZ tablets 10 mg twice daily was associated with 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 XELJANZ tablets 10 mg twice daily. Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis). Avoid use of XELJANZ/XELJANZ XR in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ/XELJANZ XR in patients:

• with chronic or recurrent infection
• who have been exposed to tuberculosis
• with a history of a serious or an opportunistic infection
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
• with underlying conditions that may predispose them to infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR. Interrupt XELJANZ/XELJANZ XR if a patient develops a serious infection, an opportunistic infection, or sepsis. In patients who develop a new infection during treatment with XELJANZ/XELJANZ XR, promptly complete diagnostic testing appropriate for an immunocompromised patient; initiate appropriate antimicrobial therapy, and monitor the patients closely. Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections. 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 are recommended [see Dosage and Administration (2.3 , 2.4 , 2.5) ].

Tuberculosis

Evaluate and test patients for latent or active tuberculosis (TB) infection prior to and per applicable guidelines during administration of XELJANZ/XELJANZ XR. Consider anti-TB therapy prior to administration of XELJANZ/XELJANZ XR in patients with a past 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. Monitor patients closely for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy. Treat patients with latent TB with standard antimycobacterial therapy before administering XELJANZ/XELJANZ XR.

Viral Reactivation

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ. Postmarketing cases of hepatitis B reactivation have been reported in patients treated with XELJANZ. The impact of XELJANZ/XELJANZ XR on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Perform screening for viral hepatitis in accordance with clinical guidelines before starting therapy with XELJANZ/XELJANZ XR. The risk of herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR and appears to be higher in patients treated with XELJANZ in Japan and Korea.

5.2 Increased Risk of Mortality Increased risk of mortality may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). Adult patients with rheumatoid arthritis (RA), 50 years of age and older, with at least one cardiovascular risk factor treated with XELJANZ tablets 5 mg or 10 mg twice a day had a higher observed rate of all-cause mortality, including sudden cardiovascular death, compared to those treated with TNF blockers in a large, randomized, postmarketing safety study (RA Safety Study 1). The incidence rate of all-cause mortality per 100 patient-years was 1.23 for XELJANZ tablets 10 mg twice a day, 0.88 for XELJANZ tablets 5 mg twice a day, and 0.69 for TNF blockers <span class="opacity-50 text-xs">[see Clinical Studies (14.6) ]</span> . Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ/XELJANZ XR. XELJANZ 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosages are not recommended for the treatment of RA, PsA, AS, or pcJIA <span class="opacity-50 text-xs">[see Dosage and Administration (2.3 , 2.4) ]</span> . For the treatment of UC, use XELJANZ/XELJANZ XR at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span> .

5.3 Malignancy and Lymphoproliferative Disorders Malignancies and lymphoproliferative disorders may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). Malignancies, including lymphomas and solid cancers, were observed in clinical studies of XELJANZ <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. Other malignancies were observed in XELJANZ clinical studies and the postmarketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. In RA Safety Study 1, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with XELJANZ tablets 5 mg or 10 mg twice a day compared with TNF blockers. The incidence rate of malignancies (excluding NMSC) per 100 patient-years was 1.13 for XELJANZ tablets 10 mg twice a day, 1.13 for XELJANZ tablets 5 mg twice a day, and 0.77 for TNF blockers. Patients who are current or past smokers are at additional increased risk <span class="opacity-50 text-xs">[see Clinical Studies (14.6) ]</span>. Lymphomas and lung cancers, which are a subset of all malignancies in RA Safety Study 1, were observed at a higher rate in patients treated with XELJANZ tablets 5 mg twice a day and XELJANZ tablets 10 mg twice a day compared to those treated with TNF blockers. The incidence rate of lymphomas per 100 patient-years was 0.11 for XELJANZ tablets 10 mg twice a day, 0.07 for XELJANZ tablets 5 mg twice a day, and 0.02 for TNF blockers. The incidence rate of lung cancers per 100 patient-years among current and past smokers was 0.59 for XELJANZ tablets 10 mg twice a day, 0.48 for XELJANZ tablets 5 mg twice a day, and 0.27 for TNF blockers <span class="opacity-50 text-xs">[see Clinical Studies (14.6) ]</span> . Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ/XELJANZ XR, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy while on treatment, and patients who are current or past smokers. XELJANZ 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosages are not recommended for the treatment of RA, PsA, AS, or pcJIA <span class="opacity-50 text-xs">[see Dosage and Administration (2.3 , 2.4) ]</span> . Non-Melanoma Skin Cancer Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ tablets. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. In the UC population, treatment with XELJANZ tablets 10 mg twice daily was associated with greater risk of NMSC than treatment with placebo.

5.4 Major Adverse Cardiovascular Events Major adverse cardiovascular events may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). In RA Safety Study 1, patients with RA who were 50 years of age and older with at least one cardiovascular risk factor and treated with XELJANZ tablets 5 mg or 10 mg twice daily had a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke, compared to those treated with TNF blockers. The incidence rate of MACE per 100 patient-years was 1.11 for XELJANZ tablets 10 mg twice a day, 0.91 for XELJANZ tablets 5 mg twice a day, and 0.79 for TNF blockers. The incidence rate of fatal or non-fatal myocardial infarction per 100 patient-years was 0.39 for XELJANZ tablets 10 mg twice a day, 0.36 for XELJANZ tablets 5 mg twice a day, and 0.2 for TNF blockers <span class="opacity-50 text-xs">[see Clinical Studies (14.6) ]</span> . Patients who are current or past smokers are at additional increased risk. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ/XELJANZ XR, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Inform patients about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue XELJANZ/XELJANZ XR in patients that have experienced a MI or stroke. XELJANZ 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosages are not recommended for the treatment of RA, PsA, AS, or pcJIA <span class="opacity-50 text-xs">[see Dosage and Administration (2.3 , 2.4) ]</span> .

5.5 Thrombosis Thrombosis may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). Thrombosis, including pulmonary embolism (PE), deep venous thrombosis (DVT), and arterial thrombosis, have occurred in patients treated with XELJANZ and other Janus kinase ( JAK) inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> . Patients with RA 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ tablets 5 mg or 10 mg twice daily compared to TNF blockers in RA Safety Study 1 had an observed increase in incidence of these thrombotic events. The incidence rate of DVT per 100 patient-years was 0.28 for XELJANZ tablets 10 mg twice a day, 0.22 for XELJANZ tablets 5 mg twice a day, and 0.16 for TNF blockers. The incidence rate of PE per 100 patient-years was 0.49 for XELJANZ tablets 10 mg twice a day, 0.18 for XELJANZ tablets 5 mg twice a day, and 0.05 for TNF blockers <span class="opacity-50 text-xs">[see Clinical Studies (14.6) ]</span> . XELJANZ 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosages are not recommended for the treatment of RA, PsA, AS, or pcJIA <span class="opacity-50 text-xs">[see Dosage and Administration (2.3 , 2.4) ]</span> . In a long-term extension study in patients with UC, five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one death in a patient with advanced cancer. Promptly evaluate patients with symptoms of thrombosis and discontinue XELJANZ/XELJANZ XR in patients with symptoms of thrombosis. Avoid XELJANZ/XELJANZ XR in patients that may be at increased risk of thrombosis. For the treatment of UC, use XELJANZ tablets or XELJANZ XR at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span> .

5.6 Gastrointestinal Perforations Gastrointestinal perforations may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ tablets, although the role of JAK inhibition in these events is not known. In these studies, many patients with RA received background therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ tablets treatment groups in clinical trials of patients with UC, and many of them were receiving background corticosteroids. Promptly evaluate patients treated with XELJANZ/XELJANZ XR who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs) and who present with new onset abdominal symptoms for early identification of gastrointestinal perforation <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

5.7 Hypersensitivity Reactions Hypersensitivity reactions may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ/XELJANZ XR. Some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue XELJANZ/XELJANZ XR while evaluating the potential cause or causes of the reaction <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .

5.8 Laboratory Abnormalities Laboratory abnormalities may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets).

Lymphocyte Abnormalities

Treatment with XELJANZ tablets was associated with initial lymphocytosis at one month of XELJANZ tablets treatment followed by a gradual decrease in mean absolute lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm 3 in these patients were associated with an increased incidence of treated and serious infections.

• Monitor lymphocyte counts at baseline and every 3 months thereafter.
• Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm 3 ). In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm 3 , treatment with XELJANZ/XELJANZ XR is not recommended.

Neutropenia

Treatment with XELJANZ tablets was associated with an increased incidence of neutropenia (less than 2000 cells/mm 3 ) compared to treatment with placebo.

• Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.
• Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm 3 ). For patients who develop a persistent ANC of 500 to 1000 cells/mm 3 , interrupt dosing until ANC is greater than or equal to 1000 cells/mm 3 . In patients who develop an ANC less than 500 cells/mm 3 , treatment with XELJANZ/XELJANZ XR is not recommended. Anemia
• Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter.
• Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low hemoglobin level (i.e., less than 9 g/dL). Interrupt treatment with XELJANZ/XELJANZ XR in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment until hemoglobin values have normalized.

Liver Enzyme Elevations

Treatment with XELJANZ tablets was associated with an increased incidence of liver enzyme elevation compared to treatment with placebo. Most of these abnormalities occurred in studies with background DMARD therapy (primarily methotrexate).

• 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, interrupt the administration of XELJANZ/XELJANZ XR until this diagnosis has been excluded.

Lipid Elevations

Treatment with XELJANZ tablets was associated with dose-dependent increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum changes in these lipid parameters were generally observed within 6 weeks. There were no clinically relevant changes in LDL/HDL cholesterol ratios. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

• Perform assessment of lipid parameters approximately 4-8 weeks following initiation of XELJANZ/XELJANZ XR therapy.
• Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.

5.9 Vaccinations Avoid use of live vaccines concurrently with XELJANZ (tablets and oral solution) or XELJANZ XR (extended-release tablets). Prior to initiating XELJANZ/XELJANZ XR therapy, update immunizations in agreement with current immunization guidelines. The interval between live vaccinations and initiation of XELJANZ/XELJANZ XR therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

5.10 Risk of Gastrointestinal Obstruction with XELJANZ XR - A Non-Deformable Extended-Release Formulation Gastrointestinal obstruction may occur with XELJANZ XR (extended-release tablets). Avoid use of XELJANZ XR in patients with pre-existing 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 non-deformable extended-release formulation.