5 WARNINGS AND PRECAUTIONS
5.1 Serious Infections
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, multidermatomal 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, XELJANZ treatment with 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 10 mg twice daily.
Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis).
- 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.
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 (2.2, 2.3, 2.4)].
Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
5.3 Malignancy and Lymphoproliferative Disorders
In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ.
During the 2 PsA controlled clinical studies there were 3 malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus nonbiologic DMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus nonbiologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus nonbiologic DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also been observed in the long-term extension study in psoriatic arthritis patients treated with XELJANZ.
During the UC controlled clinical studies (8-week induction and 52-week maintenance studies), which included 1220 patients, 0 cases of solid cancer or lymphoma were observed in XELJANZ-treated patients. In the long-term extension study, malignancies (including solid cancers and lymphomas) were observed more often in patients treated with XELJANZ 10 mg twice daily.
In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.
Other malignancies were observed in clinical studies and the postmarketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer.
Non-Melanoma Skin Cancer
Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC.
5.5 Gastrointestinal Perforations
Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ, although the role of JAK inhibition in these events is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).
There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids.
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 tofacitinib while evaluating the potential cause or causes of the reaction [see Adverse Reactions (6.2)].
5.7 Laboratory Abnormalities
Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure 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/mm3 were associated with an increased incidence of treated and serious infections.
Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo.
Avoid initiation of XELJANZ/XELJANZ XR/XELJANZ Oral Solution treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3). For patients who develop a persistent ANC of 500 to 1000 cells/mm3, interrupt XELJANZ/XELJANZ XR/XELJANZ Oral Solution dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution is not recommended.
Monitor hemoglobin at baseline and after 4–8 weeks of treatment and every 3 months thereafter. For recommended modifications based on hemoglobin results [see Dosage and Administration (2)].
Liver Enzyme Elevations
Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.
Treatment with XELJANZ 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. 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.
Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.
A patient experienced dissemination of the vaccine strain of varicella zoster virus, 16 days after vaccination with live attenuated (Zostavax) virus vaccine and 2 days after treatment start with tofacitinib 5 mg twice daily. The patient was varicella virus naïve, as evidenced by no previous history of varicella infection and no anti-varicella antibodies at baseline. Tofacitinib was discontinued and the patient recovered after treatment with standard doses of antiviral medication.
5.9 Risk of Gastrointestinal Obstruction with a Non-Deformable Extended-Release Formulation such as XELJANZ XR
As with any other non-deformable material, caution should be used when administering XELJANZ XR to 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.