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Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster and urinary tract infection [see ADVERSE REACTIONS]. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus, and BK virus 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.
Avoid use of XELJANZ in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ 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.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ. XELJANZ 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 XELJANZ 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.
Patients should be evaluated and tested for latent or active infection prior to administration of XELJANZ.
Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ in patients with a past 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 tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ.
Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ. The impact of XELJANZ on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ. The risk of herpes zoster is increased in patients treated with XELJANZ and appears to be higher in patients treated with XELJANZ in Japan.
Malignancy And Lymphoproliferative Disorders
Consider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy. Malignancies were observed in clinical studies of XELJANZ [see ADVERSE REACTIONS].
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.
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.
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.
Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ in rheumatoid arthritis patients, although the role of JAK inhibition in these events is not known.
XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation [see ADVERSE REACTIONS].
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.
Avoid initiation of XELJANZ treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm³ ). In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm³ treatment with XELJANZ is not recommended.
Monitor lymphocyte counts at baseline and every 3 months thereafter. For recommended modifications based on lymphocyte counts. [see DOSAGE AND ADMINISTRATION].
Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm³ ) compared to placebo.
Avoid initiation of XELJANZ treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm³ ). For patients who develop a persistent ANC of 500-1000 cells/mm³ , interrupt XELJANZ 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 is not recommended.
Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter. For recommended modifications based on ANC results see DOSAGE AND ADMINISTRATION.
Avoid initiation of XELJANZ treatment in patients with a low hemoglobin level (i.e., less than 9 g/dL). Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment.
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].
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.
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, the administration of XELJANZ should be interrupted until this diagnosis has been excluded.
Treatment with XELJANZ was associated with 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 should be performed approximately 4-8 weeks following initiation of XELJANZ therapy.
No data are available on the response to vaccination or on the secondary transmission of infection by live vaccines to patients receiving XELJANZ. Avoid use of live vaccines concurrently with XELJANZ.
Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Advise patients of the potential benefits and risks of XELJANZ.
Inform patients that XELJANZ may lower the ability of their immune system to fight infections. Advise patients not to start taking XELJANZ if they have an active infection. Instruct patients to contact their healthcare provider immediately during treatment if symptoms suggesting infection appear in order to ensure rapid evaluation and appropriate treatment [see WARNINGS AND PRECAUTIONS].
Advise patients that the risk of herpes zoster, some cases of which can be serious, is increased in patients treated with XELJANZ [see WARNINGS AND PRECAUTIONS].
Malignancies and Lymphoproliferative Disorders
Inform patients that XELJANZ may increase their risk of certain cancers, and that lymphoma and other cancers have been observed in patients taking XELJANZ. Instruct patients to inform their healthcare provider if they have ever had any type of cancer [see WARNINGS AND PRECAUTIONS].
Important Information on Laboratory Abnormalities
Inform patients that XELJANZ may affect certain lab test results, and that blood tests are required before and during XELJANZ treatment [see WARNINGS AND PRECAUTIONS].
Inform patients that XELJANZ should not be used during pregnancy unless clearly necessary, and advise patients to inform their doctors right away if they become pregnant while taking XELJANZ. Inform patients that Pfizer has a registry for pregnant women who have taken XELJANZ during pregnancy. Advise patients to contact the registry at 1-877-311-8972 to enroll [see Pregnancy].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a 39-week toxicology study in monkeys, tofacitinib at exposure levels approximately 6 times the MRHD (on an AUC basis at oral doses of 5 mg/kg twice daily) produced lymphomas. No lymphomas were observed in this study at exposure levels 1 times the MRHD (on an AUC basis at oral doses of 1 mg/kg twice daily).
The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib, at exposure levels approximately 34 times the MRHD (on an AUC basis at oral doses of 200 mg/kg/day) was not carcinogenic in mice.
In the 24-month oral carcinogenicity study in Sprague-Dawley rats, tofacitinib caused benign Leydig cell tumors, hibernomas (malignancy of brown adipose tissue), and benign thymomas at doses greater than or equal to 30 mg/kg/day (approximately 42 times the exposure levels at the MRHD on an AUC basis). The relevance of benign Leydig cell tumors to human risk is not known.
Tofacitinib was not mutagenic in the bacterial reverse mutation assay. It was positive for clastogenicity in the in vitro chromosome aberration assay with human lymphocytes in the presence of metabolic enzymes, but negative in the absence of metabolic enzymes. Tofacitinib was negative in the in vivo rat micronucleus assay and in the in vitro CHO-HGPRT assay and the in vivo rat hepatocyte unscheduled DNA synthesis assay.
In rats, tofacitinib at exposure levels approximately 17 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day) reduced female fertility due to increased post-implantation loss. There was no impairment of female rat fertility at exposure levels of tofacitinib equal to the MRHD (on an AUC basis at oral doses of 1 mg/kg/day). Tofacitinib exposure levels at approximately 133 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day) had no effect on male fertility, sperm motility, or sperm concentration.
Use In Specific Populations
Pregnancy Category C.
There are no adequate and well-controlled studies in pregnant women. XELJANZ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Tofacitinib has been shown to be fetocidal and teratogenic in rats and rabbits when given at exposures 146 times and 13 times, respectively, the maximum recommended human dose (MRHD).
In a rat embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 146 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively, and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day). In the rabbit embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 13 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).
In a peri-and postnatal rat study, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the MRHD (on an AUC basis at oral doses of 50 mg/kg/day). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).
To monitor the outcomes of pregnant women exposed to XELJANZ, a pregnancy registry has been established. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.
Tofacitinib was secreted in milk of lactating rats. It is not known whether tofacitinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from tofacitinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug for the mother.
The safety and effectiveness of XELJANZ in pediatric patients have not been established.
Of the 3315 patients who enrolled in Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among XELJANZ-treated subjects 65 years of age and older was higher than among those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.
Use In Diabetics
As there is a higher incidence of infection in diabetic population in general, caution should be used when treating patients with diabetes.
XELJANZ-treated patients with moderate hepatic impairment had greater tofacitinib levels than XELJANZ-treated patients with normal hepatic function [see CLINICAL PHARMACOLOGY]. Higher blood levels may increase the risk of some adverse reactions, therefore, XELJANZ dose should be reduced to 5 mg once daily in patients with moderate hepatic impairment [see DOSAGE AND ADMINISTRATION]. XELJANZ has not been studied in patients with severe hepatic impairment; therefore, use of XELJANZ in patients with severe hepatic impairment is not recommended. No dose adjustment is required in patients with mild hepatic impairment. The safety and efficacy of XELJANZ have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.
XELJANZ-treated patients with moderate and severe renal impairment had greater tofacitinib blood levels than XELJANZ-treated patients with normal renal function; therefore, XELJANZ dose should be reduced to 5 mg once daily in patients with moderate and severe renal impairment [see DOSAGE AND ADMINISTRATION]. In clinical trials, XELJANZ was not evaluated in rheumatoid arthritis patients with baseline creatinine clearance values (estimated by the Cockroft-Gault equation) less than 40 mL/min. No dose adjustment is required in patients with mild renal impairment.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 7/15/2015
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