SERIOUS INFECTIONS

Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.
 
If a serious infection develops, interrupt XELJANZ until the infection is controlled.
 
Reported infections include:
• Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ use.
 • Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
 • Bacterial, viral, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with XELJANZ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.
 
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions (5.1)].
 
MALIGNANCIES

Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus- associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications [see Warnings and Precautions (5.2)].
 

1 INDICATIONS AND USAGE
 

1.1 Rheumatoid Arthritis
 •XELJANZ (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).
 •XELJANZ should not be used in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine.
 

2 DOSAGE AND ADMINISTRATION
 
XELJANZ is given orally with or without food.
 

2.1 Rheumatoid Arthritis
 
XELJANZ may be used as monotherapy or in combination with methotrexate or other nonbiologic disease modifying antirheumatic drugs (DMARDs). The recommended dose of XELJANZ is 5 mg twice daily.
 ■Dose interruption is recommended for management of lymphopenia, neutropenia and anemia [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1)].
 ■XELJANZ dosage should be reduced to 5 mg once daily in patients: •with moderate or severe renal insufficiency
 •with moderate hepatic impairment
 •receiving potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g., ketoconazole)
 •receiving one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole).
 

2.2 General Considerations for Administration
 ■XELJANZ should not be used in patients with severe hepatic impairment.
 ■It is recommended that XELJANZ not be initiated in patients with a lymphocyte count less than 500 cells/mm3, an absolute neutrophil count (ANC) less than 1000 cells/mm3, or who have hemoglobin levels less than 9 g/dL.
 ■Coadministration of XELJANZ with potent inducers of CYP3A4 (e.g., rifampin) may result in loss of or reduced clinical response to XELJANZ.
 

2.3 Dosage Modifications
 
XELJANZ treatment should be interrupted if a patient develops a serious infection until the infection is controlled.
 
Table 1: Dose Adjustments for Lymphopenia
 

Low Lymphocyte Count [see Warnings and Precautions (5.4)]
 

Lab Value
(cells/mm3)

Recommendation
 

Lymphocyte count greater than or equal to 500

Maintain dose
 

Lymphocyte count less than 500

Discontinue XELJANZ
 

(Confirmed by repeat testing)

Table 2: Dose Adjustments for Neutropenia
 

Low ANC [see Warnings and Precautions (5.4)]
 

Lab Value
(cells/mm3)

Recommendation
 

ANC greater than 1000

Maintain dose
 

ANC 500–1000

For persistent decreases in this range, interrupt dosing until ANC is greater than 1000
 

When ANC is greater than 1000, resume XELJANZ 5 mg twice daily
 

ANC less than 500

Discontinue XELJANZ
 

(Confirmed by repeat testing)

Table 3: Dose Adjustments for Anemia
 

Low Hemoglobin Value [see Warnings and Precautions (5.4)]
 

Lab Value
(g/dL)

Recommendation
 

Less than or equal to 2 g/dL decrease and greater than or equal to 9.0 g/dL

Maintain dose
 

Greater than 2 g/dL decrease or less than 8.0 g/dL

Interrupt the administration of XELJANZ until hemoglobin values have normalized
 

(Confirmed by repeat testing)

3 DOSAGE FORMS AND STRENGTHS
 
XELJANZ is provided as 5 mg tofacitinib (equivalent to 8 mg tofacitinib citrate) tablets: White, round, immediate-release film-coated tablets, debossed with "Pfizer" on one side, and "JKI 5" on the other side.
 

4 CONTRAINDICATIONS
 
None
 

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 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 (6.1)]. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcus, 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.
 
Other serious infections that were not reported in clinical studies may also occur (e.g., histoplasmosis, coccidioidomycosis, and listeriosis).
 
XELJANZ should not be initiated in patients with an active 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.
 

Tuberculosis

Patients should be eva luated 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

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.
 

5.2 Malignancy and Lymphoproliferative Disorder
 
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 (6.1)].
 
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.
 

5.3 Gastrointestinal Perforations
 
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 eva luated promptly for early identification of gastrointestinal perforation [see Adverse Reactions (6.1)].
 

5.4 Laboratory Parameters
 

Lymphocytes

Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean 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 (2.3).
 

Neutrophils

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 (2.3).
 

Hemoglobin

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 (2.3).
 

Liver Enzymes

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.
 

Lipids

Treatment with XELJANZ was associated with increases in lipid parameters including t