Tofacitinib

Lymphocytopenia (after an initial lymphocytosis), neutropenia (3), and anemia have been observed with tofacitinib therapy. Lymphocyte counts 3 were associated with increased incidence of treated and serious infections; avoid tofacitinib initiation in patients with lymphocytes 3 at baseline. Avoid use in patients with ANC 3 at baseline; interrupt therapy if ANC is persistently between 500 to 1,000 cells/mm3 or if ANC 3 during treatment. Consider resuming tofacitinib when ANC ≥1,000 cells/mm3. Avoid use in patients with hemoglobin 2 g/dL or if hemoglobin • Cardiovascular effects: A decrease in heart rate and prolonged PR interval have been reported with tofacitinib in clinical trials. Use caution in patients with baseline heart rate • Gastrointestinal perforations: Use with caution in patients at increased risk for gastrointestinal perforation (eg, history of diverticulitis); perforations have been reported in clinical trials. Promptly evaluate new-onset abdominal symptoms in patients taking tofacitinib.

Increased incidence of liver enzyme elevation was observed in patients taking tofacitinib compared to placebo. Routine liver function test monitoring is recommended; interrupt therapy if drug-induced liver injury is suspected.

Patients receiving tofacitinib are at increased risk for serious infections, which may result in hospitalization and/or fatality; infections often developed in patients receiving concomitant immunosuppressive agents (eg, methotrexate or corticosteroids). Active tuberculosis (pulmonary or extrapulmonary), invasive fungal (including cryptococcosis and pneumocystosis [may present as disseminated rather than local disease]) and bacterial, viral (including herpes zoster) or other opportunistic infections (including esophageal candidiasis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis) have been reported in patients receiving tofacitinib. Closely monitor patients for the development of signs/symptoms of infection during and after tofacitinib treatment. If a serious infection develops, interrupt tofacitinib until the infection is controlled. Carefully consider the risks and benefits of treatment with tofacitinib prior to initiating therapy in patients with chronic or recurrent infection. The most common serious infections reported included pneumonia, cellulitis, urinary tract infections, diverticulitis, appendicitis, and herpes zoster infections, although other serious infections may occur. Reactivation of viral infections (eg, herpes zoster) was observed in clinical trials; the incidence of chronic viral hepatitis reactivation is unknown. Screen for viral hepatitis. The risk for herpes zoster is increased with tofacitinib; patients w

ILD has been reported; patients developing ILD were receiving concomitant therapy associated with ILD (eg, methotrexate). Use with caution in patients with risk/history of ILD (Xeljanz Canadian product monograph).

Increases in lipid parameters (eg, total cholesterol, LDL, and HDL cholesterol) were observed in patients receiving tofacitinib; maximum lipid increases were typically seen within 6 weeks of initiation. Assess lipids 4 to 8 weeks after tofacitinib initiation and manage lipid abnormalities accordingly.

Lymphoma and other malignancies have been reported in patients receiving tofacitinib; Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients receiving tofacitinib and concomitant immunosuppressive medications. The most common types of malignancy observed were lung, breast, gastric, colorectal, renal cell, prostate, lymphoma, pancreatic, and malignant melanoma. Consider risks versus benefits prior to use in patients with a known malignancy (other than successfully treated nonmelanoma skin cancers [NMSCs]) or when continuing tofacitinib in patients who develop a new malignancy. NMSCs have been reported; patients at increased risk for skin cancer should have periodic skin examinations.

Tuberculosis (pulmonary or extrapulmonary) has been reported in patients receiving tofacitinib. Patients should be evaluated for tuberculosis risk factors and active or latent infection (with a tuberculin skin test) before and during therapy. Treatment of latent tuberculosis should be initiated before use. Patients with initial negative tuberculin skin tests should receive continued monitoring for tuberculosis throughout treatment; active tuberculosis has developed in this population during treatment with tofacitinib. Use with caution in patients who have resided in regions where tuberculosis is endemic. Consider antituberculosis therapy if an adequate course of treatment cannot be confirmed in patients with a history of latent or active tuberculosis or for patients with risk factors despite negative skin test. Disease-related concerns:

Use with caution in patients with diabetes (patients with diabetes have a higher incidence of infections).

Use is not recommended in patients with severe hepatic impairment; dosage reduction required in patients with moderate hepatic impairment.

Patients with a history of chronic lung disease or those who develop interstitial lung disease may be more prone to infections; use with caution.

Dosage reduction required in patients with moderate or severe renal impairment. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Tofacitinib should not be administered in combination with strong immunosuppressive medications (eg, azathioprine, tacrolimus, cyclosporine) due to the risk of additive immunosuppression; such combinations have not been studied in rheumatoid arthritis.

Tofacitinib should not be administered in combination with biologic DMARDs. Special populations:

Use with caution in Asian patients; an increased incidence of adverse reactions (eg, herpes zoster, opportunistic infections, decreased WBC, interstitial lung disease, increased transaminases) has been observed (Wollenhaupt 2014; Xeljanz Canadian product monograph).

Use with caution in elderly patients; general incidence of infection is higher in elderly. Dosage form specific issues:

Use caution when administering the extended release formulation to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures following ingestion of other medications which also utilize a nondeformable extended release formulation. The inert tablet shell of the extended release tablet may be noticeable in the stool (or colostomy); the active medication will have been already absorbed. Other warnings/precautions:

Immunization status should be current before initiating therapy. Live vaccines should not be given concomitantly with tofacitinib; recommended interval between receipt of live vaccines and initiation of immunosuppressive agents, such as tofacitinib, should follow current vaccination clinical guidelines. Dissemination of the vaccine strain of varicella zoster virus has been reported in a varicella virus naive patient 16 days following vaccination with Zostavax (live attenuated zoster) and 2 days after the initiation of tofacitinib.