Tofacitinib

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as citrate:

Xeljanz: 5 mg

Xeljanz: 10 mg [contains fd&c blue #1 aluminum lake, fd&c blue #2 (indigotine)]

Tablet Extended Release 24 Hour, Oral:

Xeljanz XR: 11 mg

Tablet Extended Release 24 Hour, Oral, as citrate:

Xeljanz XR: 22 mg [contains fd&c blue #2 aluminum lake]

Pharmacology

Mechanism of Action

Tofacitinib inhibits Janus kinase (JAK) enzymes, which are intracellular enzymes involved in stimulating hematopoiesis and immune cell function through a signaling pathway. In response to extracellular cytokine or growth factor signaling, JAKs activate signal transducers and activators of transcription (STATs), which regulate gene expression and intracellular activity. Inhibition of JAKs prevents cytokine- or growth factor-mediated gene expression and intracellular activity of immune cells, reduces circulating CD16/56+ natural killer cells, serum IgG, IgM, IgA, and C-reactive protein, and increases B cells.

Pharmacokinetics/Pharmacodynamics

Absorption

Oral:

Immediate release: Rapid (74%); C_max is reduced by 32% when administered with high-fat meal, but AUC remains unchanged.

Extended release: When administered with a high-fat meal, C_max, following an 11 mg and 22 mg dose, increased by 27% and 19%, respectively, and T_max was extended by ~1 hour, but AUC remains unchanged.

Distribution

V_d: 87 L

Metabolism

Hepatic (70%): CYP3A4 and CYP2C19 to inactive metabolites

Excretion

Primarily urine (30%) as unchanged drug

Time to Peak

0.5 to 1 hour (immediate release); 4 hours (extended release)

Half-Life Elimination

~3 hours (immediate release); ~6 to 8 hours (extended release).

Protein Binding

~40% (predominantly to albumin)

Use in Specific Populations

Special Populations: Renal Function Impairment

AUC increased ~1.75- to 2.5-fold in moderate and severe renal impairment.

Special Populations: Hepatic Function Impairment

AUC and C_max increased ~1.5-fold in moderate hepatic impairment.

Use: Labeled Indications

Psoriatic arthritis: Treatment of active psoriatic arthritis in adults who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs)

Rheumatoid arthritis: Treatment of moderately to severely active rheumatoid arthritis (as monotherapy or in combination with methotrexate or other nonbiologic DMARDs) in adults who have had an inadequate response to, or are intolerant of, methotrexate

Ulcerative colitis: Treatment of moderately to severely active ulcerative colitis in adults who have had an inadequate response or intolerance to tumor necrosis factor blockers

Limitations of use: The use of tofacitinib in combination with biologic DMARDs or with potent immunosuppressants (eg, azathioprine, cyclosporine) is not recommended.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to tofacitinib or any component of the formulation; severe hepatic impairment; pregnancy; breastfeeding.

Dosage and Administration

Dosing: Adult

Note: When transitioning from immediate release to extended release, begin extended release the day following the last dose of immediate release. Tofacitinib should not be used in combination with biologic disease-modifying antirheumatic drugs or with strong immunosuppressants, such as azathioprine, tacrolimus, or cyclosporine. Do not initiate therapy in patients with an absolute lymphocyte count <500 cells/mm³, ANC <1,000 cells/mm³, or hemoglobin <9 g/dL.

Psoriatic arthritis: (use in combination with nonbiologic disease-modifying antirheumatic drugs): Oral:

Immediate release: 5 mg twice daily.

Extended release: 11 mg once daily.

Rheumatoid arthritis (monotherapy or in combination with nonbiologic disease-modifying antirheumatic drugs): Oral:

Immediate release: 5 mg twice daily.

Extended release: 11 mg once daily.

Ulcerative colitis: Oral:

Immediate release:

Induction: 10 mg twice daily for at least 8 weeks; based on therapeutic response, may continue 10 mg twice daily for a maximum of 16 weeks or transition to maintenance dose. Discontinue therapy if inadequate response achieved after 16 weeks using 10 mg twice daily.

Maintenance: 5 mg twice daily; if patient experiences loss of response on 5 mg twice daily, then use 10 mg twice daily after assessing the benefits and risks, and use for the shortest duration; use lowest effective dose to maintain response.

Extended release:

Induction: 22 mg once daily for at least 8 weeks; based on therapeutic response, may continue 22 mg once daily for a maximum of 16 weeks or transition to maintenance dose. Discontinue therapy if inadequate response achieved after 16 weeks using 22 mg once daily.

Maintenance: 11 mg once daily; if patient experiences loss of response on 11 mg once daily, then use 22 mg once daily after assessing the benefits and risks and use for the shortest duration; use lowest effective dose to maintain response.

Dosage adjustment for concomitant therapy:

CYP3A4 inducers (eg, rifampin): Coadministration is not recommended.

Strong CYP3A4 inhibitors (eg, ketoconazole):

Immediate release: Reduce dose to 5 mg twice daily (if taking 10 mg twice daily) or 5 mg once daily (if taking 5 mg twice daily).

Extended release: Reduce dose to 11 mg once daily (if taking 22 mg once daily) or transition to immediate release 5 mg once daily (if taking 11 mg once daily).

Moderate CYP3A4 inhibitors with strong CYP2C19 inhibitors (eg, fluconazole):

Immediate release: Reduce dose to 5 mg twice daily (if taking 10 mg twice daily) or 5 mg once daily (if taking 5 mg twice daily).

Extended release: Reduce dose to 11 mg once daily (if taking 22 mg once daily) or transition to immediate release 5 mg once daily (if taking 11 mg once daily).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Infection: If a patient develops a serious infection, interrupt treatment until the infection is controlled.

Lymphopenia (lymphocytes ≥500 cells/mm³): Maintain dose.

Lymphopenia (lymphocytes <500 cells/mm³) confirmed by repeat evaluation: Discontinue therapy.

Neutropenia (ANC >1,000 cells/mm³): Maintain dose.

Neutropenia (ANC persistently between 500 to 1,000 cells/mm³):

Immediate release: If taking 5 mg twice daily, interrupt therapy; may resume 5 mg twice daily when ANC >1,000 cells/mm³. If taking 10 mg twice daily, reduce dose to 5 mg twice daily; may resume 10 mg twice daily when ANC >1,000 cells/mm³ based on clinical response.

Extended release: If taking 11 mg once daily, interrupt therapy; may resume 11 mg once daily when ANC >1,000 cells/mm³. If taking 22 mg once daily, reduce dose to 11 mg once daily; may resume 22 mg once daily when ANC >1,000 cells/mm³.

Neutropenia (ANC <500 cells/mm³): Discontinue therapy.

Anemia (hemoglobin <8 g/dL or decrease >2 g/dL): Interrupt therapy until hemoglobin values have normalized.

Anemia (hemoglobin ≥8 g/dL and decrease ≤2 g/dL): Maintain dose.

Administration

Oral: May be taken with or without food.

Extended release: Swallow tablet whole and intact; do not crush, split, or chew.

Storage

Store between 20°C and 25°C (68°F to 77°F).

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: May enhance the immunosuppressive effect of Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Avoid combination

Biologic Disease-Modifying Antirheumatic Drugs (DMARDs): May enhance the immunosuppressive effect of other Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Bradycardia-Causing Agents: Tofacitinib may enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Tofacitinib. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Tofacitinib. Exceptions: Fluconazole. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Tofacitinib. Management: Tofacitinib dose reductions are recommended when combined with strong CYP3A4 inhibitors. Recommended dose adjustments vary by tofacitinib formulation and therapeutic indication. See full monograph for details. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fluconazole: May increase the serum concentration of Tofacitinib. Management: Tofacitinib dose reductions are recommended when combined with fluconazole. Recommended dose adjustments vary by tofacitinib formulation and therapeutic indication. See full monograph for details. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Immunosuppressants: May enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Methotrexate: May enhance the immunosuppressive effect of Tofacitinib. Management: Avoid the use of tofacinib in combination with potent immunosuppressive methotrexate-containing regimens. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

Incidences of adverse reactions may include unapproved dosing regimens and combination therapy.

>10%:

Infection: Infection (20% to 22%)

Respiratory: Nasopharyngitis (3% to 14%)

1% to 10%:

Cardiovascular: Hypertension (2%)

Central nervous system: Headache (3% to 9%)

Dermatologic: Skin rash (6%), acne vulgaris (≥2%)

Endocrine & metabolic: Increased serum cholesterol (5% to 9%)

Gastrointestinal: Diarrhea (3% to 5%), gastroenteritis (4%), nausea (4%)

Genitourinary: Urinary tract infection (2%)

Hematologic & oncologic: Anemia (4%)

Infection: Herpes zoster infection (5%; including disseminated cutaneous, meningoencephalitis, ophthalmologic)

Neuromuscular & skeletal: Increased creatine phosphokinase (3% to 7%)

Renal: Increased serum creatinine (<2%)

Respiratory: Upper respiratory tract infection (4% to 7%)

Miscellaneous: Fever (≥2%)

Frequency not defined:

Cardiovascular: Peripheral edema

Central nervous system: Fatigue, insomnia, paresthesia

Dermatologic: Erythema, pruritus

Endocrine & metabolic: Dehydration

Gastrointestinal: Abdominal pain, diverticulitis of the gastrointestinal tract, dyspepsia, gastritis, vomiting

Hematologic & oncologic: Malignant lymphoma, skin carcinoma (nonmelanoma)

Hepatic: Increased liver enzymes, liver steatosis

Infection: Bacterial infection, fungal infection, opportunistic infection, serious infection, viral infection

Neuromuscular & skeletal: Arthralgia, joint swelling, musculoskeletal pain, tendonitis

Respiratory: Cough, dyspnea, interstitial pulmonary disease, paranasal sinus congestion

<1%, postmarketing, and/or case reports: Angioedema, appendicitis, arterial thrombosis, BK virus, cellulitis, cryptococcosis, cytomegalovirus disease, deep vein thrombosis, esophageal candidiasis, gastric carcinoma, gastrointestinal perforation, hepatotoxicity, histoplasmosis, hypersensitivity reaction, infection due to an organism in genus pneumocystis, listeriosis, lung carcinoma, lymphocytopenia, lymphocytosis, malignant melanoma, malignant neoplasm, malignant neoplasm of breast, malignant neoplasm of colon or rectum, mycobacterium infection, neutropenia, pancreatic adenocarcinoma, pneumonia, prostate carcinoma, pulmonary embolism, reactivation of HBV, renal cell carcinoma, thrombosis (FDA Safety Alert, Aug 5, 2019), tuberculosis, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Lymphocytopenia (after an initial lymphocytosis), neutropenia (<2,000 cells/mm³), and anemia have been observed with tofacitinib therapy. Lymphocyte counts <500 cells/mm³ were associated with increased incidence of treated and serious infections; avoid tofacitinib initiation in patients with lymphocytes <500 cells/mm³ at baseline. Avoid use in patients with ANC <1,000 cells/mm³ at baseline; interrupt therapy if ANC is persistently between 500 to 1,000 cells/mm³ or if ANC <500 cells/mm³ during treatment. Consider resuming tofacitinib when ANC ≥1,000 cells/mm³. Avoid tofacitinib initiation in patients with hemoglobin <9 g/dL; interrupt therapy if hemoglobin decreases >2 g/dL or if hemoglobin <8 g/dL. Monitor lymphocyte counts at baseline and every 3 months thereafter; ANC, platelet counts, and hemoglobin should be assessed at baseline, after 4 to 8 weeks of therapy, and every 3 months thereafter.
• 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 <60 bpm, conduction abnormalities, syncope or arrhythmia, ischemic heart disease, heart failure, or receiving concomitant therapy known to decrease heart rate or prolong the PR interval (Xeljanz Canadian product monograph).
• GI perforations: Use with caution in patients at increased risk for GI perforation (eg, history of diverticulitis); perforations have been reported in clinical trials. Promptly evaluate new-onset abdominal symptoms in patients taking tofacitinib.
• Hepatotoxicity: Increased incidence of liver enzyme elevation was observed in patients taking tofacitinib compared to placebo. Routine LFT monitoring is recommended; interrupt therapy if drug-induced liver injury is suspected.
• Hypersensitivity: Hypersensitivity reactions, including angioedema and urticaria, have occurred; discontinue therapy and evaluate cause for serious reactions.
• Infections: [US Boxed Warning]: 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, corticosteroids). Active tuberculosis (TB) (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, hepatitis B) have been observed; the incidence of chronic viral hepatitis reactivation is unknown. Screen for viral hepatitis. The risk for herpes zoster is increased with tofacitinib; patients within Asian countries appear to have a higher incidence of herpes zoster cases (Winthrop 2014). Use with caution in patients that have been exposed to TB, with a history of serious or opportunistic infection, taking concomitant immunosuppressants, with comorbid conditions that predispose them to infections (eg, diabetes), or in patients who live in or travel to/from areas of endemic mycoses (ie, blastomycosis, coccidioidomycosis, histoplasmosis). Do not initiate tofacitinib in patients with active infections, including localized infections. The risk of serious infections and opportunistic herpes zoster infections may be increased with use of higher doses. Risk of infection may be higher with increasing degrees of lymphopenia; monitor lymphocyte counts.
• Interstitial lung disease: Interstitial lung disease (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).
• Lipid abnormalities: Dose-dependent increases in lipid parameters (eg, total cholesterol, low-density lipoprotein, and high-density lipoprotein 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.
• Malignancy: [US Boxed Warning]: Lymphoma and other malignancies have been reported in patients receiving tofacitinib; Epstein Barr virus-associated posttransplant 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. The risk of malignancies, including nonmelanoma skin cancers (NMSCs), may be increased with higher doses. Consider risks versus benefits prior to use in patients with a known malignancy (other than successfully treated 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.
• Thrombosis: [US Boxed Warning]: Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, have been observed at an increased incidence in rheumatoid arthritis (RA) patients who were ≥50 years of age with ≥1 cardiovascular (CV) risk factor when treated with tofacitinib 10 mg twice daily compared to tofacitinib 5 mg twice daily or tumor necrosis factor (TNF) blockers in a large, ongoing, postmarketing safety study. Many of these events were serious, and some resulted in death. Avoid use in patients with an increased risk of thrombosis. Discontinue use and promptly evaluate patients with symptoms of thrombosis. Ulcerative colitis patients should use tofacitinib at the lowest effective dose and for the shortest duration necessary to achieve/maintain therapeutic response. A tofacitinib dose of 10 mg twice daily (immediate release) or 22 mg once daily (extended release) is not approved for the treatment of RA or psoriatic arthritis.
• Treatment-related mortality: [US Boxed Warning]: RA patients ≥50 years of age with ≥1 CV risk factor treated with tofacitinib 10 mg twice per day had a higher rate of all-cause mortality, including sudden CV death, compared to those treated with tofacitinib 5 mg given twice daily or TNF blockers in a large, ongoing, postmarketing safety study. A tofacitinib dose of 10 mg twice daily (immediate release) or 22 mg once daily (extended release) is not approved for the treatment of RA or psoriatic arthritis.
• Tuberculosis: [US Boxed Warning]: TB (pulmonary or extrapulmonary) has been reported in patients receiving tofacitinib. Patients should be evaluated for TB 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 TB throughout treatment; active TB has developed in this population during treatment with tofacitinib. Use with caution in patients who have resided in regions where TB is endemic. Consider antituberculosis therapy if an adequate course of treatment cannot be confirmed in patients with a history of latent or active TB or for patients with risk factors despite negative skin test.

Disease-related concerns:

• Diabetes: Use with caution in patients with diabetes (patients with diabetes have a higher incidence of infections).
• Hepatic impairment: Use is not recommended in patients with severe hepatic impairment; dosage reduction required in patients with moderate hepatic impairment.
• Lung disease: Patients with a history of chronic lung disease or those who develop interstitial lung disease may be more prone to infections; use with caution.
• Renal impairment: Dosage reduction required in patients with moderate or severe renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: 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.
• Immunosuppressant medications: 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 RA.
• Biologic disease-modifying antirheumatic drugs: Tofacitinib should not be administered in combination with biologic disease-modifying antirheumatic drugs.

Special populations:

• Asian patients: 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).
• Elderly: Use with caution in elderly patients; general incidence of infection is higher in elderly patients.

Dosage form specific issues:

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

Other warnings/precautions:

• Immunizations: 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.

Monitoring Parameters

Lymphocyte count (baseline and every 3 months thereafter); neutrophil/platelet counts (baseline, after 4 to 8 weeks, and every 3 months thereafter); hemoglobin (baseline, after 4 to 8 weeks, and every 3 months thereafter); lipids (4 to 8 weeks after therapy initiation and periodically); LFTs; viral hepatitis (prior to initiating therapy in accordance with clinical guidelines); signs/symptoms of infections (including tuberculosis) during and after therapy; abdominal symptoms; skin examinations (periodically, in patients at increased risk for skin cancer); heart rate and blood pressure at baseline and periodically thereafter.

Pregnancy

Pregnancy Considerations

Outcome information following tofacitinib for rheumatoid arthritis or psoriasis in pregnancy is limited (Clowse 2016). Some guidelines recommend avoiding use in pregnant women until additional information is available (Götestam Skorpen 2016).

Data collection to monitor pregnancy and infant outcomes following exposure to tofacitinib is ongoing. Patients may enroll themselves in the Xeljanz Pregnancy Registry (877-311-8972).

Patient Education

What is this drug used for?

• It is used to treat rheumatoid arthritis.
• It is used to treat psoriatic arthritis.
• It is used to treat ulcerative colitis.

Frequently reported side effects of this drug

• Headache
• Diarrhea
• Stuffy nose
• Common cold symptoms
• Sore throat

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse
• Skin sores
• Shingles
• Mole changes
• Skin growths
• Bowel changes
• Night sweats
• Severe loss of strength and energy
• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood
• Severe or persistent abdominal pain
• Severe or persistent abdominal edema
• Persistent nausea
• Persistent vomiting
• Black, tarry, or bloody stools
• Vomiting blood
• Shortness of breath
• Muscle pain
• Muscle weakness
• Slow heartbeat
• Abnormal heartbeat
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.