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- CP-690, 550
- Tofacitinib Citrate
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Xeljanz: 5 mg
Tablet Extended Release 24 Hour, Oral:
Xeljanz XR: 11 mg
Brand Names: U.S.
- Xeljanz XR
- Antirheumatic Miscellaneous
- Antirheumatic, Disease Modifying
- Janus Associated Kinase Inhibitor
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.
Immediate release: Rapid (74%); Cmax is reduced by 32% when administered with high-fat meal, but AUC remains unchanged.
Extended release: Cmax increased by 27% and Tmax was extended by ~1 hour when administered with high-fat meal, but AUC remains unchanged.
Vd: 87 L
Hepatic (70%): CYP3A4 and CYP2C19 to inactive metabolites
Primarily urine (30%) as unchanged drug
Time to Peak
0.5 to 1 hour (immediate release); 4 hours (extended release)
~3 hours (immediate release); ~6 hours (extended release)
~40% (predominantly to albumin)
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 Cmax increased ~1.5-fold in moderate hepatic impairment.
Use: Labeled Indications
Rheumatoid arthritis: Treatment of moderately- to severely-active rheumatoid arthritis (as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs [DMARDs]) in adults who have had an inadequate response to, or are intolerant of, methotrexate
Limitations of use: The use of tofacitinib in combination with biologic DMARDs or with potent immunosuppressants (eg, azathioprine, cyclosporine) is not recommended.
Off Label Uses
Ulcerative colitis, moderate to severe (induction and maintenance)
Data from randomized, double-blind, placebo controlled trials, support the use of tofacitinib as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Additional trials may be necessary to further define the role of tofacitinib in this condition.[Sandborn 2017]
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to tofacitinib or any component of the formulation.
Rheumatoid arthritis (monotherapy or in combination with nonbiologic disease-modifying antirheumatic drugs (DMARDs): Oral:
Immediate release: 5 mg twice daily
Extended release: 11 mg once daily
Note: When transitioning from immediate release to extended release, begin extended release the day following the last dose of 5 mg immediate release. Tofacitinib should not be used in combination with biologic DMARDs or with strong immunosuppressants, such as azathioprine, tacrolimus, or cyclosporine. Do not initiate therapy in patients with an absolute lymphocyte count <500 cells/mm3, absolute neutrophil count <1,000 cells/mm3, or hemoglobin <9 g/dL.
Dosage adjustment for strong CYP3A4 inducers (eg, rifampin): Coadministration is not recommended
Dosage adjustment for strong CYP3A4 inhibitors (eg, ketoconazole): Reduce dose to 5 mg (immediate release) once daily (the use of the extended release formulation is not recommended)
Dosage adjustment for concomitant moderate CYP3A4 inhibitors and potent CYP2C19 inhibitors (eg, fluconazole): Reduce dose to 5 mg (immediate release) once daily
Ulcerative colitis, moderate to severe (induction and maintenance) (off-label use): Oral: Immediate release: Induction: 10 mg twice daily; Maintenance: 5 or 10 mg twice daily (Sandborn 2017)
Refer to adult dosing.
Dosing: Renal Impairment
Mild impairment: No dosage adjustment necessary.
Moderate to severe impairment: Reduce dose to 5 mg (immediate release) once daily. A supplemental dose after dialysis is not necessary in patients with severe impairment on dialysis. Note: Tofacitinib has not been studied in patients with baseline CrCl <40 mL/minute.
Dosing: Hepatic Impairment
Mild impairment: No dosage adjustment necessary.
Moderate impairment: Reduce dose to 5 mg (immediate release) once daily.
Severe impairment: Use is not recommended (has not been studied in patients with severe hepatic impairment or in patients with hepatitis B or hepatitis C viruses).
Dosing: Adjustment for Toxicity
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): Interrupt therapy; resume at 5 mg immediate release twice daily or 11 mg extended release once daily when ANC >1,000 cells/mm3.
Neutropenia (ANC <500 cells/mm3) confirmed by repeat evaluation: Discontinue therapy.
Anemia (hemoglobin ≥9 g/dL and decrease ≤2 g/dL): Maintain dose.
Anemia (hemoglobin <8 g/dL or decrease >2 g/dL) confirmed by repeat evaluation: Interrupt therapy until hemoglobin values have normalized.
May be taken with or without food.
Extended release: Swallow tablet whole and intact; do not crush, split, or chew.
Store between 20°C and 25°C (68°F to 77°F).
Abatacept: May enhance the adverse/toxic effect of Tofacitinib. Avoid combination
Anakinra: May enhance the adverse/toxic effect of Tofacitinib. Avoid combination
Anti-TNF Agents: May enhance the adverse/toxic effect of Tofacitinib. Avoid combination
Aprepitant: May increase the serum concentration of CYP3A4 Substrates. 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
Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Bradycardia-Causing Agents: Tofacitinib may enhance the bradycardic effect of Bradycardia-Causing Agents. 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. Avoid combination
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Tofacitinib. Avoid combination
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Tofacitinib. Management: Reduce the adult dose of tofacitinib to 5 mg daily in patients receiving strong CYP3A4 inhibitors. Consider therapy modification
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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. Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination
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
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: Reduce the adult dose of tofacitinib to 5 mg daily in patients receiving moderate CYP3A4 inhibitors that strongly inhibit CYP2C19 (e.g., fluconazole, sitaxentan). Consider therapy modification
Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination
Idelalisib: May increase the serum concentration of CYP3A4 Substrates. 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
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
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. 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. Monitor therapy
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
RiTUXimab: May enhance the adverse/toxic effect of Tofacitinib. Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification
Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy
St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
Stiripentol: May increase the serum concentration of CYP3A4 Substrates. 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
Tocilizumab: May enhance the adverse/toxic effect of Tofacitinib. Avoid combination
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. Avoid combination
Incidences of adverse reactions include unapproved dosing regimens. Frequency not always defined.
Cardiovascular: Hypertension (2%), peripheral edema
Central nervous system: Headache (4%), fatigue, insomnia, paresthesia
Dermatologic: Erythema, pruritus, skin rash
Endocrine & metabolic: Dehydration
Gastrointestinal: Diarrhea (4%), abdominal pain, diverticulitis, dyspepsia, gastritis, nausea, vomiting
Genitourinary: Urinary tract infection (2%)
Hematologic & oncologic: Anemia, skin carcinoma (nonmelanoma)
Hepatic: Increased serum ALT (>3 x upper limit of normal; 1%), liver steatosis
Infection: Infection (20% to 22%), serious infection (2% to 3%)
Neuromuscular & skeletal: Arthralgia, joint swelling, musculoskeletal pain, tendonitis
Renal: Increased serum creatinine (<2%)
Respiratory: Upper respiratory tract infection (5%), nasopharyngitis (4%), cough, dyspnea, sinus congestion
<1% (Limited to important or life-threatening): BK virus, cellulitis, cryptococcosis, cytomegalovirus disease, decreased heart rate, esophageal candidiasis, hepatotoxicity, herpes zoster, increased creatine kinase, increased serum AST, interstitial pulmonary disease, lymphocytopenia, malignant neoplasm, neutropenia, pneumocystosis, pneumonia, prolongation P-R interval on ECG, rhabdomyolysis, skin carcinoma, tuberculosis
Concerns related to adverse effects:
• 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 2016).
• 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 use 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.
• 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.
• Hepatotoxicity: 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.
• 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 or corticosteroids). Active tuberculosis (pulmonary or extrapulmonary), invasive fungal (including cryptococcosis and pneumocystosis [may present as disseminated rather than local disease]) and bacterial, viral or other opportunistic infections (including esophageal candidiasis, multidermatomal herpes zoster, cytomegalovirus, and BK virus) 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, 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 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 tuberculosis, 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.
• Interstitial lung disease (ILD): 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 2016).
• Lipid abnormalities: 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.
• Malignancy: [US Boxed Warning]: 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, 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: [US Boxed Warning]: 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.
• 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.
• 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 rheumatoid arthritis.
• Biologic DMARDs: Tofacitinib should not be administered in combination with biologic DMARDs.
• 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 2016).
• Elderly: Use with caution in elderly patients; general incidence of infection is higher in elderly.
Dosage form specific issues:
• Extended release: 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 non-deformable 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.
• Immunizations: Immunization status should be current before initiating therapy. Live vaccines should not be given concomitantly with tofacitinib; no data are available concerning vaccination response or secondary transmission of infection by live vaccines in patients receiving therapy.
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 Risk Factor
Adverse events have been observed in animal reproduction studies. Healthcare providers are encouraged to enroll women exposed to tofacitinib during pregnancy in the Xeljanz Pregnancy Registry (877-311-8972); patients may also enroll themselves.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience rhinorrhea, rhinitis, cough, or pharyngitis. Have patient report immediately to prescriber signs of infection; signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes); mole changes; skin growths; bruising; bleeding; severe headache; pain with urination; severe skin irritation; loss of strength and energy; severe abdominal pain; severe diarrhea; black, tarry, or bloody stools; vomiting blood; shortness of breath; muscle pain; muscle weakness; bradycardia; arrhythmia; weight loss; or swelling of arms or legs (HCAHPS).
• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.