hospitalization or death; most patients who developed these infections were taking concomitant immunosuppressants (eg, methotrexate, corticosteroid) If serious infection develops, interrupt until infection controlled Reported infections include active tuberculosis (TB), invasive fungal infections, and bacterial, viral, or other opportunistic pathogens Test for latent TB before and during tofacitinib treatment; treatment for latent TB infection should be initiated prior to tofacitinib treatment Malignancies Malignancies, including lymphoma and solid tumors, reported Lymphomas and lung cancers observed at a higher rate in patients with RA treated with 5-10 mg BID compared with those treated with TNF blockers; patients who are current or past smokers are at additional increased risk Epstein Barr virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with tofacitinib and concomitant immunosuppressive medications Mortality A higher rate of all-cause mortality, including sudden cardiovascular death, reported in RA patients ≥50 years with at least 1 cardiovascular risk factor treated with 5 or 10 mg BID compared to those treated with TNF blockers Xeljanz 5 or 10 mg BID or Xeljanz XR 22 mg qDay NOT recommended for treatment of RA or PsA Major adverse cardiovascular events Patients with RA aged ≥50 years with at least 1 CV risk factor treated with 5 or 10 mg BID had a higher rate of major adverse cardiovascular events (eg, cardiovascular death, myocardial infarction, stroke) Patients who are current or past smokers are at additional increased risk Discontinue treatment in patients that have experienced a myocardial infarction or stroke Increased risk of blood clots Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis have occurred in patients treated with Janus kinase inhibitors used to treat inflammatory conditions Patients with RA aged ≥50 years with at least 1 CV risk factor treated with 5 or 10 mg BID showed an increased incidence of thrombosis compared with TNF blockers Avoid in patients at risk Discontinue therapy and promptly evaluate patients with thrombosis symptoms For UC patients, use lowest effective dose and for shortest duration needed to achieve/maintain therapeutic response Contraindications None Cautions Malignancy and lymphoproliferative disorders reported (see Black Box Warnings); malignancies were observed in clinical studies and the postmarketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer GI perforation reported, although role of JAK inhibition in these events is unknown; caution in patients at increased risk for gastrointestinal perforation (eg, diverticulitis) Associated with gradual decrease in lymphocyte and neutrophils counts, and hemoglobin levels that may require treatment interruption Associated with increased LFTs Associated with increase lipid parameters including total cholesterol, LDL, and HDL Viral reactivation, including cases of herpes virus reactivation (eg, herpes zoster), reported; hepatitis B reactivation reported; impact on chronic viral hepatitis reactivation unknown; perform screening for viral hepatitis in accordance with clinical guidelines before starting therapy Non-melanoma skin cancers (NMSCs) reported; periodic skin examination recommended for patients at increased risk for skin cancer Use caution when treating patients with diabetes; higher incidence of infection in diabetic population in general reported Diverticulitis reported Twice daily dosing of tofacitinib 10 mg or 11 mg tofacitinib XR not recommended in patients with rheumatoid arthritis or psoriatic arthritis Rheumatoid arthritis patients ≥50 years of age with at least 1 cardiovascular (CV) risk factor treated with tofacitinib 10 mg BID had a higher rate of all-cause mortality Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, have occurred Higher rate of major adverse cardiovascular events (MACE; defined as cardiovascular death, myocardial infarction, and stroke) reported with another JAK inhibitor Vs TNF blockers in RA patients Structural joint damage progression Radiographic response data from the ORAL Scan and ORAL Start studies evaluated the efficacy of tofacitinib on structural joint damage progression as measured by mean change from baseline in van der Heijde modified Total Sharp Score (mTSS) and its components, erosion score, and joint space narrowing (JSN) score Serious infections Serious and sometimes fatal infections reported due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens; the most common serious infections reported have included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis In the UC population, treatment with 10 mg BID was associated with greater risk of serious infections compared with 5 mg BID; additionally, opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with 10 mg twice daily Use caution in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections Risk of infection may be higher with increasing degrees of lymphopenia; consideration should be given to lymphocyte counts when assessing individual patient risk of infection Avoid use in patients with an active, serious infection, including localized infections Consider the risks and benefits of tofacitinib prior to initiating treatment Patients with chronic or recurrent infection Patients who have been exposed to tuberculosis Patients with a history of a serious or an opportunistic infection Patients who have resided or traveled in areas of endemic tuberculosis or endemic mycoses Patients with underlying conditions that may predispose them to infection Extended-release tablet Patients may notice an inert tablet shell passing in the stool or via colostomy Caution when administering the extended-release tablet to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic); rare reports of obstructive symptoms with strictures in association with the ingestion of other drugs utilizing a non-deformable extended release formulation Increased risk of serious heart-related problems and cancer On September 1st, 2021, FDA is requiring revisions to the Boxed Warning for tofacitinib to include information about the risks of serious heart-related events, cancer, blood clots, and death Revisions are based on results from completed trial show a higher occurrence of serious heart-related events and cancer in tofacitinib-treated group (both doses) compared to TNF inhibitor-treated group; results also showed an increased risk of blood clots and death with lower doses of tofacitinib Consider the benefits and risks for the individual patient before initiating or continuing treatment, especially the following patients: Who are current or past smokers Who have other cardiovascular risk factors Who have developed a malignancy Who have a known malignancy other than a successfully treated nonmelanoma skin cancer Reserve JAK inhibitors (eg, tofacitinib) if patients have an inadequate response or intolerance to ≥1 TNF blockers Counsel patients about the benefits and risks of these medicines and advise them to seek emergency medical attention if they experience signs and symptoms of a heart attack, stroke, or blood clot Drug interactions overview Tofacitinib is a CYP3A4 substrate and a minor CYP2C19 substrate Strong CYP3A4 inducers may decrease clinical response Decreased dose required if coadministered with strong CYP3A4 inhibitors, or moderate CYP3A4 inhibitors plus CYP2C19 inhibitors (see Dosage Modifications) Avoid coadministration with live virus vaccines Risk of added immunosuppression when tofacitinib is concomitantly used with potent immunosuppressive drugs (eg, azathioprine, tacrolimus, cyclosporine); combined use of multiple dose tofacitinib with potent immunosuppressants has not been studied in rheumatoid arthritis and psoriatic arthritis Pregnancy There is a pregnancy exposure registry that monitors pregnancy outcomes in women during pregnancy; patients can call the toll free number 1-877-311-8972 There are no adequate and well-controlled studies therapy in pregnant women In the tofacitinib clinical development programs, birth defects and miscarriages were reported Animal data Based on animal studies, tofacitinib has the potential to affect a developing fetus Feticidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 146 times and 13 times the human dose of 5 mg BID, respectively In a peri and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73 times the human dose of 5 mg BID Based on findings in rats, females of reproductive potential taking tofacitinib may result in reduced fertility Contraception Advise females of reproductive potential to use effective contraception during treatment and for >4 weeks after the last dose Advise females to inform their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment Lactation It is not known whether the drug is excreted in human milk There are no data to assess effects of drug on breastfed child; drug is excreted in rat milk at concentrations higher than in maternal serum Women should not breastfeed while treated; a decision should be made whether to discontinue breastfeeding or to discontinue therapyPregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Janus kinases (JAKs) pathways inhibitor; JAK consists of a group of intracellular tyrosine kinases that transmit signals from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoieses and immune cell function Within the signaling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs) which modulate intracellular activity including gene expression; tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs These signals are essential in maintaining the inflammatory condition in rheumatoid arthritis (RA); inhibition of JAKs reduces production of and modulates proinflammatory cytokines central to RA Absorption Bioavailability Xeljanz: 74% Minimum plasma concentration Xeljanz: 1.41-3.1 ng/mL Xeljanz XR: 1.07-3.11 ng/mL Peak plasma concentration Xeljanz: 42.7-84.7 ng/mL Xeljanz XR: 38.2-83.8 ng/mL Peak plasma time Xeljanz or oral solution: 0.5-1 hr Xeljanz XR: 4 hr AUC Xeljanz: 263.4-539.6 ng⋅hr/mL Xeljanz XR: 269-596.6 ng⋅hr/mL Steady-state reached Xeljanz or oral solution: 24-48 hr Xeljanz XR: 48 hr Distribution Protein Bound: ~40% (predominately to albumin) Vd: 87 L (following IV administration) Distributes equally between RBCs and plasma Metabolism Clearance mechanisms: ~70% hepatic metabolism and 30% renal excretion Primarily metabolized by CYP3A4 (accounting for ~53% of total clearance) and by CYP2C19 (accounting for ~17% of total clearance) Metabolites: Potency <10% of parent compound Elimination Renal clearance: 30% Excretion: 30% urine Half-life Xeljanz or oral solution: 0.8-1 hr Xeljanz XR: 4 hr Oral Administration May take with or without food Extended-release tablets: Swallow whole; do not crush, split, or chew Switching from regular tablets to extended-release tablets Patients treated with tofacitinib 5 mg BID may switch to tofacitinib ER 11 mg qDay the day following the last dose of tofacitinib 5 mg Patients treated with tofacitinib 10 mg BID may switch to tofacitinib 22 mg qDay the day following the last dose of tofacitinib 10 mg Storage Xeljanz or Xeljanz ER: Store at 20-25ºC (68-77ºF) Oral solution Store at room temperature 20-25ºC (68-77ºF) in the original bottle and carton to protect from light Safely throw away solution that is out of date or no longer needed Use within 60 days of opening bottle; discard remaining oral solution after 60 days BRAND FORM. UNIT PRICE PILL IMAGE Xeljanz XR oral- 11 mg tabletXeljanz oral- 10 mg tabletXeljanz oral- 5 mg tabletCopyright © 2010 First DataBank, Inc.Print Patient Educationtofacitinib oral TOFACITINIB - ORAL (TOE-fa-SYE-ti-nib) COMMON BRAND NAME(S): Xeljanz WARNING: Tofacitinib may lower your ability to fight infections. This may make you more likely to get a serious (rarely fatal) infection or make any infection you have worse. The most common serious infections include pneumonia, skin infections, shingles, a certain bowel disease (diverticulitis), swelling of the appendix (appendicitis), and urinary tract infections. The risk for infections may be higher if you also take other drugs that suppress the immune system (such as cyclosporine, tacrolimus). Tell your doctor right away if you have any signs of infection (such as a sore throat that doesn't go away, fever, chills, cough, trouble breathing, painful/frequent urination, non-healing skin sores).You should have a tuberculosis (TB) skin test before and during treatment with this medication. Tell your doctor if you have been near someone with tuberculosis or have lived or traveled in areas where certain fungal infections