The FDA has concluded there is an increased risk of serious cardiovascular-related events (eg, heart attack, stroke), cancer (eg, lymphoma, lung cancer), thrombosis, and death with the use of Xeljanz and Xeljanz XR (tofacitinib) based on a review of a large, randomized safety clinical trial. The FDA is requiring revisions to the Xeljanz and Xeljanz XR prescribing information, including updates to the Boxed Warning, to include information about these risks. Additionally, 2 additional Janus kinase (JAK) inhibitors, Olumiant (baricitinib) and Rinvoq (upadacitinib), that are indicated for arthritis will require similar revisions to the prescribing information. Although Olumiant and Rinvoq have not been studied in trials similar to the Xeljanz trial, they share mechanisms of action and may have similar risks. Recommendations for health care providers will include consideration of the benefits and risks for the individual patient prior to initiating or continuing therapy, particularly in patients who are current or past smokers, those with other cardiovascular risk factors, those who develop a malignancy, and those with a known malignancy other than a successfully treated nonmelanoma skin cancer. In addition, to ensure the benefits of these 3 medicines outweigh the risks, the FDA is limiting all approved uses to certain patients who have not responded to or cannot tolerate 1 or more tumor necrosis factor blockers.
Further information may be found at https://www.fda.gov/media/151936/download.
A similar safety alert has also been reported by Health Canada.
Further information is available at https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2021/75315a-eng.php.
Most recent update(s): The National Institute of Health COVID-19 guidelines recommend tofacitinib as an alternative to baricitinib for the treatment of COVID-19, when baricitinib is not available or not feasible to use. The guidelines recommend tofacitinib, in combination with a corticosteroid or in combination with a corticosteroid and remdesivir, for the treatment of COVID-19 in recently hospitalized (eg, within 3 days of admission) patients on high-flow oxygen or noninvasive ventilation who have rapidly increasing oxygen needs and increased markers of inflammation. The IDSA COVID-19 guidelines recommend tofacitinib, in addition to standard of care, in hospitalized adults with severe COVID-19 (SpO2 ≤94% on room air, including patients on supplemental oxygen or oxygen through a high-flow device), but not on non-invasive or invasive mechanical ventilation (IDSA [Bhimraj 2021]).
As part of our response to the evolving COVID-19 pandemic, published literature and guidelines from major health organizations are continuously monitored for potential content updates. At this time, only investigational medications with data determined to be of relatively high quality and/or consistently showing positive clinical outcomes to support dosing recommendations will be included in the Lexicomp monograph, outside of this Special Alert field.
Further information may be found at:
IDSA: https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
ClinicalTrials.gov: https://www.clinicaltrials.gov/ct2/results?cond=COVID19&term=tofacitinib&cntry=&state=&city=&dist=&Search=Search
Patients treated with tofacitinib are at increased risk of developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.
If a serious infection develops, interrupt tofacitinib until the infection is controlled.
Reported infections include:
• Active tuberculosis (TB), which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent TB before tofacitinib use and during therapy. Treatment for latent infection should be initiated prior to tofacitinib use.
• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated rather than localized disease.
• Bacterial, viral (including herpes zoster), and other infections due to opportunistic pathogens.
The risks and benefits of treatment with tofacitinib 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 tofacitinib, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.
In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients ≥50 years of age with ≥1 cardiovascular risk factor comparing tofacitinib 5 mg twice a day or tofacitinib 10 mg twice a day to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with tofacitinib 5 mg twice a day or tofacitinib 10 mg twice a day. Tofacitinib 10 mg twice daily (or tofacitinib XR 22 mg once daily) dosage is not recommended for the treatment of RA or psoriatic arthritis (PsA).
Malignancies, including lymphomas and solid tumors, have occurred in patients treated with tofacitinib and other Janus kinase inhibitors used to treat inflammatory conditions. In RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]) was observed in patients treated with tofacitinib 5 mg twice a day or tofacitinib 10 mg twice a day compared TNF blockers.
Lymphomas and lung cancers were observed at a higher rate in patients treated with tofacitinib 5 mg twice a day or tofacitinib 10 mg twice a day in RA patients compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.
Epstein-Barr virus-associated posttransplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with tofacitinib and concomitant immunosuppressive medications.
RA patients ≥50 years of age with ≥1 cardiovascular risk factor, treated with tofacitinib 5 mg twice daily or tofacitinib 10 mg twice daily, had a higher rate of major adverse cardiovascular events (defined as cardiovascular death, myocardial infarction, and stroke), compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue tofacitinib in patients that have experienced a myocardial infarction or stroke.
Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, have occurred in patients treated with tofacitinib and other Janus kinase inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death. RA patients ≥50 years of age with ≥1 cardiovascular risk factor treated with tofacitinib 5 mg twice daily or tofacitinib 10 mg twice daily compared to TNF blockers had an observed increase in incidence of these events. Avoid tofacitinib in patients at risk. Discontinue tofacitinib and promptly evaluate patients with symptoms of thrombosis.
Note: ER tablets and oral solution are not interchangeable or substitutable. When transitioning from IR tablet to ER tablet, begin ER tablet the day following the last dose of IR tablet. Do not initiate therapy in patients with an absolute lymphocyte count <500 cells/mm3, ANC <1,000 cells/mm3, or hemoglobin <9 g/dL.
Ankylosing spondylitis: Oral:
IR tablet: 5 mg twice daily.
ER tablet: 11 mg once daily.
COVID-19, hospitalized patients (alternative agent) (off-label use):
Note: The role of tofacitinib in the treatment of COVID-19 varies among available guidelines; National Institutes of Health guidelines recommend use only as an alternative to baricitinib, when baricitinib is not available or not feasible to use (NIH 2021). Avoid use in combination with tocilizumab (IDSA [Bhimraj 2021]).
Oral: IR tablet: 10 mg twice daily for up to 14 days or until hospital discharge, whichever is earlier (Guimarães 2021; NIH 2021). Use as part of an appropriate combination regimen (NIH 2021). Note: Due to increased risk of thrombotic events with tofacitinib, Infectious Diseases Society of America guidelines recommend use of at least prophylactic dose anticoagulant while receiving tofacitinib (IDSA [Bhimraj 2021]).
Psoriasis (off-label): Oral: IR tablet: 5 to 10 mg twice daily (AAD/NPF [Menter 2020]; Bachelez 2015; Papp 2012; Papp 2015).
Psoriatic arthritis: (use in combination with nonbiologic disease-modifying antirheumatic drugs): Oral:
IR tablet: 5 mg twice daily.
ER tablet: 11 mg once daily.
Rheumatoid arthritis (monotherapy or in combination with nonbiologic disease-modifying antirheumatic drugs): Oral:
IR tablet: 5 mg twice daily.
ER tablet: 11 mg once daily.
Ulcerative colitis (alternative agent): Oral:
IR tablet:
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.
ER tablet:
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: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Mild impairment: No dosage adjustment necessary.
Moderate to severe impairment:
IR tablet: Reduce dose to 5 mg twice daily (if taking 10 mg twice daily) or 5 mg once daily (if taking 5 mg twice daily).
ER tablet: 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).
End-stage renal disease requiring hemodialysis: Note: Administer after dialysis session on dialysis days; if dose given prior to dialysis, supplemental dose is not recommended after dialysis session.
IR tablet: Reduce dose to 5 mg twice daily (if taking 10 mg twice daily) or 5 mg once daily (if taking 5 mg twice daily).
ER tablet: 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).
Mild impairment: No dosage adjustment necessary.
Moderate impairment:
IR tablet: Reduce dose to 5 mg twice daily (if taking 10 mg twice daily) or 5 mg once daily (if taking 5 mg twice daily).
ER tablet: 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).
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).
(For additional information see "Tofacitinib: Pediatric drug information")
Note: Oral solution and extended-release tablets are not bioequivalent and should not be substituted on a mg:mg basis; oral solution and immediate-release tablet may be converted mg:mg (5 mg oral solution may be switched to 5 mg immediate-release tablet). Assess baseline CBC; do not initiate therapy in patients with an absolute lymphocyte count <500 cells/mm3, ANC <1,000 cells/mm3, or hemoglobin <9 g/dL.
Juvenile idiopathic arthritis, polyarticular course: Children ≥2 years weighing ≥10 kg and Adolescents: Oral:
10 to <20 kg: Oral solution (1 mg/mL): 3.2 mg twice daily.
20 to <40 kg: Oral solution (1 mg/mL): 4 mg twice daily.
≥40 kg: Oral solution (1 mg/mL) or immediate-release tablet: 5 mg twice daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosage adjustment for toxicity: Children ≥2 years and Adolescents: Oral: Oral solution, immediate-release tablets:
Infection: If a patient develops a serious infection, interrupt treatment until the infection is controlled.
Anemia (hemoglobin <8 g/dL or decrease >2 g/dL): Interrupt therapy until hemoglobin values have normalized.
Lymphopenia (lymphocytes <500 cells/mm3) confirmed by repeat evaluation: Discontinue therapy.
Neutropenia:
ANC between 500 to 1,000 cells/mm3: Interrupt therapy until ANC >1,000 cells/mm3.
ANC <500 cells/mm3: Discontinue therapy.
Children ≥2 years and Adolescents: Oral: Oral solution, immediate-release tablets:
Mild kidney impairment: No adjustment necessary.
Moderate to severe kidney impairment: Reduce dose frequency to once daily.
Hemodialysis: Administer dose after dialysis session on dialysis days; if dose administered before session, a supplemental dose post-dialysis is not recommended.
Children ≥2 years and Adolescents: Oral: Oral solution, immediate-release tablet:
Mild hepatic impairment: No adjustment necessary.
Moderate hepatic impairment: Reduce dose frequency to once daily.
Severe hepatic impairment: Use is not recommended.
Refer to adult dosing.
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):
IR tablet: 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.
ER tablet: 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 and decrease ≤2 g/dL): Maintain dose.
Anemia (hemoglobin <8 g/dL or decrease >2 g/dL): Interrupt therapy until hemoglobin values have normalized.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Oral, as citrate [strength expressed as base]:
Xeljanz: 1 mg/mL (240 mL) [contains sodium benzoate]
Tablet, Oral, as citrate [strength expressed as base]:
Xeljanz: 5 mg
Xeljanz: 10 mg [contains fd&c blue #1 aluminum lake, fd&c blue #2 (indigotine)]
Tablet Extended Release 24 Hour, Oral, as citrate [strength expressed as base]:
Xeljanz XR: 11 mg
Xeljanz XR: 22 mg [contains fd&c blue #2 aluminum lake]
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as citrate [strength expressed as base]:
Xeljanz: 5 mg
Xeljanz: 10 mg [contains fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake]
Tablet Extended Release 24 Hour, Oral, as citrate [strength expressed as base]:
Xeljanz XR: 11 mg
Available through specialty/network pharmacies. Further information may be obtained from the manufacturer, Pfizer Inc, at 1-855-493-5526 or at http://www.xeljanz.com/.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Xeljanz, Xeljanz XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203214s028,208246s013,213082s003lbl.pdf#page=66
Oral: May be taken with or without food.
Extended release: Swallow tablet whole and intact; do not crush, split, or chew.
Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. IR tablet formulation is available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery.
Oral: Oral solution, immediate-release tablets: May be taken with or without food.
Oral solution: Use provided bottle adapter to attach oral syringe. After each use store bottle in carton to protect from light, rinse oral syringe with water, and allow to air dry. Discard any remaining oral solution 60 days after opening bottle.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
Ankylosing spondylitis: Treatment of active ankylosing spondylitis in adults who have had an inadequate response or intolerance to 1 or more tumor necrosis factor (TNF) blockers.
Polyarticular course juvenile idiopathic arthritis: Treatment of active polyarticular course juvenile idiopathic arthritis in patients ≥2 years of age who have had an inadequate response or intolerance to 1 or more TNF blockers.
Psoriatic arthritis: Treatment of active psoriatic arthritis (in combination with nonbiologic disease-modifying antirheumatic drugs [DMARDs]) in adults who have had an inadequate response or intolerance to 1 or more TNF blockers.
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 or intolerance to 1 or more TNF blockers.
Ulcerative colitis: Treatment of moderately to severely active ulcerative colitis in adults who have had an inadequate response or intolerance to 1 or more TNF blockers.
Limitations of use: For the above indications, the use of tofacitinib in combination with biologic DMARDs, biologic therapies (for ulcerative colitis), or with potent immunosuppressants (eg, azathioprine, cyclosporine) is not recommended.
COVID-19, hospitalized patients; Psoriasis
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. 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, tendinopathy
Respiratory: Cough, dyspnea, interstitial pulmonary disease, paranasal sinus congestion
<1%, postmarketing, and/or case reports: Acute myocardial infarction (FDA Safety Alert September 1, 2021); angioedema, appendicitis, arterial thrombosis, BK virus, cellulitis, cerebrovascular accident (FDA Safety Alert September 1, 2021); 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
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to tofacitinib or any component of the formulation; severe hepatic impairment; pregnancy; breastfeeding.
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.
• 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: Patients receiving tofacitinib are at increased risk for serious infections, which may result in hospitalization and/or fatality. 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. 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 (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: Malignancies, including lymphomas and solid cancers, have been reported in patients receiving tofacitinib. 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.
• Tuberculosis: TB (pulmonary or extrapulmonary) has been reported in patients receiving tofacitinib. Active TB has developed in patients with initial negative tuberculin skin tests 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:
• 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:
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol and/or sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol. Large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates. The "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982). Some data suggest that benzoate displaces bilirubin from protein-binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol and/or benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.
• 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.
• Non-interchangeability of dosage forms: ER tablets are not interchangeable or substitutable with the oral solution.
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.
Substrate of CYP2C19 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Anifrolumab: Biologic Disease-Modifying Antirheumatic Drugs (DMARDs) may enhance the immunosuppressive effect of Anifrolumab. Risk X: Avoid combination
Baricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Belimumab: May enhance the immunosuppressive effect of Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Risk X: Avoid combination
Bradycardia-Causing Agents: Tofacitinib may enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Brincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
Corticosteroids (Systemic): May enhance the immunosuppressive effect of Tofacitinib. Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: In the US, after receipt of the single dose COVID-19 adenovirus vector vaccine (Janssen), administer an additional 2nd dose using an mRNA COVID-19 vaccine, at least 28 days after the primary vaccine dose, in patients taking immunosuppressive therapies. Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Tofacitinib may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Consider holding tofacitinib therapy for 1 week after each vaccine dose when possible for patients with stable underlying disease. Additionally, consider a 3rd dose of COVID-19 vaccine in patients 5 years of age and older on tofacitinib. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Tofacitinib. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Tofacitinib. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Tofacitinib. Risk C: 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 Lexi Interact monograph for details. Risk D: Consider therapy modification
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. Risk D: Consider therapy modification
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Management: Consider avoiding echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. Risk D: Consider therapy modification
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
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 Lexi Interact monograph for details. Risk D: Consider therapy modification
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Immunosuppressants (Cytotoxic Chemotherapy): May enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
Immunosuppressants (Miscellaneous Oncologic Agents): May enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
Immunosuppressants (Therapeutic Immunosuppressant Agents): May enhance the immunosuppressive effect of Tofacitinib. Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Use with non-biologic disease-modifying antirheumatic drugs (DMARDs) was permitted in psoriatic arthritis clinical trials. Risk X: Avoid combination
Influenza Virus Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate 2 to 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Methotrexate: May enhance the immunosuppressive effect of Tofacitinib. Management: Concomitant use of tofacitinib with high-dose or IV methotrexate is not recommended. Use with antirheumatic doses of methotrexate is permitted, and if combined, patients should be monitored for infection. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus. Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If post-exposure rabies vaccination is required during immunosuppressant therapy, administer a 5th dose of vaccine and check for rabies antibodies. Risk D: Consider therapy modification
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Inactivated). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Recommendations for use of tofacitinib to treat rheumatic and musculoskeletal diseases in patients planning to become pregnant or who are planning to father a child are not available due to lack of data (ACR [Sammaritano 2020]).
Agents other than tofacitinib are preferred to treat inflammatory bowel disease in patients planning to become pregnant. Disease management should be optimized prior to pregnancy. Tofacitinib should be avoided or used with caution prior to a planned pregnancy; discontinue 1 week prior to conception to limit first trimester fetal exposure (Mahadevan 2019).
Outcome data following tofacitinib exposure in pregnancy are limited (Clowse 2016; Fernández-Sánchez 2021; Mahadevan 2018).
Recommendations for use of tofacitinib in pregnant patients with rheumatic and musculoskeletal diseases are not available due to lack of data. Placental transfer may be expected based on molecular weight (ACR [Sammaritano 2020]).
Inflammatory bowel disease is associated with adverse pregnancy outcomes, including an increased risk of miscarriage, premature delivery, delivery of a low-birth-weight infant, and poor maternal weight gain. Management of maternal disease should be optimized prior to pregnancy. Treatment decreases disease flares, disease activity, and the incidence of adverse pregnancy outcomes. When treatment for inflammatory bowel disease is needed in pregnant patients, use of tofacitinib should be avoided at least during the first trimester (Mahadevan 2019).
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).
Tofacitinib is under study for the treatment of COVID-19 (NIH 2021). The risk of severe illness from COVID-19 infection is increased in pregnant patients compared to nonpregnant patients. Patients with severe illness may require hospitalization, ICU admission, mechanical ventilation, or ventilatory support (ECMO). Other adverse pregnancy outcomes include preterm birth and stillbirth. The risk of preeclampsia, coagulopathy, emergency cesarean delivery, and maternal death may be increased; neonates have an increased risk for NICU admission. Maternal age and comorbidities may also increase the risk of severe illness in pregnant and recently pregnant patients (ACOG 2022; NIH 2021).
Tofacitinib is a Janus kinase (JAK) inhibitor; pregnancy outcome data for this class of drugs when used for other indications are limited. Use of a JAK inhibitor for the treatment of COVID-19 in pregnancy may be considered when the potential benefits outweigh the possible risks (NIH 2021). Information related to the treatment of COVID-19 during pregnancy continues to emerge; refer to current guidelines for the treatment of pregnant patients.
The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine have developed an algorithm to aid practitioners in assessing and managing pregnant patients with suspected or confirmed COVID-19 (https://www.acog.org/covid-19; https://www.smfm.org/covid19). Interim guidance is also available from the CDC for pregnant patients who are diagnosed with COVID-19 (https://www.cdc.gov/coronavirus/2019-ncov/hcp/inpatient-obstetric-healthcare-guidance.html).
Data collection to monitor maternal and infant outcomes following exposure to COVID-19 during pregnancy is ongoing. Health care providers are encouraged to enroll patients exposed to COVID-19 during pregnancy in the Organization of Teratology Information Specialists (OTIS) pregnancy registry (877-311-8972; https://mothertobaby.org/join-study/).
It is not known if tofacitinib is present in breast milk.
Recommendations for use of tofacitinib in breastfeeding patients with rheumatic and musculoskeletal diseases are not available due to lack of data. Transfer into breast milk may be expected based on molecular weight (ACR [Sammaritano 2020]). Tofacitinib is not recommended to treat inflammatory bowel disease in patients who are breastfeeding (Mahadevan 2019). Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer does not recommend breastfeeding during treatment and for at least 18 hours after the last dose of immediate release tofacitinib or 36 hours (~6 half-lives) after the last dose of tofacitinib extended-release.
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.
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.
Absorption: Oral:
IR tablet: Rapid (74%); Cmax is reduced by 32% when administered with high-fat meal, but AUC remains unchanged.
Extended release: When administered with high-fat meal, Cmax,following an 11 mg and 22 mg dose, increased by 27% and 19%, respectively, and Tmax was extended by ~1 hour, but AUC remains unchanged.
Distribution: Vd: 87 L.
Bioavailability: The AUC and Cmax of 11 mg extended release once daily are equivalent to 5 mg IR tablet administered twice daily.
Protein binding: ~40% (predominantly to albumin).
Metabolism: Hepatic (70%): CYP3A4 and CYP2C19 to inactive metabolites.
Half-life elimination: ~3 hours (IR solution, tablet); ~6 to 8 hours (extended release).
Time to peak: 0.5 to 1 hour (IR solution, tablet); 4 hours (extended release).
Excretion: Primarily urine (30%) as unchanged drug.
Renal function impairment: AUC increased ~1.75- to 2.5-fold in moderate and severe renal impairment.
Hepatic function impairment: AUC and Cmax increased ~1.5-fold in moderate hepatic impairment.
Solution (Xeljanz Oral)
1 mg/mL (per mL): $20.81
Tablet, 24-hour (Xeljanz XR Oral)
11 mg (per each): $208.07
22 mg (per each): $208.07
Tablets (Xeljanz Oral)
5 mg (per each): $104.03
10 mg (per each): $104.03
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