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Aug.09.2022

Tofacitinib

Indications/Dosage

Labeled

  • ankylosing spondylitis
  • polyarticular juvenile idiopathic arthritis
  • psoriatic arthritis
  • rheumatoid arthritis
  • ulcerative colitis
  • Reserve tofacitinib for patients who have an inadequate response or intolerance to 1 or more tumor necrosis factor (TNF) inhibitors. Consider the benefits and risks for the individual before initiation or continuation of therapy, particularly in those with risk factors such as smoking, cardiovascular risk factors, those who develop malignancy while receiving tofacitinib therapy, and those with a known malignancy other than successfully treated non-melanoma skin cancer. A large randomized safety clinical trial showed an increased risk of malignancy, all-cause morality (including sudden cardiac death), major adverse cardiovascular events (defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), and thrombosis (including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis) with use of tofacitinib compared to TNF inhibitors in persons with rheumatoid arthritis.[52315][66958]
  • Conversion from tofacitinib immediate-release tablets to tofacitinib extended-release tablets: Persons treated with tofacitinib 5 mg PO twice daily may be switched to the extended-release tablets at a dose of 11 mg PO once daily on the day after the last dose of the immediate-release tablets. Persons treated with tofacitinib 10 mg PO twice daily may be switched to the extended-release formulation at a dose of 22 mg once daily the day after the last dose of the immediate-release tablets.

Off-Label

  • coronavirus disease 2019 (COVID-19)
  • severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
† Off-label indication

For the treatment of moderately to severely active rheumatoid arthritis in patients who have had an inadequate response or intolerance to 1 or more tumor necrosis factor (TNF) inhibitors

Oral dosage (immediate-release tablets)

Adults

5 mg PO twice daily with or without methotrexate or other non-biologic (conventional) disease-modifying antirheumatic drugs (DMARDs). Higher doses are not recommended. Do not use in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine. ADJUSTMENTS: Coadministration of certain drugs that inhibit or induce certain CYP isoenzymes may need to be avoided or dosage adjustments may be necessary; review drug interactions. Use with potent CYP3A4 inducers may result in loss of or reduced clinical response to tofacitinib.[52315]

Oral dosage (extended-release tablets)

Adults

11 mg PO once daily. Higher doses are not recommended. Patients treated with tofacitinib 5 mg PO twice daily may be switched to the XR formulation the day following the last dose of the immediate-release tablets. May use with or without methotrexate or other non-biologic (conventional) disease-modifying antirheumatic drugs (DMARDs). Do not use in combination with biologic DMARDs or with potent immunosuppressants (e.g., azathioprine and cyclosporine). ADJUSTMENTS: Coadministration of certain drugs that inhibit or induce certain CYP isoenzymes may need to be avoided or dosage adjustments may be necessary; review drug interactions. Use with potent CYP3A4 inducers may result in loss of or reduced clinical response to tofacitinib.[52315]

For the treatment of psoriatic arthritis (PsA) in patients who have had an inadequate response or intolerance to 1 or more tumor necrosis factor (TNF) inhibitors

Oral dosage (immediate-release tablets)

Adults

5 mg PO twice daily in combination with a non-biologic (conventional) disease-modifying antirheumatic drug (DMARD). Higher doses are not recommended. Efficacy as monotherapy has not been studied. Do not use in combination with biologic DMARDs or with potent immunosuppressants (e.g., azathioprine and cyclosporine). ADJUSTMENTS: Coadministration of certain drugs that inhibit certain CYP isoenzymes may need to be avoided or dosage adjustments may be necessary; review drug interactions. Use with potent CYP3A4 inducers may result in loss of or reduced clinical response to tofacitinib.[52315]

Oral dosage (extended-release tablets)

Adults

11 mg PO once daily in combination with a non-biologic (conventional) disease-modifying antirheumatic drug (DMARD). Higher doses are not recommended. Patients treated with tofacitinib 5 mg PO twice daily may be switched to the XR formulation the day following the last dose of the immediate-release tablets. Efficacy as monotherapy has not been studied. Do not use in combination with biologic DMARDs or with potent immunosuppressants (e.g., azathioprine and cyclosporine). ADJUSTMENTS: Coadministration of certain drugs that inhibit certain CYP isoenzymes may need to be avoided or dosage adjustments may be necessary; review drug interactions. Use with potent CYP3A4 inducers may result in loss of or reduced clinical response to tofacitinib.[52315]

For the treatment of active ankylosing spondylitis in patients who have had an inadequate response or intolerance to 1 or more tumor necrosis factor (TNF) inhibitors

Oral dosage (immediate-release tablets)

Adults

5 mg PO twice daily. Higher doses are not recommended. Do not use in combination with biologic disease-modifying antirheumatic drugs (DMARDs) or with potent immunosuppressants (e.g., azathioprine and cyclosporine). ADJUSTMENTS: Coadministration of certain drugs that inhibit certain CYP isoenzymes may need to be avoided or dosage adjustments may be necessary; review drug interactions. Use with potent CYP3A4 inducers may result in loss of or reduced clinical response to tofacitinib.[52315]

Oral dosage (extended-release tablets)

Adults

11 mg PO once daily. Higher doses are not recommended. Patients treated with tofacitinib 5 mg PO twice daily may be switched to the XR formulation the day following the last dose of the immediate-release tablets. Do not use in combination with biologic disease-modifying antirheumatic drugs (DMARDs) or with potent immunosuppressants (e.g., azathioprine and cyclosporine). ADJUSTMENTS: Coadministration of certain drugs that inhibit certain CYP isoenzymes may need to be avoided or dosage adjustments may be necessary; review drug interactions. Use with potent CYP3A4 inducers may result in loss of or reduced clinical response to tofacitinib.[52315]

For the treatment of polyarticular juvenile idiopathic arthritis in patients who have had an inadequate response or intolerance to 1 or more tumor necrosis factor (TNF) inhibitors

Oral dosage

Children 2 years and older weighing 10 to 19 kg

3.2 mg PO twice daily. Do not use in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine or cyclosporine. ADJUSTMENTS: Coadministration of certain drugs that inhibit certain CYP isoenzymes may need to be avoided or dosage adjustments may be necessary; review drug interactions. Use with potent CYP3A4 inducers may result in loss of or reduced clinical response to tofacitinib.[52315]

Children and Adolescents 2 to 17 years weighing 20 to 39 kg

4 mg PO twice daily. Do not use in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine or cyclosporine. ADJUSTMENTS: Coadministration of certain drugs that inhibit certain CYP isoenzymes may need to be avoided or dosage adjustments may be necessary; review drug interactions. Use with potent CYP3A4 inducers may result in loss of or reduced clinical response to tofacitinib.[52315]

Children and Adolescents 2 to 17 years weighing 40 kg or more

5 mg PO twice daily. Do not use in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine or cyclosporine. ADJUSTMENTS: Coadministration of certain drugs that inhibit certain CYP isoenzymes may need to be avoided or dosage adjustments may be necessary; review drug interactions. Use with potent CYP3A4 inducers may result in loss of or reduced clinical response to tofacitinib.[52315]

For the treatment of moderately to severely active ulcerative colitis, in persons who have an inadequate response or intolerance to tumor necrosis factor (TNF) inhibitors

Oral dosage (immediate-release tablets)

Adults

10 mg PO twice daily for at least 8 weeks and up to 16 weeks, then 5 mg PO twice daily. Discontinue 10 mg PO twice daily after 16 weeks if inadequate response. May consider 10 mg PO twice daily for the shortest duration for persons with loss of response during maintenance treatment. Use the lowest effective dose needed to maintain response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[52315] Guidelines strongly recommend tofacitinib for induction of remission in persons with moderately to severely active ulcerative colitis who have previously failed anti-TNF therapy and for maintenance of remission in persons who respond to tofacitinib induction.[64393] [65934]

Oral dosage (extended-release tablets)

Adults

22 mg PO once daily for at least 8 weeks and up to 16 weeks, then 11 mg PO once daily. Discontinue 22 mg PO once daily after 16 weeks if inadequate response. May consider 22 mg PO once daily for the shortest duration for persons with loss of response during maintenance treatment. Use the lowest effective dose needed to maintain response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[52315] Guidelines strongly recommend tofacitinib for induction of remission in persons with moderately to severely active ulcerative colitis who have previously failed anti-TNF therapy and for maintenance of remission in persons who respond to tofacitinib induction.[64393] [65934]

INVESTIGATIONAL USE: For the treatment of coronavirus disease 2019 (COVID-19)†, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection†, in hospitalized patients requiring supplemental oxygen, including high-flow oxygen or noninvasive mechanical ventilation

Oral dosage (immediate-release tablets)

Adults

The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend 10 mg PO twice daily for up to 14 days or until hospital discharge (whichever comes first) to treat hospitalized adults on supplemental oxygen, including noninvasive ventilation, high-flow oxygen, mechanical ventilation, or ECMO. Tofacitinib MUST be given in combination with dexamethasone (with or without remdesivir). Tofacitinib is recommended for use only when baricitinib is unavailable or cannot be administered.[65314]

Therapeutic Drug Monitoring

Anemia

Monitor hemoglobin at baseline, after 4 to 8 weeks of treatment, and every 3 months thereafter. Do not initiate tofacitinib in patients with anemia defined as a hemoglobin less than 9 grams/dL. If the hemoglobin decreases to less than 8 grams/dL or decreases more than 2 grams/dL from baseline, interrupt dosing until hemoglobin values have normalized.[52315]

Lymphopenia

Monitor lymphocyte counts at baseline and every 3 months thereafter. Do not initiate tofacitinib in patients with an absolute lymphocyte count less than 500 cells/mm3. Discontinue tofacitinib if the lymphocyte count decreases to less than 500 cells/mm3 during therapy, confirmed by repeat testing.[52315]

Neutropenia

Monitor neutrophil counts at baseline, after 4 to 8 weeks of treatment, and every 3 months thereafter. Do not initiate tofacitinib in patients with an absolute neutrophil count (ANC) less than 1,000 cells/mm3. Discontinue tofacitinib if the ANC falls below 500 cells/mm3, regardless of the indication.[52315]

  • Rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis: If the ANC decreases to 500 to 1,000 cells/mm3, interrupt tofacitinib until ANC is greater than 1,000 cells/mm3, then resume immediate-release tablets 5 mg twice daily or extended-release tablets 11 mg once daily.
  • Ulcerative colitis:
    • If the ANC decreases to 500 to 1,000 cells/mm3 and the patient is taking immediate-release 10 mg twice daily or extended-release 22 mg once daily, reduce immediate-release dose to 5 mg twice daily or the extended-release dose to 11 mg once daily. When the ANC is greater than 1,000 cells/mm3, increase the immediate-release dose to 10 mg twice daily and the extended-release dose to 22 mg once daily.
    • If the ANC decreases to 500 to 1,000 cells/mm3 and the patient is taking immediate-release 5 mg twice daily or extended-release 11 mg once daily, interrupt tofacitinib until the ANC is greater than 1,000 cells/mm3.
  • Polyarticular juvenile idiopathic arthritis: If the ANC decreases to 500 to 1,000 cells/mm3, interrupt tofacitinib until ANC is greater than 1,000 cells/mm3.[52315]

Maximum Dosage Limits

  • Adults

    10 mg/day PO for immediate-release tablets or 11 mg/day PO for extended-release tablets for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis; 20 mg/day PO for immediate-release tablets or 22 mg/day PO for extended-release tablets for ulcerative colitis; investigational doses of 20 mg/day PO for immediate-release tablets have been used for COVID-19.

  • Geriatric

    10 mg/day PO for immediate-release tablets or 11 mg/day PO for extended-release tablets for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis; 20 mg/day PO for immediate-release tablets or 22 mg/day PO for extended-release tablets for ulcerative colitis; investigational doses of 20 mg/day PO for immediate-release tablets have been used for COVID-19.

  • Adolescents

    Weighing 40 kg or more: 10 mg/day PO immediate-release formulations.

    Weighing 20 to 39 kg: 8 mg/day PO immediate-release formulations.

  • Children

    2 to 12 years weighing 40 kg or more: 10 mg/day PO immediate-release formulations.

    2 to 12 years weighing 20 to 39 kg: 8 mg/day PO immediate-release formulations.

    2 to 12 years weighing 10 to 19 kg: 6.4 mg/day PO immediate-release formulations.

    1 year: Safety and efficacy have not been established.

  • Infants

    Safety and efficacy have not been established.

  • Neonates

    Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing

Mild impairment: No dosage adjustment is required.

Moderate impairment:

  • Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS): If the current dose is 5 mg PO twice daily immediate-release, reduce dose to 5 mg PO once daily. If the current dose is 11 mg PO once daily extended-release tablet, reduce to 5 mg PO once daily immediate-release.
  • Ulcerative colitis (UC): If the current dose is 10 mg PO twice daily immediate-release, reduce dose to 5 mg PO twice daily. If the current dose is 5 mg PO twice daily immediate-release, reduce dose to 5 mg PO once daily. If the current dose is 22 mg PO once daily extended-release tablets, reduce to 11 mg PO once daily extended-release. If the current dose is 11 mg PO once daily extended-release tablet, reduce dose to 5 mg PO once daily immediate-release.
  • Polyarticular juvenile idiopathic arthritis (pJIA): Reduce to once-daily dosing.

Severe impairment: Use is not recommended.[52315]

Patients with Renal Impairment Dosing

Mild impairment: No dosage adjustment is required.

Moderate to severe impairment:

  • Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS): If the current dose is 5 mg PO twice daily immediate-release, reduce to 5 mg PO once daily. If the current dose is 11 mg PO once daily extended-release tablet, reduce to 5 mg PO once daily immediate-release tablet.
  • Ulcerative colitis (UC): If the current dose is 10 mg PO twice daily immediate-release, reduce dose to 5 mg PO twice daily. If the current dose is 5 mg PO twice daily immediate-release, reduce dose to 5 mg PO once daily. If the current dose is 22 mg PO once daily extended-release tablet, reduce dose to 11 mg PO once daily extended-release. If the current dose is 11 mg PO once daily extended-release tablet, reduce to 5 mg PO once daily immediate-release.
  • Polyarticular juvenile idiopathic arthritis (pJIA): Reduce to once-daily dosing.[52315]

 

Dosage Adjustments for COVID-19 per the National Institutes of Health (NIH) treatment guidelines:

eGFR 60 mL/minute/1.73 m2 or more: No dosage adjustment is needed.

eGFR less than 60 mL/minute/1.73 m2: 5 mg PO twice daily immediate-release tablet.

 

Intermittent hemodialysis

Administer the dose after the dialysis session on dialysis days. Supplemental doses are not recommended after dialysis if the dose was taken before the dialysis procedure.[52315]

† Off-label indication
Revision Date: 08/09/2022, 02:35:08 PM

References

52315 - Xeljanz and Xeljanz XR (tofacitinib) package insert. New York, NY: Pfizer, Inc.; 2021 Dec.64393 - Rubin DT, Ananthakrishnan AN, Siegel CA, et al.; American College of Gastroenterology Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol. 2019;114:384–413.65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Diseases 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Accessed November 10, 2022. Available at on the World Wide Web at: https://covid19treatmentguidelines.nih.gov/.65934 - Feuerstein JD, Isaacs KL, Schneider Y, et al. AGA Clinical Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis. Gastroenterology. 2020 Apr;158:1450-1461.66958 - U.S. Food and Drug Administration (FDA). FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. Retrieved Sept 1, 2021. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death?utm_medium=email&utm_source=govdelivery

How Supplied

Tofacitinib Oral solution

Xeljanz 1mg/mL Oral Solution (00069-1029) (Pfizer Inc.) null

Tofacitinib Oral tablet

Xeljanz 5mg Tablet (00069-1001) (Pfizer Inc.) null

Tofacitinib Oral tablet

Xeljanz 10mg Tablet (00069-1002) (Pfizer Inc.) null

Tofacitinib Oral tablet, extended release

Xeljanz XR 11mg Extended-Release Tablet (00069-0501) (Pfizer Inc.) null

Tofacitinib Oral tablet, extended release

Xeljanz XR 22mg Extended-Release Tablet (00069-0502) (Pfizer Inc.) null

Description/Classification

Description

Tofacitinib is an oral Janus kinase (JAK) inhibitor, and is considered a targeted synthetic disease-modifying antirheumatic drug (tsDMARD). Janus kinases are intracellular enzymes that transmit signals arising from cytokine interactions on the cellular membrane to influence cellular processes of immune cell function. Tofacitinib has been shown useful for a variety of inflammatory conditions. It is indicated for adults with active moderately to severely active rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis who have had an inadequate response or intolerance to tumor necrosis factor (TNF) inhibitors, and in pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA). Tofacitinib is also used to treat adults with moderate to severe ulcerative colitis (UC) who have had an inadequate response or who are intolerant to TNF blockers.[52315] In adults with RA or PsA, the drug improves clinical signs and symptoms and improves physical function; in adults with RA, tofacitinib inhibits the radiographic progression of structural joint damage. For patients with RA, tofacitinib is used as monotherapy or in combination with methotrexate or other nonbiological DMARDs. For PsA, tofacitinib has not been studied as monotherapy and should be used in combination with non-biologic DMARDs.[52339] Guidelines for PsA state that tofacitinib may be considered in patients with contraindications or adverse effects to TNF inhibitors, with primary TNF-inhibitor failure, or in patients preferring oral medication to injectable biologic agents who do not have severe disease. Tofacitinib is also an option in treatment-naive patients with predominant enthesitis or concurrent active inflammatory bowel disease (IBD).[63834] Guidelines for RA were published before the availability of tofacitinib, but the drug, like other non-TNF targeted treatments, is usually reserved for patients with contraindications, intolerance, or inadequate response to biologic agents such as the TNF inhibitors.[56233] The ideal combination of therapy for individual patients with inflammatory arthritis conditions such as RA and PsA is determined by treat to target strategies and severity of the disease.[56233][62838][63834] Tofacitinib has shown utility in the treatment of inflammatory bowel disease, to induce and maintain remission in UC.[52315] The efficacy of tofacitinib for the treatment of moderately to severely active UC was demonstrated in 3 controlled clinical trials. Two 8-week placebo-controlled trials demonstrated that tofacitinib 10 mg twice daily induces remission in 17% to 18% of patients by week 8. Among patients who achieved a clinical response by week 8, tofacitinib 5 mg or 10 mg given twice daily was effective in inducing remission by week 52 in 34% and 41% of patients, respectively; among patients who achieved remission after 8 weeks of treatment, 35% and 47% achieved sustained corticosteroid-free remission when treated with 5 mg and 10 mg, respectively.[52315] Further research with head-to-head trials between tofacitinib and approved biologic therapies for UC could help determine where the drug or other JAK inhibitors under development fit into treatment algorithms for UC, including treat-to-target strategies; at this time tofacitinib is recommended for patients who have failed anti-TNF treatments.[64393][65934]

 

The use of tofacitinib does present some safety concerns. Serious infections and malignancy may be precipitated by tofacitinib; the drug is not to be used in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine.[52315] A large, postmarketing, randomized, safety clinical trial showed an increased risk of all-cause mortality (including sudden cardiovascular death), major adverse cardiovascular events (MACE; defined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke), thrombosis (including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis), and cancer, excluding non-melanoma skin cancer (NSMC), with the use of tofacitinib 5 mg PO twice daily or tofacitinib 10 mg PO twice daily compared to TNF inhibitors in RA patients aged 50 years or older with one or more CV risk factors. Higher rates of lung cancer and lymphoma were also observed. Current or past tobacco smokers were at increased risk of lung cancer, overall cancers, and major adverse cardiovascular events. Consider the benefits and risks for the individual patient before initiation or continuation of therapy, particular in those with risk factors such as smoking, cardiovascular risk factors, those who develop malignancy, and those with a known malignancy other than successfully treated non-melanoma skin cancer. Reserve tofacitinib for patients who have an inadequate response or intolerance to one or more TNF inhibitors. Advise patients to seek emergency medical attention if they experience signs and symptoms of a heart attack, stroke, or blood clot[52315][66958]

 

Updates for coronavirus disease 2019 (COVID-19):

Adult patients

  • According to the National Institutes of Health (NIH) COVID-19 treatment guidelines, tofacitinib may be used as an alternative to baricitinib to treat hospitalized patients with COVID-19 who require supplemental oxygen, IF the patient is exhibiting signs of systemic inflammation and rapidly increasing oxygen needs while on dexamethasone. Further, tofacitinib may be given with dexamethasone to treat patients on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO. Tofacitinib MUST be given in combination with dexamethasone (with or without remdesivir). Tofacitinib is recommended for use only when baricitinib is unavailable or cannot be administered, as efficacy data for tofacitinib is less extensive than for baricitinib.[65314]

Pediatric patients

  • The NIH COVID-19 treatment guidelines state that tofacitinib can be considered an alternative for hospitalized patients if baricitinib is not available; however, the dose of tofacitinib that should be used for COVID-19 has not been established. As with baricitinib, the dose of tofacitinib for hospitalized pediatric patients with COVID-19 likely needs to be higher than the dose typically used to treat pediatric rheumatologic diseases. Therefore, clinicians should consult with specialists experienced in treating patients with immunosuppression (e.g., pediatric infectious disease, pediatric rheumatology) when considering administering tofacitinib to hospitalized children with COVID-19.[65314]

Classifications

  • Antineoplastic and Immunomodulating Agents
    • Agents that Suppress the Immune System
      • Janus Associated Kinase (JAK) Inhibitors
  • Musculo-Skeletal System
    • Antiinflammatory Agents and Antirheumatic Agents
      • Specific Anti-Rheumatic Agents
        • Other Specific Antirheumatics
Revision Date: 08/15/2022, 04:06:11 PM

References

52315 - Xeljanz and Xeljanz XR (tofacitinib) package insert. New York, NY: Pfizer, Inc.; 2021 Dec.52339 - van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Eng J Med 2012;367:508-19.56233 - Singh JA, Furst DE, Bharat A, et al. 2012 Update of the 2008 American College of Rheumatology Recommendations for the Use of Disease-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis. Arthritis Care & Research 2012;64(5):625-639.62838 - Coates LC, Kavanaugh A, Mease PJ, et al. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2015 Treatment Recommendations for Psoriatic Arthritis. Arthritis Rheumatol. 2016;68:1060-1071. Epub 2016 Mar 23.63834 - Singh JA, Guyatt G, Ogdie A, et al. 2018 American College of Rheumatology/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis. Arthritis Care Res (Hoboken). 2018 Nov 30. doi: 10.1002/acr.23789. [Epub ahead of print]64393 - Rubin DT, Ananthakrishnan AN, Siegel CA, et al.; American College of Gastroenterology Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol. 2019;114:384–413.65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Diseases 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Accessed November 10, 2022. Available at on the World Wide Web at: https://covid19treatmentguidelines.nih.gov/.65934 - Feuerstein JD, Isaacs KL, Schneider Y, et al. AGA Clinical Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis. Gastroenterology. 2020 Apr;158:1450-1461.66958 - U.S. Food and Drug Administration (FDA). FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. Retrieved Sept 1, 2021. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death?utm_medium=email&utm_source=govdelivery

Administration Information

General Administration Information

For storage information, see the specific product information within the How Supplied section.

Hazardous Drugs Classification

  • NIOSH 2016 List: Group 2 [63664]
  • NIOSH (Draft) 2020 List: Table 2
  • Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
  • Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.[63664] [67506] [67507]

Route-Specific Administration

Oral Administration

  • Administer with or without food.[52315]

Oral Solid Formulations

Extended-release tablets

  • Administer once daily, at approximately the same time each day.
  • Swallow whole and intact. Do not crush, split, or chew.[52315]

Oral Liquid Formulations

  • Administer using the included press-in bottle adapter and oral dosing syringe.
  • Storage: Use contents of the bottle within 60 days of opening.[52315]

Clinical Pharmaceutics Information

From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
    Revision Date: 04/19/2022, 10:29:47 AM

    References

    52315 - Xeljanz and Xeljanz XR (tofacitinib) package insert. New York, NY: Pfizer, Inc.; 2021 Dec.63664 - CDC National Institute for Occupational Safety and Health (NIOSH). NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2016. DHHS (NIOSH) Publication Number 2016-161, September 2016. Available on the World Wide Web at https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf?id=10.26616/NIOSHPUB201616167506 - American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2018; 75:1996-2031.67507 - NIOSH [2016]. NIOSH Alert: Preventing Occupational Exposures to Antineoplastics and Other Hazardous Drugs in Health Care Settings. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2016-161.

    Adverse Reactions

    Mild

    • abdominal pain
    • acne vulgaris
    • arthralgia
    • cough
    • diarrhea
    • dyspepsia
    • fatigue
    • fever
    • headache
    • infection
    • insomnia
    • musculoskeletal pain
    • nasal congestion
    • nausea
    • paresthesias
    • pharyngitis
    • pruritus
    • rash
    • urticaria
    • vomiting

    Moderate

    • anemia
    • candidiasis
    • dehydration
    • elevated hepatic enzymes
    • erythema
    • gastritis
    • hypercholesterolemia
    • hyperlipidemia
    • hypertension
    • hypertriglyceridemia
    • interstitial lung disease
    • lymphocytosis
    • lymphopenia
    • neutropenia
    • peripheral edema
    • steatosis

    Severe

    • angioedema
    • GI perforation
    • hepatitis B exacerbation
    • hepatotoxicity
    • lymphoma
    • myocardial infarction
    • new primary malignancy
    • post-transplant lymphoproliferative disorder (PTLD)
    • pulmonary embolism
    • skin cancer
    • stroke
    • thromboembolism
    • thrombosis

    In trials with tofacitinib, lymphopenia, lymphocytosis, neutropenia, anemia, and fatigue were noted. Initially, lymphocytosis was noted at 1 month after tofacitinib initiation. A gradual decrease in mean lymphocyte counts of approximately 10% below the baseline was noted during 12 months of therapy. In clinical trials involving tofacitinib 5 mg and 10 mg twice daily dosing, confirmed decreases in lymphocyte counts less than 500 cells/mm3 occurred in 0.04% of all tofacitinib recipients, and the decreases were associated with an increased incidence of treated and serious infections. During the first 3 months of tofacitinib therapy in clinical trials, confirmed decreases in ANC below 1,000 cells/mm3 occurred in 0.07% of tofacitinib recipients; no confirmed decreases in ANC below 500 cells/mm3 were observed, and no clear relationship between neutropenia and the occurrence of serious infections was apparent. However, tofacitinib receipt was associated with an increased incidence of neutropenia (less than 2,000 cells/mm3) as compared with placebo. During the maintenance trial of tofacitinib in patients with ulcerative colitis, anemia was reported in 2% to 4% of tofacitinib patients compared to 2% of placebo patients. Hemoglobin and neutrophil count should be checked prior to initiation of tofacitinib therapy, after 4 to 8 weeks of treatment, and then every 3 months. Lymphocyte count should be checked prior to initiation of tofacitinib therapy, then every 3 months. Interrupt tofacitinib receipt in patients who develop hemoglobin less than 8 grams/dL or whose hemoglobin concentration drops greater than 2 grams/dL on treatment. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3 or an ANC less than 500 cells/mm3, tofacitinib treatment is not recommended. For patients who develop a persistent ANC of 500 to 1,000 cells/mm3, interrupt tofacitinib receipt until the ANC is greater than 1,000 cells/mm3.[52315]

    Tofacitinib may cause a new primary malignancy, including lymphoma, solid cancers, or non-melanoma skin cancer (NMSC), and may be associated with an increased risk of Epstein Barr virus-associated post-transplant lymphoproliferative disorder (PTLD).[52315] In a randomized, open-label, safety study in rheumatoid arthritis patients 50 years of age and older with one or more cardiovascular risk factors, a higher rate of malignancies (excluding NMSC) was observed in patients treated with tofacitinib 5 mg twice daily (1.13 events per 100 patient-years) or tofacitinib 10 mg twice daily (1.13 events per 100 patient-years) compared to patients treated with tumor necrosis factor (TNF) inhibitors (0.77 events per 100 patient-years). Patients with a current or past tobacco smoking had an additional increased risk of malignancy, including lung cancer. A higher rate of lymphomas and lung cancers, subsets of all malignancies, were also observed in patients treated with both tofacitinib doses compared to TNF inhibitors. The incidence rates for lymphomas per 100 patient-years were 0.07, 0.11, and 0.02 for tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors, respectively. Among smokers, the incidence rates of lung cancer per 100 patient-years were 0.48 for tofacitinib 5 mg twice daily, 0.59 for tofacitinib 10 mg twice daily, and 0.27 for TNF inhibitors. The tofacitinib 10 mg twice daily dosage is not recommended for the treatment of rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis. Among rheumatoid arthritis patients who were enrolled in 7 clinical trials, malignancies occurred in 5 patients receiving tofacitinib 5 mg twice daily (0.4 events per 100 patient-years) and 7 patients receiving tofacitinib 10 mg twice daily (0.6 events per 100 patient-years) within the first 12 months of treatment; tofacitinib was given with or without disease-modifying antirheumatic drugs (DMARDs). No malignancies were reported with placebo. One of the malignancies reported with tofacitinib 10 mg twice daily was lymphoma. The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma. During the psoriatic arthritis clinical trials, 3 malignancies were reported in adult patients receiving tofacitinib plus a non-biologic DMARD (n = 474) compared to no malignancies reported in the placebo plus non-biologic DMARD group (n = 106). No lymphomas were reported. Malignancies also have been reported in the long-term extension psoriatic arthritis trial. During the ulcerative colitis controlled clinical studies, which included 1,220 patients, there were no cases of solid cancer or lymphoma in patients treated with tofacitinib. In the long-term extension study, malignancies (including solid cancers and lymphomas) were observed more often in patients treated with 10 mg twice daily. Five cases of blood clots in the lungs were reported in patients taking tofacitinib 10 mg twice daily, including one fatality in a patient with advanced cancer. In a tofacitinib dose-ranging study involving de novo renal transplant patients who received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid agents, Epstein Barr virus-associated PTLD occurred in 5 tofacitinib patients (2.3%) compared to zero cyclosporine patients. Lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer have been reported with postmarketing use of tofacitinib. NMSCs have been reported with tofacitinib therapy and, among ulcerative colitis patients, the 10 mg twice daily dose was associated with a greater risk of NMSCs. Consider periodic skin examinations for all patients at increased risk for skin cancer. Consider the risks and benefits of tofacitinib prior to initiating or continuing therapy in patients with a known malignancy (excluding NSMC), patients who develop a malignancy while receiving tofacitinib, and patients who are current or past smokers.[52315] [66958]

    Hepatitis, steatosis, and elevated hepatic enzymes were noted in the clinical trials of tofacitinib. Most of the enzyme abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. For example, no differences in the incidence of ALT or AST elevations were observed between the placebo and tofacitinib 5 mg twice daily groups. However, with concurrent DMARDs, ALT elevations greater than 3 times the upper limit of normal (ULN) were observed in 1% of patients receiving placebo, 1.3% of patients receiving tofacitinib 5 mg twice daily, and 1.2% of patients receiving tofacitinib 10 mg twice daily. AST elevations greater than 3 times the ULN were observed in 0.6% of patients receiving placebo, 0.5% of patients receiving tofacitinib 5 mg twice daily, 0.4% of patients receiving tofacitinib 10 mg twice daily. One patient who received tofacitinib 10 mg twice daily for approximately 2.5 months required hospitalization and liver biopsy after developing drug-induced liver injury, symptomatic elevations of greater than 3 times the ULN in AST and ALT and elevations in bilirubin of greater than 2 times the ULN. Routine monitoring of liver function tests and prompt investigation of the causes of hepatic enzyme elevations are recommended to identify potential cases of drug-induced liver injury. If drug-induced hepatotoxicity is suspected, interrupt tofacitinib receipt until drug-induced liver injury has been excluded. In trials, reduction in the dose of concomitant DMARD, interruption of tofacitinib, or reduction in tofacitinib dose resulted in a decrease or the normalization of liver enzymes. Postmarketing cases of hepatitis B reactivation have been reported in patients treated with tofacitinib, and such reactivation may lead to hepatitis B exacerbation. The safety and efficacy of tofacitinib in patients with positive hepatitis B virus or hepatitis C virus serology are not established.[52315]

    A serious and sometimes fatal infection due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens has been reported in rheumatoid arthritis patients who received tofacitinib. In the 7 controlled trials in patients with rheumatoid arthritis (RA), during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group. The most commonly reported infections were upper respiratory tract infections, naso-pharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively). Among RA patients enrolled in 7 clinical trials (1 to 12 months duration), 34 tofacitinib 5 mg twice daily patients (2.7 events per 100 patient-years) and 33 tofacitinib 10 mg twice daily patients (2.7 events per 100 patient-years) developed serious infections. The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection. Opportunistic infections such as cryptococcus, esophageal candidiasis, pneumocystosis, cytomegalovirus, and BK virus were reported in 4 patients who received tofacitinib. The median time of tofacitinib exposure before a diagnosis of an opportunistic infection was 8 months (range, 41 to 698 days). Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids. Six patients (0.5 events per 100 patient-years) who received tofacitinib 10 mg twice daily in RA trials developed tuberculosis compared to zero patients that received tofacitinib 5 mg twice daily. The median time of tofacitinib exposure before a diagnosis of tuberculosis was 10 months (range, 152 to 960 days). In the ulcerative colitis (UC) population, treatment with 10 mg twice daily was associated with a greater risk of serious infections compared to 5 mg twice daily. Additionally, opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with tofacitinib 10 mg twice daily. During the maintenance trial of tofacitinib in patients with UC, naso-pharyngitis was reported in 10% to 14% of patients. Upper respiratory tract infection (6% to 7%), herpes zoster (1% to 5%), and fever (2% or more) were reported in patients receiving tofacitinib for UC. Viral reactivation including cases of herpes virus reactivation (e.g., herpes zoster) were observed; herpes zoster was reported in 1% to 5% of tofacitinib patients. Closely monitor patients for the development of signs and symptoms of infection including tuberculosis during and after treatment with tofacitinib. Monitoring is needed even for patients who tested negative for latent tuberculosis infection before tofacitinib initiation. For any new infection, institute prompt and complete diagnostic testing appropriate for an immunocompromised patient. Also, initiate appropriate antimicrobial therapy and closely monitor the patient. Interrupt tofacitinib if a patient develops a serious or an opportunistic infection until the infection is controlled.[52315]

    In rheumatoid arthritis trials with tofacitinib, dermatologic effects, such as erythema, pruritus, and rash (unspecified) were noted. During trials of tofacitinib in patients with ulcerative colitis (UC), rash was reported in 2% or more of patients. Acne vulgaris was reported in 2% or more of patients receiving tofacitinib for UC.[52315]

    In rheumatoid arthritis clinical trials, hypertension was reported in 2% of tofacitinib recipients compared to 1% of placebo recipients. Peripheral edema was also noted during clinical trials.[52315]

    Of tofacitinib recipients in rheumatoid arthritis clinical trials, 3% to 4% reported headache compared to 2.1% of placebo recipients. Insomnia and paresthesias were also noted in trials. During the maintenance trial of tofacitinib in patients with ulcerative colitis, headache was reported in 3% to 9% of patients compared to 6% of placebo patients.[52315]

    Tofacitinib receipt may cause dose-dependent increases in lipid parameters including hypercholesterolemia. During the first 12 weeks of rheumatoid arthritis (RA) trials, the mean LDL cholesterol increased by 15% in the 5 mg twice daily arm and by 19% in the 10 mg twice daily arm. The mean HDL cholesterol increased by 10% in the 5 mg twice daily arm and by 12% in the 10 mg twice daily arm. Of note, the mean LDL/HDL ratios were essentially unchanged among tofacitinib recipients. Dose-related elevations in total cholesterol and triglycerides were also noted. Elevations were observed at one month of exposure and remained stable thereafter. Maximum effects were generally observed within 6 weeks. During the maintenance trial of tofacitinib in patients with ulcerative colitis, elevated cholesterol levels (i.e., hypercholesterolemia, hyperlipidemia, dyslipidemia, hypertriglyceridemia, increased LDL cholesterol, or abnormal LDL cholesterol) were reported in 5% to 9% of patients. The effect of lipid parameter elevations on cardiovascular morbidity and mortality has not been determined; manage patients according to clinical guidelines for the management of hyperlipidemia. In a controlled clinical trial involving RA patients, elevations in LDL cholesterol and ApoB decreased to pretreatment concentrations in response to statin therapy. Assess lipid parameters 4 to 8 weeks after initiation of tofacitinib therapy.[52315]

    Of tofacitinib recipients in rheumatoid arthritis (RA) clinical trials, 3 to 4% had diarrhea as compared with 2% of placebo recipients. Abdominal pain, dyspepsia, vomiting, gastritis, dehydration, diverticulitis, and nausea were also during RA trials. During induction trials of tofacitinib in patients with ulcerative colitis (UC), diarrhea was reported in 5% or more of patients. During maintenance UC trials, gastroenteritis (3% to 4%), diarrhea (2% to 5%), and nausea (1% to 4%) were reported with tofacitinib therapy. Serious gastrointestinal (GI) reactions, such as GI perforation, have been noted among tofacitinib recipients, although the role of the drug in these events is unknown. Patients may be at an increased risk of perforation if they have a history of diverticulitis or are taking nonsteroidal antiinflammatory drugs (NSAIDs). In the RA studies, many patients were receiving background therapy with NSAIDs. There was no discernable difference in frequency of GI perforation between the placebo and tofacitinib arms in UC clinical trials and many of the patients were receiving background corticosteroid therapy. Promptly evaluate patients presenting with new-onset abdominal symptoms for early identification of GI perforation. Cautious use of tofacitinib is advised for patients who may be at increased risk for GI perforation, such as those taking NSAID therapy or with a history of diverticulitis.[52315]

    In clinical trials of tofacitinib, cough, nasal congestion, dyspnea, and interstitial lung disease (cases were limited to patients with rheumatoid arthritis and some were fatal) were noted. If a patient presents with dyspnea, investigate the cause.[52315]

    In clinical trials of tofacitinib, musculoskeletal pain, arthralgia, tendonitis, and joint swelling were reported. Increased blood creatine phosphokinase (CPK) was reported in 3% to 7% or more of patients receiving tofacitinib for ulcerative colitis. In trials with tofacitinib, dose-related elevations in serum creatinine (SCr) were observed. The mean increase in SCr was less than 0.1 mg/dL in the 12-month pooled safety analysis; however, up to 2% of patients discontinued tofacitinib in the long-term extensions because of protocol-specified discontinuation criteria for an increase in SCr by more than 50% of baseline. The clinical significance of the SCr elevations is unknown.[52315]

    Hypersensitivity reactions including urticaria and angioedema that may reflect drug hypersensitivity have been reported with patients receiving tofacitinib. If a serious hypersensitivity reaction occurs, discontinue treatment and evaluate the potential cause or causes of the reaction.[52315]

    Thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis have been reported in patients treated with either tofacitinib or other Janus kinase (JAK) inhibitors; many of these events were serious and some resulted in death. In a randomized, open-label, safety study in rheumatoid arthritis patients 50 years of age and older with one or more cardiovascular risk factors, higher rates of thrombosis (including DVT, PE, and arterial thrombosis), all-cause mortality (including sudden cardiac death), and major adverse cardiovascular (CV events (MACE; defined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) were observed with tofacitinib 5 mg twice daily or tofacitinib 10 mg twice daily compared to tumor necrosis factor (TNF) inhibitors. The incidence rate of DVT per 100 patient-years was 0.22, 0.28, and 0.16 for tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors, respectively. The incidence rates of PE per 100 patient-years were 0.18 for tofacitinib 5 mg twice daily, 0.49 for tofacitinib 10 mg twice daily, and 0.05 for TNF inhibitors.[52315] [66958] In a long-term extension study of ulcerative colitis patients treated with tofacitinib, there were 5 cases of pulmonary embolism (PE) reported in the group taking 10 mg of the drug twice daily, including one death in a patient with advanced cancer. Tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors had incidence rates of all-cause mortality per 100 patient-years of 0.88, 1.23, and 0.69, respectively. The incidence rate of MACE per 100 patient-years were 0.91 for tofacitinib 5 mg twice daily, 1.11 for tofacitinib 10 mg twice daily, and 0.79 for TNF inhibitors. In addition, the incidence rates of fatal or non-fatal myocardial infarction per 100 patient-years was 0.36 for tofacitinib 5 mg twice daily, 0.39 for tofacitinib 10 mg twice daily, and 0.2 for TNF inhibitors. Patients who are current or past tobacco smokers are at an additional risk of the adverse events. The tofacitinib 10 mg twice daily dosage is not recommended for the treatment of rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis.[52315] An ongoing clinical, postmarketing safety trial is evaluating the risk of CV-related events, cancer, and opportunistic infections in RA patients receiving tofacitinib 10 mg twice daily and 5 mg twice daily in combination with methotrexate compared to a tumor necrosis factor (TNF) inhibitor. Patients enrolled in the trial were at least 50 years of age and had at least 1 known CV risk factor (e.g., hypertension, cardiac disease, previous history of myocardial infarction). The committee determined that the occurrence of thrombosis, including pulmonary embolism (PE), deep venous thrombosis (DVT), and arterial thrombosis was higher with tofacitinib 10 mg twice daily compared with tofacitinib 5 mg twice daily or the use of a TNF inhibitor. Many of these events were serious and some resulted in death. The interim results in January 2019 identified 19 cases of PE out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared to 3 cases out of 3,982 patient-years in patients who received TNF inhibitors. In addition, there have been 45 cases of death from all causes out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared to 25 cases out of 3,982 patient-years in patients who received TNF inhibitors.[63972] [64501] Avoid tofacitinib therapy in patients at risk of thrombosis. Use the lowest effective dose of tofacitinib for the shortest duration necessary to achieve and maintain therapeutic response. Health care providers should consider the risks and benefits of tofacitinib when deciding to initiate or continue therapy, especially in patients with one or more CV risk factors and patients who are current or past smokers. Advise patients on the potential risks of tofacitinib therapy and to seek immediate medical attention if signs and symptoms of thromboembolism or thrombosis, myocardial infarction, or stroke develop. Discontinue tofacitinib therapy in any patient who develops a thrombosis, thromboembolism, myocardial infarction, or stroke.[52315] [66958]

    Revision Date: 12/16/2021, 01:34:14 PM

    References

    52315 - Xeljanz and Xeljanz XR (tofacitinib) package insert. New York, NY: Pfizer, Inc.; 2021 Dec.63972 - US Food and Drug Administration (FDA). FDA Medwatch: Xeljanz, Xeljanz XR (tofacitinib): Safety communication - safety trial finds increased risk of blood clots in the lungs and death with higher dose in rheumatoid arthritis patients. Retrieved February 25, 2019. Available on the World Wide Web at: http://app.info.fda.gov/e/er?utm_campaign=FDA%20MedWatch%20Xeljanz%2C%20Xeljanz%20XR%20%28tofacitinib%29%3A%20Safety%20Communication&utm_medium=email&utm_source=Eloqua&s=2027422842&lid=6654&elqTrackId=64501 - US Food and Drug Administration (FDA). FDA Medwatch: Xeljanz, Xeljanz XR (tofacitinib): Safety communication - Due to an Increased Risk of Blood Clots and Death with Higher Dose. Retrieved July 26, 2019. Available on the World Wide Web at:https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-boxed-warning-about-increased-risk-blood-clots-and-death-higher-dose-arthritis-and?utm_campaign=New%20FDA%20Drug%20Safety%20Communication%20on%20tofacitinib%20-%20Drug%20Information%20Update&ut66958 - U.S. Food and Drug Administration (FDA). FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. Retrieved Sept 1, 2021. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death?utm_medium=email&utm_source=govdelivery

    Contraindications/Precautions

    Absolute contraindications are italicized.

    • acquired immunodeficiency syndrome (AIDS)
    • anemia
    • Asian patients
    • breast-feeding
    • cardiac disease
    • contraception requirements
    • corticosteroid therapy
    • diabetes mellitus
    • diverticulitis
    • fungal infection
    • geriatric
    • GI obstruction
    • GI perforation
    • hepatic disease
    • hepatitis
    • hepatitis B exacerbation
    • herpes infection
    • human immunodeficiency virus (HIV) infection
    • hypercholesterolemia
    • hyperlipidemia
    • hypertension
    • immunosuppression
    • infection
    • infertility
    • interstitial lung disease
    • kidney transplant
    • lymphoma
    • mortality
    • myocardial infarction
    • neutropenia
    • new primary malignancy
    • post-transplant lymphoproliferative disorder (PTLD)
    • pregnancy
    • pulmonary disease
    • renal failure
    • renal impairment
    • reproductive risk
    • skin cancer
    • stroke
    • thromboembolic disease
    • thromboembolism
    • thrombosis
    • tobacco smoking
    • tuberculosis
    • vaccination
    • viral infection

    Avoid use of tofacitinib in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating tofacitinib in patients: 1) with chronic or recurrent infection; 2) who have been exposed to tuberculosis; 3) with a history of a serious or an opportunistic infection; 4) who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or 5) with underlying conditions that may predispose them to infection (e.g., diabetes mellitus, human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS), low lymphocyte counts, and pre-existing immunosuppression). Tofacitinib may induce lymphopenia and risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Discontinuation and monitoring criteria for lymphopenia have been suggested in the product label. Caution is also recommended in patients with a history of chronic pulmonary disease, or in those who develop interstitial lung disease during tofacitinib treatment, as they may be more prone to infections. Serious and sometimes fatal bacterial infection, mycobacterial infection, invasive fungal infection, viral infection, or infections due to other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving tofacitinib. Viral reactivation, including cases of herpes infection reactivation (e.g., herpes zoster), were observed in clinical studies. The risk of herpes zoster is increased in patients treated with tofacitinib and appears to be higher in Asian patients treated with the drug in Japan and Korea. The most common serious infections reported with tofacitinib included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticular infection, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with tofacitinib. Some patients have presented with disseminated rather than localized disease and were often taking concomitant immunosuppressive agents such as methotrexate or corticosteroid therapy. Other serious infections that were not reported in clinical studies may also occur (e.g., histoplasmosis and coccidioidomycosis). Ask patients if they have lived or have traveled to the Ohio and Mississippi River valleys or the Southwest because of an increased chance of acquiring certain kinds of fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis. Invasive fungal infections such as cryptococcosis and pneumocystosis may present with disseminated disease. Carefully consider the risks and benefits of tofacitinib before starting the drug in patients who have been exposed to tuberculosis. Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during tofacitinib administration. Consider anti-tuberculosis therapy before tofacitinib administration in patients with a history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tofacitinib. Therapy with tofacitinib should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with tofacitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.[52315]

    Viral infection reactivation has occurred with tofacitinib. Avoid use of tofacitinib in patients with an active, serious infection, including localized infections. While patients who screened positive for hepatitis B or C were excluded from clinical trials with tofacitinib, hepatitis B reactivation has been reported with the postmarketing use of tofacitinib. Reactivation of hepatitis B may lead to hepatitis B exacerbation. The impact of tofacitinib on chronic viral hepatitis reactivation is unknown. Screen patients for viral hepatitis, especially hepatitis B and C, in accordance with clinical guidelines before starting therapy with tofacitinib. Use tofacitinib with caution in any other patient with hepatic disease. Treated patients with moderate hepatic impairment had greater tofacitinib concentrations than patients with normal hepatic function, and increased blood concentrations may increase the risk of some adverse reactions. Tofacitinib is not recommended for patients with severe hepatic impairment, and dose modification is needed for patients with moderate hepatic impairment. Monitor liver function tests (LFTs) periodically in all patients treated with tofacitinib. Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (ULN) were observed in patients treated with the drug. In patients experiencing liver enzyme elevation, modification of treatment regimen (e.g., reduction in the dose of a concomitant disease-modifying anti-rheumatic drug, interruption of treatment, or reduction in dose of tofacitinib) resulted in decrease or normalization of liver enzymes. Rare cases of liver injury have been reported.[52315]

    Monitor lymphocyte counts at baseline and every 3 months thereafter. Monitor neutrophil counts at baseline, after 4 to 8 weeks of treatment, and every 3 months thereafter. Do not initiate tofacitinib in patients with lymphocytopenia or neutropenia, defined as an absolute lymphocyte count less than 500 cells/mm3 or an absolute neutrophil count (ANC) less than 1,000 cells/mm3, respectively. Discontinue tofacitinib if the lymphocyte count decreases to less than 500 cells/mm3 during therapy, confirmed by repeat testing. If the ANC decreases to 500 to 1,000 cells/mm3, interrupt therapy until the ANC is above 1,000 cells/mm3. For patients with ulcerative colitis taking the higher dose, dose reduce and resume previous dosing when the ANC is greater than 1,000 cells/mm3, based on clinical response. Discontinue tofacitinib if the ANC falls below 500 cells/mm3, regardless of the indication.[52315]

    Monitor hemoglobin at baseline, after 4 to 8 weeks of treatment, and every 3 months thereafter. Do not initiate tofacitinib in patients with anemia defined as a hemoglobin less than 9 grams/dL. If the hemoglobin decreases to less than 8 grams/dL or decreases more than 2 grams/dL from baseline, interrupt dosing until hemoglobin values have normalized.[52315]

    Tofacitinib may increase the risk for a new primary malignancy. Lymphomas and solid cancers have also been observed in clinical safety studies in rheumatoid arthritis patients treated with tofacitinib.[52315] A large, randomized, safety clinical trial showed an increased risk of cancer, excluding non-melanoma skin cancer (NMSC), (e.g., lymphoma, lung cancer) with use of tofacitinib 5 mg PO twice daily and tofacitinib 10 mg PO twice daily compared to tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis aged 50 years and older with one or more cardiovascular risk factor. Patients with a history of current or past tobacco smoking were at increased risk of lung cancer and overall cancers. Consider the benefits and risks for the individual patient before initiation or continuation of therapy, particular in those with risk factors such as smoking, those who develop malignancy while on treatment, and those with a known malignancy other than successfully treated NMSC. Reserve tofacitinib for patients who have an inadequate response or intolerance to one or more TNF inhibitors. The tofacitinib 10 mg twice daily dosage is not recommended for the treatment of rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.[52315] [66958] Epstein Barr virus-associated post-transplant lymphoproliferative disorder (PTLD) has been observed at an increased rate in kidney transplant patients treated with tofacitinib and concomitant immunosuppressives. In the UC population, treatment with tofacitinib 10 mg twice daily was associated with greater risk of cancer. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.[52315]

    Use tofacitinib with caution in patients with renal impairment. Tofacitinib-treated patients with moderate and severe renal impairment had greater tofacitinib blood levels than patients with normal renal function; therefore, a reduced daily dosage is recommended for these patients (e.g., those with severe insufficiency, renal failure, and those who are undergoing hemodialysis). Supplemental doses after dialysis are not necessary. In clinical trials, the drug was not evaluated in rheumatoid arthritis patients with baseline creatinine clearance (CrCl) less than 40 mL/minute. Patients with mild renal impairment require no dose adjustments.[52315]

    Update immunizations in agreement with current immunization guidelines prior to initiating tofacitinib therapy. People who are taking tofacitinib should not receive vaccination with live vaccines. These patients may receive non-live vaccines. The interval between live vaccinations and the initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.[52315]

    Cautious use of tofacitinib is advised for patients who may be at increased risk for gastrointestinal (GI) perforation (e.g., patients with a history of diverticulitis or taking NSAIDs). Events of gastrointestinal perforation have been reported in clinical studies with tofacitinib, although the role of Janus kinase (JAK) inhibition in these events is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with NSAIDs. There was no discernable difference in the frequency of GI perforation between the placebo and the tofacitinib arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids. Patients presenting with new-onset abdominal symptoms should be evaluated promptly for early identification of GI perforation. Use the extended-release formulation of tofacitinib (tofacitinib XR) with caution in patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). The tofacitinib XR tablets utilize a non-deformable extended-release system. There have been rare reports of symptoms of GI obstruction in patients with known GI stricture with the administration of other drugs utilizing a non-deformable extended-release formulation.[52315]

    Use tofacitinib with caution in patients with hyperlipidemia or hypercholesterolemia. Treatment with tofacitinib was associated with dose-dependent increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined. Assessment of lipid parameters in all patients should be performed approximately 4 to 8 weeks following initiation of tofacitinib therapy. Manage patients according to clinical guidelines such as those of the National Cholesterol Educational Program (NCEP) for the management of hyperlipidemia.[52315]

    Avoid using tofacitinib in patients that may be at increased risk of thrombosis and thromboembolism, including those with thromboembolic disease.[52315] A large randomized safety clinical trial showed an increased risk of all-cause mortality [including sudden cardiovascular death (CV)], major adverse CV events (MACE; defined as CV death, non-fatal myocardial infarction (MI), and non-fatal stroke), thrombosis (including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis) with use of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily compared to tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis aged 50 years and older with one or more CV risk factors. Many of the observed thrombotic events were serious and some resulted in death. Current or past tobacco smokers have an additional increased risk of MACE. Consider the benefits and risks for the individual patient before initiation or continuation of therapy, particular in those with cardiovascular risk factors (e.g., cardiac disease, hypertension, previous myocardial infarction). Reserve tofacitinib for patients who have an inadequate response or intolerance to one or more TNF inhibitors. Advise patients to of the potential increased risk for MACE and to seek emergency medical attention if they experience signs and symptoms of a heart attack, stroke, or blood clot. The tofacitinib 10 mg twice daily dosage is not recommended for the treatment of rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.[52315] [66958] In a long-term extension study in patients with ulcerative colitis (UC), there were 5 pulmonary embolism cases, including one death in a patient with cancer. For patients with UC, use tofacitinib at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response. If a patient develops a thromboembolic event, discontinue the drug.[52315]

    Cautious tofacitinib use among geriatric patients is warranted, as the frequency of serious infection among patients at least 65 years of age was higher than the frequency of serious infection in younger adults during clinical trials. Additionally, a safety trial of rheumatoid arthritis (RA) patients at least 50 years of age with at least one known cardiovascular risk factor for cardiac disease determined that the occurrence of pulmonary embolism and death was higher with tofacitinib 10 mg twice daily compared tofacitinib 5 mg twice daily or the use of a TNF blocker; monitor older patients carefully for symptoms of pulmonary thromboembolism, especially if they are receiving higher doses of tofacitinib.[63972] [52315]

    Tofacitinib use should be avoided during pregnancy.[61808] [62180] Human pregnancy outcomes data for tofacitinib are sparse and confounded by frequent concomitant methotrexate use. No adequate and well-controlled studies in pregnant women exist. Based on animal studies, tofacitinib has the potential to affect a developing fetus. In the tofacitinib clinical development program in rheumatoid arthritis and other registry monitoring data, birth defects (e.g., pulmonary valve stenosis), and miscarriages were reported.[62380] An ongoing prospective pregnancy registry for tofacitinib is being conducted by the Organization of Teratology Information Specialists (OTIS).[52315] Fetocidal 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 twice daily, respectively. Teratogenic effects observed include external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; cranial and skeletal malformations or variations; thoracogastroschisis, omphalocele, and membranous ventricular septal defects. In addition, reductions in live litter size, postnatal survival, and pup body weights occurred with exposure levels approximately 73 times the MRHD. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to tofacitinib; information about the registry can be obtained at mothertobaby.org/ongoing-study/xeljanz or by calling 1-877-311-8972.[52315]

    Consider pregnancy planning and prevention for females of reproductive potential; inform females of the potential reproductive risk. Fetocidal and teratogenic effects were noted when animals were given tofacitinib during the period of organogenesis, and there is potential for fetal harm. While specific contraception requirements have not been advised in the label, consider the use of adequate contraception in females of reproductive potential. Advise females to contact their healthcare provider immediately if they become pregnant or if pregnancy is suspected. The administration of tofacitinib may result in reduced fertility (infertility) in females of reproductive potential based on animal data. It is not known if this effect is reversible. Reduced fertility due to an increased post-implantation loss was observed in animals exposed to tofacitinib levels approximately 17 times the maximum recommended human dose (MRHD). There was no impairment of female animal fertility at exposure levels of tofacitinib equal to the MRHD. No effect was seen on male fertility, sperm motility, or sperm concentration.[52315] [62380]

    Advise lactating females not to breast-feed during tofacitinib therapy. Given the serious adverse reactions seen in adults treated with tofacitinib, such as increased risk of serious infections, advise patients that breast-feeding is not recommended during treatment and for at least 18 hours after the last dose of the immediate-release tablets or 36 hours after the last dose of extended-release tablets (approximately 6 elimination half-lives). It is not known if tofacitinib is excreted in human milk; however, it is was excreted in the milk of lactating rats at concentrations higher than in maternal serum. When a drug is present in animal milk, it is likely that the drug will be present in human milk.[52315] [62180] Assess indication and patient-specific factors before considering an alternative agent.[61808] [62180]

    Revision Date: 12/16/2021, 01:25:06 PM

    References

    52315 - Xeljanz and Xeljanz XR (tofacitinib) package insert. New York, NY: Pfizer, Inc.; 2021 Dec.61808 - Mahadevan U, McConnell RA, Chambers C. Drug safety and risk of adverse outcomes for pregnant patients with inflammatory bowel diseases. Gastroenterology 2017;152:451-462.e2.62180 - Gotestam Skorpen C, Hoeltzenbein M, Tincani A, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis 2016;75(5):795-810.62380 - Clowse ME, Feldman SR, Isaacs JD, et al. Pregnancy Outcomes in the Tofacitinib Safety Databases for Rheumatoid Arthritis and Psoriasis. Drug Saf. 2016;39:755-62.63972 - US Food and Drug Administration (FDA). FDA Medwatch: Xeljanz, Xeljanz XR (tofacitinib): Safety communication - safety trial finds increased risk of blood clots in the lungs and death with higher dose in rheumatoid arthritis patients. Retrieved February 25, 2019. Available on the World Wide Web at: http://app.info.fda.gov/e/er?utm_campaign=FDA%20MedWatch%20Xeljanz%2C%20Xeljanz%20XR%20%28tofacitinib%29%3A%20Safety%20Communication&utm_medium=email&utm_source=Eloqua&s=2027422842&lid=6654&elqTrackId=66958 - U.S. Food and Drug Administration (FDA). FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. Retrieved Sept 1, 2021. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death?utm_medium=email&utm_source=govdelivery

    Mechanism of Action

    Tofacitinib is an oral Janus kinase (JAK) inhibitor. Janus kinases are intracellular enzymes that transmit signals arising from cytokine or growth factor receptor interactions such as interferons, interleukins, and erythropoietin on the cellular membrane to influence cellular processes of immune cell function and hematopoiesis. JAK-mediated signaling is pivotal in immune activation, as cytokine receptors are expressed on most immune cells. Upon ligand and receptor interaction, JAKs are activated and, thus, phosphorylate their receptors and activate the signal transducers and activators of transcription proteins, which modulate intracellular activity including gene expression. Tofacitinib affects the signaling pathway at the point of JAKs. Cytokine signaling is transmitted through the pairing of JAKs such as JAK1/JAK3, JAK1/JAK2, JAK/TyK2, and JAK2/JAK2. Tofacitinib primarily inhibits JAK1 and JAK3 and, to a lesser extent, JAK2. For example, tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1,377 nM, respectively. The primary inhibition of JAK1 and JAK3 by tofacitinib is thought to be advantageous in terms of potential hematologic toxicity because hematopoietic cytokine receptors, such as the erythropoietin receptor, associate with JAK2 homodimers. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.[52315]

    Revision Date: 04/27/2020, 06:43:23 PM

    References

    52315 - Xeljanz and Xeljanz XR (tofacitinib) package insert. New York, NY: Pfizer, Inc.; 2021 Dec.

    Pharmacokinetics

    Tofacitinib is administered orally. Protein binding is approximately 40%, and it binds predominantly to albumin; it does not appear to bind to alpha1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma. A volume of distribution (Vd) of 87 L was found after intravenous administration. Metabolism of tofacitinib is primarily mediated by CYP3A4 with a minor contribution from CYP2C19. Approximately 70% is cleared by hepatic metabolism, and 30% is cleared by renal excretion of the parent drug. After oral administration of the immediate-release and extended-release tablets, the elimination half-life is around 3 hours and 6 to 8 hours, respectively. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 inactive metabolites, each accounting for less than 8% of total radioactivity. Tofacitinib pharmacokinetics were similar between rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis patients.[52315]

     

    Rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout the treatment period among patients with rheumatoid arthritis. The observed changes in CRP do not reverse fully within 2 weeks after discontinuation of tofacitinib. The results indicate a longer duration of activity as compared with the pharmacokinetic half-life.[52315]

     

    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4 and CYP2C19

    Tofacitinib is a substrate of primarily CYP3A4 with minor contributions from CYP2C19. Patients receiving potent CYP3A4 inhibitors or receiving 1 or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 require tofacitinib dose reductions.[52315] The potential for tofacitinib to inhibit transporters such as P-glycoprotein (P-gp) and organic anionic or cationic transporters at therapeutic concentrations is low. In vitro data showed that it does not significantly inhibit or induce the activity of the major human drug-metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations corresponding to the steady-state Cmax of a 10 mg twice daily dose. In vivo, no changes in the pharmacokinetic parameters of the CYP3A4 substrate midazolam were noted when coadministered. In patients with rheumatoid arthritis, the oral clearance does not vary with time and indicates that tofacitinib does not normalize CYP enzyme activity. Thus, tofacitinib is not expected to cause clinically relevant increases in the metabolism of CYP substrates.[52315]

    Route-Specific Pharmacokinetics

    Oral Route

    The absolute oral bioavailability of tofacitinib is 74%.

     

    Immediate-release formulations

    After oral administration, peak plasma concentration (Cmax) occurs within 0.5 to 1 hour, and a dose-proportional increase in systemic exposure is observed in the therapeutic dose range. After twice-daily administration, steady-state concentrations are achieved in 24 to 48 hours with negligible accumulation. Patient population pharmacokinetic analyses indicated that pharmacokinetic characteristics were similar between patients with rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. The coefficient of variation (%) in AUC of tofacitinib was generally similar across patients with different disease states, ranging from 22% to 34%. In clinical trials, tofacitinib was administered without regard to meals. Coadministration of tofacitinib with a high-fat meal resulted in no changes in systemic exposure, although the Cmax was reduced by 32%.[52315]

     

    Extended-release formulations

    After oral administration, peak plasma concentration (Cmax) occurs at approximately 4 hours. After coadministration of tofacitinib 11 mg and 22 mg extended-release tablets with a high-fat meal, the peak plasma concentrations (Cmax) were increased by 27% and 19%, respectively, and the time to maximum concentration (Tmax) was extended by 1 hour; there was no change in tofacitinib exposure (AUC). After once-daily administration, steady-state concentrations are achieved within 48 hours with negligible accumulation.[52315]

    Special Populations

    Hepatic Impairment

    Patients with moderate hepatic impairment have increased blood concentrations of tofacitinib compared to those with normal hepatic function. Higher blood concentration may increase the incidence of adverse effects of tofacitinib therapy. Dosage adjustments are recommended in patients with moderate hepatic impairment. Tofacitinib is not recommended for patients with severe hepatic impairment, as it has not been studied in this patient population.[52315]

    Renal Impairment

    Increased systemic exposure of tofacitinib occurs with moderate or severe renal impairment, and dosage adjustments are needed. The mean tofacitinib AUC was increased by about 40% in patients with end-stage renal disease (ESRD) maintained on hemodialysis compared to healthy patients; this is consistent with the approximate 30% contribution of renal clearance to the total tofacitinib clearance. Tofacitinib dosage adjustments are also recommended in patients with ESRD maintained on hemodialysis.[52315]

    Pediatrics

    Bodyweight significantly impacts tofacitinib exposure, which supports weight-based dosing in the pediatric population.[52315]

    Geriatric

    Population pharmacokinetic analysis in patients with rheumatoid arthritis indicated no clinically relevant change in tofacitinib exposure after accounting for differences in creatinine clearance between patients based on age. Of the 1,156 tofacitinib-treated patients in the UC program, a total of 77 patients (7%) were 65 years of age or older. The number of patients aged 65 years and older was not sufficient to determine whether they responded differently from younger patients.[52315]

    Gender Differences

    Population pharmacokinetic analysis in patients with rheumatoid arthritis indicated no clinically relevant change in tofacitinib exposure after accounting for differences in creatinine clearance between patients based on gender.[52315]

    Ethnic Differences

    Population pharmacokinetic analysis in patients with rheumatoid arthritis indicated no clinically relevant change in tofacitinib exposure after accounting for differences in creatinine clearance between patients based on race.[52315]

    Obesity

    Population PK analysis in rheumatoid arthritis patients indicated no clinically relevant change in tofacitinib exposure, after accounting for differences in creatinine clearance between patients based on weight. An approximately linear relationship between body weight and volume of distribution was observed, resulting in higher peak (Cmax) and lower trough (Cmin) tofacitinib concentrations in lighter patients. However, this difference is not considered to be clinically relevant.[52315]

    Revision Date: 12/17/2021, 12:30:54 PM

    References

    52315 - Xeljanz and Xeljanz XR (tofacitinib) package insert. New York, NY: Pfizer, Inc.; 2021 Dec.

    Pregnancy/Breast-feeding

    pregnancy

    Tofacitinib use should be avoided during pregnancy.[61808] [62180] Human pregnancy outcomes data for tofacitinib are sparse and confounded by frequent concomitant methotrexate use. No adequate and well-controlled studies in pregnant women exist. Based on animal studies, tofacitinib has the potential to affect a developing fetus. In the tofacitinib clinical development program in rheumatoid arthritis and other registry monitoring data, birth defects (e.g., pulmonary valve stenosis), and miscarriages were reported.[62380] An ongoing prospective pregnancy registry for tofacitinib is being conducted by the Organization of Teratology Information Specialists (OTIS).[52315] Fetocidal 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 twice daily, respectively. Teratogenic effects observed include external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; cranial and skeletal malformations or variations; thoracogastroschisis, omphalocele, and membranous ventricular septal defects. In addition, reductions in live litter size, postnatal survival, and pup body weights occurred with exposure levels approximately 73 times the MRHD. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to tofacitinib; information about the registry can be obtained at mothertobaby.org/ongoing-study/xeljanz or by calling 1-877-311-8972.[52315]

    breast-feeding

    Advise lactating females not to breast-feed during tofacitinib therapy. Given the serious adverse reactions seen in adults treated with tofacitinib, such as increased risk of serious infections, advise patients that breast-feeding is not recommended during treatment and for at least 18 hours after the last dose of the immediate-release tablets or 36 hours after the last dose of extended-release tablets (approximately 6 elimination half-lives). It is not known if tofacitinib is excreted in human milk; however, it is was excreted in the milk of lactating rats at concentrations higher than in maternal serum. When a drug is present in animal milk, it is likely that the drug will be present in human milk.[52315] [62180] Assess indication and patient-specific factors before considering an alternative agent.[61808] [62180]

    Revision Date: 05/11/2021, 04:44:13 PM

    References

    52315 - Xeljanz and Xeljanz XR (tofacitinib) package insert. New York, NY: Pfizer, Inc.; 2021 Dec.61808 - Mahadevan U, McConnell RA, Chambers C. Drug safety and risk of adverse outcomes for pregnant patients with inflammatory bowel diseases. Gastroenterology 2017;152:451-462.e2.62180 - Gotestam Skorpen C, Hoeltzenbein M, Tincani A, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis 2016;75(5):795-810.62380 - Clowse ME, Feldman SR, Isaacs JD, et al. Pregnancy Outcomes in the Tofacitinib Safety Databases for Rheumatoid Arthritis and Psoriasis. Drug Saf. 2016;39:755-62.

    Interactions

    Level 2 (Major)

    • Abatacept
    • Amoxicillin; Clarithromycin; Omeprazole
    • Anakinra
    • Apalutamide
    • Atazanavir
    • Atazanavir; Cobicistat
    • Azathioprine
    • Bacillus Calmette-Guerin Vaccine, BCG
    • Baricitinib
    • Canakinumab
    • Carbamazepine
    • Ceritinib
    • Chloramphenicol
    • Clarithromycin
    • Cobicistat
    • Cyclosporine
    • Darunavir
    • Darunavir; Cobicistat
    • Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide
    • Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir
    • Delavirdine
    • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide
    • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate
    • Enzalutamide
    • Everolimus
    • Fluconazole
    • Fluvoxamine
    • Fosamprenavir
    • Fosphenytoin
    • grapefruit juice
    • Idelalisib
    • Indinavir
    • Intranasal Influenza Vaccine
    • Isoniazid, INH; Pyrazinamide, PZA; Rifampin
    • Isoniazid, INH; Rifampin
    • Itraconazole
    • Ixekizumab
    • Ketoconazole
    • Lansoprazole; Amoxicillin; Clarithromycin
    • Letermovir
    • Levoketoconazole
    • Live Vaccines
    • Lonafarnib
    • Lopinavir; Ritonavir
    • Lumacaftor; Ivacaftor
    • Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live
    • Measles/Mumps/Rubella Vaccines, MMR
    • Mercaptopurine, 6-MP
    • Mifepristone
    • Mitotane
    • Nanoparticle Albumin-Bound Sirolimus
    • Nefazodone
    • Nelfinavir
    • Nirmatrelvir; Ritonavir
    • Ombitasvir; Paritaprevir; Ritonavir
    • Phenobarbital
    • Phenobarbital; Hyoscyamine; Atropine; Scopolamine
    • Phenytoin
    • Posaconazole
    • Primidone
    • Ribociclib
    • Ribociclib; Letrozole
    • Rifampin
    • Rifapentine
    • Ritonavir
    • Rituximab
    • Rituximab; Hyaluronidase
    • Rotavirus Vaccine
    • Rubella Virus Vaccine Live
    • Saquinavir
    • Sarilumab
    • Secukinumab
    • Sirolimus
    • Smallpox and Monkeypox Vaccine, Live, Nonreplicating
    • Smallpox Vaccine, Vaccinia Vaccine
    • St. John's Wort, Hypericum perforatum
    • Tacrolimus
    • Telithromycin
    • Tipranavir
    • Tocilizumab
    • Tucatinib
    • Tumor Necrosis Factor modifiers
    • Typhoid Vaccine
    • Upadacitinib
    • Ustekinumab
    • Varicella-Zoster Virus Vaccine, Live
    • Vonoprazan; Amoxicillin; Clarithromycin
    • Voriconazole
    • Yellow Fever Vaccine, Live

    Level 3 (Moderate)

    • Cholera Vaccine
    • Fluoxetine
    • Olanzapine; Fluoxetine
    • SARS-CoV-2 (COVID-19) vaccines
    • Ticlopidine
    Abatacept: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as abatacept, is not recommended because of the possibility of additive immunosuppression and increased infection risk. There is insufficient experience to assess the safety and efficacy of this combination. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. [31761] [52315] Amoxicillin; Clarithromycin; Omeprazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with clarithromycin. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with clarithromycin. Clarithromycin is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28238] [52315] Anakinra: (Major) Avoid concomitant use of tofacitinib with biologic DMARDs, such as anakinra; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection. [52315] Apalutamide: (Major) Coadministration of tofacitinib and apalutamide is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC and Cmax of tofacitinib by 84% and 74%, respectively. [52315] [62874] Atazanavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with atazanavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with atazanavir. Atazanavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28142] [52315] Atazanavir; Cobicistat: (Major) A dosage reduction of tofacitinib is necessary if coadministered with atazanavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with atazanavir. Atazanavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28142] [52315] (Major) A dosage reduction of tofacitinib is necessary if coadministered with cobicistat. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with cobicistat. Cobicistat is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [52315] [58000] Azathioprine: (Major) Concomitant use of tofacitinib with azathioprine is not recommended because of the possibility of additive immunosuppression and increased infection risk. There is insufficient experience to assess the safety and efficacy of this combination. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. [52315] Bacillus Calmette-Guerin Vaccine, BCG: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines. [52315] Baricitinib: (Major) Concomitant use of baricitinib with tofacitinib is not recommended because of the duplication of the mechanism of action (both are Janus kinase inhibitors, also known as JAK inhibitors) and the possibility of increased immunosuppression and increased infection risk. Both drugs are known to cause elevations in hepatic enzymes and gastrointestinal perforation, and a possibility for increased thrombotic risk. [63229] Canakinumab: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as canakinumab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. [52315] Carbamazepine: (Major) Coadministration of tofacitinib and carbamazepine is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer. [41237] [52315] [56579] Ceritinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ceritinib. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [52315] [57094] Chloramphenicol: (Major) A dosage reduction of tofacitinib is necessary if coadministered with chloramphenicol. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with chloramphenicol. Chloramphenicol is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [29624] [52315] Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine. [60871] Clarithromycin: (Major) A dosage reduction of tofacitinib is necessary if coadministered with clarithromycin. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with clarithromycin. Clarithromycin is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28238] [52315] Cobicistat: (Major) A dosage reduction of tofacitinib is necessary if coadministered with cobicistat. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with cobicistat. Cobicistat is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [52315] [58000] Cyclosporine: (Major) Concomitant use of tofacitinib with cyclosporine is not recommended. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Cyclosporine is also an inhibitor of CYP3A4, and tofacitinib is a CYP3A4 substrate. Increased systemic exposure of tofacitinib has been noted with concurrent cyclosporine administration, and dosage adjustment may be necessary. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis. [52315] Darunavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with darunavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with darunavir. Darunavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [32432] [52315] Darunavir; Cobicistat: (Major) A dosage reduction of tofacitinib is necessary if coadministered with cobicistat. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with cobicistat. Cobicistat is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [52315] [58000] (Major) A dosage reduction of tofacitinib is necessary if coadministered with darunavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with darunavir. Darunavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [32432] [52315] Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) A dosage reduction of tofacitinib is necessary if coadministered with cobicistat. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with cobicistat. Cobicistat is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [52315] [58000] (Major) A dosage reduction of tofacitinib is necessary if coadministered with darunavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with darunavir. Darunavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [32432] [52315] Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ritonavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with ritonavir. Ritonavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28315] [52315] [56579] Delavirdine: (Major) A dosage reduction of tofacitinib is necessary if coadministered with delavirdine. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with delavirdine. Delavirdine is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28476] [52315] Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) A dosage reduction of tofacitinib is necessary if coadministered with cobicistat. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with cobicistat. Cobicistat is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [52315] [58000] Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) A dosage reduction of tofacitinib is necessary if coadministered with cobicistat. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with cobicistat. Cobicistat is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [52315] [58000] Enzalutamide: (Major) Coadministration of tofacitinib and enzalutamide is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer. [51727] [52315] Everolimus: (Major) Concomitant use of tofacitinib with potent immunosuppressants, such as everolimus, is not recommended; coadministration may result in additive immunosuppression and increased risk of infection. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis. [52315] Fluconazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with fluconazole chronically (beyond 1 dosage). In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with fluconazole. Fluconazole is a strong CYP2C19 and moderate CYP3A4 inhibitor; tofacitinib is a CYP3A4/CYP2C19 substrate. Coadministration with fluconazole increased tofacitinib exposure by 1.75-fold. [28674] [52315] Fluoxetine: (Moderate) A reduction in tofacitinib dose may be necessary if tofacitinib is coadministered with fluoxetine (a strong CYP2C19 inhibitor) and a medication that is a moderate CYP3A4 inhibitor. Tofacitinib exposure is increased when coadministered with both a strong CYP2C19 and a moderate CYP3A4 inhibitor. Review the patient's other medications for this potential drug interaction and the possible need for tofacitinib dose reduction. Tofacitinib is a CYP3A4 and CYP2C19 substrate. Coadministration of tofacitinib with both a strong CYP2C19 and a moderate CYP3A4 inhibitor increased tofacitinib exposure by 1.75-fold. [52315] [56579] Fluvoxamine: (Major) A dosage reduction of tofacitinib is necessary if coadministered with fluvoxamine. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with fluvoxamine. Fluvoxamine is a strong CYP2C19 and moderate CYP3A4 inhibitor; tofacitinib is a CYP3A4/CYP2C19 substrate. Coadministration with another strong CYP2C19 and moderate CYP3A4 inhibitor increased tofacitinib exposure by 1.75-fold. [47184] [52315] [56579] Fosamprenavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with fosamprenavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with fosamprenavir. Fosamprenavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [29012] [52315] Fosphenytoin: (Major) Coadministration of tofacitinib and fosphenytoin is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; phenytoin (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer. [28535] [52315] Grapefruit juice: (Major) It is best to avoid taking Tofacitinib with grapefruit juice. The exposure to tofacitinib may be significantly increased in patients who regularly consume grapefruit or grapefruit juice, a strong CYP3A4 inhibitor. FDA-approved labeling recommends in patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. No specific guidance is provided for grapefruit or grapefruit juice. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [52315] Idelalisib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with idelalisib. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with idelalisib. Idelalisib is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [52315] [57675] Indinavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with indinavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with indinavir. Indinavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28731] [52315] Intranasal Influenza Vaccine: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines. [52315] Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Coadministration of tofacitinib and rifampin is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with rifampin. [30314] [52315] [56579] Isoniazid, INH; Rifampin: (Major) Coadministration of tofacitinib and rifampin is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with rifampin. [30314] [52315] [56579] Itraconazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with itraconazole. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with itraconazole. Itraconazole is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [27983] [52315] [56579] Ixekizumab: (Major) Concomitant use of tofacitinib with biologic immunosuppressants, such as ixekizumab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. [52315] Ketoconazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ketoconazole. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with ketoconazole. Ketoconazole is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with ketoconazole increased tofacitinib exposure by 2-fold. [27982] [52315] [56579] Lansoprazole; Amoxicillin; Clarithromycin: (Major) A dosage reduction of tofacitinib is necessary if coadministered with clarithromycin. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with clarithromycin. Clarithromycin is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28238] [52315] Letermovir: (Major) A clinically relevant increase in the plasma concentration of tofacitinib may occur if given with letermovir. A dosage reduction of tofacitinib is necessary if coadministered with letermovir and cyclosporine because the magnitude of this interaction may be amplified. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. [52315] [62611] Levoketoconazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ketoconazole. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with ketoconazole. Ketoconazole is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with ketoconazole increased tofacitinib exposure by 2-fold. [27982] [52315] [56579] Live Vaccines: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines. [52315] Lonafarnib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with lonafarnib. In patients receiving tofacitinib 5 mg twice daily, reduce to 5 mg once daily; in patients receiving tofacitinib 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving tofacitinib extended-release 11 mg once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is a CYP3A4 and CYP2C19 substrate and lonafarnib is a strong CYP3A4 and moderate CYP2C19 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [52315] [66129] Lopinavir; Ritonavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ritonavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with ritonavir. Ritonavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28315] [52315] [56579] Lumacaftor; Ivacaftor: (Major) Coadministration of tofacitinib and lumacaftor; ivacaftor is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer. [52315] [59891] Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines. [52315] Measles/Mumps/Rubella Vaccines, MMR: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines. [52315] Mercaptopurine, 6-MP: (Major) Concomitant use of tofacitinib in combination with potent immunosuppressants such as mercaptopurine is not recommended. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis. [52315] Mifepristone: (Major) A dosage reduction of tofacitinib is necessary if coadministered with chronic mifepristone therapy. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily.. Tofacitinib exposure is increased when coadministered with mifepristone. Mifepristone is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. When mifepristone is given chronically, the half-life of the drug is prolonged, and drug-interaction potential is extended. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. The clinical significance of this interaction when mifepristone is used in a regimen for pregnancy termination is unknown. [28003] [48697] [52315] Mitotane: (Major) Coadministration of tofacitinib and mitotane is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer. [41934] [52315] Nanoparticle Albumin-Bound Sirolimus: (Major) Concomitant use of tofacitinib with potent immunosuppressants, such as sirolimus, is not recommended; coadministration may result in additive immunosuppression and increased risk of infection. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis. [52315] Nefazodone: (Major) A dosage reduction of tofacitinib is necessary if coadministered with nefazodone. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with nefazodone. Nefazodone is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28683] [52315] [56579] Nelfinavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with nelfinavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with nelfinavir. Nelfinavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28839] [52315] Nirmatrelvir; Ritonavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ritonavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with ritonavir. Ritonavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28315] [52315] [56579] (Major) Consider withholding tofacitinib, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the tofacitinib dose. In patients receiving tofacitinib 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Coadministration may increase tofacitinib exposure resulting in increased toxicity. Tofacitinib is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. [65314] [67203] Olanzapine; Fluoxetine: (Moderate) A reduction in tofacitinib dose may be necessary if tofacitinib is coadministered with fluoxetine (a strong CYP2C19 inhibitor) and a medication that is a moderate CYP3A4 inhibitor. Tofacitinib exposure is increased when coadministered with both a strong CYP2C19 and a moderate CYP3A4 inhibitor. Review the patient's other medications for this potential drug interaction and the possible need for tofacitinib dose reduction. Tofacitinib is a CYP3A4 and CYP2C19 substrate. Coadministration of tofacitinib with both a strong CYP2C19 and a moderate CYP3A4 inhibitor increased tofacitinib exposure by 1.75-fold. [52315] [56579] Ombitasvir; Paritaprevir; Ritonavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ritonavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with ritonavir. Ritonavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28315] [52315] [56579] Phenobarbital: (Major) Coadministration of tofacitinib and phenobarbital is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer. [28596] [52315] [56579] Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Coadministration of tofacitinib and phenobarbital is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer. [28596] [52315] [56579] Phenytoin: (Major) Coadministration of tofacitinib and phenytoin is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer. [46974] [52315] [56579] Posaconazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with posaconazole. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with posaconazole. Posaconazole is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [32723] [52315] Primidone: (Major) Coadministration of tofacitinib and primidone is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate. Tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. Primidone is metabolized to phenobarbital, a potent CYP3A4 inducer. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer. [22005] [28597] [52315] [56579] Ribociclib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ribociclib. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [52315] [61816] Ribociclib; Letrozole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ribociclib. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [52315] [61816] Rifampin: (Major) Coadministration of tofacitinib and rifampin is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with rifampin. [30314] [52315] [56579] Rifapentine: (Major) Coadministration of tofacitinib and rifapentine is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC and Cmax of tofacitinib by 84% and 74%, respectively. [52315] [65685] Ritonavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ritonavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with ritonavir. Ritonavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28315] [52315] [56579] Rituximab: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as rituximab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. [52315] Rituximab; Hyaluronidase: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as rituximab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. [52315] Rotavirus Vaccine: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines. [52315] Rubella Virus Vaccine Live: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines. [52315] Saquinavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with saquinavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with saquinavir. Saquinavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28995] [52315] [56579] Sarilumab: (Major) Avoid the concomitant use of sarilumab with other biological DMARDs such as tofacitinib; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection. [52315] [61976] SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] Secukinumab: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as secukinumab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. [52315] Sirolimus: (Major) Concomitant use of tofacitinib with potent immunosuppressants, such as sirolimus, is not recommended; coadministration may result in additive immunosuppression and increased risk of infection. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis. [52315] Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines. [52315] Smallpox Vaccine, Vaccinia Vaccine: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines. [52315] St. John's Wort, Hypericum perforatum: (Major) Coadministration of tofacitinib and St. John's Wort, Hypericum perforatum is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; St. John's Wort, Hypericum perforatum is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer. [4935] [52315] Tacrolimus: (Major) Concomitant use of tofacitinib with potent immunosuppressants, such as tacrolimus, is not recommended; coadministration may result in additive immunosuppression and increased risk of infection. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis. [52315] Telithromycin: (Major) A dosage reduction of tofacitinib is necessary if coadministered with telithromycin. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with telithromycin. Telithromycin is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28156] [52315] [56579] Ticlopidine: (Moderate) A reduction in tofacitinib dose may be necessary if tofacitinib is coadministered with ticlopidine (a strong CYP2C19 inhibitor) and a medication that is a moderate CYP3A4 inhibitor. Tofacitinib exposure is increased when coadministered with both a strong CYP2C19 and a moderate CYP3A4 inhibitor. Review the patient's other medications for this potential drug interaction and the possible need for tofacitinib dose reduction. Tofacitinib is a CYP3A4 and CYP2C19 substrate. Coadministration of tofacitinib with both a strong CYP2C19 and a moderate CYP3A4 inhibitor increased tofacitinib exposure by 1.75-fold. [28436] [52315] [56579] Tipranavir: (Major) A dosage reduction of tofacitinib is necessary if coadministered with tipranavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with tipranavir. Tipranavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [31320] [52315] Tocilizumab: (Major) Avoid the concomitant use of tocilizumab with other biological DMARDs such as tofacitinib; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection. [38283] [52315] Tucatinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with tucatinib. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [52315] [65295] Tumor Necrosis Factor modifiers: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. [52315] Typhoid Vaccine: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines. [52315] Upadacitinib: (Major) Concomitant use of tofacitinib with upadacitinib is not recommended because of the duplication of the mechanism of action (both are Janus kinase inhibitors, also known as JAK inhibitors) and the possibility of increased immunosuppression and increased infection risk. Both drugs are known to cause elevations in hepatic enzymes and gastrointestinal perforation, and a possibility for increased thrombotic risk. [52315] [64572] Ustekinumab: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as ustekinumab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. [52315] Varicella-Zoster Virus Vaccine, Live: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines. [52315] Vonoprazan; Amoxicillin; Clarithromycin: (Major) A dosage reduction of tofacitinib is necessary if coadministered with clarithromycin. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with clarithromycin. Clarithromycin is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [28238] [52315] Voriconazole: (Major) A dosage reduction of tofacitinib is necessary if coadministered with voriconazole. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with voriconazole. Voriconazole is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. [52315] [54713] [56579] Yellow Fever Vaccine, Live: (Major) Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines. [52315]
    Revision Date: 11/04/2022, 02:26:00 AM

    References

    4935 - Henderson L, Yue QY, Bergquist C, et al. St John's wort (Hypericum perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol 2002;54:349-56.22005 - Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 2006;61(3):246-255.27982 - Ketoconazole tablets package insert. Morgantown, WV: Mylan Pharmaceuticals, Inc.; 2017 Sept.27983 - Sporanox (itraconazole) capsules package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2019 Mar.28003 - Mifepristone, RU-486 package insert. New York, NY: GenBioPro, Inc.; 2019 Feb.28142 - Reyataz (atazanavir) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2020 Sept.28156 - Ketek (telithromycin) package insert. Bridgewater, NJ: Sanofi-Aventis Pharmaceuticals; 2015 Oct.28238 - Biaxin (clarithromycin) package insert. North Chicago, IL: AbbVie, Inc.; 2019 Sep.28315 - Norvir (ritonavir capsules) package insert. North Chicago, IL: AbbVie Inc; 2020 Oct.28436 - Ticlid (ticlopidine) package insert. Nutley, NJ: Roche Laboratories, Inc.; 2005 Dec.28476 - Rescriptor (delavirdine) package insert. Research Triangle Park, NC: ViiV Healthcare; 2019 Aug.28535 - Cerebyx (fosphenytoin sodium) package insert. New York, NY: Pfizer Labs; 2022 Apr.28596 - Phenobarbital Tablets, USP package insert. Huntsville, AL: Qualitest Pharmaceuticals; 2007 Nov.28597 - Mysoline (primidone) package insert. Bridgewater, NJ: Bausch Health Companies, Inc.; 2020 Jun.28674 - Diflucan oral tablet and suspension (fluconazole) package insert. New York, NY: Pfizer; 2022 Mar.28683 - Nefazodone tablet package insert. North Wales, PA: Teva Pharmaceuticals USA, Inc.; 2015 Sept.28731 - Crixivan (indinavir) package insert. Whitehouse Station, NJ: Merck & Co., Inc.; 2016 Sept.28839 - Viracept (nelfinavir mesylate) package insert. Research Triangle Park, NC: ViiV Healthcare Company; 2021 Mar.28995 - Invirase (saquinavir) package insert. South San Francisco, CA: Genentech Inc.; 2020 Sept.29012 - Lexiva (fosamprenavir calcium) package insert. Research Triangle Park, NC: ViiV Healthcare; 2019 Mar29624 - Park JY, Kim KA, Kim SL. Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes. Antimicrob Agents Chemother 2003;47:3464-9.30314 - Rifadin capsules and injection (rifampin) package insert. Bridgewater, NJ: Sanofi-Aventis, LLC; 2021 Dec.31320 - Aptivus (tipranavir) package insert. Ridgefield, CT: Boehringer Ingelheim; 2020 Jun.31761 - Orencia (abatacept) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2021 Dec.32432 - Prezista (darunavir) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2022 Oct.32723 - Noxafil (posaconazole) package insert. Whitehouse Station, NJ: Merck & Co. Inc.: 2022 Jan.38283 - Actemra (tocilizumab) injection package insert. South San Francisco, CA: Genentech, Inc.; 2022 Feb.41237 - Tegretol (carbamazepine) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2018 Mar.41934 - Lysodren (mitotane) package insert. Princeton, NJ: Bristol-Myers Squibb Oncology; 2021 June.46974 - Dilantin (phenytoin sodium) injection package insert. New York, NY: Parke-Davis Division of Pfizer Inc.; 2017 Aug.47184 - Luvox (fluvoxamine) package insert. Baudette, MN: ANI Pharmaceuticals, Inc.; 2021 July48697 - Korlym (mifepristone) tablet package insert. Menlo Park, CA: Corcept Therapeutics; 2019 Nov.51727 - Xtandi (enzalutamide) capsule and tablet package insert. Northbrook, IL:Astellas Pharma US, Inc.; 2022 Sept.52315 - Xeljanz and Xeljanz XR (tofacitinib) package insert. New York, NY: Pfizer, Inc.; 2021 Dec.54713 - VFEND (voriconazole) injection package insert. New York, NY: Pfizer Inc; 2014 Sept.56579 - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Updated Mar 10, 2020. Retrieved from the World Wide Web at www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm57094 - Zykadia (ceritinib) package insert. Indianapolis, IN: Novartis; 2021 Oct.57675 - Zydelig (idelalisib) tablet package insert. Foster City, CA:Gilead Sciences, Inc.; 2022 Feb.58000 - Tybost (cobicistat) package insert. Foster City, CA: Gilead Sciences, Inc; 2021 Sept.59891 - Orkambi (lumacaftor; ivacaftor) tablet package insert. Boston, MA: Vertex Pharmaceuticals, Inc. 2022 Sept60871 - Vaxchora (Cholera Vaccine, live, oral) package insert. Redwood City, CA: Emergent Travel Health Inc.; 2020 Dec.61816 - Kisqali (ribociclib) tablets package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021 Sept.61976 - Kevzara (sarilumab) package insert. Bridgewater, NJ: Sanofi-Aventis US. LLC; 2018 Apr.62611 - Prevymis (letermovir) package insert. Whitehouse Station, NJ: Merck and Co, Inc.; 2020 Mar.62874 - Erleada (apalutamide) tablets package insert. Horsham, PA: Janssen Products, LP; 2022 Nov.63229 - Olumiant (baricitinib) tablets package insert. Indianapolis, IN: Lilly USA, LLC; 2022 Jun.64572 - Rinvoq (upadacitinib) package insert. North Chicago, IL: Abbvie Inc.; 2022 Oct.65107 - Kroger A, Bahta L, Hunter P. General Best Practice Guidelines for Immunization. Best Practices Guidance of the Advisory Committee on Immunization Practices (ACIP).Available on the world wide web at https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf. Revised April 27, 2022. Accessed on July 14, 2022.65295 - Tukysa (tucatinib) tablets package insert. Bothell, WA: Seattle Genetics, Inc.; 2020 April.65314 - COVID-19 Treatment Guidelines Panel. Coronavirus Diseases 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Accessed November 10, 2022. Available at on the World Wide Web at: https://covid19treatmentguidelines.nih.gov/.65685 - Dooley KE, Bliven-Sizemore EE, Weiner M, et al. Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers. Clin Pharmacol Ther 2012; 91:566080 - Food and Drug Administration (FDA). Fact Sheet for Healthcare Providers Administering Vaccine: Emergency Use Authorization (EUA) of Pfizer-BioNTech COVID-19 Vaccine to Prevent Coronavirus Disease 2019 (COVID-19) for 12 years and older. Purple cap and purple border. Retrieved August 31, 2022.66129 - Zokinvy (lonafarnib) capsules package insert. Palo Alto, CA: Eiger BioPharmaceuticals, Inc.; 2020 Nov.67203 - Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for Paxlovid. Retrieved September 28, 2022. Available on the World Wide Web at https://www.fda.gov/media/155050/download?utm_medium=email&utm_source=govdelivery

    Monitoring Parameters

    • CBC with differential
    • hemoglobin/hematocrit
    • LFTs
    • platelet count
    • serum cholesterol profile
    • serum creatinine/BUN
    • skin cancer screening exam
    • tuberculin skin test

    US Drug Names

    • Xeljanz
    • Xeljanz Oral
    • Xeljanz XR
    ;