VA CFU Criteria Formulary Advisor Reference
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UPADACITINIB TAB,SA (EXTENDED RELEASE)

Generic Name
UPADACITINIB TAB
Brand Names
RINVOQ
Drug Class
ANTIRHEUMATICS,OTHER
Formulary Status
N
Copay Tier
3
Last Updated
2019-08-29

Clinical Criteria Summary

Document 206

Infections & Screening Requirements

  • Active, serious, systemic or localized infection, including undrained abscess (may start/restart once controlled)
  • Untreated latent or active tuberculosis infection
  • Hepatitis B surface antigen (HBsAg)-positive and not on antiviral prophylaxis
  • HBsAg-negative but antibody-to-hepatitis-B-core-antigen (anti-HBc)-positive and not on antiviral prophylaxis
  • Untreated HIV infection (treated, well-controlled, asymptomatic HIV-positive patients may be treated)
  • Must complete tuberculosis (TB) test using tuberculin skin test or interferon-gamma release assay [IGRA]
  • Must complete hepatitis B screening (at minimum, HBsAg, total anti-HBc and antibody to hepatitis B surface antigen [anti-HBs])
  • Must have current or past completion of hepatitis C screening

Malignancy & Cardiovascular/Thrombotic Risk

  • Malignancy within the previous 5 years other than successfully treated nonmelanoma skin cancer or successfully treated cervical cancer
  • At increased risk of thrombosis or major adverse cardiovascular events where potential harms are expected to outweigh anticipated benefits

Laboratory & Organ Function Parameters

  • Lymphocytes < 500 cells/mm3 confirmed by repeat testing, neutrophils < 1000 cells/mm3, or hemoglobin < 8 g/dL (may start/restart once resolved)
  • Severe hepatic impairment (Child-Pugh class C)

Concomitant Medications, Vaccines & Reproductive Health

  • Concomitant therapy with biologic disease-modifying antirheumatic drugs (bDMARDs), other immunosuppressive biologics or potent immunosuppressants (e.g., azathioprine, cyclosporine, tacrolimus), except overlaps during treatment transition
  • Concomitant therapy with strong CYP3A4 inducers (e.g., rifampin)
  • Pregnancy
  • Breastfeeding
  • Concomitant live or live-attenuated vaccines or administration of inactivated, live, or live-attenuated vaccines less than 2 weeks before initiation

Provider Oversight & Diagnostic Requirements

  • Prescribed and monitored by a VA/VA Community Care rheumatologist, dermatologist, or locally designated expert
  • Has inflammatory articular disease (joint, spine, and/or entheseal) and a definite or provisional diagnosis of active psoriatic arthritis

Prior Biologic Therapy & Adjudication Considerations

  • ONE tumor necrosis factor inhibitor (TNFI) therapy is medically inadvisable, not tolerated, or not adequate after 3 months
  • For patients who can become pregnant and patients with partners who can become pregnant: Counseling provided on potential risks vs benefits of treatment and the use of effective contraception
  • TNFI may be medically inadvisable for reasons including heart failure, demyelinating disease, multiple sclerosis in first-degree relative, lupus, recurrent/serious infections, or aversity to injections/barriers to in-clinic administration (adjudicated case-by-case)
  • IL-17A inhibitor (ixekizumab preferred) may be medically inadvisable due to inflammatory bowel disease (IBD), as they can worsen IBD
  • Ustekinumab may be medically inadvisable for axial psoriatic arthritis, as it is ineffective for ankylosing spondylitis

Document 323

Indication & Disease Severity

  • Diagnosis of chronic atopic dermatitis
  • Within 2 weeks of starting upadacitinib therapy, determination of severity by Gestalt Assessment (GA) of “moderate” or “severe” OR Eczema Area and Severity Index (EASI) ≥ 16 (scale 0–72)
  • When practical, SCORing Atopic Dermatitis (SCORAD) index and Patient Oriented Eczema Measure (POEM) may be considered

Exclusion Criteria & Contraindications

  • Uncontrolled active infection (may start/restart once treatment for the infection is initiated)
  • Untreated latent or active tuberculosis
  • Hepatitis B surface antigen (HBsAg)-positive and not on antiviral prophylaxis (may initiate after starting antiviral prophylaxis; agents with high genetic barrier to resistance such as entecavir or tenofovir should be used)
  • Untreated HIV infection (treated, well-controlled, asymptomatic HIV-positive patients can be treated)
  • Congenital or acquired immunodeficiency
  • Malignancy within the previous 5 years other than successfully treated nonmelanoma skin cancer or successfully treated cervical cancer (unless dermatologist and oncologist agree risk-benefits favor use)
  • Thrombosis or major adverse cardiovascular events in which potential harms are expected to outweigh anticipated benefits
  • Lymphocytes < 500 cells/mm3 confirmed by repeat testing, neutrophils < 1000 cells/mm3, or hemoglobin < 8 g/dL (may start/restart once values normalize)
  • Severe hepatic impairment (Child-Pugh class C)
  • Concomitant therapy with biologic disease-modifying antirheumatic drugs (bDMARDs), other immunosuppressive biologics, or potent immunosuppressants (e.g., azathioprine, cyclosporine, tacrolimus) [except overlaps during treatment transition; co-use with antirheumatic doses of conventional immunomodulators such as methotrexate or leflunomide is acceptable]
  • Pregnancy
  • Breastfeeding
  • Administration of inactivated, live, or live-attenuated vaccines within 2 weeks before initiation

Infectious Disease Screening & Monitoring

  • Completed tuberculosis (TB) test using tuberculin skin test or interferon-gamma release assay [IGRA]
  • Completed hepatitis B screening (HBsAg, total antibody to hepatitis B core antigen [anti-HBc], and antibody to hepatitis B surface antigen [anti-HBs])
  • Current or past completion of hepatitis C screening (may initiate while waiting for test results)
  • Routine retesting not required for prescription renewals; consider in high-risk patients

Prior Therapy Requirements

  • Dupilumab OR tralokinumab-ldrm therapy is medically inadvisable, not tolerated, not adequate, or lost response (NO response after 12 weeks or inadequate response after 16 weeks)
  • If dupilumab or tralokinumab-ldrm is contraindicated, therapies required prior to those biologic agents must still be tried

Vaccination Requirements

  • Offered all age-appropriate vaccinations prior to initiating therapy
  • When possible, vaccinations should be updated before initiation
  • Unless contraindicated, recombinant zoster (SHINGRIX equivalent) vaccine should be completed or at least initiated by the end of the first year of treatment, preferably when dosage is low, disease is stable, or at other times when a robust immune response can be expected

Special Populations & Counseling

  • For females who can become pregnant: Counseling provided on potential risks vs benefits and use of effective contraception
  • For females who are breastfeeding/providing breastmilk to an infant: Counseling provided on potential risks vs benefits
  • If HBsAg-negative but anti-HBc-positive and consult deemed indicated: GI/liver or infectious diseases expert consulted for advice on antiviral prophylaxis or preemptive monitoring for HBV reactivation

Provider Oversight

  • Prescribed and monitored by a VA/VA Community Care dermatologist OR an immunologist, allergist, or locally designated expert in the management of atopic dermatitis in consultation with a VA/VA Community Care dermatologist

Document 324

Indication & Patient Population

  • • Adults with refractory, moderate to severe atopic dermatitis
  • • Patients who are candidates for systemic therapy

Treatment History & Place in Therapy

  • • Indicated when other systemic drug products, including biologics, have provided an inadequate response or when use of those therapies is medically inadvisable
  • • May be used following inadequate response or intolerance to other systemic therapies, including but not limited to phototherapy, short-term induction therapy with cyclosporine or a systemic corticosteroid (if indicated), two conventional maintenance therapies, and dupilumab
  • • Place in therapy is equivalent to abrocitinib

Limitations of Use

  • • Not recommended for co-administration with other JAK inhibitors (JAKIs)
  • • Not recommended for co-administration with biologic immunomodulators
  • • Not recommended for co-administration with other immunosuppressants

Dosing & Administration

  • • Adults < 65 years: Initiate at 15 mg once daily; if response is inadequate, increase to 30 mg once daily; discontinue if response to 30 mg is inadequate; use the lowest effective dose to maintain response
  • • Adults ≥ 65 years: 15 mg once daily
  • • Severe renal impairment (CrCL < 30 mL/min): 15 mg once daily
  • • Mild or moderate renal impairment (CrCL > 30 mL/min): No dosage adjustment is needed

Pre-treatment Requirements

  • • Refer to the prescribing information for important pre-treatment assessments

Document 325

Indication & Patient Population

  • • Adults with active psoriatic arthritis (PsA)
  • • Patients who have had an inadequate response or intolerance to one or more TNFIs
  • • Patients who refuse TNFI therapy due to safety concerns

Treatment History & Sequencing

  • • Placed after TNFIs in the treatment sequence
  • • May be used despite therapy with one TNFI
  • • May be preferred over ustekinumab, IL-23 inhibitors, apremilast, and abatacept for patients requiring treatment for axial PsA or ankylosing spondylitis
  • • May be less preferable than tofacitinib and other agents (except abatacept) for patients with psoriatic nail involvement
  • • Tofacitinib may be preferred over upadacitinib when a JAKI is indicated due to cost considerations

Dosing & Administration

  • • 15 mg once daily (only dose approved for PsA; escalation to 30 mg is only approved for atopic dermatitis)
  • • No dosage adjustment required for renal impairment in PsA
  • • May be used as monotherapy

Treatment Duration & Response Assessment

  • • A 12-week trial may be adequate; if nonresponse occurs by 12 weeks, an alternative treatment may be considered. For partial responders at 12 weeks, therapy may continue up to 24 weeks to improve response.

Limitations & Safety Considerations

  • • Not recommended in combination with other JAKIs, biologic DMARDs, or potent immunosuppressants (e.g., azathioprine, cyclosporine)
  • • Not recommended in severe (Child-Pugh class C) liver disease
  • • Carries Boxed Warnings for mortality, malignancy, major adverse cardiovascular events, and thrombosis regardless of indication

Pre-treatment Requirements

  • • Refer to the prescribing information for important pre-treatment assessments

Document 335

Exclusion Criteria

  • Uncontrolled active infection (may start/restart once treatment for the infection is initiated)
  • Untreated latent or active tuberculosis infection
  • Hepatitis B surface antigen (HBsAg)-positive and not on antiviral prophylaxis (may initiate after starting antiviral prophylaxis)
  • Untreated HIV infection (treated, well-controlled, asymptomatic HIV-positive patients are permitted)
  • Congenital or acquired immunodeficiency
  • Malignancy within the previous 5 years other than successfully treated nonmelanoma skin cancer or successfully treated cervical cancer (unless treating rheumatologist and oncologist agree risk-benefits favor use)
  • At increased risk of thrombosis where potential harms are expected to outweigh anticipated benefits
  • Lymphopenia, neutropenia, or anemia (may start/restart once resolved; defined as lymphocyte count <500 cells/mm3, absolute neutrophil count <1000 cells/mm3, hemoglobin <8 g/dL)
  • Severe hepatic impairment (Child-Pugh class C)
  • Concomitant therapy with biologic disease-modifying antirheumatic drugs (bDMARDs), other immunosuppressive biologics, or potent immunosuppressants (except during treatment transition overlaps)
  • Concomitant therapy with strong CYP3A4 inducers (e.g., rifampin)
  • Pregnancy
  • Breastfeeding
  • Concomitant live or live-attenuated vaccines, or administration of inactivated, live, or live-attenuated vaccines less than 2 weeks before initiation

Inclusion Criteria

  • Prescribed and monitored by a VA/VA Community Care rheumatologist or locally designated expert
  • Moderate to severe active rheumatoid arthritis
  • Prescribed at the FDA-recommended dose for rheumatoid arthritis, adjusting for CYP3A4 drug interactions, moderate or severe renal impairment, moderate hepatic impairment, and hematocytopenias
  • Offered all age-appropriate vaccinations prior to initiating therapy
  • Completed tuberculosis (TB) test using tuberculin skin test or interferon-gamma release assay (IGRA)
  • Completed hepatitis B screening (HBsAg, total antibody-to-hepatitis-B-core-antigen [anti-HBc], and antibody to hepatitis B surface antigen [anti-HBs])
  • Current or past completion of hepatitis C screening (may initiate while waiting for test results)
  • Tumor necrosis factor inhibitor (TNFI) therapy is medically inadvisable, not tolerated, not adequate (no response to one TNFI after 3 months, partial response to 3-month trials of two TNFIs totaling 6 months), or lost response

Additional Inclusion/Justification Criteria

  • If HBsAg-negative but anti-HBc-positive and consult is deemed indicated: Consultation with a GI/liver or infectious diseases expert for advice on starting antiviral prophylaxis or preemptively monitoring for HBV reactivation
  • For females who can become pregnant: Counseling provided on potential risks vs benefits of treatment and use of effective contraception during therapy and for 5 months after stopping treatment
  • For females who are breastfeeding/providing breastmilk to an infant: Counseling provided on potential risks vs benefits of treatment

Document 444

Indication & Diagnosis

  • Current or prior moderate to severe ulcerative colitis (UC) confirmed by endoscopy or imaging
  • Prescribed and monitored by a VA/VA Community Care gastroenterologist or UC expert

Exclusion Criteria

  • Uncontrolled, active, severe infection (including C. difficile and undrained abscess) [may start/restart once infection treatment initiated]
  • Untreated latent or active tuberculosis infection
  • Hepatitis B surface antigen (HBsAg)-positive and not on antiviral prophylaxis [may initiate after starting antiviral prophylaxis]
  • Untreated HIV infection [treated, well-controlled, asymptomatic HIV-positive patients may be treated]
  • Malignancy within the previous 5 years other than successfully treated nonmelanoma skin cancer or cervical cancer (unless treating gastroenterologist and oncologist agree risk-benefits favor use)
  • At increased risk of thrombosis or major adverse cardiovascular events where potential harms outweigh anticipated benefits
  • Lymphocytes < 500 cells/mm3, neutrophils < 1000 cells/mm3, or hemoglobin < 8 g/dL [may start/restart once values normalize]
  • End stage renal disease (eGFR < 15 mL/min/1.73 m2)
  • Severe hepatic impairment (Child-Pugh class C)
  • Concomitant live or live-attenuated vaccines, or administration of inactivated/live/live-attenuated vaccines < 2 weeks before initiation
  • Concomitant JAK inhibitors, biologic immunomodulators, or potent immunosuppressants (e.g., azathioprine, cyclosporine)
  • Concomitant strong CYP3A4 inducers
  • Pregnancy (during therapy and for 4 weeks after last dose)
  • Breastfeeding/providing breastmilk to an infant (during therapy and for 6 days after last dose)

Inclusion Criteria (All Must Be Met)

  • Completed tuberculosis (TB) test using tuberculin skin test or interferon-gamma release assay (IGRA)
  • Completed hepatitis B screening (at minimum: HBsAg, total anti-HBc, anti-HBs)
  • Current or past completion of hepatitis C screening [may initiate while waiting for results]

Additional Inclusion Criteria (One Must Be Met)

  • Tumor necrosis factor inhibitor (TNFI) is medically inadvisable (Infliximab/biosimilar is preferred TNFI in UC)
  • Primary nonresponse, inadequate partial response, or loss of response after 12 weeks of one TNFI in presence of adequate TNFI levels (mechanistic failure)
  • Loss of response to a TNFI despite therapeutic drug monitoring (TDM)-based optimized dosing to address pharmacokinetic failure

Additional Inclusion Criteria (Select if Appropriate)

  • If HBsAg-negative but anti-HBc-positive: GI/liver or infectious diseases expert consulted for advice on antiviral prophylaxis vs. preemptive monitoring for HBV reactivation
  • For women who can become pregnant: Pregnancy status verified; counseling provided on risks vs benefits and use of effective contraception during therapy and for 4 weeks after discontinuation

Dosing & Sequencing Requirements

  • Prescribe at FDA-recommended dose for UC, adjusting for severe renal impairment (eGFR 15 to <30 mL/min/1.73 m2), mild/moderate hepatic impairment (Child-Pugh A or B), and strong CYP3A4 inhibitors
  • Sequencing: 1L Infliximab (preferred) or adalimumab; 2L/3L includes upadacitinib (one drug must be risankizumab-rzaa as 2L or 3L); 4L Mirikizumab-mrkz, guselkumab, or ustekinumab
  • Routine retesting for TB, HBV, HCV not required for prescription renewals; retest in high-risk patients

Document 469

Indications & Patient Population

  • • Treatment of adults with active ankylosing spondylitis (AS) who have had an inadequate response or intolerance to one or more tumor necrosis factor inhibitors (TNFIs).
  • • Treatment of adults with active nonradiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation who have had an inadequate response or intolerance to TNFIs.
  • • Limitations of Use: Not recommended for use in combination with other JAKIs, biologic immunomodulators, or potent immunosuppressants such as azathioprine and cyclosporine.

Dosage & Administration

  • • 15 mg once daily.
  • • Form: Extended-release tablets.

Dose Modifications & Interruptions

  • • Renal impairment: No dosage adjustment recommended for mild, moderate, or severe renal impairment in patients treated for AS or nr-axSpA.
  • • Hepatic impairment: Use is not recommended in severe hepatic impairment. No dosage adjustment needed for mild or moderate hepatic impairment (Child-Pugh A or B) in patients treated for AS or nr-axSpA.
  • • Strong CYP3A4 inducers: Use is not recommended.
  • • Strong CYP3A4 inhibitors: No dosage modification recommendation for AS or nr-axSpA.
  • • Infections: Interrupt treatment; may restart when infection is controlled.
  • • Hematologic parameters: Interrupt treatment if absolute neutrophil count < 1000 cells/mm3, absolute lymphocyte count < 500 cells/mm3, or hemoglobin < 8 g/dL; may restart once values return to above these thresholds.
  • • Hepatic transaminases: Interrupt treatment for elevated hepatic transaminases or suspected drug-induced liver injury until diagnosis is excluded.

Safety Monitoring & Precautions

  • • Pretreatment tests and evaluations are similar to those for previously approved indications.
  • • Boxed warnings, contraindications, and other warnings/precautions are the same as for other approved indications.
  • • Common adverse events (≥1%): Upper respiratory tract infections, acne, herpes simplex, headache, blood creatine phosphokinase increased, cough, hypersensitivity, folliculitis, nausea, abdominal pain, pyrexia, increased weight, herpes zoster, influenza, fatigue, neutropenia, myalgia, and influenza-like illness.

Place in Therapy / Clinical Context

  • • May be used for active AS/r-axSpA or active nr-axSpA with objective signs of inflammation who have an inadequate response or intolerance to TNFIs or for whom TNFIs are medically inadvisable.
  • • For active nr-axSpA candidates for JAKI therapy, upadacitinib may be preferred over tofacitinib due to lack of evidence supporting tofacitinib's off-label use for nr-axSpA.
  • • JAKIs may be used as alternatives to IL-17AIs when TNFI therapy is inadequate, not tolerated, or medically inadvisable.
  • • Evidence does not support use of targeted biologic or synthetic immunomodulators for treatment of patients without inflammatory disease; objective signs of inflammation (e.g., elevated high-sensitivity CRP and/or sacroiliitis on MRI) are required.

Document 470

Infectious Disease

  • Active, serious systemic or localized infection (including undrained abscess)
  • Untreated latent or active tuberculosis infection
  • Hepatitis B surface antigen (HBsAg)-positive without antiviral prophylaxis
  • Untreated HIV infection (treated, well-controlled, asymptomatic HIV-positive patients are permitted)

Malignancy & Hematology

  • Malignancy in the previous 5 years (except successfully treated nonmelanoma skin cancer or cervical cancer, unless rheumatologist and oncologist agree risk-benefit favors use)
  • Lymphocytes < 500 cells/mm3, neutrophils < 1000 cells/mm3, or hemoglobin < 8 g/dL

Hepatic Function

  • Severe hepatic impairment (Child-Pugh class C)

Cardiovascular & Thrombotic Risk

  • Increased risk of thrombosis or major adverse cardiovascular events where potential harms are expected to outweigh anticipated benefits

Concomitant Medications & Vaccines

  • Concomitant JAK inhibitors, biologic immunomodulators, or potent immunosuppressants (azathioprine, cyclosporine), except during treatment transitions
  • Concomitant strong CYP3A4 inducers (e.g., rifampin)
  • Concomitant live or live-attenuated vaccines, or administration of inactivated, live, or live-attenuated vaccines less than 2 weeks before initiation

Reproductive Status

  • Pregnancy
  • Breastfeeding

Diagnosis & Provider Requirements

  • Prescribed and monitored by a VA/VA Community Care rheumatologist or locally designated expert
  • Definite or provisional diagnosis of active axial spondyloarthritis (ankylosing spondylitis/radiographic axial spondyloarthritis or nonradiographic axial spondyloarthritis) made by a VA/VA Community Care rheumatologist

Prior Therapy Requirements

  • One tumor necrosis factor inhibitor (TNFi) is medically inadvisable, not tolerated, or not adequate after 3 months

Laboratory & Screening Requirements

  • Completed tuberculosis test using tuberculin skin test or interferon-gamma release assay (IGRA)
  • Completed hepatitis B screening (HBsAg, total antibody-to-hepatitis-B-core-antigen [anti-HBc], and antibody to hepatitis B surface antigen [anti-HBs])
  • Current or past completion of hepatitis C screening

Additional Inclusion Criteria

  • If HBsAg-negative but anti-HBc-positive and consult indicated: GI/liver or ID expert consulted for advice on antiviral prophylaxis or preemptive monitoring for HBV reactivation
  • For patients who can become pregnant: Pregnancy status verified; counseling provided on potential risks vs benefits of treatment and use of effective contraception

Clinical Context & Monitoring Notes

  • Use with extreme caution in patients 65 years or older due to higher risks of serious infections, fatal infection, and possibly increased mortality
  • Upadacitinib may be used with methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine
  • Vaccinations should be updated before initiation; recombinant zoster vaccine should be completed or initiated by end of first year, preferably when dosage is low, disease is stable, or immune response can be expected
  • Applies only to new starts; stable patients should not be switched for nonmedical reasons

Document 490

Indication & Patient Population

  • Adults with moderately to severely active Crohn’s disease
  • Patients who have had an inadequate response or intolerance to one or more tumor necrosis factor inhibitors (TNFIs)
  • Limited to second-line use

Dosage & Administration Criteria

  • Induction: 45 mg once daily for 12 weeks
  • Maintenance: 15 mg once daily; a dosage of 30 mg once daily may be considered for refractory, severe, or extensive disease
  • Discontinue upadacitinib if an adequate response is not achieved with 30 mg daily
  • Use the lowest effective dosage needed to maintain response
  • Formulation: Extended-release tablets (15 mg, 30 mg, 45 mg)

Limitations & Contraindications

  • Not recommended for use in combination with other JAKIs
  • Not recommended for use in combination with biologic therapies for Crohn’s disease
  • Not recommended for use in combination with potent immunosuppressants such as azathioprine and cyclosporine

Laboratory Monitoring Requirements

  • Lipid panel (total cholesterol, LDL, HDL) about 12 weeks after initiation of therapy, then per lipid guidelines
  • Complete blood count as per routine management
  • Latent TB testing and TB activation screening
  • Liver panel as per routine management
  • Viral hepatitis reactivation screening per guidelines

Efficacy & Clinical Response Criteria

  • Clinical remission: CDAI < 150; stool frequency ≤ 2.8 daily and average daily abdominal pain score ≤ 1.0 with neither worse than baseline (PRO-2)
  • Endoscopic response: >50% decrease from baseline in SES-CD, or ≥2-point reduction from baseline if baseline SES-CD is 4
  • Clinical response: ≥30% decrease in stool frequency and/or abdominal pain, or ≥100-point decrease from baseline in CDAI
  • Onset of clinical response (CDAI-100) observed at Week 2

Safety Considerations

  • Monitor for gastrointestinal perforations
  • Safety profile is consistent with other approved indications

Place in Therapy & Selection Criteria

  • Appropriate for induction and maintenance therapy of moderate to severe, active luminal CD
  • May be less preferred than risankizumab-rzaa and ustekinumab in patients with co-existing plaque psoriasis
  • Preferred over vedolizumab in patients with extraintestinal involvement

Document 493

Exclusion Criteria

  • Uncontrolled, active, severe infection including evidence of C. difficile and undrained abscess (may start/restart once infection treatment initiated)
  • Untreated latent or active tuberculosis infection
  • Hepatitis B surface antigen (HBsAg)-positive and not on antiviral prophylaxis (may initiate after starting antiviral prophylaxis)
  • Untreated HIV infection (treated, well-controlled, asymptomatic HIV-positive patients may be treated)
  • Malignancy within the previous 5 years other than successfully treated nonmelanoma skin cancer or cervical cancer unless treating gastroenterologist and oncologist agree risk-benefits favor use
  • At increased risk of thrombosis or major adverse cardiovascular events where potential harms are expected to outweigh anticipated benefits
  • Lymphocytes < 500 cells/mm3 confirmed by repeat testing, neutrophils < 1000 cells/mm3, or hemoglobin < 8 g/dL (may start/restart once values normalize)
  • End stage renal disease (eGFR < 15 mL/min/1.73 m2)
  • Severe hepatic impairment (Child-Pugh C)
  • Concomitant live or live-attenuated vaccines or administration of inactivated, live, or live-attenuated vaccines less than 2 weeks before initiation
  • Concomitant JAK inhibitors, biologic immunomodulators, or potent immunosuppressants such as azathioprine and cyclosporine
  • Concomitant strong CYP3A4 inducers
  • Pregnancy (during therapy and for 4 weeks after the last dose)
  • Breastfeeding / providing breastmilk to an infant (during therapy and for 6 days after the last dose)

Inclusion Criteria

  • Prescribed and monitored by a VA/VA Community Care gastroenterologist or locally designated Crohn’s disease expert
  • Current or prior moderate to severe Crohn’s disease (CD) confirmed by endoscopy or imaging
  • Completed tuberculosis (TB) test using tuberculin skin test or interferon-gamma release assay [IGRA]
  • Completed hepatitis B screening (at minimum, HBsAg, total antibody-to-hepatitis-B-core-antigen [anti-HBc] and antibody to hepatitis B surface antigen [anti-HBs])
  • Current or past completion of hepatitis C screening (may initiate while waiting for test results)

Additional Inclusion Criteria (One Required)

  • Tumor necrosis factor inhibitor (TNFI) is medically inadvisable (Infliximab/biosimilar and adalimumab/biosimilar are preferred TNFIs in CD)
  • Primary nonresponse, inadequate partial response, or loss of response after 12 weeks of TNFI in the presence of adequate TNFI levels (mechanistic failure)
  • Loss of response to infliximab/biosimilar and another TNFI for CD despite therapeutic drug monitoring (TDM)-based optimized dosing to address pharmacokinetic failure

Adjudication & Supplemental Considerations

  • HBsAg-negative but anti-HBc-positive: GI/liver or infectious diseases expert must be consulted for advice on starting antiviral prophylaxis vs preemptive monitoring for HBV reactivation
  • Women who can become pregnant: Pregnancy status must be verified; counseling provided on risks vs benefits and use of effective contraception during therapy and for 4 weeks after discontinuation
  • Routine retesting for TB, Hepatitis B, and Hepatitis C screening is not required for prescription renewals (retesting in high-risk patients should be considered)
  • Drug Sequencing: First-line = Infliximab or adalimumab; Second/Third-line = Vedolizumab, upadacitinib, or risankizumab-rzaa (one drug must be risankizumab-rzaa as 2L or 3L); Fourth-line = Mirikizumab-mrkz or ustekinumab
  • Dosing: Prescribe at FDA-recommended dose for ulcerative colitis, adjusting for severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m2), mild to moderate hepatic impairment (Child-Pugh A or B), and strong CYP3A4 inhibitors
  • Vaccinations: Update before initiation when possible; recombinant zoster vaccine should be completed/initiated by end of first year, preferably at low dose/stable disease/robust immune response expected

Document 449

Indication & Patient Selection

  • • Treatment of adults with moderately to severely active ulcerative colitis (UC) who have had an inadequate response or intolerance to one or more tumor necrosis factor inhibitors (TNFIs)
  • • Limitation of Use: Not recommended for use in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs, or potent immunosuppressants such as azathioprine and cyclosporine

Pretreatment Tests & Evaluations

  • • Tuberculosis (TB) screening
  • • Viral hepatitis screening (hepatitis B, hepatitis C)
  • • Complete blood count (noting neutrophils, lymphocytes, hemoglobin)
  • • Liver panel
  • • Pregnancy status
  • • Update immunizations, including for varicella zoster or herpes zoster prophylaxis per immunization guidelines

Dosing & Administration

  • • Induction: 45 mg once daily for 8 weeks (extended-release tablets)
  • • Maintenance: 15 mg once daily; a dose of 30 mg once daily may be considered for patients with refractory, severe, or extensive disease
  • • Discontinue upadacitinib if an adequate response is not achieved with 30 mg
  • • Use the lowest effective dosage needed to maintain response

Monitoring During Therapy

  • • Lipid panel (total cholesterol, LDL, HDL) approximately 12 weeks after initiation of therapy, then per lipid guidelines
  • • Complete blood count per routine management
  • • Latent TB testing and TB activation monitoring
  • • Liver panel per routine management
  • • Viral hepatitis reactivation monitoring per guidelines

Efficacy & Response Criteria

  • • Clinical remission defined as Adapted Mayo score ≤ 2, with stool frequency score (SFS) ≤ 1 and not greater than baseline, rectal bleeding score (RBS) = 0, and endoscopic subscore ≤ 1 without friability
  • • Onset of treatment benefit: Earliest significant treatment difference occurred at Week 2; post hoc analysis demonstrated significant differences as early as Day 1 based on SFS ≤ 1/0, RBS = 0, and a 2-item patient-reported outcome (SFS ≤ 1 and RBS = 0)
  • • Duration of an adequate therapeutic trial: Approximately 16 weeks (based on extended induction substudy where 58.4% of Week 8 nonresponders achieved clinical response at Week 16); no FDA-approved extended induction dosage regimen is available

Safety Considerations & Warnings

  • • Boxed warnings, contraindications, and other warnings/precautions are consistent with other approved indications for upadacitinib
  • • Common adverse events (≥5%): Induction therapy (upper respiratory tract infection, acne, increased blood creatine phosphokinase, neutropenia); Maintenance therapy (upper respiratory tract infection, increased blood creatine phosphokinase, neutropenia, elevated liver enzymes, rash)
  • • Specific safety risks noted: Venous thromboembolism, herpes zoster infection, hepatic disorder (mostly transaminase elevations), neutropenia, and CPK elevation
  • • Avoid pregnancy during upadacitinib therapy and for 4 weeks after the end of therapy

Place in Therapy Context

  • • Alternative to tofacitinib for patients with moderate to severely active UC who have an inadequate response to vedolizumab (if TNFIs are medically inadvisable) or nonresponse, inadequate response, loss of response, or intolerance to TNFIs
  • • Network meta-analyses indicate upadacitinib may be significantly more effective than tofacitinib in inducing clinical remission, with similar efficacy for maintenance of clinical remission and glucocorticoid-free remission
  • • Associated with the lowest probability of discontinuations due to adverse events relative to infliximab, vedolizumab, and adalimumab, but a higher risk of adverse events than all other drugs except adalimumab 80/40 mg

Document 768

Infection & Screening

  • Uncontrolled active infection, including undrained abscess; upadacitinib may be started/restarted once the infection treatment has been initiated
  • Untreated latent or active tuberculosis infection
  • Completed tuberculosis (TB) test using tuberculin skin test or interferon-gamma release assay [IGRA]
  • Hepatitis B surface antigen (HBsAg)-positive and not on antiviral prophylaxis; upadacitinib may be initiated after starting antiviral prophylaxis
  • Untreated HIV infection; treated, well-controlled, asymptomatic HIV-positive patients can be treated with upadacitinib
  • Current or past completion of hepatitis C screening; upadacitinib may be initiated while waiting for test results
  • If HBsAg-negative but anti-HBc-positive and patient’s practitioner deems consult is indicated, a GI/liver or infectious diseases expert has been (e-)consulted for advice on whether to start antiviral prophylaxis or to preemptively monitor for HBV reactivation

Malignancy & Cardiovascular Risk

  • Malignancy within the previous 5 years other than successfully treated nonmelanoma skin cancer or cervical cancer, unless it is documented that the treating rheumatologist and oncologist agree that risk-benefits favor using the drug
  • At increased risk of thrombosis or major adverse cardiovascular events where potential harms are expected to outweigh the anticipated benefits

Laboratory Values & Organ Function

  • Lymphocytes < 500 cells/mm3 confirmed by repeat testing, neutrophils < 1000 cells/mm3 , or hemoglobin < 8 g/dL; upadacitinib may be started/restarted once values normalize
  • Severe hepatic impairment (Child-Pugh class C)

Gastrointestinal Risk

  • At increased risk of gastrointestinal perforation (e.g., history of diverticulitis, concomitant glucocorticoids) where potential harms of therapy are expected to outweigh the anticipated benefits

Concomitant Medications & Vaccinations

  • Concomitant JAK inhibitors, biologic immunomodulators (e.g., tocilizumab, abatacept), or potent immunosuppressants such as azathioprine and cyclosporine
  • Concomitant methotrexate at antirheumatic doses (≤25 mg/WEEK) is allowable but may increase risks of immunosuppression and infection
  • Concomitant live or live-attenuated vaccines or administration of inactivated, live, or live-attenuated vaccines less than 2 weeks before initiation of upadacitinib; when possible, vaccinations should be updated before the patient initiates upadacitinib, with recombinant zoster (SHINGRIX) vaccine completed or at least initiated by the end of the first year of treatment
  • Concomitant strong CYP3A4 inDUCers

Pregnancy & Lactation

  • Pregnancy (during therapy and for 4 weeks after the last dose of upadacitinib)
  • Breastfeeding/providing breastmilk to an infant (during therapy and for 6 days after the last dose)
  • For females who can become pregnant: pregnancy status verified; counseling provided on potential risks vs benefits of treatment and the use of effective contraception during therapy and for 4 weeks after discontinuation of therapy

Dietary Restrictions

  • Ingestion of food or drink containing grapefruit during therapy

Diagnosis & Clinical Monitoring

  • Definite or provisional diagnosis of active giant cell arteritis
  • Prescribed and monitored by a VA/VA Community Care rheumatologist or locally designated expert
  • Initiated concurrently or after glucocorticoid therapy unless glucocorticoids are medically inadvisable

Screening & Renewal Procedures

  • Routine rescreening for hepatitis B or hepatitis C is not required for prescription renewals; retesting in high-risk patients should be considered

Source Documents

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