What is the proper usage of upadacitinib (Janus kinase inhibitor) for treatment?

How to Use Upadacitinib

Upadacitinib is dosed at 15 mg once daily for rheumatoid arthritis and atopic dermatitis, with higher doses (30 mg daily for maintenance, 45 mg daily for induction) used for inflammatory bowel disease, and dose adjustments required for severe renal impairment (maximum 15 mg daily) but not for mild-to-moderate hepatic or renal dysfunction. 1, 2

Disease-Specific Dosing

Rheumatoid Arthritis

• Standard dose: 15 mg once daily 1, 2
• This dose demonstrated superiority over adalimumab when combined with methotrexate in head-to-head trials 2, 3
• The 30 mg dose is not approved for RA due to unfavorable risk-benefit ratio 1

Atopic Dermatitis

• Standard dosing: 15 mg or 30 mg once daily 1, 2
• Higher doses (30 mg daily) demonstrate superior efficacy in reducing EASI scores and were superior to dupilumab in head-to-head trials 2
• Use the lowest effective dose, particularly in patients with risk factors for adverse events 1

Ulcerative Colitis

• Induction: 45 mg once daily for 8 weeks (may extend to 16 weeks if inadequate benefit) 1, 2
• Maintenance: 15 mg or 30 mg once daily 1, 2
• In TNF-inhibitor inadequate responders, 30 mg twice daily maintenance may be used 1
• The American Gastroenterological Association considers upadacitinib a "higher efficacy medication" for ulcerative colitis 2

Crohn's Disease

• Typical dosing: 45 mg for induction, followed by 15 mg or 30 mg for maintenance 2
• Phase II trials showed promising results, with Phase III trials ongoing 1

Psoriatic Arthritis

• Standard dose: 15 mg once daily 1
• The 30 mg dose showed superiority over adalimumab but is not the approved dose 3

Dose Adjustments for Organ Dysfunction

Renal Impairment

• Mild-to-moderate renal impairment (eGFR ≥30 mL/min or CrCl ≥30 mL/min): No dose adjustment needed 1
• Severe renal impairment (CrCl <30 mL/min): Maximum dose 15 mg daily 1, 2
• Upadacitinib undergoes 20% renal excretion 1

Hepatic Impairment

• Mild-to-moderate hepatic impairment (Child-Pugh A/B): No dose adjustment needed 1
• Severe hepatic disease (Child-Pugh C): Contraindicated—do not use 1, 2

Age Considerations

• Patients aged ≥75 years: Consider dose reduction to 15 mg daily 2
• Patients aged ≥65 years have increased risk of serious infections and malignancies 1, 2

Drug Interactions Requiring Dose Adjustment

CYP3A4 Inhibitors

• Ketoconazole and other strong CYP3A4 inhibitors: Reduce upadacitinib dose 1
• Upadacitinib undergoes hepatic oxidation with minor CYP3A4 metabolism 1

CYP3A4 Inducers

• Rifampicin: Consider dose increase of upadacitinib 1
• Strong CYP3A4 inducers: Coadministration not recommended 4
• Rifampicin increases hepatic metabolism, potentially reducing therapeutic effect 1

Administration and Food Effects

• Take once daily, with or without food 5
• High-fat meals increase Cmax by only 20% and AUC by 17%—clinically insignificant 5
• Extended-release formulation achieves steady state by day 4 5
• Median time to peak plasma concentration: 2-4 hours 5

Pre-Treatment Screening and Baseline Monitoring

Required Laboratory Tests at Baseline

• Complete blood count with differential 2
• Liver enzymes (ALT, AST) 2
• Lipid panel 2
• Renal function (creatinine, eGFR) 1
• Viral hepatitis screening (HBV, HCV) 2
• Tuberculosis testing (IGRA or PPD) 2
• Pregnancy test in women of childbearing potential 2

Ongoing Monitoring Schedule

• CBC with differential and liver enzymes: After initiation or dose escalation 2
• Lipids: 4 weeks after initiation for abrocitinib, 12 weeks for upadacitinib 2
• CPK: Monitor if clinically indicated 4, 6

Contraindications and High-Risk Populations

Absolute Contraindications

• Severe active infections (acute or chronic, including active tuberculosis) 1
• Severe hepatic disease (Child-Pugh C) 1, 2
• Uncontrolled malignancy or ongoing chemotherapy 1

Relative Contraindications Requiring Careful Risk-Benefit Assessment

• History of venous thromboembolism (VTE) 1, 2
• Age >65 years, particularly with cardiovascular risk factors 1, 2
• Current or previous long-term smokers 2
• History of cardiovascular disease 2
• History of malignancy 1, 2
• Pregnancy and lactation 1, 2, 4

Special Considerations for VTE Risk

• Assess for inherited thrombophilias (factor V Leiden), exogenous estrogen use, recent surgery, immobility, uncontrolled hypertension, obesity 1
• In upadacitinib trials, VTE rates were <0.1/100 patient-years, occurring only in patients with VTE history and risk factors 1
• Use lowest effective dose in high-risk patients 1

Vaccination Recommendations

Before Starting Upadacitinib

• Inactivated vaccines: Pneumococcal, influenza, and two-dose Shingrix series for patients >18 years 1
• Live zoster vaccine (Zostavax): Administer at least 3-4 weeks before initiating upadacitinib if recombinant vaccine unavailable 1
• COVID-19 vaccines: Use nonlive vaccines with higher efficacy 1
• Ideally complete vaccine series before starting treatment, though clinical scenarios may make delays challenging 1

Vaccination During Treatment

• European Task Force recommends 1-week pause after COVID-19 vaccination to prevent insufficient response 1
• Follow local and national health authority guidelines 1

Pregnancy and Contraception

Pregnancy Risk

• Contraception required for both female and male patients during treatment 1
• Animal studies show teratogenicity (skeletal malformations in rats, cardiovascular malformations in rabbits) at exposures ≥1.6 times the 15 mg dose 4
• Limited human data: 54 reported pregnancies resulted in 17 healthy newborns, 14 spontaneous abortions (10 on concomitant MTX), 12 ongoing pregnancies 1
• Pregnancy surveillance program available: 1-800-633-9110 4

Lactation

• Breastfeeding not recommended during treatment and for 6 days after last dose 4
• Animal data shows excretion in milk 4

Common and Serious Adverse Events

Most Common Adverse Events

• Upper respiratory tract infection, nasopharyngitis, urinary tract infection 6
• Acne (1.3% vs 0.3% placebo in psoriatic arthritis) 4
• Bronchitis (3.9% vs 2.7% placebo) 4

Serious Infections

• Rates similar between upadacitinib 15 mg and adalimumab but higher than methotrexate 6
• Herpes zoster rates higher with upadacitinib versus adalimumab and methotrexate 6
• In psoriatic arthritis: herpes zoster 1.1%, herpes simplex 1.4% with 15 mg dose 4

Laboratory Abnormalities Requiring Monitoring

• Hepatic transaminase elevations ≥3x ULN: 2.1% (ALT), 1.5% (AST) with 15 mg 4
• CPK elevations >5x ULN: 1.0% with 15 mg, mostly transient 4, 6
• Neutropenia <1000 cells/mm³: 1.1% with 15 mg 4
• Lymphopenia <500 cells/mm³: 0.9% with 15 mg 4
• Lipid elevations: Mean LDL increased 14.81 mg/dL, HDL increased 8.16 mg/dL, LDL/HDL ratio stable 4

Cardiovascular and Thrombotic Events

• Rates of major adverse cardiovascular events (MACE) similar across upadacitinib, methotrexate, and adalimumab 6
• VTE rates similar across treatment groups in pooled analysis 6
• Arterial thrombosis rare: 0.2 per 100 patient-years with 30 mg dose 4

Malignancy Risk

• Rates similar between upadacitinib and adalimumab through 156 weeks 1
• Almost all malignancies occurred in patients aged ≥53 years 1
• Boxed warning for increased malignancy risk, though absolute risk remains low 1

Clinical Positioning and Regulatory Guidance

FDA Recommendations

• Use JAK inhibitors in patients with prior failure or intolerance to TNF antagonists 2
• This reflects safety concerns from post-marketing surveillance data 2

European Medicines Agency Recommendations

• Use cautiously as first-line agents in patients at risk for adverse cardiovascular outcomes 2
• Consider cardiovascular risk factors, age, smoking status before initiating 2

Common Pitfalls to Avoid

• Do not use in severe hepatic disease (Child-Pugh C)—this is an absolute contraindication 1
• Do not forget dose adjustment to maximum 15 mg daily in severe renal impairment 1
• Do not overlook VTE risk factors before initiating therapy, particularly in older patients 1, 2
• Do not use strong CYP3A4 inducers concomitantly—may reduce therapeutic effect 4
• Do not initiate without tuberculosis screening—latent TB can reactivate 2
• Do not use higher than approved doses for each indication—the 30 mg dose for RA has unfavorable risk-benefit 1