Introduction
Upadacitinib (brand name Rinvoq®) is an oral, selective, and reversible Janus kinase (JAK) inhibitor approved for the treatment of several immune-mediated inflammatory conditions. As a small molecule targeted synthetic disease-modifying antirheumatic drug (tsDMARD), it represents a significant advancement in the management of autoimmune disorders by specifically inhibiting intracellular signaling pathways involved in inflammation.
Mechanism of Action
Upadacitinib preferentially inhibits JAK1 over JAK2, JAK3, and TYK2 through a reversible mechanism. JAK enzymes mediate signaling of cytokines and growth factors involved in immune cell function, inflammation, and hematopoiesis. By inhibiting JAK1-dependent cytokine signaling pathways (including IL-6, IL-7, IL-15, and interferon), upadacitinib modulates the immune response and reduces inflammation in affected tissues.
Indications
FDA-approved indications include:
- Moderate to severe rheumatoid arthritis (as monotherapy or in combination with methotrexate)
- Active psoriatic arthritis
- Moderate to severe ulcerative colitis
- Moderate to severe atopic dermatitis
- Active ankylosing spondylitis
Dosage and Administration
Standard dosing:- Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis: 15 mg once daily
- Ulcerative colitis: 45 mg once daily for 8 weeks, then 15 mg once daily for maintenance
- Atopic dermatitis: 15 mg or 30 mg once daily based on disease severity
- Renal impairment: No dosage adjustment needed for mild to moderate impairment; use caution in severe impairment
- Hepatic impairment: Not recommended in severe hepatic impairment
- Elderly: Consider higher risk of infections and malignancies
- Pregnancy: Category C - use only if potential benefit justifies potential risk
Pharmacokinetics
Absorption: Rapidly absorbed with median Tmax of 2-4 hours; bioavailability approximately 88% Distribution: Volume of distribution ~118 L; 50% protein-bound Metabolism: Primarily via CYP3A4 with minor contributions from CYP2D6 Elimination: Half-life ~8-14 hours; excreted primarily in feces (69%) and urine (24%)Contraindications
- Hypersensitivity to upadacitinib or any component
- Active serious infections
- Severe hepatic impairment
- Concomitant use with strong CYP3A4 inhibitors in patients with rheumatoid arthritis or psoriatic arthritis receiving 15 mg daily
Warnings and Precautions
Black Box Warning:- Serious infections leading to hospitalization or death
- Increased risk of all-cause mortality, major adverse cardiovascular events, and malignancies
- Thrombosis, including deep vein thrombosis and pulmonary embolism
- Gastrointestinal perforations
- Laboratory abnormalities (neutropenia, lymphopenia, anemia, lipid elevations)
- Hypersensitivity reactions
- Avoid live vaccines during and immediately prior to therapy
Drug Interactions
Significant interactions:- Strong CYP3A4 inhibitors (ketoconazole, clarithromycin): Increase upadacitinib exposure
- Moderate CYP3A4 inhibitors: May require dose modification
- Immunosuppressants: Increased risk of infections
- Live vaccines: Avoid concomitant administration
Adverse Effects
Common (≥10%):- Upper respiratory tract infections
- Nausea
- Increased creatine phosphokinase
- Headache
- Increased LDL and HDL cholesterol
- Serious infections (pneumonia, cellulitis, herpes zoster)
- Malignancies (lymphoma, lung cancer)
- Cardiovascular events
- Thrombosis
- Gastrointestinal perforations
Monitoring Parameters
Baseline:- CBC with differential
- Liver function tests
- Lipid panel
- Tuberculosis screening
- Viral hepatitis screening
- Pregnancy testing
- CBC monthly for first 3 months, then every 3 months
- Lipid panel at 12 weeks and periodically thereafter
- Liver enzymes periodically
- Signs/symptoms of infection
- Cardiovascular risk assessment
- Skin examination for malignancies
Patient Education
- Take medication exactly as prescribed, typically once daily with or without food
- Report any signs of infection (fever, cough, fatigue)
- Seek immediate medical attention for symptoms of thrombosis (shortness of breath, chest pain, leg swelling)
- Avoid live vaccines during treatment
- Use effective contraception during treatment
- Regular monitoring appointments are essential
- Report any new or worsening symptoms promptly
References
1. FDA Prescribing Information: Rinvoq (upadacitinib). 2023 2. Cohen SB, et al. Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT phase III clinical programme. Ann Rheum Dis. 2021;80(3):304-311 3. Burmester GR, et al. Efficacy and safety of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic DMARDs: results from SELECT-NEXT. Ann Rheum Dis. 2020;79(1):95-103 4. phase III trials. Lancet. 2021;397(10292):2151-2167 5. Guttman-Yassky E, et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials. Lancet. 2021;397(10290):2151-2168
Note: This monograph provides general information and should not replace clinical judgment. Always consult current prescribing information and clinical guidelines before making treatment decisions.