UPADACITINIB
Clinical safety rating: caution
Comprehensive clinical and safety monograph for UPADACITINIB (UPADACITINIB).
Upadacitinib is a selective and reversible Janus kinase (JAK) inhibitor. It preferentially inhibits JAK1 over JAK2, JAK3, and TYK2. By inhibiting JAK1, it modulates the signaling of multiple cytokines (e.g., IL-6, IL-2, IL-15, and interferons) involved in inflammatory pathways.
| Metabolism | Primarily metabolized by CYP3A4, with minor contributions from CYP2D6. Upadacitinib is a substrate of P-glycoprotein (P-gp). |
| Excretion | Renal (approximately 24% unchanged in urine), fecal (approximately 34% unchanged in feces); total recovery of radiolabeled dose: 88% (36% urine, 52% feces). |
| Half-life | Terminal elimination half-life is approximately 9 hours (range 5–13 hours), supporting once-daily dosing. |
| Protein binding | Approximately 52% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Apparent volume of distribution (Vd/F) is approximately 1.2 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Absolute oral bioavailability is approximately 76%. |
| Onset of Action | Oral: Clinical effects observed within 1–2 weeks, with maximal benefit by 12–16 weeks. |
| Duration of Action | Duration of action corresponds to dosing interval; therapeutic effect maintained with once-daily dosing; drug levels decline over 24 hours. |
15 mg orally once daily for rheumatoid arthritis; 15 mg once daily for psoriatic arthritis; 15 mg once daily for ankylosing spondylitis; 15 mg once daily for atopic dermatitis; 45 mg once daily for 8 weeks then 15 mg once daily for ulcerative colitis; 45 mg once daily for 8 weeks then 15 mg once daily for Crohn disease.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR ≥15 mL/min). Not recommended for use in patients with severe renal impairment (eGFR <15 mL/min) or end-stage renal disease. |
| Liver impairment | Contraindicated in patients with severe hepatic impairment (Child-Pugh C). No dose adjustment recommended for mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. |
| Pediatric use | Approved for atopic dermatitis in patients aged 12 years and older: 15 mg orally once daily; for ulcerative colitis in patients aged 12 years and older: weight ≥40 kg: 45 mg once daily for 8 weeks then 15 mg once daily; weight <40 kg: dosing not established. For Crohn disease in patients aged 12 years and older: weight ≥40 kg: 45 mg once daily for 8 weeks then 15 mg once daily; weight <40 kg: dosing not established. |
| Geriatric use |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for UPADACITINIB (UPADACITINIB).
| Breastfeeding | No human data on upadacitinib in breast milk; however, it is secreted in rat milk. M/P ratio unknown. Potential for serious adverse reactions in breastfed infant (immunosuppression, infection risk). Discontinue breastfeeding during treatment and for 6 days after last dose. |
| Teratogenic Risk | Upadacitinib is contraindicated in pregnancy. Animal studies show teratogenicity at clinically relevant doses. First trimester: increased risk of structural anomalies (neural tube, cardiovascular). Second/third trimester: potential fetal harm from maternal immunosuppression, and late gestation exposure may cause neonatal myelosuppression. Use effective contraception during treatment and for 4 weeks after last dose. |
■ FDA Black Box Warning
WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, THROMBOSIS, and MAJOR ADVERSE CARDIOVASCULAR EVENTS. Upadacitinib increases the risk of serious infections leading to hospitalization or death, including tuberculosis, invasive fungal infections, and bacterial/viral/opportunistic infections. Higher rates of all-cause mortality, including sudden cardiovascular death, have been observed with another JAK inhibitor. Lymphoma and other malignancies have occurred. Thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, has been reported. Major adverse cardiovascular events (MACE) such as myocardial infarction and stroke have been observed with another JAK inhibitor.
| Serious Effects |
["Hypersensitivity to upadacitinib or any excipient.","Active serious infections, including localized infections."]
| Precautions | ["Serious infections: Monitor for signs/symptoms; interrupt treatment if infection occurs.","Malignancies: Avoid use in patients with known malignancy except for treated non-melanoma skin cancers.","Thrombosis: Use with caution in patients at risk; discontinue if symptoms occur.","MACE: Consider risks in patients with cardiovascular risk factors.","Gastrointestinal perforations: Has been reported; use caution in patients with history of diverticulitis or GI ulcers.","Laboratory abnormalities: Monitor neutrophils, lymphocytes, hemoglobin, liver enzymes, and lipids.","Hypersensitivity: Discontinue if serious hypersensitivity reactions occur.","Vaccinations: Avoid live vaccines during therapy."] |
Loading safety data…
| No specific dose adjustment recommended. Use with caution due to potential increased risk of infections and adverse events; monitor renal function (eGFR) and consider age-related hepatic impairment. |
| Fetal Monitoring | Pregnancy testing prior to initiation; monthly pregnancy tests during therapy if childbearing potential. Monitor for infections (maternal and neonatal), hematologic parameters (CBC with differential), liver function tests. Fetal ultrasound for anomaly screening if exposed during pregnancy. |
| Fertility Effects | In animal studies, upadacitinib adversely affected female fertility (decreased implantation, increased preimplantation loss) at clinically relevant exposures. No effect on male fertility observed. In humans, potential for reversible impairment of female fertility; ovulation may be affected due to JAK inhibition on gonadotropin signaling. Contraception recommended for women of reproductive potential. |