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. |
| Molecular Weight | 380.42 |
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 | 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. |
| 1st trimester | Avoid use. Human data limited; animal studies show teratogenicity in rats and rabbits. Exposure may increase risk of spontaneous abortion and malformations. |
| 2nd trimester | Avoid use. Potential for fetal harm due to JAK-STAT inhibition, which is involved in placental development. Limited human data, but animal studies show adverse effects. |
| 3rd trimester | Avoid use in third trimester due to potential neonatal toxicity, including bone marrow suppression and increased infection risk. |
Clinical note
Comprehensive clinical and safety monograph for UPADACITINIB (UPADACITINIB).
| Placental transfer | Upadacitinib crosses the placenta in animal studies; human data not available. Molecular weight 380.42 Da suggests placental transfer expected. |
| Breastfeeding | Unknown if excreted in human breast milk. Present in rat milk. JAK inhibition could pose risk to infant immune system. Not recommended due to potential for serious adverse reactions in breastfed infants. |
■ 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 excipientsActive tuberculosisSevere hepatic impairment (Child-Pugh C)Pregnancy
| 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. |
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| Lactation Rating | L5 |
| 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. |
| 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. |
| Food/Dietary | No specific food interactions. Grapefruit and grapefruit juice may increase upadacitinib exposure due to CYP3A4 inhibition; avoid excessive consumption (e.g., more than 8 oz per day) or consider dose adjustment if concurrent intake is regular. |
| Clinical Pearls | Upadacitinib is a JAK1-selective inhibitor; monitor for thrombosis, serious infections, and laboratory abnormalities (neutropenia, lymphopenia, anemia, elevated liver enzymes, lipids). Avoid use with strong CYP3A4 inhibitors unless dose adjusted. Screen for TB before initiation. Not recommended in patients with severe hepatic impairment. |
| Patient Advice | Take once daily with or without food, swallow whole (do not crush or chew). · Increased risk of infections; seek medical attention for fever, chills, or other signs of infection. · Report any signs of blood clots (sudden shortness of breath, chest pain, leg swelling) to your doctor. · Do not receive live vaccines during treatment; update vaccinations before starting. · Tell your doctor about all medications you take, especially antifungal or antibiotic medicines. · Regular blood tests will be needed to monitor blood counts, liver function, and cholesterol levels. |