Upadacitinib

Upadacitinib is used for: Rheumatoid Arthritis, Psoriatic Arthritis, Atopic Dermatitis, Ankylosing Spondylitis, Ulcerative Colitis, Nonradiographic Axial Spondyloarthritis

Oral Rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis Indicated for RA, PsA and AS in adults who have had an inadequate response or intolerance to >1 TNF blockers The recommended dose is 15 mg once daily. Consideration should be given to discontinuing treatment in patients with axial spondyloarthritis who have shown no clinical response after 16 weeks of treatment. Atopic Dermatitis Indicated for refractory moderate-to-severe atopic dermatitis (AD) in adults whose disease is not adequately controlled with other systemic therapies or if those therapies are inadvisable <65 years 15 mg PO once daily initially; consider increasing to 30 mg once daily if an adequate response is not achieved Discontinue if 30-mg dose if adequate response is not achieved Use the lowest effective dose needed to maintain response Ulcerative Colitis Indicated for moderate to severe active ulcerative colitis (UC) in adults who had inadequate response or intolerance to ?1 TNF blocker Induction: The recommended induction dose of upadacitinib is 45 mg once daily for 8 weeks. For patients who do not achieve adequate therapeutic benefit by week 8, upadacitinib 45 mg once daily may be continued for an additional 8 weeks. Upadacitinib should be discontinued in any patient who shows no evidence of therapeutic benefit by week 16. Maintenance 15 mg PO once daily Refractory, severe, or extensive disease: Consider 30 mg Maintenance The recommended maintenance dose of upadacitinib is 15 mg or 30 mg once daily based on individual patient presentation: The lowest effective dose for maintenance should be considered. For patients > 65 years of age, the recommended dose is 15 mg once daily. Discontinue if unable to achieve adequate therapeutic response with 30 mg/day In patients who have responded to treatment with upadacitinib, corticosteroids may be reduced and/or discontinued in accordance with the standard of care. Hepatic impairment RA, PsA, AS, nr-axSpA, or AD Mild or moderate (Child-Pugh A or B): No dose adjustment is required Severe (Child-Pugh C): Not recommended UC Mild or moderate (Child-Pugh A or B): 30 mg qDay x 8 weeks for induction, then 15 mg qDay for maintenance Severe (Child-Pugh C): Not recommended

Atopic Dermatitis Indicated for refractory moderate-to-severe atopic dermatitis (AD) in adults and pediatric patients aged >12 years whose disease is not adequately with other systemic therapies or if those therapies are inadvisable >12 years and >40 kg 15 mg PO once daily initially; consider increasing to 30 mg once daily if an adequate response is not achieved Discontinue if 30-mg dose if adequate response not achieved Use lowest effective dose needed to maintain response

Renal impairment RA, PsA, AS, or nr-axSpA Mild, moderate, or severe: No dose adjustment necessary ESRD: Not studied AD Mild or moderate (eGFR >30 mL/min/1.73 m2): No dose adjustment necessary Severe (eGFR <30 mL/min/1.73 m2): 15 mg PO qDay ESRD: Not studied UC Mild or moderate (eGFR >30 mL/min/1.73 m2): No dose adjustment necessary Severe (eGFR 15 to <30 mL/min/1.73 m2): 30 mg qDay x 8 weeks for induction, then 15 mg qDay for maintenance ESRD (eGFR <15 mL/min/1.73 m2): Not recommended

May be taken with or without food

Hypersensitivity to upadacitinib or any of its excipients. Active TB or serious infections. Severe hepatic impairment. Pregnancy.

Malignancies reported; consider risks and benefits of treatment before initiating in patients with known malignancy, other than previously treated nonmelanoma skin cancer; screen for malignancies during treatment according to guidelines Thrombosis reported, including DVT, PE, and arterial thrombosis Gastrointestinal perforation reported; unknown if JAK inhibition is implicated in these events; many patients were also receiving NSAIDs May cause neutropenia, lymphopenia, anemia, elevated lipids, or elevated liver enzymes; monitor for abnormal laboratory values and assess the need to interrupt dosing Based on findings in animal studies, may cause fetal harm when administered to pregnant women Patients with RA aged >50 years with at least 1 cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed Serious and fatal infections reported Most frequent infections reported included pneumonia and cellulitis Opportunistic infections reported included TB, multidermatomal herpes zoster, oral/esophageal candidiasis, and cryptococcosis Viral reactivation, including cases of herpes virus reactivation (eg, herpes zoster) and hepatitis B virus reactivation, were reported A higher rate of all-cause mortality, including sudden cardiovascular death, was observed in patients treated with the JAK inhibitor compared with TNF blockers; consider benefits and risks for individual patient before initiating or continuing treatment, especially the following patients: Who are current or past smokers Who have other cardiovascular risk factors Who have developed a malignancy Who have a known malignancy other than a successfully treated nonmelanoma skin cancer

Pregnancy Limited human data on use in pregnant women are not sufficient to evaluate a drug-associated risk for major birth defects or miscarriage Verify pregnancy status of females of reproductive potential before starting treatment Animal data Based on animal studies, upadacitinib has the potential to adversely affect a developing fetus In animal embryofetal development studies, oral upadacitinib administration to pregnant rats and rabbits at exposures greater or equal than ~1.6 and 15 times the maximum recommended human dose (MRHD), respectively, resulted in dose-related increases in skeletal malformations (rats only), an increased incidence of cardiovascular malformations (rabbits only), increased postimplantation loss (rabbits only), and decreased fetal body weights in both rats and rabbits Contraception Females of reproductive potential: Use effective contraception during treatment and for 4 weeks after final dose Clinical considerations Published data suggest that increased disease activity is associated with risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth Lactation No data available on the presence of upadacitinib in human milk, the effects on the breastfed infant, or the effects on milk production Available data in animals have shown upadacitinib excreted in milk If a drug is present in animal milk, it is likely the drug will be present in human milk Because of the potential for serious adverse reactions in the breastfed infant, advise patients that breastfeeding is not recommended during treatment with upadacitinib, and for 6 days (~10 half-lives) after the last dose

Increased exposure w/ strong CYP3A4 inhibitors eg, ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, grapefruit. Decreased exposure w/ strong CYP3A4 inducers eg, rifampin, phenytoin. Decreased AUC & Cmax of midazolam, rosuvastatin, atorvastatin.

Side effects of Upadacitinib : >10% RA Upper respiratory tract infection (13.5%) AD Upper respiratory tract infection (23-25%) Acne (10-16%) 1-10% RA Nausea (3.5%) Neutropenia (1.1-2.4%) Lymphopenia (0.3-2.4%) Cough (2.2%) Elevated ALT (0.8-2.1%) Increased creatine phosphokinase (0.3-1.6%) Elevated AST (1-1.5%) Pyrexia (1.2%) PsA Bronchitis (3.9%) Herpes simplex (1.4%) Acne (1.3%) Herpes zoster (1.1%) AD Herpes simplex virus (4-8%) Headache (6%) Increased blood creatine phosphokinase (5-6%) Cough (3%) Hypersensitivity (2-3%) Folliculitis (2-3%) Nausea (3%) Abdominal pain (2-3%) Pyrexia (2%) Increased weight (2%) Herpes zoster (2%) Influenza (2%) Fatigue (1-2%) Neutropenia (1-2%) Myalgia (1-2%) Influenza like illness (1-2%) <1% RA Pneumonia Herpes zoster Herpes simplex (includes oral herpes) Oral candidiasis Anemia (<0.1%) Frequency Not Defined RA Tuberculosis Malignancies, excluding nonmelanoma skin cancer Venous thrombosis Elevated LDL Elevated HDL

Janus kinase-1 (JAK1)-selective inhibitor; JAK1 is essential for signaling for certain cytokines to elicit signals from various interleukins, cardiotrophin, neurotrophin, and interferons These signals are essential in maintaining the inflammatory condition in rheumatoid arthritis (RA); inhibition of JAK reduces production of and modulates proinflammatory cytokines central to RA