Upadacitinib (Monograph)

Brand name: Rinvoq
Drug class: Janus Kinase Inhibitors, Miscellaneous

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Introduction

Immunomodulating agent and disease-modifying antirheumatic drug (DMARD); Janus kinase (JAK) inhibitor.

Uses for Upadacitinib

Rheumatoid Arthritis in Adults

Management of moderately to severely active rheumatoid arthritis in adults who have had an inadequate response or intolerance to one or more tumor necrosis factor (TNF) blocking agents; can be used alone or in combination with methotrexate or other nonbiologic (conventional) DMARDs (e.g., hydroxychloroquine, leflunomide, sulfasalazine).

Concomitant use with other JAK inhibitors, potent immunosuppressants (e.g., azathioprine, cyclosporine), or biologic DMARDs not recommended.

Psoriatic Arthritis

Management of active psoriatic arthritis in adults and pediatric patients ≥2 years of age who have had an inadequate response or intolerance to one or more TNF blocking agents.

Concomitant use with other JAK inhibitors, potent immunosuppressants (e.g., azathioprine, cyclosporine), or biologic DMARDs not recommended.

Atopic Dermatitis

Treatment of adult and pediatric patients ≥12 years of age with refractory, moderate to severe atopic dermatitis who have had an inadequate response to other systemic therapies or who are not eligible for other systemic therapies; can be used alone or concomitantly with topical corticosteroids.

Concomitant use with other JAK inhibitors, immunosuppressants, or biologic immunomodulators not recommended.

Ulcerative Colitis

Treatment of moderately to severely active ulcerative colitis in adults who have had an inadequate response or intolerance to one or more TNF blocking agents. Can be used alone or in combination with aminosalicylates, methotrexate, and/or oral corticosteroids.

Concomitant use with other JAK inhibitors, potent immunosuppressants (e.g., azathioprine, cyclosporine), or biologic therapies for ulcerative colitis not recommended.

Crohn Disease

Treatment of moderately to severely active Crohn disease in adults who have had an inadequate response or intolerance to one or more TNF blocking agents. Can be used alone or in combination with aminosalicylates or methotrexate.

Concomitant use with other JAK inhibitors, potent immunosuppressants (e.g., azathioprine, cyclosporine), or biologic therapies for Crohn disease not recommended.

Ankylosing Spondylitis

Treatment of active ankylosing spondylitis in adults who have had an inadequate response or intolerance to one or more TNF blocking agents. Can be used alone or in combination with conventional DMARDs.

Concomitant use with other JAK inhibitors, potent immunosuppressants (e.g., azathioprine, cyclosporine), or biologic DMARDs not recommended.

Nonradiographic Axial Spondyloarthritis

Treatment of active nonradiographic axial spondyloarthritis with objective signs of inflammation in adults who have had an inadequate response or intolerance to TNF blocking agents. Can be used alone and in combination with conventional DMARDs, NSAIAs, and oral corticosteroids.

Concomitant use with other JAK inhibitors, potent immunosuppressants (e.g., azathioprine, cyclosporine), or biologic DMARDs not recommended.

Polyarticular Juvenile Idiopathic Arthritis

Treatment of polyarticular juvenile idiopathic arthritis in patients ≥2 years of age who have had an inadequate response or intolerance to TNF blocking agents.

Concomitant use of upadacitinib with other JAK inhibitors, potent immunosuppressants (e.g., azathioprine, cyclosporine), or biologic DMARDs is not recommended.

Related/similar drugs

Entyvio, Otezla, prednisone, naproxen, methotrexate, dexamethasone, hydroxychloroquine

Upadacitinib Dosage and Administration

General

Pretreatment Screening

• Evaluate for active and latent tuberculosis infection prior to initiation of therapy; initiate antimycobacterial therapy if indicated.

• Evaluate for risk of thrombosis prior to initiation of therapy.

• Evaluate for risk of major cardiovascular events prior to initiation of therapy, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors.

• Measure absolute lymphocyte count, absolute neutrophil count (ANC), and hemoglobin prior to initiation of therapy. Do not initiate therapy in patients with an absolute lymphocyte count of <500 cells/mm³, ANC <1000 cells/mm³, or hemoglobin concentration <8 g/dL.

• Monitor liver function prior to initiation of therapy. Evaluate for viral hepatitis.

• Verify pregnancy status in females of reproductive potential prior to initiation of therapy.

• Consider benefits and risks of all-cause mortality prior to initiating therapy with upadacitinib.

• Consider benefits and risks of developing malignancies prior to initiating therapy with upadacitinib, particularly in patients with a known malignancy (other than successfully treated nonmelanoma skin cancer [NMSC]), patients who develop a malignancy, and patients who are current or past smokers.

Patient Monitoring

• Monitor closely for signs or symptoms of infection, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis prior to initiating therapy, during and after treatment with upadacitinib.

• Monitor for reactivation of viral hepatitis periodically during therapy.

• Perform dermatologic examinations periodically throughout therapy for patients at increased risk for skin cancer.

• Periodically monitor for thrombosis during therapy.

• Monitor patients at risk of GI perforation for onset of new abdominal symptoms.

• Monitor lymphocyte count, ANC, and hemoglobin concentrations periodically during therapy.

• Monitor lipids approximately 12 weeks after therapy initiation, then periodically thereafter.

• Monitor liver enzymes periodically during therapy.

• Consider benefits and risk of all-cause mortality prior to continuing therapy with the drug.

• Consider benefits and risks of developing malignancies prior to continuing therapy with upadacitinib, particularly in patients with a known malignancy (other than successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.

Other General Considerations

• Upadacitinib can be used in combination with methotrexate or other nonbiologic (conventional) DMARDs.

• Do not use concomitantly with other Janus kinase (JAK) inhibitors, biologic therapies, or potent immunosuppressive agents.

• Update immunizations according to current immunization guidelines prior to initiating therapy.

Administration

Oral Administration

Available as extended-release tablets and an oral solution.

Administer extended-release tablets orally once daily without regard to food.

Administer oral solution twice daily using the provided press-in bottle adapter and oral dosing syringe without regard to food.

Swallow the extended-release tablets whole; do not chew, crush, or split.

Oral solution is not substitutable with extended-release tablets. Changes between the oral solution and extended-release tablets should be performed by a healthcare provider.

Dosage

Pediatric Patients

Psoriatic Arthritis

Oral

Pediatric patients 2 to <18 years of age: Recommended dosage is based on body weight and dosage formulation.

Extended-release tabletnot recommended for use in pediatric patients 10 to <30 kg. In pediatric patients weighing ≥30 kg: 15 mg extended-release tablet once daily.

Oral solution dosage: 3 mg (3 mL) twice daily in pediatric patients who weigh 10 to <20 kg; 4 mg (4 mL) twice daily in those weighing 20 to <30 kg; 6 mg (6 mL) twice daily in those weighing ≥30 kg.

Atopic Dermatitis

Oral

Pediatric patients ≥12 years of age and weighing ≥40 kg: 15 mg extended-release tablet once daily. If an adequate response is not achieved, may increase dosage to 30 mg once daily; however, if an adequate response is not achieved on a dosage of 30 mg once daily, discontinue upadacitinib. Use lowest effective dosage to maintain response.

Polyarticular Juvenile Idiopathic Arthritis

Oral

Pediatric patients ≥2 years of age: Recommended dosage is based on body weight and dosage formulation.

Extended-release tabletnot recommended for use in pediatric patients 10 to <30 kg. In pediatric patients weighing ≥30 kg: 15 mg extended-release tablet once daily.

Oral solution dosage: 3 mg (3 mL) twice daily in pediatric patients who weigh 10 to <20 kg; 4 mg (4 mL) twice daily in those weighing 20 to <30 kg; 6 mg (6 mL) twice daily in those weighing ≥30 kg.

Adults

Rheumatoid Arthritis

Oral

15 mg extended-release tablet once daily.

Psoriatic Arthritis

Oral

15 mg extended-release tablet once daily.

Atopic Dermatitis

Oral

Adults <65 years of age: 15 mg extended-release tablet once daily. If an adequate response is not achieved, may increase dosage to 30 mg once daily; however, if an adequate response is not achieved on a dosage of 30 mg once daily, discontinue upadacitinib. Use lowest effective dosage to maintain response.

Adults ≥65 years of age: 15 mg extended-release tablet once daily.

Ulcerative Colitis

Oral

Induction phase: 45 mg extended-release tablet once daily for 8 weeks.

Maintenance phase: 15 mg extended-release tablet once daily. In refractory, severe, or extensive disease, consider increasing the dosage to 30 mg once daily; however, if an adequate response is not achieved on a dosage of 30 mg once daily, discontinue upadacitinib. Use lowest effective dosage to maintain response.

Crohn Disease

Oral

Induction phase: 45 mg extended-release tablet once daily for 12 weeks.

Maintenance phase: 15 mg extended-release tablet once daily. In refractory, severe, or extensive disease, consider increasing the dosage to 30 mg once daily; however, if an adequate response is not achieved on a dosage of 30 mg once daily, discontinue upadacitinib. Use lowest effective dosage to maintain response.

Ankylosing Spondylitis

Oral

15 mg extended-release tablet once daily.

Nonradiographic Axial Spondyloarthritis

Oral

15 mg extended-release tablet once daily.

Dosage Modifications for Drug Interactions

Rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ankylosing spondylitis, nonradiographic axial spondyloarthritis, polyarticular juvenile idiopathic arthritis: No dosage adjustment required with concomitant potent CYP3A4 inhibitors.

Atopic dermatitis: Recommended dosage of extended-release tablet with concomitant potent CYP3A4 inhibitors is 15 mg once daily.

Ulcerative colitis: Recommended dosage of extended-release tablet with concomitant potent CYP3A4 inhibitors is 30 mg once daily for 8 weeks for induction and 15 mg once daily for maintenance.

Crohn disease: Recommended dosage of extended-release tablet with concomitant potent CYP3A4 inhibitors is 30 mg once daily for 12 weeks for induction and 15 mg once daily for maintenance.

Treatment Interruption for Toxicity

Infection

If a serious infection, including serious opportunistic infection, develops, interrupt treatment until the infection is controlled.

Hematologic Toxicity

If absolute lymphocyte count <500 cells/mm³, interrupt treatment until lymphocyte count >500 cells/mm³.

If ANC <1000 cells/mm³, interrupt treatment until ANC >1000 cells/mm³.

If hemoglobin concentration <8 g/dL, interrupt treatment until hemoglobin concentration >8 g/dL.

Hepatic Toxicity

If drug-induced hepatic injury is suspected, interrupt treatment until such diagnosis excluded.

Special Populations

Hepatic Impairment

Rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ankylosing spondylitis, nonradiographic axial spondyloarthritis, polyarticular juvenile idiopathic arthritis: No dosage adjustment needed in mild or moderate hepatic impairment (Child-Pugh class A or B).

Ulcerative colitis: In mild to moderate hepatic impairment (Child-Pugh class A or B), maximum recommended dosage of extended-release tablet is 30 mg once daily for 8 weeks for induction and 15 mg once daily for maintenance.

Crohn disease: In mild to moderate hepatic impairment (Child-Pugh class A or B), maximum recommended dosage of extended-release tablet is 30 mg once daily for 12 weeks for induction and 15 mg once daily for maintenance.

All indications: Not evaluated in severe hepatic impairment (Child-Pugh class C); use not recommended.

Renal Impairment

Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, nonradiographic axial spondyloarthritis, polyarticular juvenile idiopathic arthritis: No dosage adjustment needed in patients with mild, moderate, or severe renal impairment.

Atopic dermatitis: For patients with severe renal impairment (eGFR 15 to <30 mL/minute/1.73 m²), recommended dosage of extended-release tablet is 15 mg once daily. No dosage adjustment needed in patients with mild or moderate renal impairment (eGFR >30 mL/minute/1.73 m²). Not recommended in patients with end-stage renal disease (ESRD; eGFR <15 mL/minute/1.73 m²).

Ulcerative colitis: For patients with severe renal impairment (eGFR 15 to <30 mL/minute/1.73 m²), recommended dosage of extended-release tablet is 30 mg once daily for 8 weeks for induction and 15 mg once daily for maintenance. No dosage adjustment needed in patients with mild or moderate renal impairment (eGFR >30 mL/minute/1.73 m²). Not recommended in patients with ESRD (eGFR <15 mL/minute/1.73 m²).

Crohn disease: For patients with severe renal impairment (eGFR 15 to <30 mL/minute/1.73 m²), recommended dosage is 30 mg once daily for 12 weeks for induction and 15 mg once daily for maintenance. No dosage adjustment needed in patients with mild or moderate renal impairment (eGFR >30 mL/minute/1.73 m²). Not recommended in patients with ESRD (eGFR <15 mL/minute/1.73 m²).

Geriatric Patients

Atopic dermatitis: Patients ≥65 years of age, 15 mg extended-release tablet once daily.

Other indications: no specific dosage recommendations.

Cautions for Upadacitinib

Contraindications

• Known hypersensitivity to upadacitinib or any ingredient in the preparation.

Warnings/Precautions

Warnings

Serious Infections

Serious, sometimes fatal infections (including pneumonia, cellulitis, tuberculosis, multidermatomal herpes zoster, oral or esophageal candidiasis, pneumocystosis, cryptococcosis) reported, particularly in patients receiving concomitant therapy with immunosuppressive agents (e.g., methotrexate, corticosteroids) or higher doses of upadacitinib (See boxed warning). Infections may be disseminated.

Do not initiate upadacitinib in patients with serious active infections, including localized infections. Consider potential risks and benefits of the drug prior to initiating therapy in patients with a history of chronic, recurring, serious, or opportunistic infections; patients with underlying conditions that may predispose them to infections; and patients who have been exposed to tuberculosis or who have resided or traveled in regions where tuberculosis or mycoses are endemic.

Closely monitor patients during and after treatment with upadacitinib for the development of signs or symptoms of infection. If new infection occurs during therapy, perform thorough diagnostic evaluation (appropriate for immunocompromised patient), initiate appropriate anti-infective therapy, and closely monitor patient. If serious or opportunistic infection develops or if an infection fails to respond to anti-infective therapy, interrupt upadacitinib treatment until the infection is controlled.

Evaluate patients for active or latent tuberculosis prior to and periodically during therapy. Do not use in patients with active tuberculosis. When indicated, initiate appropriate antimycobacterial regimen for treatment of latent tuberculosis infection prior to upadacitinib therapy. Consider initiation of antimycobacterial therapy prior to initiation of upadacitinib in individuals with a history of latent or active tuberculosis in whom an adequate course of antimycobacterial treatment cannot be confirmed and in individuals with a negative test for latent tuberculosis who have risk factors for tuberculosis. Consultation with a tuberculosis specialist is recommended when deciding whether to initiate antimycobacterial therapy. Monitor patients, including those with a negative test for latent tuberculosis, for tuberculosis during therapy.

Viral reactivation, including varicella zoster virus reactivation and development of zoster (shingles), reported. If zoster develops, consider interrupting upadacitinib therapy until the episode has resolved.

HBV reactivation also reported. Clinical trials excluded patients testing positive for HCV antibody and HCV RNA, HBV surface antigen, or HBV DNA; however, cases of HBV reactivation still reported. Screen for viral hepatitis and monitor for reactivation in accordance with current standards of care prior to and during upadacitinib therapy; consultation with a hepatologist recommended if HBV DNA detected during therapy.

Mortality

Higher rate of all-cause mortality, including sudden cardiovascular death, reported in a postmarketing safety study in patients with rheumatoid arthritis receiving another JAK inhibitor compared with those who received a TNF blocking agent (See boxed warning). All study patients were ≥50 years of age and had ≥1 cardiovascular risk factor.

Consider the risks and benefits of upadacitinib prior to initiating or continuing therapy.

Malignancies and Lymphoproliferative Disorders

Lymphoma and other malignancies observed (See boxed warning).

In a large, randomized, postmarketing safety study of another JAK inhibitor in patients with rheumatoid arthritis, a higher rate of malignancies (excluding nonmelanoma skin cancer) was observed in patients treated with the JAK inhibitor compared to those treated with a TNF blocking agent. Patients who are current or past smokers are at additional risk of lung cancer and of overall malignancies.

Consider risks and benefits of upadacitinib prior to initiating therapy or when considering whether to continue upadacitinib, particularly in patients with a known malignancy (other than successfully treated nonmelanoma skin cancer), in those who develop a malignancy, and those who are current or past smokers.

Periodic dermatologic examinations recommended for patients at increased risk for skin cancer.

Limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a broad-spectrum sunscreen.

Major Adverse Cardiovascular Events (MACE)

Major adverse cardiovascular events (i.e., cardiovascular death, nonfatal MI, nonfatal stroke) reported in patients receiving upadacitinib (See boxed warning). Patients who are current or past smokers are at additional risk.

Consider risks and benefits of upadacitinib prior to initiating therapy or when considering whether to continue upadacitinib, particularly in patients who are current or past smokers and in those with other cardiovascular risk factors.

Inform patients of symptoms of serious cardiovascular events. Discontinue upadacitinib if a patient experiences an MI or stroke.

Thrombosis

Serious, sometimes fatal thromboembolic events (e.g., DVT, PE, arterial thrombosis) reported in patients with inflammatory conditions receiving JAK inhibitors, including upadacitinib (See boxed warning).

In a postmarketing study evaluating safety of another JAK inhibitor in patients ≥50 years of age with rheumatoid arthritis, analysis revealed higher incidences of thromboembolic events, including pulmonary embolism and DVT, in patients receiving the JAK inhibitor compared with those receiving a TNF blocking agent.

Consider risks and benefits of upadacitinib prior to initiating therapy in patients who may be at increased risk of thrombosis. Avoid use in patients who may be at increased risk of thrombosis.

Promptly evaluate patients with signs or symptoms suggestive of thrombosis and initiate treatment as appropriate.

Other Warnings and Precautions

Hypersensitivity Reactions

Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) reported.

If a clinically significant hypersensitivity reaction occurs, discontinue upadacitinib and initiate appropriate therapy.

GI Perforation

GI perforation reported.

Monitor patients at increased risk for GI perforation (e.g., patients with history of diverticulitis or receiving concomitant NSAIAs or corticosteroids). Promptly evaluate patients with new-onset abdominal symptoms for early identification of GI perforation.

Hematologic Effects

Possible lymphopenia, neutropenia, and anemia. May require interruption of upadacitinib therapy.

Do not initiate upadacitinib in patients with lymphocyte count <500 cells/mm³, ANC <1000 cells/mm³, or hemoglobin concentration <8 g/dL.

Monitor lymphocyte count, ANC, and hemoglobin concentrations at baseline and thereafter in accordance with current standards of care.

Effects on Serum Lipids

Dose-related increases in total cholesterol and LDL-cholesterol concentrations reported; increases in HDL-cholesterol concentrations also observed. Elevations in LDL-cholesterol concentrations responded to statin therapy. Effect of upadacitinib-associated lipid elevations on cardiovascular morbidity and mortality not determined.

Monitor lipid concentrations 12 weeks after initiation of therapy and thereafter in accordance with current standards of care. Manage dyslipidemia according to current standards of care.

Hepatic Effects

Elevated hepatic enzyme concentrations reported.

Monitor liver function tests at baseline and thereafter according to current standards of care. In case of elevations, promptly evaluate patient for drug-induced hepatotoxicity. If drug-induced hepatic injury is suspected, interrupt upadacitinib therapy until such diagnosis excluded.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal toxicity (e.g., decreased fetal weight, postimplantation loss) and teratogenicity (e.g., cardiovascular and skeletal abnormalities) demonstrated in animals at exposure levels higher than the human exposure at the maximum recommended dosage. Limited data regarding use in pregnant women; insufficient to evaluate drug-associated risk for major birth defects or spontaneous abortion.

Avoid pregnancy during upadacitinib therapy. Verify pregnancy status prior to initiating therapy. Females of reproductive potential should use effective methods of contraception during therapy and for 4 weeks following the last dose. Apprise patients of potential fetal hazard if used during pregnancy.

Pregnancy surveillance program exists to monitor outcomes in exposed pregnant women; if exposure occurs during pregnancy, report the pregnancy by calling 1-800-633-9110.

Immunization

Avoid live, attenuated vaccines during or immediately prior to upadacitinib therapy. Administer all indicated immunizations, including immunization against varicella zoster or herpes zoster, according to current immunization guidelines prior to initiation of upadacitinib.

Medication Residue in Stool

Medication residue in stool or ostomy output reported, primarily in patients with anatomic conditions (e.g., ileostomy, colostomy, intestinal resection) or functional GI conditions with decreased GI transit times. Advise patients to contact healthcare provider if repeated medication residue observed. Clinically monitor patients and consider alternative treatments if there is inadequate therapeutic response.

Specific Populations

Pregnancy

May cause fetal harm.

Monitor pregnancy outcomes in women exposed to upadacitinib by reporting a pregnancy at 1-800-633-9110.

Lactation

Distributes into milk in rats. Detected in milk of lactating rats at concentrations approximately 30 times greater than maternal plasma concentrations, with 97% present as unchanged drug. Not known whether upadacitinib distributes into human milk, affects nursing infants, or affects milk production.

Because of potential for serious adverse reactions in nursing infants, breast-feeding is not recommended during upadacitinib therapy and for 6 days following the last dose.

Females and Males of Reproductive Potential

Verify pregnancy status in females of reproductive potential prior to initiation of upadacitinib. Advise females of reproductive potential to use effective contraception during treatment and for 4 weeks following the last dose.

Pediatric Use

Atopic dermatitis: Safety and efficacy for treatment of atopic dermatitis in pediatric patients ≥12 years of age and weighing ≥40 kg supported by data from 344 pediatric patients (12–17 years of age) with moderate to severe atopic dermatitis. Safety and efficacy were consistent between pediatric patients and adults. Safety and efficacy of upadacitinib extended-release tablets in pediatric patients <12 years of age with atopic dermatitis not established. Safety and efficacy of upadacitinib oral solution in pediatric patients with atopic dermatitis not established.

Polyarticular juvenile idiopathic arthritis, psoriatic arthritis: Safety and efficacy for treatment of polyarticular juvenile idiopathic arthritis and psoriatic arthritis in pediatric patients 2 to <18 years of age supported by data from well-controlled stuides in adults with rheumatoid arthritis and psoriatic arthritis, pharmacokinetic data from adults with rheumatoid arthritis and psoriatic arthritis and pediatric patients with juvenile idiopathic arthritis with active polyarthritis, and safety data from pediatric patients with juvenile idiopathic arthritis with active polyarthritis.

Safety and effiacy of upadacitinib in pediatric patients <2 years of age with polyarticular juvenile idiopathic arthritis and psoriatic arthritis not established.

Ankylosing spondylitis, nonradiographic axial spondyloarthritis: Safety and efficacy not established in pediatric patients with ankylosing spondylitis or nonradiographic axial spondyloarthritis^{† [off-label]} .

Ulcerative colitis, Crohn disease: Safety and efficacy not established in pediatric patients with ulcerative colitis or Crohn disease^{† [off-label]}.

Geriatric Use

Rheumatoid arthritis and psoriatic arthritis: No differences in efficacy observed between geriatric patients and younger adults; however, overall frequency of adverse events, including serious infections, increased in geriatric patients.

Atopic dermatitis: No differences in efficacy were observed between geriatric patients and younger adults; however, serious infections and malignancies occurred at a higher rate in patients ≥65 years of age receiving upadacitinib 30 mg once daily in long-term trials.

Ankylosing spondylitis, nonradiographic axial spondyloarthritis, ulcerative colitis, Crohn disease: Insufficient number of patients ≥65 years of age included in these studies to assess differences in response compared to younger adults.

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): Systemic exposure increased 28 and 24%, respectively, compared to normal hepatic function; dosage adjustment not needed in patients with rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ankylosing spondylitis, nonradiographic axial spondyloarthritis, or polyarticular juvenile idiopathic arthritis. Dosage adjustment necessary in patients with ulcerative colitis or Crohn disease (30 mg once daily recommended for induction; 15 mg once daily recommended for maintenance).

Severe hepatic impairment (Child-Pugh class C): Not studied; use not recommended.

Renal Impairment

Renal impairment does not increase peak plasma concentrations of upadacitinib compared with patients with normal renal function; however, systemic exposure of upadacitinib increased by 18, 33, or 44% in patients with mild, moderate, or severe renal impairment, respectively. Clinically relevant changes in upadacitinib exposure not expected in patients with mild or moderate renal impairment receiving upadacitinib 15 mg, 30 mg, or 45 mg once daily. Use of upadacitinib in patients with end-stage renal disease (eGFR <15 mL/minute/1.73 m²) not studied.

Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, nonradiographic axial spondyloarthritis, or polyarticular juvenile idiopathic arthritis: No dosage adjustment needed in patients with mild (eGFR 60 to <90 mL/minute/1.73 m²), moderate (eGFR 30 to <60 mL/minute/1.73 m²), or severe renal impairment (eGFR 15 to <30 mL/minute/1.73 m²).

Atopic dermatitis: For patients with atopic dermatitis and severe renal impairment, maximum recommended dosage of upadacitinib extended-release tablet is 15 mg once daily. No dosage adjustment needed in patients with atopic dermatitis and mild or moderate renal impairment. Use not recommended in patients with end-stage renal disease.

Ulcerative colitis and Crohn disease: For patients with ulcerative colitis or Crohn disease and severe renal impairment, maximum recommended dosage of upadacitinib extended-release tablet is 30 mg once daily for induction and 15 mg once daily for maintenance. No dosage adjustment needed in patients with ulcerative colitis or Crohn disease and mild or moderate renal impairment. Use not recommended in patients with end-stage renal disease.

Common Adverse Effects

Adverse effects occurring in ≥1% of patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or nonradiographic axial spondyloarthritis: Upper respiratory tract infections, herpes zoster infection, herpes simplex infection, bronchitis, nausea, cough, pyrexia, acne, headache.

Adverse effects occurring in ≥1% of patients with atopic dermatitis: Upper respiratory tract infections, acne, herpes simplex infection, headache, increased serum creatine phosphokinase, cough, hypersensitivity, folliculitis, nausea, abdominal pain, pyrexia, increased weight, herpes zoster infection, influenza, fatigue, neutropenia, myalgia, influenza-like illness.

Adverse effects occurring in ≥5% of patients with ulcerative colitis during induction and maintenance phases: Upper respiratory tract infections, increased serum creatine phosphokinase, acne, neutropenia, elevated transaminases, rash.

Adverse effects occurring in ≥5% of patients with Crohn disease during induction and maintenance phases: Upper respiratory tract infections, anemia, pyrexia, acne, herpes zoster, headache.

Drug Interactions

Metabolized mainly by CYP3A4 and to a minor extent by CYP2D6.

Does not inhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro at clinically relevant concentrations. Induces CYP3A4, but not CYP2B6 or 1A2 in vitro at clinically relevant concentrations. Similar effects on CYP1A2, CYP3A, CYP2C9, and CYP2C19, but not CYP2D6 observed with dosages of 30 mg and 45 mg once daily. Weak induction of CYP3A4 observed with upadacitinib 30 mg and 45 mg once daily, while weak inhibition of CYP2D6 observed with 45 mg once daily, but not 30 mg once daily.

Does not inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transport polypeptide (OATP) 1B1 or 1B3, organic cation transporter (OCT) 1 or 2, organic anion transporter (OAT) 1 or 3, or multidrug and toxin extrusion transporter (MATE) 1 or 2-K in vitro at clinically relevant concentrations.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Increased upadacitinib exposure and possible increased risk of adverse effects. In patients receiving upadacitinib 15 mg once daily for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, nonradiographic axial spondyloarthritis, or polyarticular juvenile idiopathic arthritis, closely monitor for adverse reactions during concomitant use with potent CYP3A4 inhibitors. Coadministration of upadacitinib 30 mg once daily for atopic dermatitis with potent CYP3A4 inhibitors is not recommended. Concomitant use of potent CYP3A4 inhibitors in patients receiving upadacitinib for ulcerative colitis or Crohn disease necessitates a dosage reduction of upadacitinib to 30 mg once daily for induction and 15 mg once daily for maintenance.

Potent CYP3A4 inducers: Decreased upadacitinib exposure; possible reduced efficacy of upadacitinib. Concomitant use not recommended.

CYP2D6 inhibitors: No clinically important effect on upadacitinib exposure expected.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP substrates: No clinically important effects on pharmacokinetics of sensitive CYP 1A2, 2B6, 2C9, 2C19, 2D6, or 3A substrates.

Drugs Affecting Gastric pH

Not expected to affect upadacitinib exposure.

Vaccines

Avoid live, attenuated vaccines during or immediately prior to initiating upadacitinib.

Specific Drugs

Upadacitinib Pharmacokinetics

Pharmacokinetics of upadacitinib are comparable among patients with rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn disease, ankylosing spondylitis, and nonradiographic axial spondyloarthritis.

Extended-release tablets and oral solution are not bioequivalent; dosage forms not interchangeable on a mg-per-mg basis.

Absorption

Bioavailability

Exposure to upadacitinib is dose proportional over the therapeutic dosage range evaluated.

Peak plasma concentrations achieved approximately 2–4 hours after oral administration of upadacitinib extended-release tablets.

With once-daily administration, steady-state concentrations achieved within 4 days with minimal accumulation.

Following administration of the oral solution (6 mg), median time to peak plasma concentrations is 1 hour.

Food

Administration with high-fat, high-calorie meal increases AUC and peak plasma concentrations by 29% and 39—60%, respectively; not considered clinically important.

Coadministration of oral solution with food not expected to have a clinically relevant exposure effect.

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B): AUC increased by 28 or 24%, respectively; peak concentrations not altered or increased by 43%, respectively. Changes in exposure not considered clinically important.

Mild, moderate, or severe renal impairment: AUC increased by 18, 33, or 44%, respectively; peak concentrations not altered. Changes in exposure not considered clinically important.

Sex, body weight, and race do not have clinically important effects on upadacitinib pharmacokinetics in adults.

No clinically relevant differences in exposure for pediatric patients ≥12 years of age weighing ≥40 kg with atopic dermatitis compared to adult patients.

Clearance increased with increasing body weight in pediatric patients with juvenile idiopathic arthritis with active polyarthritis.

No clinically relevant differences in exposure for geriatric patients ≥65 years of age compared to younger adults.

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

52%.

Elimination

Metabolism

Metabolized mainly by CYP3A4 and to minor extent by CYP2D6. No active metabolites identified.

Elimination Route

Eliminated principally as unchanged drug in urine (24%) and feces (38%); approximately 34% of dose excreted as metabolites.

Half-life

8–14 hours.

Stability

Storage

Oral

Tablets, extended-release

2–25°C; store in original bottle to protect from moisture.

Solution

2-30°C; discard remaining solution 60 days after opening bottle.

Actions

• JAK inhibitor. JAKs mediate signaling of cytokines and growth factors important for hematopoiesis and immune function.

• Binding of cytokines to receptors on the cell surface activates pairing of JAKs (e.g., JAK1/JAK2, JAK1/JAK3, JAK1/tyrosine kinase 2 [TYK2], JAK2/JAK2, JAK2/TYK2), which leads to phosphorylation and subsequent localization of signal transducer and activator of transcription (STAT) proteins to the nucleus and modulation of gene expression. Upadacitinib prevents phosphorylation and activation of STATs.

• Inhibited JAK1 and JAK2 to greater extent than JAK3 and TYK2 in a cell-free isolated enzyme assay. Inhibited cytokine-induced STAT phosphorylation mediated by JAK1 and JAK1/JAK3 more potently than JAK2/JAK2-mediated STAT phosphorylation in human leukocyte cellular assays. Relevance of inhibition of specific JAKs to therapeutic efficacy not known.

• Administration of upadacitinib caused dose- and concentration-dependent inhibition of interleukin-6 (IL-6)-induced phosphorylation of STAT3 (JAK1/JAK2 dependent) and IL-7-induced phosphorylation of STAT5 (JAK1/JAK3 dependent) in whole blood in healthy individuals.

Advice to Patients

• Advise patients to read the manufacturer's patient information (medication guide).

• Advise patients not to chew, crush, or split upadacitinib extended-release tablets. Instruct patients and caregivers to read and follow the instructions for use for the oral solution. Advise patients to avoid consuming grapefruit-containing food or drink while receiving upadacitinib.

• Advise patients to inform their healthcare provider if they notice repeated medication residue, including intact tablets or fragments of tablets, in their stool or ostomy output.

• Increased susceptibility to infection. Increased risk of herpes zoster, which may be serious. Importance of promptly informing clinician if any signs or symptoms of infection (e.g., fever, sweating, chills, myalgia, cough, bloody sputum, dyspnea, fatigue, weight loss, dysuria, erythema) develop.

• Risk of lymphoma and other malignancies. Importance of periodic dermatologic examinations during therapy. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a broad-spectrum sunscreen.

• Risk of major adverse cardiovascular events, including MI, stroke, and cardiovascular death. Instruct all patients, especially current or past smokers and those with other cardiovascular risk factors, to monitor for the development of signs and symptoms of cardiovascular events.

• Risk of thromboembolic events. Importance of contacting clinician if symptoms of thromboembolism (e.g., shortness of breath; chest pain; swelling, pain, or tenderness in the leg) develop and seeking immediate medical attention.

• Risk of hypersensitivity reactions. Importance of seeking immediate medical attention if signs or symptoms of allergic reactions develop.

• Risk of GI perforation; risk factors include concomitant use of NSAIAs or corticosteroids or a history of diverticulitis. Importance of promptly notifying clinician of fever, abdominal pain, chills, nausea, or vomiting.

• Risk of retinal detachment. Importance of promptly contacting clinician if sudden changes in vision occur during therapy.

• Advise patients to avoid use of live vaccines with upadacitinib. Instruct patients to inform their healthcare practitioner that they are taking the drug prior to a potential vaccination. Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses or any history of cancer, thromboembolism, diverticulitis, gastric or intestinal ulcers, tuberculosis, herpes zoster, hepatitis B virus or hepatitis C virus infection, or other chronic or recurring infections.

• Importance of periodic laboratory monitoring.

• Risk of fetal harm. Importance of informing clinician of known or suspected pregnancy. Advise females with reproductive potential that effective contraceptive methods should be used during upadacitinib therapy and for 4 weeks following the last dose of the drug. If pregnancy occurs during upadacitinib therapy, advise patients that there is a pregnancy surveillance program that monitors pregnancy outcomes.

• Advise women to avoid breast-feeding during upadacitinib therapy and for 6 days following the last dose of the drug.

• Importance of informing patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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