Upadacitinib (Monograph)

Brand name: Rinvoq
Drug class: Disease-modifying Antirheumatic Drugs
- JAK Inhibitor
- Janus Kinase Inhibitor
Chemical name: (3S,4R)-3-ethyl-4-(1,5,7,10-tetrazatricyclo[7.3.0.02,6]dodeca-2(6),3,7,9,11-pentaen-12-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide
Molecular formula: C₁₇H₁₉F₃N₆O
CAS number: 1310726-60-3

Medically reviewed by Drugs.com on Mar 21, 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 agent; 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.

Guidelines generally support use of JAK inhibitors, including upadacitinib, as add on therapy to methotrexate in patients who do not meet treatment goals with methotrexate alone.

Psoriatic Arthritis in Adults

Management of active psoriatic arthritis in adults 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.

Related/similar drugs

Entyvio, Cimzia, Otezla, Taltz, prednisone, naproxen, dexamethasone

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), 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 at-risk patients 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 disease-modifying antirheumatic drugs (DMARDs), or potent immunosuppressive agents.

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

Administration

Oral Administration

Administer orally once daily without regard to food.

Swallow the extended-release tablets whole with water at the same time each day; do not chew, crush, or split.

Dosage

Pediatric Patients

Atopic Dermatitis

Oral

Pediatric patients ≥12 years of age and weighing ≥40 kg: 15 mg 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

Rheumatoid Arthritis

Oral

15 mg once daily.

Psoriatic Arthritis

Oral

15 mg once daily.

Atopic Dermatitis

Oral

Adults <65 years of age: 15 mg 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 once daily.

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

Mild or moderate hepatic impairment: No dosage adjustment needed.

Severe hepatic impairment: Not evaluated; use not recommended.

Renal Impairment

Rheumatoid arthritis and psoriatic arthritis: No dosage adjustment needed in patients with mild, moderate, or severe renal impairment.

Atopic dermatitis: For patients with severe renal impairment (Cl_cr <30 mL/minute), maximum recommended dosage is 15 mg once daily. No dosage adjustment needed in patients with mild or moderate renal impairment (Cl_cr >30 mL/minute).

End-stage renal disease: Not evaluated; use not recommended.

Geriatric Patients

No specific dosage recommendations.

Cautions for Upadacitinib

Contraindications

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

Warnings/Precautions

Warnings

Infectious Complications

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). 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. 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.

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.

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. 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 a MI or stroke.

Thromboembolic Events

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

In a postmarketing study evaluating safety of another JAK inhibitor (i.e., tofacitinib) in patients ≥50 years of age with rheumatoid arthritis, analysis revealed higher incidences of thromboembolic events, including pulmonary embolism and DVT, in patients receiving tofacitinib 10 mg twice daily compared with those receiving either tofacitinib 5 mg twice daily or a TNF blocking agent, each given in combination with methotrexate.

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 (i.e., anaphylaxis, angioedema) reported.

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

GI Perforation

GI perforation reported; role of JAK inhibition by upadacitinib not known. Many of the patients were receiving concomitant NSAIA therapy.

Monitor patients at increased risk for GI perforation (e.g., patients with history of diverticulitis or receiving NSAIAs). 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, LDL-cholesterol, and triglyceride concentrations reported; increases in HDL-cholesterol concentrations also observed. Maximum increases in LDL- and HDL-cholesterol concentrations observed by week 8 and remained stable thereafter. 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 of 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.

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.

Specific Populations

Pregnancy

May cause fetal harm.

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.

Pediatric Use

Atopic dermatitis: Safety and efficacy 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 in pediatric patients <12 years of age with atopic dermatitis not been established.

Juvenile idiopathic arthritis and psoriatic arthritis: Safety and efficacy not established in pediatric patients with juvenile idiopathic arthritis and psoriatic arthritis^{† [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.

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): Systemic exposure not substantially altered; dosage adjustment not needed.

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. Severe renal impairment is likely to increase systemic exposure of upadacitinib in patients with atopic dermatitis receiving upadacitinib 30 mg once daily. Use of upadacitinib in patients with end-stage renal disease not studied; use is not recommended.

Rheumatoid arthritis and psoriatic arthritis: No dosage adjustment needed in patients with rheumatoid arthritis or psoriatic arthritis and mild, moderate, or severe renal impairment.

Atopic dermatitis: For patients with atopic dermatitis and severe renal impairment (Cl_cr <30 mL/minute), maximum recommended dosage of upadacitinib is 15 mg once daily. No dosage adjustment needed in patients with atopic dermatitis and mild or moderate renal impairment.

Common Adverse Effects

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

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, and influenza-like illness.

Drug Interactions

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

Does not inhibit or induce CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro at clinically relevant concentrations.

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 adverse effects. In patients receiving upadacitinib 15 mg once daily, closely monitor for adverse reactions during concomitant use with potent CYP3A4 inhibitors. Coadministration of upadacitinib 30 mg once daily with potent CYP3A4 inhibitors is not recommended.

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.

Specific Drugs

Upadacitinib Pharmacokinetics

Pharmacokinetics of upadacitinib are comparable between patients with rheumatoid arthritis, psoriatic arthritis, and atopic dermatitis.

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.

Food

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

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.

Age, sex, body weight, and race do not have clinically important effects on upadacitinib pharmacokinetics.

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.

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.

• 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.

• 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. 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.

• 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.

• 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. (See Cautions.)

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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Frequently asked questions

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