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Upadacitinib

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
Brands: Rinvoq

Medically reviewed by Drugs.com on Aug 3, 2020. Written by ASHP.

Warning

    Serious Infections
  • Serious and sometimes fatal infections, including tuberculosis (pulmonary or extrapulmonary disease), bacterial and viral infections, invasive fungal infections (may be disseminated), and other opportunistic infections, reported. (See Infectious Complications under Cautions.)

  • Carefully consider risks and benefits prior to initiating upadacitinib therapy in patients with chronic or recurring infections.

  • Evaluate patients for latent tuberculosis infection prior to and periodically during treatment; if indicated, initiate appropriate antimycobacterial regimen prior to initiating upadacitinib therapy.

  • Closely monitor patients for infection, including active tuberculosis in those with a negative test for latent tuberculosis, during and after treatment. If serious infection develops, interrupt upadacitinib therapy until infection is controlled.

    Malignancies
  • Lymphoma and other malignancies reported. (See Malignancies and Lymphoproliferative Disorders under Cautions.)

    Thrombosis
  • Serious and sometimes fatal thromboembolic events, including DVT, PE, and arterial thrombosis, reported.

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

  • Promptly evaluate patients with symptoms of thrombosis. (See Thromboembolic Events under Cautions.)

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 methotrexate; 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 (e.g., baricitinib, tofacitinib), potent immunosuppressants (e.g., azathioprine, cyclosporine), or biologic DMARDs, such as tumor necrosis factor (TNF; TNF-α) blocking agents (e.g., adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), interleukin-1 (IL-1) receptor antagonists (e.g., anakinra), anti-CD20 monoclonal antibodies (e.g., rituximab), selective costimulation modulators (e.g., abatacept), and anti-interleukin-6-receptor monoclonal antibodies (e.g., sarilumab, tocilizumab), not recommended.

Upadacitinib Dosage and Administration

General

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

  • Evaluate patients for tuberculosis infection prior to initiation of therapy and initiate appropriate antimycobacterial treatment if indicated. Do not use in patients with active tuberculosis or other serious active infection. (See Infectious Complications under Cautions.)

Concomitant Therapy

  • Do not use concomitantly with other JAK inhibitors, biologic DMARDs, or potent immunosuppressive agents. (See Rheumatoid Arthritis in Adults under Uses.)

Administration

Oral Administration

Administer orally once daily without regard to food.

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

Dosage

Adults

Rheumatoid Arthritis
Oral

15 mg once daily.

Treatment Interruption for Toxicity
Treatment Interruption for Infection

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

Treatment Interruption for 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.

Treatment Interruption for 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. (See Special Populations under Pharmacokinetics.)

Severe hepatic impairment: Not evaluated; use not recommended.

Renal Impairment

Mild, moderate, or severe renal impairment: No dosage adjustment needed. (See Special Populations under Pharmacokinetics.)

End-stage renal disease: Not evaluated.

Geriatric Patients

No specific dosage recommendations. (See Geriatric Use under Cautions.)

Cautions for Upadacitinib

Contraindications

  • Manufacturer states none known.

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 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.

Malignancies and Lymphoproliferative Disorders

Lymphoma and other malignancies observed.

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

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

Thromboembolic Events

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

Consider risks and benefits of upadacitinib prior to initiating therapy 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

GI Perforation

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

Use with caution in 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. (See Treatment Interruption for Hematologic Toxicity under Dosage and Administration.)

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 approximately 1.6 times (in rats) or 15 times (in rabbits) 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. Confirm pregnancy status prior to initiating therapy. Women 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 zoster, according to current immunization guidelines prior to initiation of upadacitinib.

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

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

Safety and efficacy not established in pediatric patients (from birth to 18 years of age).

Geriatric Use

In clinical trials in patients with rheumatoid arthritis, no differences in efficacy observed between geriatric patients and younger adults; however, increased overall frequency of adverse events observed in geriatric patients.

Hepatic Impairment

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

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

Renal Impairment

Mild, moderate, or severe renal impairment: Systemic exposure not substantially altered; dosage adjustment not needed. (See Special Populations under Pharmacokinetics.)

End-stage renal disease: Not evaluated.

Common Adverse Effects

Upper respiratory tract infections, nausea, cough, pyrexia.

Interactions for Upadacitinib

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. Use upadacitinib with caution in patients receiving long-term therapy with potent CYP3A4 inhibitors.

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. (See Immunization under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Antacids

Effects on gastric pH not expected to alter upadacitinib exposure

Antilipemic agents

Atorvastatin, rosuvastatin: No clinically important effect on pharmacokinetics of the statin

Bupropion

No clinically important effect on pharmacokinetics of bupropion (CYP2B6 substrate)

Caffeine

No clinically important effect on pharmacokinetics of caffeine (CYP1A2 substrate)

Contraceptives, oral

No clinically important effect on pharmacokinetics of ethinyl estradiol or levonorgestrel

Dextromethorphan

No clinically important effect on pharmacokinetics of dextromethorphan (CYP2D6 substrate)

DMARDs, biologic

Concomitant use not recommended (see Rheumatoid Arthritis in Adults under Uses)

Immunosuppressive agents (e.g., azathioprine, cyclosporine)

Potent immunosuppressive agents (e.g., azathioprine, cyclosporine): Concomitant use not recommended

JAK inhibitors (e.g., baricitinib, tofacitinib)

Concomitant use not recommended

Ketoconazole

Peak concentration and AUC of upadacitinib increased by 70 and 75%, respectively

Use upadacitinib with caution in patients receiving long-term therapy with potent CYP3A4 inhibitors (e.g., ketoconazole)

Methotrexate

No clinically important effect on pharmacokinetics of methotrexate or upadacitinib

Midazolam

No clinically important effect on pharmacokinetics of midazolam (CYP3A substrate)

Proton-pump inhibitors

Omeprazole: No clinically important effect on pharmacokinetics of omeprazole (CYP2C19 substrate)

Omeprazole and other proton-pump inhibitors: Effects on gastric pH not expected to alter upadacitinib exposure

Rifampin

Peak concentration and AUC of upadacitinib decreased by 51 and 61%, respectively

Concomitant use with potent CYP3A4 inducers (e.g., rifampin) not recommended

Warfarin

No clinically important effect on pharmacokinetics of warfarin (CYP2C9 substrate)

Upadacitinib Pharmacokinetics

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.

  • 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.

  • Risk of GI perforation. Importance of promptly notifying clinician of fever and abdominal pain or changes in bowel function.

  • 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, HBV or HCV 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 therapy and for 4 weeks following the last dose of the drug.

  • Advise women to avoid breast-feeding during 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.

Upadacitinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release

15 mg

Rinvoq

AbbVie

AHFS DI Essentials™. © Copyright 2021, Selected Revisions August 3, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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