RINVOQ

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RINVOQ

Classes

Janus Associated Kinase (JAK) Inhibitors

Administration
Oral Administration Oral Solid Formulations

Administer the extended-release tablets with or without food. Do not administer with grapefruit or grapefruit juice.
Swallow the tablets whole. Do not split, crush or chew.
Instruct patients to contact their health care provider if medication residue is observed in stool or ostomy output repeatedly. Reports of medication residue in stool or ostomy output have occurred in patients taking upadacitinib, mostly in persons with anatomic (e.g., ileostomy, colostomy, intestinal resection) or functional gastrointestinal conditions with shortened gastrointestinal transit times.[64572]

Adverse Reactions
Severe

skin cancer / Delayed / 0-1.0
retinal detachment / Delayed / 0-1.0
hepatotoxicity / Delayed / Incidence not known
thromboembolism / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
thrombosis / Delayed / Incidence not known
stroke / Early / Incidence not known
pulmonary embolism / Delayed / Incidence not known
GI perforation / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known
lymphoma / Delayed / Incidence not known
anaphylactic shock / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known

Moderate

anemia / Delayed / 0-7.0
elevated hepatic enzymes / Delayed / 0.4-6.0
neutropenia / Delayed / 1.0-6.0
hypercholesterolemia / Delayed / 2.0-4.0
lymphopenia / Delayed / 0.5-3.0
candidiasis / Delayed / 0-2.0
leukopenia / Delayed / 1.0-2.0
hyperlipidemia / Delayed / 2.0-2.0
hypertriglyceridemia / Delayed / Incidence not known

Mild

infection / Delayed / 13.5-25.0
acne vulgaris / Delayed / 1.3-16.0
fever / Early / 1.2-7.0
headache / Early / 3.3-6.0
rash / Early / 4.0-5.0
folliculitis / Delayed / 2.0-4.0
nausea / Early / 3.0-3.5
cough / Delayed / 1.0-3.0
influenza / Delayed / 2.0-3.0
abdominal pain / Early / 2.0-3.0
urticaria / Rapid / 2.0-3.0
fatigue / Early / 1.0-3.0
weight gain / Delayed / 2.0-2.0
myalgia / Early / 1.0-2.0
laryngitis / Delayed / Incidence not known
pharyngitis / Delayed / Incidence not known
rhinitis / Early / Incidence not known
sinusitis / Delayed / Incidence not known
blepharedema / Early / Incidence not known

Boxed Warning
Acquired immunodeficiency syndrome (AIDS), corticosteroid therapy, fungal infection, herpes infection, human immunodeficiency virus (HIV) infection, immunosuppression, infection, pulmonary disease, tuberculosis, viral infection

Avoid the use of upadacitinib in patients with an active, serious infection, including localized infections. Serious and sometimes fatal bacterial infection, mycobacterial infection, invasive fungal infection, viral infection, or infections due to other opportunistic pathogens have been reported in patients receiving upadacitinib. Consider the risks and benefits of treatment prior to initiating upadacitinib therapy in patients: 1) with chronic or recurrent infection; 2) who have been exposed to tuberculosis; 3) with a history of a serious or an opportunistic infection; 4) who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or 5) with underlying conditions that may predispose them to infection [e.g., diabetes mellitus, human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS), chronic pulmonary disease, low lymphocyte counts, and pre-existing immunosuppression]. The most common serious infections reported with upadacitinib therapy were pneumonia and cellulitis. Among opportunistic infections, tuberculosis, cryptococcosis, multidermatomal herpes zoster, oral candidiasis, and esophageal candidiasis were reported with upadacitinib. Most patients who developed an infection were taking concomitant immunosuppressive agents, such as methotrexate or corticosteroid therapy. Ask patients if they have lived or have traveled to the Ohio or Mississippi River valleys or the Southwest because of an increased chance of acquiring certain kinds of fungal infections, such as histoplasmosis, coccidioidomycosis, or blastomycosis. Viral reactivation, including cases of herpes infection reactivation (e.g., herpes zoster), were observed in clinical studies. The risk of herpes zoster appears to be higher in patients treated with upadacitinib in Japan. If a patient develops herpes zoster, consider stopping upadacitinib therapy until the episode resolves. Prior to starting and during upadacitinib therapy, patients should be evaluated and tested for latent or active tuberculosis (TB) infection. Upadacitinib should not be administered to patients with active tuberculosis infection. Carefully consider the risks and benefits of upadacitinib before starting the drug in patients who have been exposed to tuberculosis. Consider anti-tuberculosis therapy before starting upadacitinib in patients with active or previously untreated latent tuberculosis in whom an adequate course of treatment cannot be confirmed and for patients with a negative test for latent tuberculosis but with risk factors for tuberculosis infection. It is recommended to consult with a physician with expertise in the treatment of tuberculosis to aid in the decision of whether to start anti-tuberculosis therapy. All patients, including those who tested negative for latent tuberculosis infection prior to starting therapy, should be monitored for signs and symptoms of tuberculosis during upadacitinib treatment. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with upadacitinib. If a patient develops a serious infection, an opportunistic infection, or sepsis, upadacitinib therapy should be interrupted. Patients who develop a new infection should undergo prompt and complete diagnostic evaluation appropriate for an immunocompromised patient, initiated on antimicrobial therapy, and closely monitored.[64572]

Lymphoma, new primary malignancy, skin cancer, sunlight (UV) exposure, tobacco smoking

Upadacitinib may increase the risk for a new primary malignancy. In a large, postmarketing, randomized safety clinical trial in rheumatoid arthritis patients 50 years of age and older with one or more CV risk factors, higher rates of cancer [excluding non-melanoma skin cancer (NMSC)] and lymphoma were observed with use of tofacitinib, another JAK inhibitor, compared to tumor necrosis factor (TNF) inhibitors. Upadacitinib has not been studied in similar trials; however, the risks may be similar for all JAK inhibitors used for inflammatory conditions. A higher rate of lung cancer was also observed in patients with a history of current or past tobacco smoking treated with the JAK inhibitor compared to those taking a TNF inhibitor. Patients with a history of current or past tobacco smoking were at also at an increased risk of overall cancers. Consider the benefits and risks for the individual patient before initiation or continuation of therapy, particular in those with risk factors such as smoking, those who develop malignancy, and those with a known malignancy other than successfully treated non-melanoma skin cancer (NMCS). Reserve upadacitinib for patients who have an inadequate response or intolerance to other therapies. Lymphoma and other cancers, including NMSCs, have been observed in patients taking upadacitinib. Patients at increased risk of skin cancer should undergo periodic skin examinations. Instruct patients to limit sunlight (UV) exposure by wearing protective clothing and using broad-spectrum sunscreen.

Cardiac disease, hypertension, mortality, myocardial infarction, stroke, thromboembolic disease, thromboembolism, thrombosis

Avoid upadacitinib treatment in patients at increased risk of thrombosis or thromboembolism, including those with previous thromboembolic disease. Consider the risks and benefits of initiating or continuing upadacitinib therapy in patients who are current or past smokers and patients with cardiovascular (CV) risk factors (e.g., cardiac disease, hypertension, previous myocardial infarction). In a large, postmarketing, randomized safety clinical trial in rheumatoid arthritis patients 50 years of age and older with one or more CV risk factors, higher rates of all-cause mortality (including sudden CV death), major adverse CV events (MACE; defined as CV death, non-fatal myocardial infarction (MI), and non-fatal stroke), and thrombosis (including deep venous thrombosis (DVT) and pulmonary embolism (PE)) were observed in patients taking tofacitinib, another Janus kinase (JAK) inhibitor, compared to patients taking tumor necrosis factor (TNF) inhibitors. Many of the observed thrombotic events were serious and some resulted in death. Upadacitinib has not been studied in similar trials; however, the risks may be similar for all JAK inhibitors used for inflammatory conditions. Current or past tobacco smokers have an additional increased risk of major CV adverse events. Reserve upadacitinib for patients who have an inadequate response or intolerance to one or more TNF inhibitors. Advise patients of the potential increased risk for major adverse CV events and to seek emergency medical attention if they experience signs and symptoms of a heart attack, stroke, or blood clot. If a patient develops a thromboembolic event or experiences a stroke or MI, discontinue the drug.

Common Brand Names

RINVOQ

Dea Class

Rx

Description

Oral Janus kinase (JAK) inhibitor, a target specific DMARD
Used in adults with moderate to severe rheumatoid arthritis, ulcerative colitis, Crohn's disease, active psoriatic arthritis, active ankylosing spondylitis, and active non-radiographic axial spondyloarthritis; used in pediatric patients 12 years and older with refractory, moderate to severe atopic dermatitis
Serious infections, blood clots, and malignancy may occur; reserve for those with an inadequate response or intolerant of one or more TNF inhibitors

Dosage And Indications
For the treatment of moderately to severely active rheumatoid arthritis in persons who have had an inadequate response or intolerance to tumor necrosis factor (TNF) inhibitors. Oral dosage Adults

15 mg PO once daily, with or without methotrexate or other non-biologic (conventional) disease-modifying antirheumatic drugs (DMARDs). Do not use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of active psoriatic arthritis in patients who have had an inadequate response or intolerance to 1 or more Tumor Necrosis Factor (TNF) inhibitors. Oral dosage Adults

15 mg PO once daily. Do not use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine. ADJUSTMENTS:Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of refractory, moderate to severe atopic dermatitis (eczema) in persons whose disease is not adequately controlled with other systemic medications, including biologics, or when use of those therapies is not advisable.
NOTE: Not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or other immunosuppressants; however, upadacitinib may be administered with or without topical corticosteroids.
Oral dosage Adults 18 to 64 years

15 mg PO once daily, initially. Consider increasing the dose to 30 mg PO once daily if an adequate response is not achieved. Discontinue use if an adequate response is not achieved with the 30 mg dose. Use the lowest effective dose needed to maintain response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Adults 65 years and older

15 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Children and Adolescents 12 to 17 years weighing at least 40 kg

15 mg PO once daily, initially. Consider increasing the dose to 30 mg PO once daily if an adequate response is not achieved. Discontinue use if an adequate response is not achieved with the 30 mg dose. Use the lowest effective dose needed to maintain response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of moderately to severely active ulcerative colitis, in persons who have an inadequate response or intolerance to tumor necrosis factor (TNF) inhibitors. Oral dosage Adults

45 mg PO once daily for 8 weeks, then 15 mg PO once daily. May consider 30 mg PO once daily for refractory, severe, or extensive disease. Discontinue if an adequate response is not achieved with 30 mg/day. Use the lowest effective dose needed to maintain response. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of active ankylosing spondylitis in patients who have had an inadequate response or intolerance to 1 or more tumor necrosis factor (TNF) inhibitors. Oral dosage Adults

15 mg PO once daily. Do not use in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or with potent immunosuppressants such as azathioprine or cyclosporine. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of active non-radiographic axial spondyloarthritis with objective signs of inflammation in patients who have had an inadequate response or intolerance to tumor necrosis factor (TNF) inhibitor therapy. Oral dosage Adults

15 mg PO once daily. Do not use in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or with potent immunosuppressants such as azathioprine or cyclosporine. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of moderately to severely active Crohn's disease, in persons who have had an inadequate response or intolerance to tumor necrosis factor (TNF) inhibitors. Oral dosage Adults

45 mg PO once daily for 12 weeks, then 15 mg PO once daily. May consider 30 mg PO once daily for refractory, severe, or extensive disease. Discontinue if an adequate therapeutic response is not achieved with 30 mg/day. Use the lowest effective dosage needed to maintain response. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Dosing Considerations
Hepatic Impairment

Rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis:
Mild (Child Pugh A) or moderate (Child Pugh B) impairment: No dosage adjustments are required.
Severe (Child Pugh C) impairment: Use is not recommended.
 
For Ulcerative colitis:
Mild (Child Pugh A) or moderate (Child Pugh B) impairment: The recommended dose is 30 mg PO once daily for 8 weeks for induction. Then, 15 mg PO daily for maintenance.
Severe (Child Pugh C) impairment: Use is not recommended.
 
For Crohn's disease:
Mild (Child Pugh A) or moderate (Child Pugh B) impairment: The recommended dose is 30 mg PO once daily for 12 weeks for induction. Then, 15 mg PO daily for maintenance.
Severe (Child Pugh C) impairment: Use is not recommended.
 
Abnormalities in hepatic transaminases occurring during treatment
If increases in ALT or AST are observed during routine patient management and drug-induced liver injury is suspected, interrupt upadacitinib treatment until this diagnosis is excluded. Prompt investigation of the cause of liver enzyme elevation is recommended.

Renal Impairment

Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis:
Mild, Moderate, or Severe renal impairment: No dosage adjustments are needed.
End stage renal disease (eGFR less than 15 mL/minute/1.73 m2): Use is not recommended.[64572]
 
Atopic dermatitis:
Mild or moderate renal impairment (eGFR 30 mL/minute/1.73 m2 or more): No dosage adjustments are needed.
Severe renal impairment (eGFR 15 to less than 30 mL/minute/1.73 m2): The recommended dose is 15 mg PO once daily.
End stage renal disease (eGFR less than 15 mL/minute/1.73 m2): Use is not recommended.
 
Ulcerative colitis:
Mild or moderate renal impairment (eGFR 30 mL/minute/1.73 m2 or more): No dosage adjustments are needed.
Severe renal impairment (eGFR 15 to less than 30 mL/minute/1.73 m2): The recommended dose is 30 mg PO once daily for 8 weeks for induction. Then, 15 mg PO daily for maintenance.
End stage renal disease (eGFR less than 15 mL/minute/1.73 m2): Use is not recommended.
 
Crohn's disease:
Mild or moderate renal impairment (eGFR 30 mL/minute/1.73 m2 or more): No dosage adjustments are needed.
Severe renal impairment (eGFR 15 to less than 30 mL/minute/1.73 m2): The recommended dose is 30 mg PO once daily for 12 weeks for induction. Then, 15 mg PO daily for maintenance.
End stage renal disease (eGFR less than 15 mL/minute/1.73 m2): Use is not recommended.
 
Intermittent hemodialysis
Upadacitinib has not been studied in patients with end-stage renal disease (ESRD); use not recommended.[64572]

Drug Interactions

Abatacept: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as abatacept, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Adagrasib: (Major) During concomitant use of upadacitinib and adagrasib reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Adalimumab: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Amoxicillin; Clarithromycin; Omeprazole: (Major) During concomitant use of upadacitinib and clarithromycin reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Anakinra: (Major) Avoid the concomitant use of upadacitinib with biologic DMARDs, such as anakinra; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Antithymocyte Globulin: (Major) Do not use upadacitinib in combination with potent immunosuppressants such as anti-thymocyte immune globulin. A risk of added immunosuppression exists when upadacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose upadacitinib with potent immunosuppressives has not been studied.
Apalutamide: (Major) Coadministration of upadacitinib with apalutamide is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
Atazanavir: (Major) During concomitant use of upadacitinib and atazanavir reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Atazanavir; Cobicistat: (Major) During concomitant use of upadacitinib and atazanavir reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold. (Major) During concomitant use of upadacitinib and cobicistat reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Azathioprine: (Major) Do not use upadacitinib in combination with potent immunosuppressants such as azathioprine. A risk of added immunosuppression exists when upadacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose upadacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Bacillus Calmette-Guerin Vaccine, BCG: (Major) Avoid use of live vaccines during or immediately prior to upadacitinib therapy initiation. Before initiating upadacitinib, it is recommended that patients be brought up to date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current vaccination guidelines.
Baricitinib: (Major) Concomitant use of baricitinib with upadacitinib is not recommended because of the duplication of the mechanism of action (both are Janus kinase inhibitors, also known as JAK inhibitors) and the possibility of increased immunosuppression and increased infection risk. Both drugs are known to cause elevations in hepatic enzymes and gastrointestinal perforation, and a possibility for increased thrombotic risk.
Brodalumab: (Major) Do not use upadacitinib in combination with biologic immunosuppressives, such as brodalumab, because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. Most patients taking upadacitinib who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids.
Canakinumab: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as canakinumab, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Carbamazepine: (Major) Coadministration of upadacitinib with carbamazepine is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
Ceritinib: (Major) During concomitant use of upadacitinib and ceritinib reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Certolizumab pegol: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Chloramphenicol: (Major) During concomitant use of upadacitinib and chloramphenicol reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clarithromycin: (Major) During concomitant use of upadacitinib and clarithromycin reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Cobicistat: (Major) During concomitant use of upadacitinib and cobicistat reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Cyclosporine: (Major) Do not use upadacitinib in combination with potent immunosuppressants such as cyclosporine. A risk of added immunosuppression exists when upadacitinib is coadministered with potent immunosuppressives. Cyclosporine is also an inhibitor of CYP3A4, and upadacitinib is a CYP3A4 substrate. Combined use of multiple-dose upadacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Darunavir: (Major) During concomitant use of upadacitinib and darunavir reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Darunavir; Cobicistat: (Major) During concomitant use of upadacitinib and cobicistat reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold. (Major) During concomitant use of upadacitinib and darunavir reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) During concomitant use of upadacitinib and cobicistat reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold. (Major) During concomitant use of upadacitinib and darunavir reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Delavirdine: (Major) During concomitant use of upadacitinib and delavirdine reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) During concomitant use of upadacitinib and cobicistat reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) During concomitant use of upadacitinib and cobicistat reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Enzalutamide: (Major) Coadministration of upadacitinib with enzalutamide is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
Etanercept: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Everolimus: (Major) Avoid use upadacitinib in combination with potent immunosuppressants such as everolimus. A risk of added immunosuppression exists when upadacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose upadacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Fosphenytoin: (Major) Coadministration of upadacitinib with fosphenytoin is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
Golimumab: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during upadacitinib treatment due to the risk of increased upadacitinib exposure and adverse reactions. Upadacitinib is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor.
Guselkumab: (Major) Do not use upadacitinib in combination with biologic immunosuppressives, such as guselkumab, because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. Most patients taking upadacitinib who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids.
Idelalisib: (Major) During concomitant use of upadacitinib and idelalisib reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Indinavir: (Major) During concomitant use of upadacitinib and indinavir reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Infliximab: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Intranasal Influenza Vaccine: (Major) Avoid use of live vaccines during or immediately prior to upadacitinib therapy initiation. Before initiating upadacitinib, it is recommended that patients be brought up to date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current vaccination guidelines.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Coadministration of upadacitinib with rifampin is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Concurrent use of upadacitinib with rifampin 600 mg once daily for 9 days decreased upadacitinib exposure by 61%.
Isoniazid, INH; Rifampin: (Major) Coadministration of upadacitinib with rifampin is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Concurrent use of upadacitinib with rifampin 600 mg once daily for 9 days decreased upadacitinib exposure by 61%.
Itraconazole: (Major) During concomitant use of upadacitinib and itraconazole reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Ixekizumab: (Major) Do not use upadacitinib in combination with biologic immunosuppressives, such as ixekizumab, because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. Most patients taking upadacitinib who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids.
Ketoconazole: (Major) During concomitant use of upadacitinib and ketoconazole reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use increased upadacitinib overall exposure 1.75-fold.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) During concomitant use of upadacitinib and clarithromycin reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Levoketoconazole: (Major) During concomitant use of upadacitinib and ketoconazole reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use increased upadacitinib overall exposure 1.75-fold.
Live Vaccines: (Major) Avoid use of live vaccines during or immediately prior to upadacitinib therapy initiation. Before initiating upadacitinib, it is recommended that patients be brought up to date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current vaccination guidelines.
Lonafarnib: (Major) During concomitant use of upadacitinib and lonafarnib reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Lopinavir; Ritonavir: (Major) During concomitant use of upadacitinib and ritonavir reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Lumacaftor; Ivacaftor: (Major) Coadministration of upadacitinib with lumacaftor; ivacaftor is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
Lumacaftor; Ivacaftor: (Major) Coadministration of upadacitinib with lumacaftor; ivacaftor is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Avoid use of live vaccines during or immediately prior to upadacitinib therapy initiation. Before initiating upadacitinib, it is recommended that patients be brought up to date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current vaccination guidelines.
Measles/Mumps/Rubella Vaccines, MMR: (Major) Avoid use of live vaccines during or immediately prior to upadacitinib therapy initiation. Before initiating upadacitinib, it is recommended that patients be brought up to date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current vaccination guidelines.
Mercaptopurine, 6-MP: (Major) The use of upadacitinib in combination with potent immunosuppressants such as mercaptopurine is not recommended. A risk of added immunosuppression exists when upadacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose upadacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Mifepristone: (Major) During concomitant use of upadacitinib and mifepristone reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Mitotane: (Major) Coadministration of upadacitinib with mitotane is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid use of upadacitinib in combination with potent immunosuppressants such as sirolimus. A risk of added immunosuppression exists when upadacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose upadacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Nefazodone: (Major) During concomitant use of upadacitinib and nefazodone reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Nelfinavir: (Major) During concomitant use of upadacitinib and nelfinavir reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Nirmatrelvir; Ritonavir: (Major) Consider withholding upadacitinib, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the upadacitinib dose. Do not exceed an upadacitinib induction dose of 30 mg PO once daily for 8 weeks and a maintenance dose of 15 mg once daily if coadministered with ritonavir-boosted nirmatrelvir in patients with ulcerative colitis. Do not exceed an upadacitinib dose of 15 mg PO once daily if coadministered with ritonavir-boosted nirmatrelvir in patients with arthritis or dermatitis. Monitor closely for adverse reactions. Concurrent use may increase upadacitinib exposure resulting in increased toxicity. Upadacitinib is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Major) During concomitant use of upadacitinib and ritonavir reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Phenobarbital: (Major) Coadministration of upadacitinib with phenobarbital is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Coadministration of upadacitinib with phenobarbital is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
Phenytoin: (Major) Coadministration of upadacitinib with phenytoin is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
Posaconazole: (Major) During concomitant use of upadacitinib and posaconazole reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Primidone: (Major) Coadministration of upadacitinib with primidone is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
Ribociclib: (Major) During concomitant use of upadacitinib and ribociclib reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Ribociclib; Letrozole: (Major) During concomitant use of upadacitinib and ribociclib reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Rifampin: (Major) Coadministration of upadacitinib with rifampin is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Concurrent use of upadacitinib with rifampin 600 mg once daily for 9 days decreased upadacitinib exposure by 61%.
Rifapentine: (Major) Coadministration of upadacitinib with rifapentine is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; rifapentine is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
Ritonavir: (Major) During concomitant use of upadacitinib and ritonavir reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Rituximab: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as rituximab, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Rituximab; Hyaluronidase: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as rituximab, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Rotavirus Vaccine: (Major) Avoid use of live vaccines during or immediately prior to upadacitinib therapy initiation. Before initiating upadacitinib, it is recommended that patients be brought up to date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current vaccination guidelines.
Ruxolitinib: (Major) Concomitant use of ruxolitinib with upadacitinib is not recommended because of the duplication of the mechanism of action (both are Janus kinase inhibitors, also known as JAK inhibitors) and the possibility of increased immunosuppression and increased infection risk. Both drugs are known to cause elevations in hepatic enzymes and gastrointestinal perforation, and a possibility for increased thrombotic risk.
Saquinavir: (Major) During concomitant use of upadacitinib and saquinavir reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Sarilumab: (Major) Avoid the concomitant use of sarilumab with other biological DMARDs, such as upadacitinib; coadministration has not been studied and may result in additive immunosuppression and an increased risk of infection.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Secukinumab: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as secukinumab, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Sirolimus: (Major) Avoid use of upadacitinib in combination with potent immunosuppressants such as sirolimus. A risk of added immunosuppression exists when upadacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose upadacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Major) Avoid use of live vaccines during or immediately prior to upadacitinib therapy initiation. Before initiating upadacitinib, it is recommended that patients be brought up to date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current vaccination guidelines.
Smallpox Vaccine, Vaccinia Vaccine: (Major) Avoid use of live vaccines during or immediately prior to upadacitinib therapy initiation. Before initiating upadacitinib, it is recommended that patients be brought up to date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current vaccination guidelines.
St. John's Wort, Hypericum perforatum: (Major) Coadministration of upadacitinib with St. John's Wort is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
Tacrolimus: (Major) Avoid use of upadacitinib in combination with potent immunosuppressants such as tacrolimus. A risk of added immunosuppression exists when upadacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose upadacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Tipranavir: (Major) During concomitant use of upadacitinib and tipranavir reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Tocilizumab: (Major) Avoid the concomitant use of tocilizumab with other biological DMARDs such as upadacitinib; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Tofacitinib: (Major) Concomitant use of tofacitinib with upadacitinib is not recommended because of the duplication of the mechanism of action (both are Janus kinase inhibitors, also known as JAK inhibitors) and the possibility of increased immunosuppression and increased infection risk. Both drugs are known to cause elevations in hepatic enzymes and gastrointestinal perforation, and a possibility for increased thrombotic risk.
Tucatinib: (Major) During concomitant use of upadacitinib and tucatinib reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Tumor Necrosis Factor modifiers: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Typhoid Vaccine: (Major) Avoid use of live vaccines during or immediately prior to upadacitinib therapy initiation. Before initiating upadacitinib, it is recommended that patients be brought up to date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current vaccination guidelines.
Ustekinumab: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as ustekinumab, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Varicella-Zoster Virus Vaccine, Live: (Major) Avoid use of live vaccines during or immediately prior to upadacitinib therapy initiation. Before initiating upadacitinib, it is recommended that patients be brought up to date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current vaccination guidelines.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) During concomitant use of upadacitinib and clarithromycin reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Voriconazole: (Major) During concomitant use of upadacitinib and voriconazole reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Yellow Fever Vaccine, Live: (Major) Avoid use of live vaccines during or immediately prior to upadacitinib therapy initiation. Before initiating upadacitinib, it is recommended that patients be brought up to date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current vaccination guidelines.

How Supplied

RINVOQ Oral Tab ER: 15mg, 30mg, 45mg

Maximum Dosage
Adults

15 mg/day PO for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis; 30 mg/day PO for atopic dermatitis; 30 mg/day PO for maintenance treatment of ulcerative colitis (UC); 45 mg/day PO during induction for UC; 30 mg/day PO for maintenance treatment of Crohn's disease; 45 mg/day PO during induction for Crohn's disease.

Geriatric

15 mg/day PO for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis; 15 mg/day PO for atopic dermatitis; 30 mg/day PO for maintenance treatment of ulcerative colitis (UC); 45 mg/day PO during induction for UC; ; 30 mg/day PO for maintenance treatment of Crohn's disease; 45 mg/day PO during induction for Crohn's disease.

Adolescents

weighing 40 kg or more: 30 mg/day PO for atopic dermatitis; safety and efficacy have not been established for other indications.
weighing less than 40 kg: Safety and efficacy have not been established.

Children

12 years and weighing 40 kg or more: 30 mg/day PO for atopic dermatitis; safety and efficacy have not been established for other indications.
12 years and weighing less than 40 kg: Safety and efficacy have not been established.
1 to 11 years: Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Mechanism Of Action

Upadacitinib is an oral Janus kinase (JAK) inhibitor. Janus kinases, part of the tyrosine kinase enzyme family, are intracellular enzymes that transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of immune cell function and hematopoiesis. JAK-mediated signaling is pivotal in immune activation, as cytokine receptors are expressed on most immune cells. JAKs are responsible for the intracellular signaling in type I and type II cytokine receptors located on over 50 cytokines, interleukins, interferons, colony-stimulating factors, and hormones. Upon ligand and receptor interaction, JAKs phosphorylate and activate signal transducers and activators of transcription proteins (STATs), which modulate intracellular activity including gene expression. Upadacitinib modulates the signaling pathway by inhibiting JAKs and preventing phosphorylation and activation of STATs preventing intracellular signal transduction. Cytokine signaling is transmitted through the pairing of JAKs, such as JAK1/JAK3, JAK1/JAK2, and JAK2/JAK2. Upadacitinib has a greater affinity for JAK1 and JAK2 compared to JAK3 and TYK2. In cellular assays, upadacitinib had a 74-fold higher selectivity for JAK1 compared to JAK2 and, in biochemical assays, a 58-fold higher selectivity for JAK1 compared to JAK3. In human leukocytes, upadacitinib exhibited greater inhibition of cytokine-induced STAT phosphorylation mediated by JAK1 and JAK1/JAK3 compared to JAK2/JAK2. The selectivity for JAK1 may be advantageous due to the potential decreased risk of adverse effects. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.[64572] [64573] [64574] [64575]

Pharmacokinetics

Upadacitinib is administered orally. Plasma protein binding is 52%. Upadacitinib distributes equally between red blood cells and plasma with a blood to plasma ratio of 1. Metabolism is primarily mediated by hepatic CYP3A4 with a minor contribution from CYP2D6. In a human radiolabeled study, 79% of the total circulating radioactivity was accounted for by unchanged upadacitinib, with 13% attributed to the main metabolite. The pharmacologic activity of upadacitinib is attributed to the parent molecule; no active metabolites have been identified for upadacitinib. Following single dose administration, upadacitinib was eliminated predominantly as unchanged drug in the urine (24%) and feces (38%). Approximately 34% of the dose was excreted as metabolites. The mean terminal elimination half-life ranged from 8 to 14 hours. Upadacitinib pharmacokinetics were similar between rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis patients.[64572]
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4, CYP2C19
Upadacitinib is primarily a substrate of CYP3A4, with minor contributions from CYP2C19. The Cmax and AUC of upadacitinib are increased when coadministered with strong CYP3A4 inhibitors; caution is recommended. Due to a reduction in Cmax and AUC, there is a potential for reduced therapeutic effect when upadacitinib is coadministered with strong CYP3A4 inducers and concomitant use is not recommended.[64572]
 
In vitro studies demonstrated that upadacitinib does not inhibit or induce the activity CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 at clinically relevant concentrations. Upadactinib was not found to inhibit the transporters P-glycoprotein (P-gp), BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, and MATE2K at clinically relevant concentrations during these studies.[64572]

Oral Route

Median time to peak concentration (Tmax) was 2 to 4 hours after oral administration of upadacitinib. In clinical trials, upadactinib was given without regard to meals. Coadministration of upadacitinib with high fat and high-calorie meals increased the AUC by 29% and Cmax by 39% to 60%; however, these increases were not found to be clinically relevant. Upadacitinib can be given with or without food.

Pregnancy And Lactation
Pregnancy

Sufficient data are not available to inform a drug-associated risk for major birth defects or miscarriage with the use of upadacitinib during human pregnancy. Based on animal studies, upadacitinib has the potential to adversely affect a developing fetus. Advise women of reproductive potential of the possible risks of upadacitinib therapy during pregnancy and the importance of using contraception during treatment and for 4 weeks following the last dose. Verify that the female patient isn't pregnant prior to starting upadacitinib. In animal studies, oral administration to pregnant rats at exposures as low as 0.9 times the maximum recommended human dose (MRHD) during organogenesis resulted in skeletal malformations (e.g., misshapen humerus, bent scapula, and bent humerus). Bent forelimbs, bent hindlimbs, rib defects, vertebral defects, and decreased fetal body weights occurred with exposures of approximately 48 times the MRHD in pregnant rats. In studies of pregnant rabbits that received oral upadacitinib at approximately 8.5 times the MRHD, embryolethality, decreased fetal body weights, and cardiovascular malformations were observed. No developmental toxicity was observed at exposures approximately 0.2 and 1.3 times the MRHD in rats and rabbits, respectively. Published data suggest that increased disease activity in women with rheumatoid arthritis is associated with an increased risk for adverse pregnancy outcomes such as preterm delivery, low birth weight, and small for gestational age at birth. Report exposures during pregnancy to the manufacturer's Adverse Event reporting line at 1-888-633-9110 or to the FDA at 1-800-FDA-1088.[64572]

Females of reproductive potential should undergo pregnancy testing prior to starting upadacitinib therapy to determine pregnancy status. Advise patients of the potential reproductive risk (e.g., potential for fetal harm) when upadacitinib is administered during pregnancy. Females of reproductive potential should be advised of contraception requirements and that they should use effective contraception during upadacitinib therapy and for 4 weeks following the last dose.