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Upadacitinib

Medically reviewed by Drugs.com. Last updated on Feb 15, 2019.

Pronunciation

(ue PAD a SYE ti nib)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet Extended Release 24 Hour, Oral:

Rinvoq: 15 mg

Brand Names: U.S.

  • Rinvoq

Pharmacologic Category

  • Antirheumatic Miscellaneous
  • Antirheumatic, Disease Modifying
  • Janus Associated Kinase Inhibitor

Pharmacology

Upadacitinib inhibits Janus kinase (JAK) enzymes, which are intracellular enzymes involved in stimulating hematopoiesis and immune cell function through a signaling pathway. JAKs activate signal transducers and activators of transcription (STATs), which regulate gene expression and intracellular activity. The inhibition of JAKs prevents the activation of STATs.

Metabolism

Hepatic, primarily via CYP3A4

Excretion

Urine (24% as unchanged drug); feces (38% as unchanged drug)

Time to Peak

2 to 4 hours

Half-Life Elimination

Terminal: 8 to 14 hours

Protein Binding

52% (plasma proteins)

Special Populations: Renal Function Impairment

AUCinf 18%, 33%, and 44% higher in mild, moderate, and severe renal impairment, respectively, compared to subjects with normal renal function. Cmax similar in subjects with normal and impaired renal function.

Special Populations: Hepatic Function Impairment

AUCinf 28% and 24% higher in mild and moderate hepatic impairment, respectively, compared to subjects with normal hepatic function. Cmax unchanged in mild hepatic impairment and 43% higher in moderate hepatic impairment compared to subjects with normal hepatic function. Not studied in patients with severe hepatic impairment (Child-Pugh C).

Use: Labeled Indications

Rheumatoid arthritis: Treatment of moderately to severely active rheumatoid arthritis in adults who have had an inadequate response or intolerance to methotrexate

Limitation of use: Use of upadacitinib in combination with other Janus-associated kinase inhibitors, biologic disease-modifying antirheumatic drugs, or with potent immunosuppressants such as azathioprine and cyclosporine, is not recommended.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosing: Adult

Note: May be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs); use in combination with biologic DMARDS or potent immunosuppressants (eg, azathioprine, cyclosporine) is not recommended. Do not initiate therapy in patients with an absolute lymphocyte count <500/mm3, ANC <1,000/mm3, or hemoglobin <8 g/dL.

Rheumatoid arthritis: Oral: 15 mg once daily.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Hematologic:

Absolute lymphocyte count (ALC) <500/mm3: Interrupt therapy until ALC ≥500/mm3.

ANC <1,000/mm3: Interrupt therapy until ANC ≥1,000/mm3.

Hemoglobin <8 g/dL: Interrupt therapy until hemoglobin ≥8 g/dL.

Infection (serious), including herpes zoster: Interrupt treatment until the infection is controlled.

Administration

Oral: Administer with or without food. Swallow tablet whole; do not crush, split, or chew.

Storage

Store at 2°C to 25°C (36°F to 77°F). Store in the original bottle to protect from moisture.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: May enhance the immunosuppressive effect of Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Avoid combination

Biologic Disease-Modifying Antirheumatic Drugs (DMARDs): May enhance the immunosuppressive effect of other Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Upadacitinib. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Upadacitinib. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Upadacitinib. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Methotrexate: May enhance the immunosuppressive effect of Upadacitinib. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

ALERT: U.S. Boxed Warning

Serious infections

Patients treated with upadacitinib are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt upadacitinib until the infection is controlled. Reported infections include:

Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before upadacitinib use and during therapy. Treatment for latent infection should be considered prior to upadacitinib use.

Invasive fungal infections, including cryptococcosis and pneumocystosis.

Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with upadacitinib should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with upadacitinib, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy

Malignancies

Lymphoma and other malignancies have been observed in patients treated with upadacitinib.

Thrombosis

Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis have occurred in patients treated with Janus kinase inhibitors used to treat inflammatory conditions. Many of these adverse events were serious and some resulted in death. Consider the risks and benefits prior to treating patients who may be at increased risk. Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately.

Warnings/Precautions

Concerns related to adverse effects:

• GI perforation: Use with caution in patients at increased risk for GI perforation (eg, history of diverticulitis, concomitant nonsteroidal anti-inflammatory drugs); perforations have been reported in clinical trials. Promptly evaluate new-onset abdominal symptoms in patients taking upadacitinib.

Hematologic toxicity: Hematologic toxicity, including lymphopenia, anemia, and neutropenia, may occur and is generally reversible and managed by treatment interruption. Do not initiate therapy in patients with an absolute lymphocyte count <500/mm3, ANC <1,000/mm3, or hemoglobin <8 g/dL. Monitor CBC at baseline and periodically thereafter.

• Hepatic effects: Liver enzyme elevation has been observed. Monitor LFTs at baseline and periodically thereafter; interrupt therapy if LFTs increased and drug-induced liver injury is suspected.

• Infections: [US Boxed Warning]: Patients receiving upadacitinib are at increased risk for serious infections, which may result in hospitalization and/or fatality; infections often developed in patients receiving concomitant immunosuppressive agents (eg, methotrexate, corticosteroids). Invasive fungal (including cryptococcosis and pneumocystosis [may present as disseminated rather than local disease]) and bacterial, viral (including herpes zoster), or other opportunistic infections (including esophageal candidiasis, multidermatomal herpes zoster) have been reported. Closely monitor patients for the development of signs/symptoms of infection during and after treatment. If a serious infection develops, interrupt upadacitinib until the infection is controlled. Carefully consider the risks and benefits of treatment with upadacitinib prior to initiating therapy in patients with chronic or recurrent infections. The most common serious infections reported included pneumonia and cellulitis. Reactivation of viral infections (eg, herpes zoster, hepatitis B) have been observed; the incidence of chronic viral hepatitis reactivation is unknown. Screen for viral hepatitis before and during therapy. If herpes zoster is reported, consider interrupting therapy until herpes zoster has resolved. Consultation with a hepatologist may be necessary if hepatitis B virus DNA is detected.

• Lipid abnormalities: Increased lipid parameters (eg, total, low-density lipoprotein [LDL], and high-density lipoprotein [HDL] cholesterol) have been observed. Mean LDL and HDL increased by ~15 mg/dL and ~8 mg/dL, respectively, 2 months after starting upadacitinib. Assess lipids 12 weeks after upadacitinib initiation and manage lipid abnormalities according to current clinical guidelines.

• Malignancy: [US Boxed Warning]: Lymphoma and other malignancies have been reported in patients receiving upadacitinib. Consider risks versus benefits prior to use in patients with a known malignancy (other than successfully treated nonmelanoma skin cancers [NMSCs]) or when continuing upadacitinib in patients who develop a new malignancy. NMSCs have been reported; patients at increased risk for skin cancer should have periodic skin examinations.

• Thrombosis: [US Boxed Warning]: Thrombosis, including deep vein thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis have been observed; may be serious and life-threatening. Promptly evaluate new-onset symptoms of DVT, PE, or arterial thrombosis. Consider risks versus benefits prior to use in patients with an increased risk of thrombosis.

• Tuberculosis: [US Boxed Warning]: Tuberculosis (TB) (pulmonary or extrapulmonary) has been reported in patients receiving upadacitinib. Patients should be evaluated for latent TB infection prior to and during therapy. Treatment of latent TB should be considered before use. Monitor for development of TB throughout treatment, including patients who initially tested negative for latent TB infection prior to initiating therapy. Use with caution in patients who have resided or traveled in regions where TB is endemic. Consider anti-TB therapy if an adequate course of treatment cannot be confirmed in patients with a history of latent or active TB or for patients with risk factors despite negative skin test.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Immunizations: Immunization status should be current before initiating therapy. Live vaccines should not be given concomitantly, or immediately prior to, upadacitinib; recommended interval between receipt of live vaccines and initiation of immunosuppressive agents such as upadacitinib should follow current vaccination clinical guidelines.

Monitoring Parameters

Lymphocyte count, neutrophil count, hemoglobin, and LFTs (baseline and periodically thereafter); lipids (12 weeks after therapy initiation and periodically thereafter); viral hepatitis (prior to initiating therapy and periodically thereafter); tuberculosis (TB) screen at baseline; signs/symptoms of infection (including TB) during and after therapy; skin examinations (periodically, in patients at increased risk for skin cancer); symptoms of thrombosis

Pregnancy Considerations

Based on data from animal reproduction studies, in utero exposure to upadacitinib may cause fetal harm. Evaluate pregnancy status prior to use in females of reproductive potential. Females of reproductive potential should use adequate contraception during treatment and for 4 weeks following the last dose of upadacitinib.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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