Upadacitinib

Last updated on: 09.08.2022

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Definition
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Upadacitinib is a selective and reversible JAK inhibitor. In adult patients, upadacitinib has been approved since December 2019 for the treatment of moderate-to-severe active rheumatoid art hritis and active psoriatic arthritis that have had an inadequate response to or are intolerant of one or more disease-modifying antirheumatic drugs(DMARDs). Upadacitinib can be used as monotherapy or in combination with methotrexate. It is also approved for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents 12 years of age and older who are eligible for systemic therapy*. Furthermore, the drug may be used in adult patients for the treatment of active ankylosing spondylitis who have responded inadequately to conventional therapy.

Pharmacodynamics (Effect)
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Upadacitinib is a selective and reversible JAK inhibitor. In human cell-based assays, upadacitinib preferentially inhibits JAK1 or JAK1/3 signaling pathways compared to other cytokine signaling pathways mediated through JAK2 pairs. This results in inhibition of STAT3 phosphorylation induced by IL-6 and STAT5 phosphorylation induced by IL-7. Maximal inhibition was observed one hour after ingestion and fell back to near initial levels by the end of the application interval. The mean terminal elimination half-life is 9 to 14 hours; this allows for once-daily (oral) administration.

Spectrum of action
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In the clinical trials, patients treated with upadacitinib achieved significant improvements in patient-reported quality of life as measured by the physical domain of the short-form-36 health questionnaire (SF-36) compared to placebo and MTX. In addition, patients treated with upadacitinib reported significant improvement in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) compared to patients treated with placebo.

Psoriatic arthritis: The efficacy and safety of upadacitinib 15 mg once daily were evaluated in two randomized, double-blind, multicenter, placebo-controlled Phase III studies in patients 18 years of age and older with moderate-to-severe active psoriatic arthritis. Significant improvement in psoriatic arthritis (classified according to CASPAR Classification Criteria for Psoriatic Arthritis - at least 3 tender joints and at least 3 swollen joints, plus active plaque psoriasis or a history of plaque psoriasis) was also demonstrated in these patients.

SELECT-PsA 1 was a 24-week study of 1,705 patients with inadequate response to or intolerance to at least one nonbiologic DMARD. Upadacitinib monotherapy showed statistically significant improvements in clinical and functional outcomes compared with methotrexate continuation (Smolen JS et al 2019).

Dosage and method of use
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The recommended dose of upadacitinib is 15 mg or 30 mg orally once daily. In patients with ankylosing spondylitis who do not show a clinical response after 16 weeks of treatment, consider discontinuing treatment. Some patients with an initial partial response may improve during the course of continued treatment beyond 16 weeks. Treatment shouldnot beinitiated in patients with an absolute lymphocyte count (ALC) < 500 cells/mm3, an absolute neutrophil count (ANC) of < 1,000 cells/mm3, or a hemoglobin level of < 8 g/dL . In elderly patients No dose adjustment is required in patients 65 years of age or older.

Renal Insufficiency: No dose adjustment is required in patients with mild or moderate renal insufficiency. Upadacitinib should be used with caution in patients with severe renal impairment.

Hepatic Insufficiency: No dose adjustment is required in patients with mild(Child-Pugh A) or moderate (Child-Pugh B) hepatic insufficiency. Upadacitinib should not be used in patients with severe hepatic insufficiency (Child-Pugh C).

Children and Adolescents: The safety and effectiveness of upadacitinib in children and adolescents aged 0 to less than 18 years have not been established. No data are available.

Routeof administration: Upadacitinib is to be taken once daily with or without a meal at any time of day, orally.

Monitoring of the following laboratory parameters is recommended:

  • Absolute neutrophil count (ANC): Treatment should be discontinued when ANC is < 1,000 cells/mm3 and restarted after ANC rises above this value.
  • Absolute lymphocyte count (ALC): Treatment should be discontinued at an ALC of < 500 cells/mm3 and restarted after ALC rises above this value. Hemoglobin (Hb): Treatment should be discontinued when Hb is < 8 g/dL and restarted only after Hb rises above this level.
  • Liver transaminases: Treatment should be temporarily interrupted if drug-induced liver damage is suspected.
  • Lipids: Patients should be managed according to international clinical guidelines for hyperlipidaemia.

Undesirable effects
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Very often there are upper respiratory tract infections, often neutropenia, hypercholesterolemia, cough, nausea, fever, increase in liver transaminases. Increase in creatine kinase and weight gain.

Occasional side effects include pneumonia, herpes zoster and herpes simplex infections, and oral candidiasis and hypertriglyceridemia.

Contraindication
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Hypersensitivity to the active substance.

Active tuberculosis (TB) or active serious other infections.

Severe hepatic insufficiency.

Pregnancy

Preparations
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Rinvoq®

Note(s)
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Combination with other potent immunosuppressants such as azathioprine, ciclosporin, tacrolimus and biological DMARDs or other Janus kinase (JAK) inhibitors has not been studied in clinical trials and is not recommended because the risk of additional immunosuppressive effects cannot be excluded. In patients with active serious infection, including local infections, treatment with upadacitinib must not be started.

Vaccinations: No data are available on the response to vaccination with live or inactivated vaccines in patients receiving upadacitinib treatment. The use of live attenuated vaccines during or immediately prior to treatment with upadacitinib is not recommended.

Prior to initiation of therapy with upadacitinib, it is recommended that patients' vaccination status be reviewed according to current vaccination guidelines and that all required vaccinations be obtained; this includes prophylactic vaccination against herpes zoster.

Tuberculosis: Tuberculosis (TB) screening should be performed prior to initiation of therapy with upadacitinib. In patients with untreated latent TB or in patients with risk factors for TB infection, consider anti-TB therapy prior to initiation of treatment with upadacitinib.

Literature
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  1. Fleischmann R et al (2019) Upadacitinib Versus Placebo or Adalimumab in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomized Controlled Trial. Arthritis Rheumatol 71:1788-1800.
  2. Guttman-Yassky E et al (2019) Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial. J Allergy Clin Immunol 145:877-884.
  3. Rubbert-Roth A et al (2020) Trial of upadacitinib or abatacept in rheumatoid arthritis. N Engl J Med 383:1511-1521.
  4. Serhal L et al (2019) Upadacitinib for the treatment of rheumatoid arthritis.Expert Rev Clin Immunol 15:13-25.
  5. Smolen JS et al. (2019) Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study. Lancet 393:2303-2311.

Last updated on: 09.08.2022