RINVOQ

/ AbbVie

Rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis
The recommended dose of upadacitinib is 15 mg once daily.
Consideration should be given to discontinuing treatment in patients with axial spondyloarthritis who have shown no clinical response after 16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks.
Atopic dermatitis
Adults
The recommended dose of upadacitinib is 15 mg or 30 mg once daily based on individual patient presentation.
Adolescents (from 12 to 17 years of age)
The recommended dose of upadacitinib is 15 mg once daily for adolescents weighing at least 30 kg.
Ulcerative colitis
Induction
The recommended induction dose of upadacitinib is 45 mg once daily for 8 weeks. For patients who do not achieve adequate therapeutic benefit by week 8, upadacitinib 45 mg once daily may be continued for an additional 8 week period. Upadacitinib should be discontinued in any patient who shows no evidence of therapeutic benefit by week 16.
Maintenance
The recommended maintenance dose of upadacitinib is 15 mg or 30 mg once daily based on individual patient presentation.
Crohn’s disease
Induction
The recommended induction dose of upadacitinib is 45 mg once daily for 12 weeks. For patients who have not achieved adequate therapeutic benefit after the initial 12-week induction, prolonged induction for an additional 12 weeks with a dose of 30 mg
once daily may be considered. For these patients, upadacitinib should be discontinued if there is no evidence of therapeutic benefit after 24 weeks of treatment.
Maintenance
The recommended maintenance dose of upadacitinib is 15 mg or 30 mg once daily based on individual patient presentation.
Juvenile psoriatic arthritis and Polyarticular Juvenile Idiopathic Arthritis
The recommended dosage for patients 2 years and older is based on body weight.
See prescribing information for full details.

Rheumatoid arthritis
Treatment of moderate to severe active rheumatoid arthritis in adult who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs). upadacitinib may be used as monotherapy or in combination with methotrexate.
Psoriatic arthritis
Treatment of active psoriatic arthritis in adult who have responded inadequately to, or who are intolerant to one or more DMARDs. upadacitinib may be used as monotherapy or in combination with methotrexate.
Axial spondyloarthritis
Non-radiographic axial spondyloarthritis (nr-axSpA)
Treatment of active non-radiographic axial spondyloarthritis in adult with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI), who have responded inadequately to nonsteroidal anti-inflammatory drugs (NSAIDs).
Ankylosing spondylitis (AS, radiographic axial spondyloarthritis)
Treatment of active ankylosing spondylitis in adult patients who have
responded inadequately to conventional therapy.
Atopic dermatitis
Treatment of moderate to severe atopic dermatitis in adults and
adolescents 12 years and older who are candidates for systemic therapy.
Ulcerative colitis
Treatment of adult patients with moderately to severely active ulcerative colitis who has had an inadequate response, lost response or were intolerant to either conventional therapy or a biologic agent.
Crohn’s disease
Treatment of adult with moderately to severely active Crohn’s disease who has had an inadequate response, lost response or were intolerant to either conventional therapy or a biologic agent.
Juvenile psoriatic arthritis
Upadacitinib 15mg is indicated for the treatment of patients 2 years of age and older with active juvenile psoriatic arthritis (JPsA) who have had an inadequate response or intolerance to one or more TNF blockers.
Limitations of Use:
Not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine.
Polyarticular Juvenile Idiopathic Arthritis
Upadacitinib 15mg is indicated for the treatment of patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis (pJIA) who have had an inadequate response or intolerance to one or more TNF blockers.
Limitations of Use:
Not recommended for use in combination with other JAK inhibitors, biologic
DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine.

* Hypersensitivity to the active substance or to any of the excipients
* Active tuberculosis (TB) or active serious infections.
* Severe hepatic impairment.
* Pregnancy

Use in patients 65 years of age and older
Considering the increased risk of MACE, malignancies, serious infections, and all-cause mortality in patients 65 years of age and older, as observed in a large randomised study of tofacitinib (another Janus Kinase (JAK) inhibitor), upadacitinib should only be used in these patients if no suitable treatment alternatives are available.
In patients 65 years of age and older, there is an increased risk of adverse reactions with upadacitinib 30 mg once daily. Consequently, the recommended dose for long-term use in this patient population is 15 mg once daily.
Immunosuppressive medicinal products
Combination with other potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporin, tacrolimus, and biologic DMARDs or other JAK inhibitors has not been evaluated in clinical studies and is not recommended as a risk of additive immunosuppression cannot be excluded.
Serious infections
Serious and sometimes fatal infections have been reported in patients receiving upadacitinib. The most frequent serious infections reported with upadacitinib included pneumonia and cellulitis. Cases of bacterial meningitis and sepsis have been reported in patients receiving upadacitinib. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, oral/oesophageal candidiasis, and cryptococcosis were reported with upadacitinib.
Upadacitinib should not be initiated in patients with an active, serious infection, including localized infections.
If a patient develops a new infection while receiving upadacitinib, prompt and thorough diagnostic evaluation should be conducted, considering the patient’s immunocompromised status. Suitable antimicrobial treatment should be initiated, and the patient should be closely monitored. Upadacitinib should be temporarily discontinued if there is no response to antimicrobial therapy. Treatment with upadacitinib may be resumed once the infection is adequately controlled.
A higher rate of serious infections was observed with upadacitinib 30 mg compared to upadacitinib 15 mg.
As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes. In patients 65 years of age and older, upadacitinib should only be used if no suitable treatment alternatives are available.
Tuberculosis
Patients should be screened for tuberculosis (TB) before starting upadacitinib therapy. Upadacitinib should not be given to patients with active TB. Anti-TB therapy should be considered prior to initiation of upadacitinib in patients with previously untreated latent TB or in patients with risk factors for TB infection. Patients should be monitored for the development of signs and symptoms of TB, including patients
who tested negative for latent TB infection prior to initiating therapy.
Viral reactivation
Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), was reported in clinical studies. The risk of herpes zoster appears to be higher in Japanese patients treated with upadacitinib. If a patient develops herpes zoster, interruption of upadacitinib therapy should be considered until the episode resolves.
Screening for viral hepatitis and monitoring for reactivation should be performed before starting and during therapy with upadacitinib. If hepatitis B virus DNA is
detected while receiving upadacitinib, a liver specialist should be consulted.
Vaccination
Use of live, attenuated vaccines during or immediately prior to upadacitinib therapy is
not recommended. Prior to initiating upadacitinib treatment, it is recommended that patients be brought up to date with all immunisations, including prophylactic zoster vaccinations, in agreement with current immunisation guidelines.
Malignancy
Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, including upadacitinib.
In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of malignancies, particularly lung cancer, lymphoma and non-melanoma skin cancer (NMSC) was observed with tofacitinib compared to tumour necrosis factor (TNF) inhibitors.
A higher rate of malignancies was observed with upadacitinib 30 mg compared to upadacitinib 15 mg.
In patients 65 years of age and older, patients who are current or past long-time smokers, or with other
malignancy risk factors (e.g., current malignancy or history of malignancy) upadacitinib should only be used if no suitable treatment alternatives are available.
Non-melanoma skin cancer (NMSC)
NMSCs have been reported in patients treated with upadacitinib (see section 4.8). A higher rate of NMSC was observed with upadacitinib 30 mg compared to upadacitinib 15 mg. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
Haematological abnormalities
Treatment should not be initiated, or should be temporarily interrupted, in patients with an ANC < 1 x 109 cells/L, ALC < 0.5 x 109 cells/L or haemoglobin < 8 g/dL observed during routine patient management.
Gastrointestinal perforations
Events of diverticulitis and gastrointestinal perforations have been reported. Upadacitinib should be used with caution in patients who may be at risk for gastrointestinal perforation (e.g., patients with diverticular disease, a history of diverticulitis, or who are taking nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids or opioids) Patients with active Crohn’s disease are at increased risk for developing intestinal perforation Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of
diverticulitis or gastrointestinal perforation.
Major adverse cardiovascular events
Events of MACE were observed in clinical studies of upadacitinib.
In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of MACE, defined as cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke, was observed with tofacitinib compared to TNF inhibitors. Therefore, in patients 65 years of age and older, patients who are current or past long-time smokers, and patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, upadacitinib should only be used if no suitable treatment alternatives are available.
Lipids
Treatment with upadacitinib was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol.
Hepatic transaminase elevations
Hepatic transaminases must be evaluated at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury.
If increases in ALT or AST are observed during routine patient management and drug-induced liver injury is suspected, upadacitinib therapy should be interrupted until this diagnosis is excluded.
Venous thromboembolism
Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) were observed in clinical trials for upadacitinib.
In patients with known VTE risk factors other than cardiovascular or malignancy risk factors, upadacitinib should be used with caution. VTE risk factors other than cardiovascular or malignancy risk factors include previous VTE, patients undergoing major surgery, immobilisation, use of combined hormonal contraceptives or hormone replacement therapy, and inherited coagulation disorder. Patients should be re-evaluated periodically during upadacitinib treatment to assess for changes in VTE risk. Patients with signs and symptoms of VTE should be promptly evaluated and
treatment should be discontinued in patients with suspected VTE, regardless of dose.
Retinal vein occlusion
Retinal vein occlusion has been reported in patients treated with JAK inhibitors, including upadacitinib.
Hypersensitivity reactions
Serious hypersensitivity reactions such as anaphylaxis and angioedema have been reported in patients receiving upadacitinib. If a clinically significant hypersensitivity reaction occurs, treatment with upadacitinib must be discontinued and appropriate therapy must be instituted.
Hypoglycaemia in patients treated for diabetes
There have been reports of hypoglycaemia following initiation of JAK inhibitors, including upadacitinib, in patients receiving treatment for diabetes. Dose adjustment of anti-diabetic medicinal products may be necessary in the event that hypoglycaemia occurs.
Medication Residue in Stool
Reports of medication residue in stool or ostomy output have occurred in patients taking upadacitinib. Most reports described anatomic (e.g., ileostomy, colostomy, intestinal resection) or functional gastrointestinal conditions with shortened gastrointestinal transit times.
See prescribing information for full details.

Very common: Upper respiratory tract infections (URTI), Acne
Common: Bronchitis, Herpes zoster, Herpes simplex, Folliculitis, Influenza
Urinary tract infection, Pneumonia, Non-melanoma skin cancer, Anaemia, Neutropenia, Lymphopenia, Urticaria, Hypercholesterolaemia, Hyperlipidaemia, Headache, Dizziness, Vertigo, Cough, Abdominal pain, Nausea, Rash, Fatigue
Pyrexia, Peripheral oedema, Blood CPK increased, ALT increased, AST increased, Weight increased.

Potential for other medicinal products to affect the pharmacokinetics of upadacitinib
Upadacitinib is metabolised mainly by CYP3A4. Therefore, upadacitinib plasma exposures can be affected by medicinal products that strongly inhibit or induce CYP3A4.
Co-administration with CYP3A4 inhibitors
Upadacitinib exposure is increased when co-administered with strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, and grapefruit).
Upadacitinib 15 mg once daily should be used with caution in patients receiving chronic treatment with strong CYP3A4 inhibitors. Upadacitinib 30 mg once daily
dose is not recommended for patients with atopic dermatitis receiving chronic treatment with strong CYP3A4 inhibitors. For patients with ulcerative colitis or Crohn’s disease using strong CYP3A4 inhibitors, the recommended induction dose is 30 mg once daily and the recommended maintenance dose is 15 mg once daily.
Co-administration with CYP3A4 inducers
Upadacitinib exposure is decreased when co-administered with strong CYP3A4 inducers (such as rifampin and phenytoin), which may lead to reduced therapeutic effect of upadacitinib.
Potential for upadacitinib to affect the pharmacokinetics of other medicinal products
No dose adjustment is recommended for CYP3A substrates, CYP2D6
substrates, rosuvastatin or atorvastatin when co-administered with upadacitinib.
Upadacitinib has no relevant effects on plasma exposures of ethinylestradiol, levonorgestrel, methotrexate, or medicinal products that are substrates for metabolism by CYP1A2, CYP2B6, CYP2C9 or CYP2C19.
See prescribing information for full details.

Women of childbearing potential
Women of childbearing potential have to use effective contraception during treatment and for 4 weeks following the final dose of upadacitinib
Pregnancy: There are no or limited data on the use of upadacitinib in pregnant women. Upadacitinib is contraindicated during pregnancy.
Lactation: It is unknown whether upadacitinib/metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded.
Upadacitinib should not be used during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue upadacitinib therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Upadacitinib was administered in clinical studies up to doses equivalent in daily AUC to 60 mg prolonged-release once daily. Adverse reactions were comparable to those seen at lower doses and no specific toxicities were identified. Approximately 90% of upadacitinib in the systemic circulation is eliminated within 24 hours of dosing (within the range of doses evaluated in clinical studies). In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment.