The information below is based on the summary of product characteristics approved by regulatory authorities. For full details from the SmPC ,please click here: https://www.medicines.org.uk/emc/product/10972/smpc
Additional related ECCO e-Learning resources can be found under IBD Curriculum Topic 6.1-6.11
Introduction and Mechanism of Action
Upadacitinib is a selective and reversible Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes that transmit cytokine or growth factor signals involved in a broad range of cellular processes including inflammatory responses, hematopoiesis, and immune surveillance. The JAK family of enzymes contains four members, JAK1, JAK2, JAK3 and TYK2 which work in pairs to phosphorylate and activate signal transducers and activators of transcription (STATs). This phosphorylation, in turn, modulates gene expression and cellular function. JAK1 is important in inflammatory cytokine signals while JAK2 is important for red blood cell maturation and JAK3 signals play a role in immune surveillance and lymphocyte function.
Therapeutic indications
Ulcerative colitis
Upadacitinib is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, lost response or were intolerant to either conventional therapy or a biologic agent.
Crohn's disease
Upadacitinib is indicated for the treatment of adult patients with moderately to severely active Crohn's disease who have had an inadequate response, lost response or were intolerant to either conventional therapy or a biologic agent.
Dosing, administration
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 (see section 5.1). 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:
• A dose of 15 mg is recommended for patients at higher risk of VTE, MACE and malignancy.
• A dose of 30 mg once daily may be appropriate for some patients, such as those with high disease burden or requiring 16-week induction treatment who are not at higher risk of VTE, MACE and malignancy or who do not show adequate therapeutic benefit to 15 mg once daily.
• The lowest effective dose to maintain response should be used.
For patients 65 years of age and older, the recommended dose is 15 mg once daily.
In patients who have responded to treatment with upadacitinib, corticosteroids may be reduced and/or discontinued in accordance with standard of care.
Crohn's disease
Induction
The recommended induction dose of upadacitinib is 45 mg once daily for 12 weeks.
Maintenance
The recommended maintenance dose of upadacitinib is 15 mg or 30 mg once daily based on individual patient presentation:
• A dose of 15 mg is recommended for patients at higher risk of VTE, MACE and malignancy.
• A dose of 30 mg once daily may be appropriate for patients with high disease burden who are not at higher risk of VTE, MACE and malignancy or who do not show adequate therapeutic benefit to 15 mg once daily.
• A dose of 30 mg once daily may be appropriate for patients who have not achieved adequate therapeutic benefit after the initial 12-week induction. For these patients, upadacitinib should be discontinued if there is no evidence of therapeutic benefit after 24 weeks of treatment.
• The lowest effective dose to maintain response should be used.
For patients 65 years of age and older, the recommended maintenance dose is 15 mg once daily.
In patients who have responded to treatment with upadacitinib, corticosteroids may be reduced and/or discontinued in accordance with standard of care.
Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in SmPC.
• Active tuberculosis (TB) or active serious infections.
• Severe hepatic impairment.
• Pregnancy
Adverse effects
In the placebo-controlled ulcerative colitis and Crohn's disease induction and maintenance clinical trials, the most commonly reported adverse reactions (≥3% of patients) with upadacitinib 45 mg, 30 mg or 15 mg were upper respiratory tract infection (19.9%), pyrexia (8.7%), blood CPK increased (7.6%), anaemia (7.4%), headache (6.6%), acne (6.3%), neutropenia (6.0%), rash (5.2%), herpes zoster (6.1%), pneumonia (4.1%), hypercholesterolemia (4.0%), bronchitis (3.9%), aspartate transaminase increased (3.9%), fatigue (3.9%), alanine transaminase increased (3.5%), folliculitis (3.6%), herpes simplex (3.2%), and influenza (3.2%).
The most common serious adverse reactions were serious infections.
Tabulated list of ARs
The following list of adverse reactions is based on experience from clinical studies and post-marketing experience.
The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100). The frequencies in Table are based on the higher of the rates for adverse reactions reported with RINVOQ in clinical trials of rheumatologic disease (15 mg), atopic dermatitis (15 mg and 30 mg), ulcerative colitis (15 mg, 30 mg and 45 mg), or Crohn's disease (15 mg, 30 mg, and 45 mg). When notable differences in frequency were observed between indications, these are presented in the footnotes below the table.
Table Adverse reactions
|
System Organ Class |
Very common |
Common |
Uncommon |
|
Infections and infestations |
Upper respiratory tract infections (URTI)a |
Bronchitisa,b Herpes zostera Herpes simplexa Folliculitis Influenza Urinary tract infection Pneumoniaa,f |
Oral candidiasis Diverticulitis Sepsis |
|
Neoplasms benign, malignant and unspecified (including cysts and polyps) |
-- |
Non-melanoma skin cancerg
|
-- |
|
Blood and lymphatic system disorders |
-- |
Anaemiaa Neutropeniaa Lymphopenia |
-- |
|
Immune system disorders |
-- |
Urticariac,e
|
Serious hypersensitivity reactionsa,h |
|
Metabolism and nutrition disorders |
-- |
Hypercholesterolaemiaa,b Hyperlipidaemiaa,b |
Hypertriglyceridaemia |
|
Nervous system disorders |
-- |
Headachea,j Dizziness |
-- |
|
Ear and labyrinth disorders |
-- |
Vertigoa |
-- |
|
Respiratory, thoracic and mediastinal disorders |
-- |
Cough |
-- |
|
Gastrointestinal disorders |
-- |
Abdominal paina Nausea |
Gastrointestinal perforationi |
|
Skin and subcutaneous tissue disorders |
Acnea,c,d,e
|
Rasha |
-- |
|
General disorders and administration site conditions |
-- |
Fatigue Pyrexia Peripheral oedemaa,k |
-- |
|
Investigations |
-- |
Blood CPK increased ALT increasedb AST increasedb Weight increasede |
-- |
Interactions with other Drugs
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 juice). In a clinical study, co-administration of upadacitinib with ketoconazole resulted in 70% and 75% increases in upadacitinib Cmax and AUC, respectively. 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 (see section 4.2). Alternatives to strong CYP3A4 inhibitors should be considered when used in the long-term.
Co-administration of upadacitinib with grapefruit may increase exposure to upadacitinib. Food or drink containing grapefruit should be avoided during treatment with upadacitinib.
C-oadministration 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. In a clinical study, co-administration of upadacitinib after multiple doses of rifampicin (strong CYP3A inducer) resulted in approximately 50% and 60% decreases in upadacitinib Cmax and AUC, respectively. Patients should be monitored for changes in disease activity if upadacitinib is co-administered with strong CYP3A4 inducers.
Methotrexate and pH modifying medicinal products (e.g., antacids or proton pump inhibitors) have no effect on upadacitinib plasma exposures.
Potential for upadacitinib to affect the pharmacokinetics of other medicinal products
Administration of multiple 30 mg or 45 mg once daily doses of upadacitinib to healthy subjects had a limited effect on midazolam (sensitive substrate for CYP3A) plasma exposures (24-26% decrease in midazolam AUC and Cmax), indicating that upadacitinib 30 mg or 45 mg once daily may have a weak induction effect on CYP3A. In a clinical study, rosuvastatin and atorvastatin AUC were decreased by 33% and 23%, respectively, and rosuvastatin Cmax was decreased by 23% following the administration of multiple 30 mg once daily doses of upadacitinib to healthy subjects. Upadacitinib had no relevant effect on atorvastatin Cmax or on plasma exposures of ortho-hydroxyatorvastatin (major active metabolite for atorvastatin). Administration of multiple 45 mg once daily doses of upadacitinib to healthy subjects led to a limited increase in AUC and Cmax of dextromethorphan (sensitive CYP2D6 substrate) by 30% and 35%, respectively, indicating that upadacitinib 45 mg once daily has a weak inhibitory effect on CYP2D6. No dose adjustment is recommended for CYP3A substrates, CYP2D6 substrates, rosuvastatin or atorvastatin when coadministered 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.
Special situations
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. Female paediatric patients and/or their parents/caregivers should be informed about the need to contact the treating physician once the patient experiences menarche while taking upadacitinib.
Pregnancy
There are no or limited data on the use of upadacitinib in pregnant women. Studies in animals have shown reproductive toxicity. Upadacitinib was teratogenic in rats and rabbits with effects in bones in rat foetuses and in the heart in rabbit foetuses when exposed in utero.
Upadacitinib is contraindicated during pregnancy.
If a patient becomes pregnant while taking upadacitinib the parents should be informed of the potential risk to the foetus.
Breast-feeding
It is unknown whether upadacitinib/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of upadacitinib in 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.
Fertility
The effect of upadacitinib on human fertility has not been evaluated. Animal studies do not indicate effects with respect to fertility.