Ulcerative colitis

RINVOQ 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.

Treatment with upadacitinib should be initiated and supervised by physicians experienced in the diagnosis and treatment of conditions for which upadacitinib is indicated.

Posology

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 weeks (see sections 4.8 and 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 (see section 4.4).

·        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 (see section 4.4) 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 (see section 4.4).

In patients who have responded to treatment with upadacitinib, corticosteroids may be reduced and/or discontinued in accordance with standard of care.

Interactions

For patients with ulcerative colitis receiving strong inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole, clarithromycin), the recommended induction dose is 30 mg once daily and the recommended maintenance dose is 15 mg once daily (see section 4.5).

Dose initiation

Treatment should not be initiated in patients with an absolute lymphocyte count (ALC) that is < 0.5 x 10⁹ cells/L, an absolute neutrophil count (ANC) that is < 1 x 10⁹ cells/L or who have haemoglobin (Hb) levels that are < 8 g/dL (see sections 4.4 and 4.8).

Dose interruption

Treatment should be interrupted if a patient develops a serious infection until the infection is controlled.

Interruption of dosing may be needed for management of laboratory abnormalities as described in Table 1.

Table 1 Laboratory measures and monitoring guidance

Special populations

Ulcerative colitis

For ulcerative colitis, doses higher than 15 mg once daily for maintenance therapy are not recommended in patients aged 65 years and older (see section 4.8). The safety and efficacy of upadacitinib in patients aged 75 and older have not yet been established.

Renal impairment

No dose adjustment is required in patients with mild or moderate renal impairment. There are limited data on the use of upadacitinib in subjects with severe renal impairment (see section 5.2). Upadacitinib should be used with caution in patients with severe renal impairment as described in Table 2. The use of upadacitinib has not been studied in subjects with end stage renal disease and is therefore not recommended for use in these patients.

Table 2 Recommended dose for severe renal impairment^a

Hepatic impairment

No dose adjustment is required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment (see section 5.2). Upadacitinib should not be used in patients with severe (Child-Pugh C) hepatic impairment (see section 4.3).

Paediatric population

The safety and efficacy of RINVOQ in children with atopic dermatitis below the age of 12 years have not been established. No data are available. No clinical exposure data are available in adolescents < 40 kg (see section 5.2).

The safety and efficacy of RINVOQ in children and adolescents with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and ulcerative colitis aged 0 to less than 18 years have not yet been established. No data are available.

Method of administration

RINVOQ is to be taken orally once daily with or without food and may be taken at any time of the day. Tablets should be swallowed whole and should not be split, crushed, or chewed in order to ensure the entire dose is delivered correctly.

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 (see sections 4.2 and 4.8).

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 (see section 4.8). 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 localised infections.

Consider the risks and benefits of treatment prior to initiating upadacitinib in patients:

·             with chronic or recurrent infection

·             who have been exposed to tuberculosis

·             with a history of a serious or an opportunistic infection

·             who have resided or travelled in areas of endemic tuberculosis or endemic mycoses; or

·             with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with upadacitinib. Upadacitinib therapy should be interrupted if a patient develops a serious or opportunistic infection. A patient who develops a new infection during treatment with upadacitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and upadacitinib therapy should be interrupted if the patient is not responding to antimicrobial therapy. Upadacitinib therapy may be resumed once the infection is 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 (see section 4.2).

Tuberculosis

Patients should be screened for tuberculosis (TB) before starting upadacitinib therapy. Upadacitinib should not be given to patients with active TB (see section 4.3). 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.

Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient.

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 (see section 4.8). 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. Patients who were positive for hepatitis C antibody and hepatitis C virus RNA were excluded from clinical studies. Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical studies. If hepatitis B virus DNA is detected while receiving upadacitinib, a liver specialist should be consulted.

Vaccination

No data are available on the response to vaccination with live vaccines in patients receiving upadacitinib. Use of live, attenuated vaccines during or immediately prior to upadacitinib therapy is not recommended. Prior to initiating upadacitinib, it is recommended that patients be brought up to date with all immunisations, including prophylactic zoster vaccinations, in agreement with current immunisation guidelines. (see section 5.1 for data on inactivated pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) and concomitant use with upadacitinib).

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

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

Absolute Neutrophil Count (ANC) < 1 x 10⁹ cells/L, Absolute Lymphocyte Count (ALC) < 0.5 x 10⁹ cells/L and haemoglobin < 8 g/dL were reported in ≤1 % of patients in clinical trials (see section 4.8). 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 (see section 4.2).

Diverticulitis

Events of diverticulitis have been reported in clinical trials and from post-marketing sources.

Diverticulitis may cause gastrointestinal perforation. Upadacitinib should be used with caution in patients with diverticular disease and especially in patients chronically treated with concomitant medications associated with an increased risk of diverticulitis: nonsteroidal anti-inflammatory drugs, corticosteroids, and opioids. Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis to prevent gastrointestinal perforation.

Diverticulitis

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 (see section 4.8). Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy, although evidence is limited. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined (see section 4.2 for monitoring guidance).

Hepatic transaminase elevations

Treatment with upadacitinib was associated with an increased incidence of liver enzyme elevation compared to placebo.

Evaluate 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 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 dose‑dependent higher rate of VTE including DVT and PE was observed with tofacitinib compared to TNF inhibitors.

In patients with cardiovascular or malignancy risk factors (see also section 4.4 “Major adverse cardiovascular events” and “Malignancy”) upadacitinib should only be used if no suitable treatment alternatives are available.

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. Promptly evaluate patients with signs and symptoms of VTE and discontinue upadacitinib in patients with suspected VTE, regardless of dose.

Hypersensitivity reactions

Serious hypersensitivity reactions such as anaphylaxis and angioedema have been reported in patients receiving upadacitinib. If a clinically significant hypersensitivity reaction occurs, discontinue upadacitinib and institute appropriate therapy (see sections 4.3 and 4.8).

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.

Coadministration with CYP3A4 inhibitors

Upadacitinib exposure is increased when co-administered with strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, and grapefruit). In a clinical study, coadministration of upadacitinib with ketoconazole resulted in 70% and 75% increases in upadacitinib C_max 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 using strong CYP3A4 inhibitors, the recommended induction dose is 30 mg once daily (for up to 16 weeks) and the recommended maintenance dose is 15 mg once daily (see section 4.2). Alternatives to strong CYP3A4 inhibitor medications should be considered when used in the long-term. Food or drink containing grapefruit should be avoided during treatment with upadacitinib.

Coadministration 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 C_max 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 C_max), 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 C_max 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 C_max 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 C_max 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.

Women of childbearing potential

Women of childbearing potential should be advised 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 (see section 5.3). 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 (see section 4.3).

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 (see section 5.3).

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 (see section 5.3).

Upadacitinib has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

In the placebo-controlled clinical trials for rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis, the most commonly reported adverse reactions (≥2% of patients in at least one of the indications with the highest rate among indications presented) with upadacitinib 15 mg were upper respiratory tract infections (19.5%), blood creatine phosphokinase (CPK) increased (8.6%), alanine transaminase increased (4.3%), bronchitis (3.9%), nausea (3.5%), neutropaenia (2.8%), cough (2.2%), aspartate transaminase increased (2.2%), and hypercholesterolaemia (2.2%).

In the placebo-controlled atopic dermatitis clinical trials, the most commonly reported adverse reactions (≥2% of patients) with upadacitinib 15 mg or 30 mg were upper respiratory tract infection (25.4%), acne (15.1%), herpes simplex (8.4%), headache (6.3%), blood CPK increased (5.5%), cough (3.2%), folliculitis (3.2%), abdominal pain (2.9%), nausea (2.7%), neutropaenia (2.3%), pyrexia (2.1%), and influenza (2.1%).

The most common serious adverse reactions were serious infections (see section 4.4).

The safety profile of upadacitinib with long‑term treatment was generally similar to the safety profile during the placebo‑controlled period across indications.

In the placebo-controlled ulcerative colitis induction and maintenance clinical trial, 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%), anemia (7.4%), headache (6.6%), acne (6.3%), herpes zoster (6.1%), neutropaenia (6.0%), rash (5.2%), herpes zoster (4.4%), pneumonia (4.1%), hypercholesterolemia (4.0%), bronchitis (3.9%), aspartate transaminase increased (3.9%), fatigue (3.9%), folliculitis (3.6%), 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 (see section 4.4).

The safety profile of upadacitinib with long‑term treatment was generally similar to the safety profile during the placebo‑controlled period across indications.

Tabulated list of adverse reactions

The following list of adverse reactions is based on experience from clinical studies.

The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100). The frequencies in Table 3 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), or or ulcerative colitis (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 3 Adverse reactions

Description of selected adverse reactions

Ulcerative colitis

The overall safety profile observed in patients with ulcerative colitis was generally consistent with that observed in patients with rheumatoid arthritis.

A higher rate of herpes zoster was observed with an induction treatment period of 16 weeks vs 8 weeks.

Infections

In the placebo‑controlled induction studies, the frequency of infection over 8 weeks in the upadacitinib 45 mg group compared to the placebo group was 20.7% and 17.5%, respectively. In the placebo‑controlled maintenance study, the frequency of infection over 52 weeks in the upadacitinib 15 mg and 30 mg groups was 38.4% and 40.6%, respectively, compared to 37.6% in the placebo group. The long-term rate of infections for upadacitinib 15 mg and 30 mg was 73.8 and 82.6 events per 100 patient-years, respectively.

In the placebo‑controlled induction studies, the frequency of serious infection over 8 weeks in both the upadacitinib 45 mg group and the placebo group was 1.3%. No additional serious infections were observed over 8-week extended treatment with upadacitinib 45 mg. In the placebo‑controlled maintenance study, the frequency of serious infection over 52 weeks in the upadacitinib 15 mg and 30 mg groups was 3.2% and 2.4%, respectively, compared to 3.3% in the placebo group. The long-term rate of serious infections for the upadacitinib 15 mg and 30 mg groups was 4.1 and 3.9 events per 100 patient-years, respectively. The most frequently reported serious infection in the induction and maintenance phases was COVID‑19 pneumonia.

Opportunistic infections (excluding tuberculosis)

In the placebo‑controlled induction studies over 8 weeks, the frequency of opportunistic infection (excluding tuberculosis and herpes zoster) in the upadacitinib 45 mg group was 0.4% and 0.3% in the placebo group. No additional opportunistic infections (excluding tuberculosis and herpes zoster) were observed over 8‑week extended treatment with upadacitinib 45 mg. In the placebo‑controlled maintenance study over 52 weeks, the frequency of opportunistic infection (excluding tuberculosis and herpes zoster) in the upadacitinib 15 mg and 30 mg groups was 0.8% and 0.4%, respectively, compared to 0.8% in the placebo group. The long‑term rate of opportunistic infections (excluding tuberculosis and herpes zoster) for the upadacitinib 15 mg and 30 mg groups was 0.6 and 0.3 events per 100 patient-years, respectively.

In the placebo-controlled induction studies over 8 weeks, the frequency of herpes zoster in the upadacitinib 45 mg group was 0.6% and 0% in the placebo group. The frequency of herpes zoster was 3.9% over 16-week treatment with upadacitinib 45 mg. In the placebo‑controlled maintenance study over 52 weeks, the frequency of herpes zoster in the upadacitinib 15 mg and 30 mg groups was 4.4% and 4.0%, respectively, compared to 0% in the placebo group. The long‑term rate of herpes zoster for the upadacitinib 15 mg and 30 mg groups was 5.7 and 6.3 events per 100 patient-years, respectively.

Laboratory abnormalities

In the induction and maintenance clinical studies, the laboratory changes in ALT increased and/or AST increased (≥ 3 x ULN), CPK values (> 5 x ULN), and neutropaenia (ANC < 1 x 10⁹ cells/L) associated with upadacitinib treatment were generally similar to what was observed in the rheumatologic disease and atopic dermatitis clinical studies. Dose-dependent changes for these laboratory parameters associated with 15 mg and 30 mg upadacitinib treatment were observed.

In the placebo‑controlled induction studies for up to 8 weeks, decreases in lymphocyte counts below 0.5 x 10⁹ cells/L in at least one measurement occurred in 2.0% and 0.8% of patients in the upadacitinib 45 mg and placebo groups, respectively. In the placebo-controlled maintenance study, for up to 52 weeks, decreases in lymphocyte counts below 0.5 x 10⁹ cells/L in at least one measurement occurred in 1.6%, 0.8% and 0.8% of patients in the upadacitinib 15 mg, 30 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to ALC < 0.5 x 10⁹ cells/L (see section 4.2). No notable mean changes of lymphocyte counts were observed during upadacitinib treatment over time.

Elevations in lipid parameters were observed at 8 weeks of treatment with upadacitinib 45 mg and remained generally stable with longer-term treatment with upadacitinib 15 mg and 30 mg. Among patients in the placebo-controlled induction studies with baseline values below the specified limits, the following frequencies of patients were observed to shift to above the specified limits on at least one occasion during 8 weeks (including patients who had an isolated elevated value):

·             Total cholesterol ≥ 5.17 mmol/L (200 mg/dL): 49% vs. 11%, in the upadacitinib 45 mg and placebo groups, respectively

·             LDL cholesterol ≥ 3.36 mmol/L (130 mg/dL): 27% vs. 9%, in the upadacitinib 45 mg and placebo groups, respectively

·             HDL cholesterol ≥ 1.03 mmol/L (40 mg/dL): 79% vs. 36%, in the upadacitinib 45 mg and placebo groups, respectively

·             Triglycerides ≥ 2.26 mmol/L (200 mg/dL): 6% vs 4% in the upadacitinib 45 mg and placebo groups, respectively

Elderly

Based on limited data in atopic dermatitis patients 65 years of age and older, there was a higher rate of overall adverse reactions with the upadacitinib 30 mg dose compared to the 15 mg dose.

Based on the limited data in ulcerative colitis and Crohn’s disease patients 65 years of age and older, there was a higher rate of overall adverse reactions with the upadacitinib 30 mg dose compared to the 15 mg dose with maintenance treatment (see section 4.4).

Paediatric population

A total of 343 adolescents aged 12 to 17 years with atopic dermatitis were treated in the Phase 3 studies, of whom 167 were exposed to 15 mg. The safety profile for upadacitinib 15 mg in adolescents was similar to that in adults. The safety and efficacy of the 30 mg dose in adolescents are still being investigated.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via The National Pharmacovigilance Center (NPC)

·       Saudi Arabia

The National Pharmacovigilance Center (NPC)

Fax: +966-11-205-7662

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

·       Other GCC States:

-        Please contact the relevant competent authority.

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.

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants ATC code: L04AA44

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.

In human cellular assays, upadacitinib preferentially inhibits signalling by JAK1 or JAK1/3 with functional selectivity over cytokine receptors that signal via pairs of JAK2. Atopic dermatitis is driven by pro-inflammatory cytokines (including IL-4, IL-13, IL-22, TSLP, IL-31 and IFN-γ) that transduce signals via the JAK1 pathway. Inhibiting JAK1 with upadacitinib reduces the signaling of many mediators which drive the signs and symptoms of atopic dermatitis such as eczematous skin lesions and pruritus. Pro‑inflammatory cytokines (primarily IL‑6, IL‑7, IL‑15 and IFNγ) transduce signals via the JAK1 pathway and are involved in the pathology of inflammatory bowel diseasesulcerative colitis pathogenesis. JAK1 inhibition with upadacitinib modulates the signalling of the JAK-dependent cytokines underlying the inflammatory burden and signs and symptoms of inflammatory bowel diseasesulcerative colitis.

Pharmacodynamic effects

Inhibition of IL-6 induced STAT3 and IL-7 induced STAT5 phosphorylation

In healthy volunteers, the administration of upadacitinib (immediate-release formulation) resulted in a dose- and concentration-dependent inhibition of IL-6 (JAK1/JAK2) - induced STAT3 and IL-7 (JAK1/JAK3)-induced STAT5 phosphorylation in whole blood. The maximal inhibition was observed 1 hour after dosing which returned to near baseline by the end of dosing interval.

Lymphocytes

In patients with rheumatoid arthritis, treatment with upadacitinib was associated with a small, transient increase in mean ALC from baseline up to week 36 which gradually returned to at or near baseline levels with continued treatment.

hsCRP

In patients with rheumatoid arthritis, treatment with upadacitinib was associated with decreases from baseline in mean hsCRP levels as early as week 1 which were maintained with continued treatment.

Vaccine study

The influence of upadacitinib on the humoral response following the administration of inactivated pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) was evaluated in 111 patients with rheumatoid arthritis under stable treatment with upadacitinib 15 mg (n=87) or 30 mg (n=24). 97% of patients (n=108) were on concomitant methotrexate. The primary endpoint was the proportion of patients with satisfactory humoral response defined as ≥ 2-fold increase in antibody concentration from baseline to week 4 in at least 6 out of the 12 pneumococcal antigens (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F). Results at week 4 demonstrated a satisfactory humoral response in 67.5% (95% CI: 57.4, 77.5) and 56.5% (95% CI: 36.3, 76.8) of patients treated with upadacitinib 15 mg and 30 mg, respectively.

Clinical efficacy and safety

Ulcerative colitis

The efficacy and safety of upadacitinib was evaluated in three multicentre, double‑blind, placebo‑controlled Phase 3 clinical studies: two replicate induction studies, UC‑1 (U‑ACHIEVE Induction) and UC‑2 (U‑ACCOMPLISH), and a maintenance study UC‑3 (U‑ACHIEVE Maintenance).

Disease activity was based on the adapted Mayo score (aMS, Mayo scoring system excluding Physician's Global Assessment), which ranged from 0 to 9 and has three subscores that were each scored 0 (normal) to 3 (most severe): stool frequency subscore (SFS), rectal bleeding subscore (RBS) and a centrally‑reviewed endoscopy subscore (ES).

Induction studies (UC‑1 and UC‑2)

In UC‑1 and UC‑2, 988 patients (473 and 515 patients, respectively) were randomised to upadacitinib 45 mg once daily or placebo for 8 weeks with a 2:1 treatment allocation ratio and included in the efficacy analysis. All enrolled patients had moderately to severely active ulcerative colitis defined as an aMS of 5 to 9 with an ES of 2 or 3 and demonstrated prior treatment failure including inadequate response, loss of response, or intolerance to prior conventional and/or biologic treatment. Prior treatment failure to at least 1 biologic therapy (prior biologic failure) was seen in 52% (246/473) and 51% (262/515) of patients, respectively. Previous treatment failure to conventional therapy but not biologics (without prior biologic failure) was seen in 48% (227/473) and 49% (253/515) of patients, respectively.

At baseline in UC‑1 and UC‑2, 39% and 37% of patients received corticosteroids, 1.1% and 0.6% of patients received methotrexate and 68% and 69% of patients received aminosalicylates. Concomitant use of thiopurine was not allowed during the studies. Patient disease activity was moderate (aMS ≥5, ≤7) in 61% and 60% of patients and severe (aMS >7) in 39% and 40% of patients.

The primary endpoint was clinical remission per aMS at week 8. Table 4 shows the primary and key secondary endpoints including clinical response, mucosal healing, histologic-endoscopic mucosal healing and deep mucosal healing.

Table 4 Proportion of patients meeting primary and key secondary efficacy endpoints at week 8 in the induction studies UC-1 and UC-2

Disease activity and symptoms

The partial adapted Mayo score (paMS) is composed of SFS and RBS. Symptomatic response per paMS is defined as a decrease of ≥1 point and ≥30% from baseline and a decrease in RBS ≥ 1 or an absolute RBS ≤1. Statistically significant improvement compared to placebo per paMS was seen as early as week 2 (UC-1: 60.1% vs 27.3% and UC-2: 63.3% vs 25.9%).

Extended induction

A total of 125 patients in UC‑1 and UC‑2 who did not achieve clinical response after 8 weeks of treatment with upadacitinib 45 mg once daily entered an 8-week open-label extended induction period. After the treatment of an additional 8 weeks (16 weeks total) of upadacitinib 45 mg once daily, 48.3% of patients achieved clinical response per aMS. Among patients who responded to treatment of 16‑week upadacitinib 45 mg once daily, 35.7% and 66.7% of patients maintained clinical response per aMS and 19.0% and 33.3% of patients achieved clinical remission per aMS at week 52 with maintenance treatment of upadacitinib 15 mg and 30 mg once daily, respectively.

Maintenance study (UC‑3)

The efficacy analysis for UC‑3 was evaluated in 451 patients who achieved clinical response per aMS with 8‑week upadacitinib 45 mg once daily induction treatment. Patients were randomised to receive upadacitinib 15 mg, 30 mg or placebo once daily for up to 52 weeks.

The primary endpoint was clinical remission per aMS at week 52. Table 5 shows the key secondary endpoints including maintenance of clinical remission, corticosteroid-free clinical remission, mucosal healing, histologic-endoscopic mucosal healing and deep mucosal healing.

Table 5 Proportion of patients meeting primary and key secondary efficacy endpoints at week 52 in the maintenance study UC‑3

Disease symptoms

Symptomatic remission per paMS, defined as SFS ≤ 1 and RBS = 0, was achieved over time through week 52 in more patients treated with both upadacitinib 15 mg and 30 mg once daily compared with placebo (Figure 1).

Figure 1 Proportion of patients with symptomatic remission per partial adapted Mayo score over time in maintenance study UC-3

Endoscopic assessment

Endoscopic remission (normalisation of the endoscopic appearance of the mucosa) was defined as ES of 0. At week 8, a significantly greater proportion of patients treated with upadacitinib 45 mg once daily compared to placebo achieved endoscopic remission (UC-1: 13.7% vs 1.3%, UC-2: 18.2% vs 1.7%). In UC-3, a significantly greater proportion of patients treated with upadacitinib 15 mg and 30 mg once daily compared to placebo achieved endoscopic remission at week 52 (24.2% and 25.9% vs 5.6%). Maintenance of mucosal healing at week 52 (ES ≤1 without friability) was seen in a significantly greater proportion of patients treated with upadacitinib 15 mg and 30 mg once daily compared to placebo (61.6% and 69.5% vs 19.2%) among patients who achieved mucosal healing at the end of induction.

Quality of life

Patients treated with upadacitinib demonstrated significantly greater and clinically meaningful improvement in health‑related quality of life measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) total score compared to placebo. Improvements were seen in all 4 domain scores: systemic symptoms (including fatigue), social function, emotional function and bowel symptoms (including abdominal pain and bowel urgency). Changes in IBDQ total score at week 8 from baseline with upadacitinib 45 mg once daily compared to placebo were 55.3 and 21.7 in UC-1 and 52.2 and 21.1 in UC-2, respectively. Changes in IBDQ total score at week 52 from baseline were 49.2, 58.9 and 17.9 in patients treated with upadacitinib 15 mg, 30 mg once daily and placebo, respectively.

Paediatric population

A total of 344 adolescents aged 12 to 17 years with moderate to severe atopic dermatitis were randomised across the three Phase 3 studies to receive either 15 mg (N=114) or 30 mg (N=114) upadacitinib or matching placebo (N=116), in monotherapy or combination with topical corticosteroids. Efficacy was consistent between the adolescents and adults. The safety profile in adolescents was generally similar to that in adults, with dose‑dependent increases in the rate of some adverse events, including neutropaenia and herpes zoster. At both doses, the rate of neutropaenia was slightly increased in adolescents compared to adults. The rate of herpes zoster in adolescents at the 30 mg dose was comparable to that in adults. The safety and efficacy of the 30 mg dose in adolescents are still being investigated.

Table 6 Efficacy results of upadacitinib for adolescents at week 16

The European Medicines Agency has deferred the obligation to submit the results of studies with RINVOQ in one or more subsets of the paediatric population in chronic idiopathic arthritis (including rheumatoid arthritis, psoriatic arthritis, spondyloarthritis and juvenile idiopathic arthritis)  atopic dermatitis, and ulcerative colitis (see section 4.2 for information on paediatric use).

Upadacitinib plasma exposures are proportional to dose over the therapeutic dose range. Steady‑state plasma concentrations are achieved within 4 days with minimal accumulation after multiple once daily administrations.

Absorption

Following oral administration of upadacitinib prolonged-release formulation, upadacitinib is absorbed with a median T_max of 2 to 4 hours. Coadministration of upadacitinib with a high-fat meal had no clinically relevant effect on upadacitinib exposures (increased AUC by 29% and C_max by 39% to 60%). In clinical trials, upadacitinib was administered without regard to meals (see section 4.2). In vitro, upadacitinib is a substrate for the efflux transporters P-gp and BCRP.

Distribution

Upadacitinib is 52% bound to plasma proteins. Upadacitinib partitions similarly between plasma and blood cellular components, as indicated by the blood to plasma ratio of 1.0.

Metabolism

Upadacitinib metabolism is mediated by CYP3A4 with a potential minor contribution from CYP2D6. The pharmacologic activity of upadacitinib is attributed to the parent molecule. In a human radiolabeled study, unchanged upadacitinib accounted for 79% of the total radioactivity in plasma while the main metabolite (product of monooxidation followed by glucuronidation) accounted for 13% of the total plasma radioactivity. No active metabolites have been identified for upadacitinib.

Elimination

Following single dose administration of [¹⁴C]-upadacitinib immediate-release solution, upadacitinib was eliminated predominantly as the unchanged parent substance in urine (24%) and faeces (38%). Approximately 34% of upadacitinib dose was excreted as metabolites. Upadacitinib mean terminal elimination half-life ranged from 9 to 14 hours.

Special populations

Renal impairment

Upadacitinib AUC was 18%, 33%, and 44% higher in subjects with mild (estimated glomerular filtration rate 60 to 89 mLml/min/1.73 m²), moderate (estimated glomerular filtration rate 30 to 59 mLml/min/1.73 m²), and severe (estimated glomerular filtration rate 15 to 29 mLml/min/1.73 m²) renal impairment, respectively, compared to subjects with normal renal function. Upadacitinib C_max was similar in subjects with normal and impaired renal function. Mild or moderate renal impairment has no clinically relevant effect on upadacitinib exposure (see section 4.2).

Hepatic impairment

Mild (Child‑Pugh A) and moderate (Child‑Pugh B) hepatic impairment has no clinically relevant effect on upadacitinib exposure. Upadacitinib AUC was 28% and 24% higher in subjects with mild and moderate hepatic impairment, respectively, compared to subjects with normal liver function. Upadacitinib C_max was unchanged in subjects with mild hepatic impairment and 43% higher in subjects with moderate hepatic impairment compared to subjects with normal liver function. Upadacitinib was not studied in patients with severe (Child‑Pugh C) hepatic impairment.

Paediatric population

The pharmacokinetics of upadacitinib have not yet been evaluated in paediatric patients with rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and and ulcerative colitis (see section 4.2).

Upadacitinib pharmacokinetics and steady-state concentrations are similar for adults and adolescents 12 to 17 years of age with atopic dermatitis. The posology in adolescent patients 30 kg to < 40 kg was determined using population pharmacokinetic modelling and simulation.

The pharmacokinetics of upadacitinib in paediatric patients (< 12 years of age) with atopic dermatitis have not been established.

Intrinsic factors

Age, sex, body weight, race, and ethnicity did not have a clinically meaningful effect on upadacitinib exposure. Upadacitinib pharmacokinetics are consistent between rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, atopic dermatitis, and and ulcerative colitis patients.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology.

Upadacitinib, at exposures (based on AUC) approximately 4 and 10 times the clinical dose of 15 mg, 2 and 5 times the clinical dose of 30 mg, and 1.61.7 and 4 times the clinical dose of 45 mg in male and female Sprague-Dawley rats, respectively, was not carcinogenic in a 2‑year carcinogenicity study in Sprague-Dawley rats. Upadacitinib was not carcinogenic in a 26‑week carcinogenicity study in CByB6F1-Tg(HRAS)2Jic transgenic mice.

Upadacitinib was not mutagenic or genotoxic based on the results of in vitro and in vivo tests for gene mutations and chromosomal aberrations.

Upadacitinib had no effect on fertility in male or female rats at exposures up to approximately 16 17 and 31 34 times the maximum recommended human dose (MRHD) of 45 mg in males and females, respectively, on an AUC basis in a fertility and early embryonic development study. Dose‑related increases in foetal resorptions associated with post-implantation losses in this fertility study in rats were attributed to the developmental/teratogenic effects of upadacitinib. No adverse effects were observed at exposures below clinical exposure (based on AUC). Post‑implantation losses were observed at exposures 8 9 times the clinical exposure at the MRHD of 45 mg (based on AUC).

In animal embryo-foetal development studies, upadacitinib was teratogenic in both rats and rabbits. Upadacitinib resulted in increases in skeletal malformations in rats at 1.6, 0.8, and 0.6 times the clinical exposure (AUC-based) at the 15, 30, and 45 mg (MRHD) doses, respectively. In rabbits an increased incidence of cardiovascular malformations was observed at 15, 7.6, and 5.66 times the clinical exposure at the 15, 30, and 45 mg doses (AUC-based), respectively.

Following administration of upadacitinib to lactating rats, the concentrations of upadacitinib in milk over time generally paralleled those in plasma, with approximately 30‑fold higher exposure in milk relative to maternal plasma. Approximately 97% of upadacitinib-related material in milk was the parent molecule, upadacitinib.

Tablet contents

Microcrystalline cellulose (131.8 mg)

Hypromellose (96 mg)

Mannitol (100.6 mg)

Tartaric acid (96.0 mg)

Silica, colloidal anhydrous (2.4 mg)

Magnesium stearate (7.2 mg)

Film coating

Poly(vinyl alcohol) (5.18)

Macrogol (2.62 mg)

Talc (1.92)

Titanium dioxide (E171) (2.3)

Iron oxide red (E172) (0.03)

Iron oxide yellow (E172) (1.18)

Not applicable.

Store below 30˚C

Store in the original blister or bottle in order to protect from moisture.

Keep the bottle tightly closed.

RINVOQ 45 mg prolonged-release tablets

Polyvinylchloride/polyethylene/polychlorotrifluoroethylene - aluminium calendar blisters in packs containing 28 prolonged-release tablets.

HDPE bottles with desiccant and polypropylene cap in carton containing 28 prolonged-release tablets.

Not all pack sizes may be marketed

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.