Rinvoq · 4.3 Contraindications · 1

HOS-098689 · has-adverse-reaction-information · PDF-Seite 15

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%), neutropenia (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%), neutropenia (2.3%), pyrexia (2.1%), and influenza (2.1%). 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%), herpes zoster (6.1%), neutropenia (6.0%), rash (5.2%), 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%), 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 clinical studies and post-marketing experience in adults and adolescents. 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); rare (≥ 1/10 000 to < 1/1 000). The frequencies in Table 4 are based on the higher of the rates for adverse reactions reported with RINVOQ in clinical trials of rheumatologic disease (15 mg tablet), atopic dermatitis (15 mg and 30 mg tablets), alopecia area

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HOS-098695 · has-adverse-reaction-information · PDF-Seite 73

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%), neutropenia (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%), neutropenia (2.3%), pyrexia (2.1%), and influenza (2.1%). 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%), herpes zoster (6.1%), neutropenia (6.0%), rash (5.2%), 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%), 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 clinical studies and post-marketing experience in adults and adolescents with upadacitinib tablets. The frequency of adverse reactions listed below is 73 defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000). The frequencies in Table 3 are based on the higher of the rates for adverse reactions reported with RINVOQ in clinical trials of rheumatologic d

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HOS-098691 · has-contraindication-information · PDF-Seite 67

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Active tuberculosis (TB) or active serious infections (see section 4.4). • Severe hepatic impairment (see section 4.2). • Pregnancy (see section 4.6).

HOS-098685 · has-contraindication-information · PDF-Seite 9

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Active tuberculosis (TB) or active serious infections (see section 4.4). • Severe hepatic impairment (see section 4.2). • Pregnancy (see section 4.6).

HOS-098684 · has-indication-information · PDF-Seite 2

Rheumatoid arthritis RINVOQ is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs). RINVOQ may be used as monotherapy or in combination with methotrexate. 2 Psoriatic arthritis RINVOQ is indicated for the treatment of active psoriatic arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more DMARDs. RINVOQ may be used as monotherapy or in combination with methotrexate. Polyarticular juvenile idiopathic arthritis RINVOQ is indicated for the treatment of active polyarticular juvenile idiopathic arthritis (polyarticular rheumatoid factor positive [RF+] or negative [RF-], extended oligoarticular), in patients 2 years of age and older who have responded inadequately to, or who are intolerant to one or more DMARDs. RINVOQ may be used as monotherapy or in combination with methotrexate. Axial spondyloarthritis Non-radiographic axial spondyloarthritis (nr-axSpA) RINVOQ is indicated for the treatment of active non-radiographic axial spondyloarthritis in adult patients 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) RINVOQ is indicated for the treatment of active ankylosing spondylitis in adult patients who have responded inadequately to conventional therapy. Giant cell arteritis RINVOQ is indicated for the treatment of giant cell arteritis in adult patients. Atopic dermatitis RINVOQ is indicated for the treatment of moderate to severe atopic dermatitis in adults and adolescents 12 years and older who are candidates for systemic therapy. Alopecia areata RINVOQ is indicated for the treatment of severe alopecia areata in adults and adolescents 12 years and older (see section 5.1). Vitiligo RINVOQ is indicated for the treatment of non-segmental vitiligo in adults and adolescents 12 years and older who are candidates for systemic therapy. 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

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HOS-098690 · has-indication-information · PDF-Seite 65

RINVOQ is indicated for the treatment of active polyarticular juvenile idiopathic arthritis (polyarticular rheumatoid factor positive [RF+] or negative [RF-], extended oligoarticular), in patients 2 years of age and older who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs). RINVOQ may be used as monotherapy or in combination with methotrexate.

HOS-098687 · has-interaction-information · PDF-Seite 13

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). 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 tablets once daily or 3 mg, 4 mg, or 6 mg of the oral solution twice daily should be used with caution in patients receiving chronic treatment with strong CYP3A4 inhibitors. For patients with atopic dermatitis or alopecia areata using strong CYP3A4 inhibitors, the recommended dose of upadacitinib is 15 mg once daily. 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. Food or drink containing grapefruit should be avoided during treatment with upadacitinib. 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. 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 a

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HOS-098693 · has-interaction-information · PDF-Seite 71

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). 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 tablets once daily or 3 mg, 4 mg, or 6 mg of the oral solution twice daily should be used with caution in patients receiving chronic treatment with strong CYP3A4 inhibitors. Alternatives to strong CYP3A4 inhibitors should be considered when used in the long-term. Food or drink containing grapefruit should be avoided during treatment with upadacitinib. 71 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. 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 tablets 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 tablet 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 tablet once daily doses of upadacitinib to healthy subjects. Upadacitinib had no relevant effect on atorvastatin Cmax or on plasma exp

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HOS-098694 · has-pregnancy-information · PDF-Seite 72

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 (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. 72 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).

HOS-098688 · has-pregnancy-information · PDF-Seite 14

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 (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). 14

HOS-098686 · has-warning-information · PDF-Seite 9

Upadacitinib should only be used if no suitable treatment alternatives are available in patients: - 65 years of age and older; - patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors (such as current or past long-time smokers); - patients with malignancy risk factors (e.g. current malignancy or history of malignancy) 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 (see section 4.8) 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 localised infections (see section 4.3). 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. 9 Patients should be closely monitored for the d

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HOS-098692 · has-warning-information · PDF-Seite 67

Upadacitinib should only be used if no suitable treatment alternatives are available in patients: - 65 years of age and older; - patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors (such as current or past long-time smokers); - patients with malignancy risk factors (e.g. current malignancy or history of malignancy) 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. 67 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 (see section 4.8) 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 localised infections (see section 4.3). 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 o

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