Olumiant

HOS-097623 · has-adverse-reaction-information · PDF-Seite 12

Summary of the safety profile The most commonly reported adverse reactions with baricitinib are increased LDL cholesterol (26.0 %), upper respiratory tract infections (16.9 %), headache (5.2 %), herpes simplex (3.2 %), and urinary tract infections (2.9 %). Serious pneumonia (0.2 %) and serious herpes zoster (0.2 %) occurred uncommonly in patients with rheumatoid arthritis. Tabulated list of adverse reactions Frequency estimate: 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), very rare (< 1/10 000). The frequencies in Table 2 are based on integrated data from clinical trials in adults and/or postmarketing setting across rheumatoid arthritis, atopic dermatitis, and alopecia areata indications unless stated otherwise; where notable differences in frequency between indications are observed, these are presented in the footnotes below the table. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Table 2. Adverse reactions System organ Very common Common Uncommon class Infections and Upper respiratory tract Pneumoniad infestations infections Herpes zosterb Urinary tract infections Gastroenteritis Herpes simplex Folliculitisg Blood and Thrombocytosis Neutropenia lymphatic > 600 x 109 cells/La, d < 1 x 109 cells/La system disorders Immune system Swelling of the face, disorders Urticaria Metabolism and Hypercholesterolaemiaa Hypertriglyceridaemiaa nutrition disorders Nervous system Headache disorders Vascular Deep vein thrombosisb disorders Respiratory, Pulmonary embolismf thoracic, mediastinal disorders Gastrointestinal Abdominal paind Diverticulit

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HOS-097629 · has-adverse-reaction-information · PDF-Seite 48

Summary of the safety profile The most commonly reported adverse reactions with baricitinib are increased LDL cholesterol (26.0 %), upper respiratory tract infections (16.9 %), headache (5.2 %), herpes simplex (3.2 %), and urinary tract infections (2.9 %). Serious pneumonia (0.2 %) and serious herpes zoster (0.2 %) occurred uncommonly in patients with rheumatoid arthritis. Tabulated list of adverse reactions Frequency estimate: 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), very rare (< 1/10 000). The frequencies in Table 2 are based on integrated data from clinical trials in adults and/or postmarketing setting across rheumatoid arthritis, atopic dermatitis, and alopecia areata indications unless stated otherwise; where notable differences in frequency between indications are observed, these are presented in the footnotes below the table. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. 48 Table 2. Adverse reactions System organ Very common Common Uncommon class Infections and Upper respiratory tract Pneumoniad infestations infections Herpes zosterb Urinary tract infections Gastroenteritis Herpes simplex Folliculitisg Blood and Thrombocytosis Neutropenia lymphatic > 600 x 109 cells/La, d < 1 x 109 cells/La system disorders Immune system Swelling of the face, disorders Urticaria Metabolism and Hypercholesterolaemiaa Hypertriglyceridaemiaa nutrition disorders Nervous system Headache disorders Vascular Deep vein thrombosisb disorders Respiratory, Pulmonary embolismf thoracic, mediastinal

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HOS-097625 · has-contraindication-information · PDF-Seite 41

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Pregnancy (see section 4.6). 41

HOS-097619 · has-contraindication-information · PDF-Seite 6

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Pregnancy (see section 4.6).

HOS-097624 · has-indication-information · PDF-Seite 38

Rheumatoid arthritis Baricitinib 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). Baricitinib may be used as monotherapy or in combination with methotrexate (see sections 4.4, 4.5 and 5.1 for available data on different combinations). Atopic dermatitis Baricitinib is indicated for the treatment of moderate to severe atopic dermatitis in adult and paediatric patients 2 years of age and older who are candidates for systemic therapy. Alopecia areata Baricitinib is indicated for the treatment of severe alopecia areata in adult and adolescent patients 12 years of age and older (see section 5.1). Juvenile idiopathic arthritis Baricitinib is indicated for the treatment of active juvenile idiopathic arthritis in patients 2 years of age and older who have had an inadequate response or intolerance to one or more prior conventional synthetic or biologic DMARDs: - Polyarticular juvenile idiopathic arthritis (polyarticular rheumatoid factor positive [RF+] or negative [RF-], extended oligoarticular), - Enthesitis-related arthritis, and - Juvenile psoriatic arthritis. 38 Baricitinib may be used as monotherapy or in combination with methotrexate.

HOS-097618 · has-indication-information · PDF-Seite 2

Rheumatoid arthritis Baricitinib 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). Baricitinib may be used as monotherapy or in combination with methotrexate (see sections 4.4, 4.5 and 5.1 for available data on different combinations). 2 Atopic dermatitis Baricitinib is indicated for the treatment of moderate to severe atopic dermatitis in adult and paediatric patients 2 years of age and older who are candidates for systemic therapy. Alopecia areata Baricitinib is indicated for the treatment of severe alopecia areata in adult and adolescent patients 12 years of age and older (see section 5.1). Juvenile idiopathic arthritis Baricitinib is indicated for the treatment of active juvenile idiopathic arthritis in patients 2 years of age and older who have had an inadequate response or intolerance to one or more prior conventional synthetic or biologic DMARDs: - Polyarticular juvenile idiopathic arthritis (polyarticular rheumatoid factor positive [RF+] or negative [RF-], extended oligoarticular), - Enthesitis-related arthritis, and - Juvenile psoriatic arthritis. Baricitinib may be used as monotherapy or in combination with methotrexate.

HOS-097627 · has-interaction-information · PDF-Seite 46

Pharmacodynamic interactions Immunosuppressive medicinal products Combination with biological DMARDs, biological immunomodulators or other JAK inhibitors has not been studied. In rheumatoid arthritis and juvenile idiopathic arthritis, use of baricitinib with potent immunosuppressive medicinal products such as azathioprine, tacrolimus, or ciclosporin was limited in clinical studies, and a risk of additive immunosuppression cannot be excluded. In atopic dermatitis and alopecia areata, combination with ciclosporin or other potent immunosuppressants has not been studied and is not recommended (see section 4.4). Potential for other medicinal products to affect the pharmacokinetics of baricitinib Transporters In vitro, baricitinib is a substrate for organic anionic transporter (OAT)3, P-glycoprotein (Pgp), breast cancer resistance protein (BCRP) and multidrug and toxic extrusion protein (MATE)2-K. In a clinical pharmacology study, dosing of probenecid (an OAT3 inhibitor with strong inhibition potential) resulted in approximately a 2-fold increase in AUC(0-∞) with no change in tmax or Cmax of baricitinib. Consequently, in patients taking OAT3 inhibitors with a strong inhibition potential, such as probenecid, the recommended dose of baricitinib should be reduced by half (see section 4.2). No clinical pharmacology study has been conducted with OAT3 inhibitors with less inhibition potential. The prodrug leflunomide rapidly converts to teriflunomide which is a weak OAT3 inhibitor and therefore may lead to an increase in baricitinib exposure. Since dedicated interaction studies have not been conducted, caution should be used when leflunomide or teriflunomide are given concomitantly with baricitinib. Concomitant use of the OAT3 inhibitors ibuprofen and diclofenac may lead to 46 increased exposure of baricitinib, however their inhibition potential of OAT3 is less compared to probenecid and thus a clinically relevant interaction is not expected. Coadministration of baricitinib with ciclosporin (Pgp/BCRP inhibitor) or methotrexate (substrate of several transporters including OATP1B1, OAT1, OAT3, BCRP, MRP2, MRP3, and MRP4) resulted in no clinically meaningful effects on baricitinib exposure. Cytochrome P450 enzymes In vitro, baricitinib is a cytochrome P450 enzyme (CYP)3A4 substrate although less than 10 % of the dose is metabolised via oxidation. In clinical pharmacology studies, coadministration of baricitinib with

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HOS-097621 · has-interaction-information · PDF-Seite 10

Pharmacodynamic interactions Immunosuppressive medicinal products Combination with biological DMARDs, biological immunomodulators or other JAK inhibitors has not been studied. In rheumatoid arthritis and juvenile idiopathic arthritis, use of baricitinib with potent immunosuppressive medicinal products such as azathioprine, tacrolimus, or ciclosporin was limited in clinical studies, and a risk of additive immunosuppression cannot be excluded. In atopic dermatitis and alopecia areata, combination with ciclosporin or other potent immunosuppressants has not been studied and is not recommended (see section 4.4). Potential for other medicinal products to affect the pharmacokinetics of baricitinib Transporters In vitro, baricitinib is a substrate for organic anionic transporter (OAT)3, P-glycoprotein (Pgp), breast cancer resistance protein (BCRP) and multidrug and toxic extrusion protein (MATE)2-K. In a clinical pharmacology study, dosing of probenecid (an OAT3 inhibitor with strong inhibition potential) resulted in approximately a 2-fold increase in AUC(0-∞) with no change in tmax or Cmax of baricitinib. Consequently, in patients taking OAT3 inhibitors with a strong inhibition potential, such as probenecid, the recommended dose of baricitinib should be reduced by half (see section 4.2). No clinical pharmacology study has been conducted with OAT3 inhibitors with less inhibition potential. The prodrug leflunomide rapidly converts to teriflunomide which is a weak OAT3 inhibitor and therefore may lead to an increase in baricitinib exposure. Since dedicated interaction studies have not been conducted, caution should be used when leflunomide or teriflunomide are given concomitantly with baricitinib. Concomitant use of the OAT3 inhibitors ibuprofen and diclofenac may lead to increased exposure of baricitinib, however their inhibition potential of OAT3 is less compared to probenecid and thus a clinically relevant interaction is not expected. Coadministration of baricitinib with ciclosporin (Pgp/BCRP inhibitor) or methotrexate (substrate of several transporters including OATP1B1, OAT1, OAT3, BCRP, MRP2, MRP3, and MRP4) resulted in no clinically meaningful effects on baricitinib exposure. Cytochrome P450 enzymes In vitro, baricitinib is a cytochrome P450 enzyme (CYP)3A4 substrate although less than 10 % of the dose is metabolised via oxidation. In clinical pharmacology studies, coadministration of baricitinib with ketoconazole (strong CYP3A inhibitor) resulted in no c

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HOS-097628 · has-pregnancy-information · PDF-Seite 47

Pregnancy The JAK/STAT pathway has been shown to be involved in cell adhesion and cell polarity which can affect early embryonic development. There are no adequate data from the use of baricitinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Baricitinib was teratogenic in rats and rabbits. Animal studies indicate that baricitinib may have an adverse effect on bone development in utero at higher doses. Baricitinib is contraindicated during pregnancy (see section 4.3). Women of childbearing potential have to use effective contraception during and for at least 1 week after treatment. If a patient becomes pregnant while taking baricitinib the parents should be informed of the potential risk to the foetus. Breast-feeding It is unknown whether baricitinib/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of baricitinib in milk (see section 5.3). A risk to newborns/infants cannot be excluded and baricitinib should not be used during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. 47 Fertility Studies in animals suggest that treatment with baricitinib has the potential to decrease female fertility while on treatment, but there was no effect on male spermatogenesis (see section 5.3).

HOS-097622 · has-pregnancy-information · PDF-Seite 11

Pregnancy The JAK/STAT pathway has been shown to be involved in cell adhesion and cell polarity which can affect early embryonic development. There are no adequate data from the use of baricitinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Baricitinib was teratogenic in rats and rabbits. Animal studies indicate that baricitinib may have an adverse effect on bone development in utero at higher doses. Baricitinib is contraindicated during pregnancy (see section 4.3). Women of childbearing potential have to use effective contraception during and for at least 1 week after treatment. If a patient becomes pregnant while taking baricitinib the parents should be informed of the potential risk to the foetus. Breast-feeding It is unknown whether baricitinib/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of baricitinib in milk (see section 5.3). A risk to newborns/infants cannot be excluded and baricitinib should not be used during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Studies in animals suggest that treatment with baricitinib has the potential to decrease female fertility while on treatment, but there was no effect on male spermatogenesis (see section 5.3).

HOS-097620 · has-warning-information · PDF-Seite 6

Baricitinib 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 of JAK inhibitors 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 JAK inhibitor), baricitinib should only be used in these patients if no suitable treatment alternatives are available. Infections Serious and sometimes fatal infections, including opportunistic infections, have been reported in patients receiving other JAK inhibitors. Baricitinib is associated with an increased rate of infections such as upper respiratory tract infections compared to placebo (see section 4.8). In rheumatoid arthritis clinical studies, combination with methotrexate resulted in increased frequency of infections compared to baricitinib monotherapy. The risks and benefits of treatment should be carefully considered prior to initiating baricitinib in patients with active, chronic or recurrent infections (see section 4.2). If an infection develops, the patient should be monitored carefully and therapy should be temporarily interrupted if the patient is not responding to standard therapy. Treatment should not be resumed until the infection resolves. 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 over 65 years of age, baricitinib should only be used if no suitable treatment alternatives are available. Tuberculosis Patients should be screened for tuberculosis (TB) before starting therapy. Baricitinib should not be given to patients with active TB. Anti-TB therapy should be considered prior to initiation of treatment in patients with previously untreated latent TB. 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 clinical trials. Treatment should not be initiated, or should be temporarily interrupted, in patients with an ANC < 1 x 109 cells/L, ALC < 0.5

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HOS-097626 · has-warning-information · PDF-Seite 42

Baricitinib 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 of JAK inhibitors 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 JAK inhibitor), baricitinib should only be used in these patients if no suitable treatment alternatives are available. Infections Serious and sometimes fatal infections, including opportunistic infections, have been reported in patients receiving other JAK inhibitors. Baricitinib is associated with an increased rate of infections such as upper respiratory tract infections compared to placebo (see section 4.8). In rheumatoid arthritis clinical studies, combination with methotrexate resulted in increased frequency of infections compared to baricitinib monotherapy. The risks and benefits of treatment should be carefully considered prior to initiating baricitinib in patients with active, chronic or recurrent infections (see section 4.2). If an infection develops, the patient should be monitored carefully and therapy should be temporarily interrupted if the patient is not responding to standard therapy. Treatment should not be resumed until the infection resolves. 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 over 65 years of age, baricitinib should only be used if no suitable treatment alternatives are available. Tuberculosis Patients should be screened for tuberculosis (TB) before starting therapy. Baricitinib should not be given to patients with active TB. Anti-TB therapy should be considered prior to initiation of treatment in patients with previously untreated latent TB. 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 clinical trials. Treatment should not be initiated, or should be temporarily interrupted, in patients with an ANC < 1 x 109 cells/L, ALC < 0.5

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