Brilique · 4.3 Contraindications · 3

HOS-095708 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The safety profile of ticagrelor has been evaluated in two large phase 3 outcome trials (PLATO and PEGASUS) including more than 39,000 patients (see section 5.1). In PLATO, patients on ticagrelor had a higher incidence of discontinuation due to adverse events than clopidogrel (7.4% vs. 5.4%). In PEGASUS, patients on ticagrelor had a higher incidence of discontinuation due to adverse events compared to ASA therapy alone (16.1% for ticagrelor 60 mg with ASA vs. 8.5% for ASA therapy alone). The most commonly reported adverse reactions in patients treated with ticagrelor were bleeding and dyspnoea (see section 4.4). Tabulated list of adverse reactions The following adverse reactions have been identified following studies or have been reported in post-marketing experience with ticagrelor (Table 1). Adverse reactions are listed by MedDRA System Organ Class (SOC). Within each SOC the adverse reactions are ranked by frequency category. Frequency categories are defined according to the following conventions: 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), not known (cannot be estimated from the available data). Table 1 – Adverse reactions by frequency and system organ class (SOC) SOC Very common Common Uncommon Not known Neoplasms Tumour benign, bleedingsa malignant and unspecified (including cysts and polyps) Blood and Blood disorder Thrombotic lymphatic bleedingsb Thrombocytopenic system disorders Purpurac Immune system Hypersensitivity disorders including angioedemac 9  SOC Very common Common Uncommon Not known Metabolism and Hyperuricaemiad Gout/Gouty nutrition Arthritis disorders Psychiatric Confusion disorde

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HOS-095720 · has-adverse-reaction-information · PDF-Seite 54

Summary of the safety profile The safety profile of ticagrelor has been evaluated in two large phase 3 outcome trials (PLATO and PEGASUS) including more than 39,000 patients (see section 5.1). In PLATO, patients on ticagrelor had a higher incidence of discontinuation due to adverse events than clopidogrel (7.4% vs. 5.4%). In PEGASUS, patients on ticagrelor had a higher incidence of discontinuation due to adverse events compared to ASA therapy alone (16.1% for ticagrelor 60 mg with ASA vs. 8.5% for ASA therapy alone). The most commonly reported adverse reactions in patients treated with ticagrelor were bleeding and dyspnoea (see section 4.4). Tabulated list of adverse reactions The following adverse reactions have been identified following studies or have been reported in post-marketing experience with ticagrelor (Table 1). Adverse reactions are listed by MedDRA System Organ Class (SOC). Within each SOC the adverse reactions are ranked by frequency category. Frequency categories are defined according to the following conventions: 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), not known (cannot be estimated from the available data). Table 1 – Adverse reactions by frequency and system organ class (SOC) SOC Very common Common Uncommon Not known Neoplasms Tumour benign, bleedingsa malignant and unspecified (including cysts and polyps) 54  SOC Very common Common Uncommon Not known Blood and Blood disorder Thrombotic lymphatic system bleedingsb Thrombocytopenic disorders Purpurac Immune system Hypersensitivity disorders including angioedemac Metabolism and Hyperuricaemiad Gout/Gouty nutrition Arthritis disorders Psychiatric Confusion disorders Nervous system Dizziness, Intracran

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HOS-095714 · has-adverse-reaction-information · PDF-Seite 31

Summary of the safety profile The safety profile of ticagrelor has been evaluated in two large phase 3 outcome trials (PLATO and PEGASUS) including more than 39,000 patients (see section 5.1). In PLATO, patients on ticagrelor had a higher incidence of discontinuation due to adverse events than clopidogrel (7.4% vs. 5.4%). In PEGASUS, patients on ticagrelor had a higher incidence of discontinuation due to adverse events compared to ASA therapy alone (16.1% for ticagrelor 60 mg with ASA vs. 8.5% for ASA therapy alone). The most commonly reported adverse reactions in patients treated with ticagrelor were bleeding and dyspnoea (see section 4.4). Tabulated list of adverse reactions The following adverse reactions have been identified following studies or have been reported in post-marketing experience with ticagrelor (Table 1). Adverse reactions are listed by MedDRA System Organ Class (SOC). Within each SOC the adverse reactions are ranked by frequency category. Frequency categories are defined according to the following conventions: 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), not known (cannot be estimated from the available data). Table 1 – Adverse reactions by frequency and system organ class (SOC) SOC Very common Common Uncommon Not known Neoplasms Tumour benign, bleedingsa malignant and unspecified (including cysts and polyps) Blood and Blood disorder Thrombotic lymphatic system bleedingsb Thrombocytopenic disorders Purpurac Immune system Hypersensitivity disorders including angioedemac 31  SOC Very common Common Uncommon Not known Metabolism and Hyperuricaemiad Gout/Gouty nutrition Arthritis disorders Psychiatric

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HOS-095710 · has-contraindication-information · PDF-Seite 25

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.8). • Active pathological bleeding. • History of intracranial haemorrhage (see section 4.8). • Severe hepatic impairment (see sections 4.2, 4.4 and 5.2). • Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir), as co-administration may lead to a substantial increase in exposure to ticagrelor (see section 4.5).

HOS-095704 · has-contraindication-information · PDF-Seite 3

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.8). • Active pathological bleeding. • History of intracranial haemorrhage (see section 4.8). • Severe hepatic impairment (see sections 4.2, 4.4 and 5.2). • Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir), as co-administration may lead to a substantial increase in exposure to ticagrelor (see section 4.5).

HOS-095716 · has-contraindication-information · PDF-Seite 48

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.8). • Active pathological bleeding. • History of intracranial haemorrhage (see section 4.8). • Severe hepatic impairment (see sections 4.2, 4.4 and 5.2). • Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir), as co-administration may lead to a substantial increase in exposure to ticagrelor (see section 4.5).

HOS-095715 · has-indication-information · PDF-Seite 47

Brilique, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with - acute coronary syndromes (ACS) or - a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic event (see sections 4.2 and 5.1).

HOS-095709 · has-indication-information · PDF-Seite 24

Brilique, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with - acute coronary syndromes (ACS) or - a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic event (see sections 4.2 and 5.1).

HOS-095703 · has-indication-information · PDF-Seite 2

Brilique, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with - acute coronary syndromes (ACS) or - a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic event (see sections 4.2 and 5.1).

HOS-095712 · has-interaction-information · PDF-Seite 28

Ticagrelor is primarily a CYP3A4 substrate and a mild inhibitor of CYP3A4. Ticagrelor is also a P-glycoprotein (P-gp) substrate and a weak P-gp inhibitor and may increase the exposure of P-gp substrates. Ticagrelor is a breast cancer resistance protein (BCRP) inhibitor. Effects of medicinal and other products on ticagrelor CYP3A4 inhibitors • Strong CYP3A4 inhibitors – Co-administration of ketoconazole with ticagrelor increased the ticagrelor Cmax and AUC equal to 2.4-fold and 7.3-fold, respectively. The Cmax and AUC of the active metabolite were reduced by 89% and 56%, respectively. Other strong inhibitors of CYP3A4 (clarithromycin, nefazodone, ritonavir and atazanavir) would be expected to have similar effects and therefore concomitant use of strong CYP3A4 inhibitors with ticagrelor is contraindicated (see section 4.3). • Moderate CYP3A4 inhibitors – Co-administration of diltiazem with ticagrelor increased the ticagrelor Cmax by 69% and AUC to 2.7-fold and decreased the active metabolite Cmax by 38% and AUC was unchanged. There was no effect of ticagrelor on diltiazem plasma levels. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, erythromycin and fluconazole) would be expected to have a similar effect and can as well be co-administered with ticagrelor. • A 2-fold increase of ticagrelor exposure was observed after daily consumption of large quantities of grapefruit juice (3 x 200 ml). This magnitude of increased exposure is not expected to be clinically relevant to most patients. CYP3A inducers Co-administration of rifampicin with ticagrelor decreased ticagrelor Cmax and AUC by 73% and 86%, respectively. The Cmax of the active metabolite was unchanged and the AUC was decreased by 46%, respectively. Other CYP3A inducers (e.g. phenytoin, carbamazepine and phenobarbital) would be expected to decrease the exposure to ticagrelor as well. Co-administration of ticagrelor with potent CYP3A inducers may decrease exposure and efficacy of ticagrelor, therefore, their concomitant use with ticagrelor is discouraged. 28 Cyclosporine (P-gp and CYP3A inhibitor) Co-administration of cyclosporine (600 mg) with ticagrelor increased ticagrelor Cmax and AUC equal to 2.3-fold and 2.8-fold, respectively. The AUC of the active metabolite was increased by 32% and Cmax was decreased by 15% in the presence of cyclosporine. No data are available on concomitant

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HOS-095718 · has-interaction-information · PDF-Seite 51

Ticagrelor is primarily a CYP3A4 substrate and a mild inhibitor of CYP3A4. Ticagrelor is also a P-glycoprotein (P-gp) substrate and a weak P-gp inhibitor and may increase the exposure of P-gp substrates. Ticagrelor is a breast cancer resistance protein (BCRP) inhibitor. Effects of medicinal and other products on ticagrelor CYP3A4 inhibitors • Strong CYP3A4 inhibitors – Co-administration of ketoconazole with ticagrelor increased the ticagrelor Cmax and AUC equal to 2.4-fold and 7.3-fold, respectively. The Cmax and AUC of the active metabolite were reduced by 89% and 56%, respectively. Other strong inhibitors of CYP3A4 (clarithromycin, nefazodone, ritonavir and atazanavir) would be expected to have similar effects and therefore concomitant use of strong CYP3A4 inhibitors with ticagrelor is contraindicated (see section 4.3). • Moderate CYP3A4 inhibitors – Co-administration of diltiazem with ticagrelor increased the ticagrelor Cmax by 69% and AUC to 2.7-fold and decreased the active metabolite Cmax by 38% and AUC was unchanged. There was no effect of ticagrelor on diltiazem plasma levels. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, erythromycin and fluconazole) would be expected to have a similar effect and can as well be co-administered with ticagrelor. • A 2-fold increase of ticagrelor exposure was observed after daily consumption of large quantities of grapefruit juice (3 x 200 ml). This magnitude of increased exposure is not expected to be clinically relevant to most patients. CYP3A inducers Co-administration of rifampicin with ticagrelor decreased ticagrelor Cmax and AUC by 73% and 86%, respectively. The Cmax of the active metabolite was unchanged and the AUC was decreased by 46%, respectively. Other CYP3A inducers (e.g. phenytoin, carbamazepine and phenobarbital) would be expected to decrease the exposure to ticagrelor as well. Co-administration of ticagrelor with potent 51 CYP3A inducers may decrease exposure and efficacy of ticagrelor, therefore, their concomitant use with ticagrelor is discouraged. Cyclosporine (P-gp and CYP3A inhibitor) Co-administration of cyclosporine (600 mg) with ticagrelor increased ticagrelor Cmax and AUC equal to 2.3-fold and 2.8-fold, respectively. The AUC of the active metabolite was increased by 32% and Cmax was decreased by 15% in the presence of cyclosporine. No data are available on concomitant u

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HOS-095706 · has-interaction-information · PDF-Seite 6

Ticagrelor is primarily a CYP3A4 substrate and a mild inhibitor of CYP3A4. Ticagrelor is also a P-glycoprotein (P-gp) substrate and a weak P-gp inhibitor and may increase the exposure of P-gp substrates. Ticagrelor is a breast cancer resistance protein (BCRP) inhibitor. Effects of medicinal and other products on ticagrelor CYP3A4 inhibitors • Strong CYP3A4 inhibitors – Co-administration of ketoconazole with ticagrelor increased the ticagrelor Cmax and AUC equal to 2.4-fold and 7.3-fold, respectively. The Cmax and AUC of the active metabolite were reduced by 89% and 56%, respectively. Other strong inhibitors of CYP3A4 (clarithromycin, nefazodone, ritonavir and atazanavir) would be expected to have similar effects and therefore concomitant use of strong CYP3A4 inhibitors with ticagrelor is contraindicated (see section 4.3). • Moderate CYP3A4 inhibitors – Co-administration of diltiazem with ticagrelor increased the ticagrelor Cmax by 69% and AUC to 2.7-fold and decreased the active metabolite Cmax by 38% and AUC was unchanged. There was no effect of ticagrelor on diltiazem plasma levels. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, erythromycin and fluconazole) would be expected to have a similar effect and can as well be co-administered with ticagrelor. • A 2-fold increase of ticagrelor exposure was observed after daily consumption of large quantities of grapefruit juice (3 x 200 ml). This magnitude of increased exposure is not expected to be clinically relevant to most patients. CYP3A inducers Co-administration of rifampicin with ticagrelor decreased ticagrelor Cmax and AUC by 73% and 86%, respectively. The Cmax of the active metabolite was unchanged and the AUC was decreased by 46%, respectively. Other CYP3A inducers (e.g. phenytoin, carbamazepine and phenobarbital) would be expected to decrease the exposure to ticagrelor as well. Co-administration of ticagrelor with potent CYP3A inducers may decrease exposure and efficacy of ticagrelor, therefore, their concomitant use with ticagrelor is discouraged. 6 Cyclosporine (P-gp and CYP3A inhibitor) Co-administration of cyclosporine (600 mg) with ticagrelor increased ticagrelor Cmax and AUC equal to 2.3-fold and 2.8-fold, respectively. The AUC of the active metabolite was increased by 32% and Cmax was decreased by 15% in the presence of cyclosporine. No data are available on concomitant u

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HOS-095707 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential Women of childbearing potential should use appropriate contraceptive measures to avoid pregnancy during ticagrelor therapy. Pregnancy There are no or limited amount of data from the use of ticagrelor in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Ticagrelor is not recommended during pregnancy. 8 Breast-feeding Available pharmacodynamic/toxicological data in animals have shown excretion of ticagrelor and its active metabolites in milk (see section 5.3). A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ticagrelor therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Ticagrelor had no effect on male or female fertility in animals (see section 5.3).

HOS-095713 · has-pregnancy-information · PDF-Seite 30

Women of childbearing potential Women of childbearing potential should use appropriate contraceptive measures to avoid pregnancy during ticagrelor therapy. Pregnancy There are no or limited amount of data from the use of ticagrelor in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Ticagrelor is not recommended during pregnancy. 30 Breast-feeding Available pharmacodynamic/toxicological data in animals have shown excretion of ticagrelor and its active metabolites in milk (see section 5.3). A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ticagrelor therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Ticagrelor had no effect on male or female fertility in animals (see section 5.3).

HOS-095719 · has-pregnancy-information · PDF-Seite 53

Women of childbearing potential Women of childbearing potential should use appropriate contraceptive measures to avoid pregnancy during ticagrelor therapy. 53 Pregnancy There are no or limited amount of data from the use of ticagrelor in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Ticagrelor is not recommended during pregnancy. Breast-feeding Available pharmacodynamic/toxicological data in animals have shown excretion of ticagrelor and its active metabolites in milk (see section 5.3). A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ticagrelor therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Ticagrelor had no effect on male or female fertility in animals (see section 5.3).

HOS-095711 · has-warning-information · PDF-Seite 25

Bleeding risk The use of ticagrelor in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events (see sections 4.8 and 5.1). If clinically indicated, ticagrelor should be used with caution in the following patient groups: • Patients with a propensity to bleed (e.g. due to recent trauma, recent surgery, coagulation disorders, active or recent gastrointestinal bleeding) or who are at increased risk of trauma. The use of ticagrelor is contraindicated in patients with active pathological bleeding, in those with a 25  history of intracranial haemorrhage, and in patients with severe hepatic impairment (see section 4.3). • Patients with concomitant administration of medicinal products that may increase the risk of bleeding (e.g. non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of ticagrelor dosing. In two randomised controlled studies (TICO and TWILIGHT) in patients with ACS who have undergone a PCI procedure with a drug-eluting stent, discontinuing ASA after 3 months dual antiplatelet therapy with ticagrelor and ASA (DAPT), and continuing with ticagrelor as single antiplatelet therapy (SAPT) for 9 and 12 months, respectively, has been shown to decrease the risk of bleeding with no observed increase in risk of major adverse cardiovascular events (MACE) compared with continued DAPT. The decision to discontinue ASA after 3 months and continue with ticagrelor as single antiplatelet therapy for 9 months in patients with an increased risk of bleeding should be based on clinical judgment considering the risk of bleeding versus the risk of thrombotic events (see section 4.2). Platelet transfusion did not reverse the antiplatelet effect of ticagrelor in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding. Since co-administration of ticagrelor with desmopressin did not decrease template-bleeding time, desmopressin is unlikely to be effective in managing clinical bleeding events (see section 4.5). Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa therapy may increase haemostasis. Ticagrelor may be resumed after the cause of bleeding has been identified and controlled. Surgery Patients should be advised to inform physicians and dentists that they are taking ticagrelor

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HOS-095705 · has-warning-information · PDF-Seite 3

Bleeding risk The use of ticagrelor in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events (see sections 4.8 and 5.1). If clinically indicated, ticagrelor should be used with caution in the following patient groups: • Patients with a propensity to bleed (e.g. due to recent trauma, recent surgery, coagulation disorders, active or recent gastrointestinal bleeding) or who are at increased risk of trauma. The use of ticagrelor is contraindicated in patients with active pathological bleeding, in those with a 3  history of intracranial haemorrhage, and in patients with severe hepatic impairment (see section 4.3). • Patients with concomitant administration of medicinal products that may increase the risk of bleeding (e.g. non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of ticagrelor dosing. In two randomised controlled studies (TICO and TWILIGHT) in patients with ACS who have undergone a PCI procedure with a drug-eluting stent, discontinuing ASA after 3 months dual antiplatelet therapy with ticagrelor and ASA (DAPT), and continuing with ticagrelor as single antiplatelet therapy (SAPT) for 9 and 12 months, respectively, has been shown to decrease the risk of bleeding with no observed increase in risk of major adverse cardiovascular events (MACE) compared with continued DAPT. The decision to discontinue ASA after 3 months and continue with ticagrelor as single antiplatelet therapy for 9 months in patients with an increased risk of bleeding should be based on clinical judgment considering the risk of bleeding versus the risk of thrombotic events (see section 4.2). Platelet transfusion did not reverse the antiplatelet effect of ticagrelor in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding. Since co-administration of ticagrelor with desmopressin did not decrease template-bleeding time, desmopressin is unlikely to be effective in managing clinical bleeding events (see section 4.5). Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa therapy may increase haemostasis. Ticagrelor may be resumed after the cause of bleeding has been identified and controlled. Surgery Patients should be advised to inform physicians and dentists that they are taking ticagrelor

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HOS-095717 · has-warning-information · PDF-Seite 48

Bleeding risk The use of ticagrelor in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events (see sections 4.8 and 5.1). If clinically indicated, ticagrelor should be used with caution in the following patient groups: 48  • Patients with a propensity to bleed (e.g. due to recent trauma, recent surgery, coagulation disorders, active or recent gastrointestinal bleeding) or who are at increased risk of trauma. The use of ticagrelor is contraindicated in patients with active pathological bleeding, in those with a history of intracranial haemorrhage, and in patients with severe hepatic impairment (see section 4.3). • Patients with concomitant administration of medicinal products that may increase the risk of bleeding (e.g. non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of ticagrelor dosing. In two randomised controlled studies (TICO and TWILIGHT) in patients with ACS who have undergone a PCI procedure with a drug-eluting stent, discontinuing ASA after 3 months dual antiplatelet therapy with ticagrelor and ASA (DAPT), and continuing with ticagrelor as single antiplatelet therapy (SAPT) for 9 and 12 months, respectively, has been shown to decrease the risk of bleeding with no observed increase in risk of major adverse cardiovascular events (MACE) compared with continued DAPT. The decision to discontinue ASA after 3 months and continue with ticagrelor as single antiplatelet therapy for 9 months in patients with an increased risk of bleeding should be based on clinical judgment considering the risk of bleeding versus the risk of thrombotic events (see section 4.2). Platelet transfusion did not reverse the antiplatelet effect of ticagrelor in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding. Since co-administration of ticagrelor with desmopressin did not decrease template-bleeding time, desmopressin is unlikely to be effective in managing clinical bleeding events (see section 4.5). Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa therapy may increase haemostasis. Ticagrelor may be resumed after the cause of bleeding has been identified and controlled. Surgery Patients should be advised to inform physicians and dentists that they are taking ticagrelor be

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