Rivaroxaban Accord · 4.4 Special warnings and precautions for use · 2

HOS-099410 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The safety of rivaroxaban has been evaluated in thirteen pivotal phase III studies (see Table 1). Overall, 69,608 adult patients in nineteen phase III studies and 488 paediatric patients in two phase II and two phase III studies were exposed to rivaroxaban. Table 1: Number of patients studied, total daily dose and maximum treatment duration in adult and paediatric phase III studies Indication Number of Total daily dose Maximum patients* treatment duration Prevention of venous thromboembolism 6,097 10 mg 39 days (VTE) in adult patients undergoing elective hip or knee replacement surgery Prevention of VTE in medically ill patients 3,997 10 mg 39 days Treatment of deep vein thrombosis (DVT), 6,790 Day 1-21: 30 mg 21 months pulmonary embolism (PE) and prevention of Day 22 and onwards: recurrence 20 mg After at least 6 months: 10 mg or 20 mg Treatment of VTE and prevention of VTE 329 Body weight-adjusted 12 months recurrence in term neonates and children aged dose to achieve a similar less than 18 years following initiation of exposure as that standard anticoagulation treatment observed in adults treated for DVT with 20 mg rivaroxaban once daily Prevention of stroke and systemic embolism 7,750 20 mg 41 months in patients with non-valvular atrial fibrillation Prevention of atherothrombotic events in 10,225 5 mg or 10 mg 31 months patients after an ACS respectively,

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HOS-099416 · has-adverse-reaction-information · PDF-Seite 37

Summary of the safety profile The safety of rivaroxaban has been evaluated in thirteen pivotal phase III studies (see Table 1). Overall, 69,608 adult patients in nineteen phase III studies and 488 paediatric patients in two phase II and two phase III studies were exposed to rivaroxaban. Table 1: Number of patients studied, total daily dose and maximum treatment duration in adult and paediatric phase III studies Indication Number of Total daily dose Maximum patients* treatment duration Prevention of venous thromboembolism 6,097 10 mg 39 days (VTE) in adult patients undergoing elective hip or knee replacement surgery Prevention of VTE in medically ill patients 3,997 10 mg 39 days Treatment of deep vein thrombosis (DVT), 6,790 Day 1 - 21: 30 mg 21 months pulmonary embolism (PE) and prevention of Day 22 and onwards: recurrence 20 mg After at least 6 months: 10 mg or 20 mg Treatment of VTE and prevention of VTE 329 Body weight-adjusted 12 months recurrence in term neonates and children aged dose to achieve a less than 18 years following initiation of similar exposure as that standard anticoagulation treatment observed in adults treated for DVT with 20 mg rivaroxaban once daily Prevention of stroke and systemic embolism 7,750 20 mg 41 months in patients with non-valvular atrial fibrillation Prevention of atherothrombotic events in 10,225 5 mg or 10 mg 31 months patients after an acute coronary syndrome respectively, (ACS) co-ad

Auszug; vollständigen Abschnitt im Original lesen.

HOS-099422 · has-adverse-reaction-information · PDF-Seite 63

Summary of the safety profile 63 The safety of rivaroxaban has been evaluated in thirteen pivotal phase III studies (see Table 1). Overall, 69,608 adult patients in nineteen phase III studies and 488 paediatric patients in two phase II and two phase III studies were exposed to rivaroxaban. Table 1: Number of patients studied, total daily dose and maximum treatment duration in adult and paediatric phase III studies Indication Number of Total daily dose Maximum patients* treatment duration Prevention of venous thromboembolism 6,097 10 mg 39 days (VTE) in adult patients undergoing elective hip or knee replacement surgery Prevention of VTE in medically ill patients 3,997 10 mg 39 days Treatment of deep vein thrombosis (DVT), 6,790 Day 1-21: 30 mg 21 months pulmonary embolism (PE) and prevention Day 22 and onwards: of recurrence 20 mg After at least 6 months: 10 mg or 20 mg Treatment of VTE and prevention of VTE 329 Body weight-adjusted 12 months recurrence in term neonates and children dose to achieve a aged less than 18 years following initiation similar exposure as of standard anticoagulation treatment that observed in adults treated for DVT with 20 mg rivaroxaban once daily Prevention of stroke and systemic embolism 7,750 20 mg 41 months in patients with non-valvular atrial fibrillation Prevention of atherothrombotic events in 10,225 5 mg or 10 mg 31 months patients after an ACS respectively, co-admin

Auszug; vollständigen Abschnitt im Original lesen.

HOS-099434 · has-adverse-reaction-information · PDF-Seite 127

Summary of the safety profile The safety of rivaroxaban has been evaluated in thirteen pivotal phase III studies (see Table 1). Overall, 69,608 adult patients in nineteen phase III studies and 488 paediatric patients in two phase II and two phase III studies were exposed to rivaroxaban. 127 Table 1: Number of patients studied, total daily dose and maximum treatment duration in adult and paediatric phase III studies Indication Number of Total daily dose Maximum patients* treatment duration Prevention of venous thromboembolism 6,097 10 mg 39 days (VTE) in adult patients undergoing elective hip or knee replacement surgery Prevention of VTE in medically ill patients 3,997 10 mg 39 days Treatment of deep vein thrombosis (DVT), 6,790 Day 1 - 21: 30 mg 21 months pulmonary embolism (PE) and prevention Day 22 and onwards: of recurrence 20 mg After at least 6 months: 10 mg or 20 mg Treatment of VTE and prevention of VTE 329 Body weight-adjusted 12 months recurrence in term neonates and children dose to achieve a aged less than 18 years following initiation similar exposure as of standard anticoagulation treatment that observed in adults treated for DVT with 20 mg rivaroxaban once daily Prevention of stroke and systemic embolism 7,750 20 mg 41 months in patients with non-valvular atrial fibrillation Prevention of atherothrombotic events in 10,225 5 mg or 10 mg 31 months patients after an acute coronary syndrome respectively, co- (ACS) administered with

Auszug; vollständigen Abschnitt im Original lesen.

HOS-099428 · has-adverse-reaction-information · PDF-Seite 97

Summary of the safety profile The safety of rivaroxaban has been evaluated in thirteen pivotal phase III studies (see Table 1). Overall, 69,608 adult patients in nineteen phase III studies and 488 paediatric patients in two phase II and two phase III studies were exposed to rivaroxaban. Table 1: Number of patients studied, total daily dose and maximum treatment duration in adult and paediatric phase III studies Indication Number of Total daily dose Maximum patients* treatment duration Prevention of venous thromboembolism 6,097 10 mg 39 days (VTE) in adult patients undergoing elective hip or knee replacement surgery Prevention of VTE in medically ill patients 3,997 10 mg 39 days Treatment of deep vein thrombosis (DVT), 6,790 Day 1-21: 30 mg 21 months pulmonary embolism (PE) and prevention Day 22 and onwards: of recurrence 20 mg After at least 6 months: 10 mg or 20 mg Treatment of VTE and prevention of VTE 329 Body weight- adjusted 12 months recurrence in term neonates and children dose to achieve a aged less than 18 years following initiation similar exposure as of standard anticoagulation treatment that observed in adults treated for DVT with 20 mg rivaroxaban once daily Prevention of stroke and systemic embolism 7,750 20 mg 41 months in patients with non-valvular atrial fibrillation Prevention of atherothrombotic events in 10,225 5 mg or 10 mg 31 months patients after an acute coronary syndrome respectively, (ACS) co-administered with

Auszug; vollständigen Abschnitt im Original lesen.

HOS-099412 · has-contraindication-information · PDF-Seite 31

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Active clinically significant bleeding. Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5). Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section 5.2). Pregnancy and breastfeeding (see section 4.6).

HOS-099430 · has-contraindication-information · PDF-Seite 122

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Active clinically significant bleeding. Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5). Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section 5.2). Pregnancy and breast-feeding (see section 4.6).

HOS-099424 · has-contraindication-information · PDF-Seite 90

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 90 Active clinically significant bleeding. Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5). Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section 5.2). Pregnancy and breast-feeding (see section 4.6).

HOS-099418 · has-contraindication-information · PDF-Seite 57

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Active clinically significant bleeding. Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, 57 known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5). Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section 5.2). Pregnancy and breast-feeding (see section 4.6).

HOS-099406 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Active clinically significant bleeding. Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5). Concomitant treatment of ACS with antiplatelet therapy in patients with a prior stroke or a transient ischaemic attack (TIA) (see section 4.4). Concomitant treatment of CAD/PAD with ASA in patients with previous haemorrhagic or lacunar stroke, or any stroke within a month (see section 4.4). Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section 5.2). Pregnancy and breast-feeding (see section 4.6).

HOS-099405 · has-indication-information · PDF-Seite 2

Rivaroxaban Accord, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers (see sections 4.3, 4.4 and 5.1). Rivaroxaban Accord, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD) at high risk of ischaemic events.

HOS-099429 · has-indication-information · PDF-Seite 119

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients.)

HOS-099423 · has-indication-information · PDF-Seite 86

Adults Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack. Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients.) Paediatric population Treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children and adolescents aged less than 18 years and weighing more than 50 kg after at least 5 days of initial parenteral anticoagulation treatment.

HOS-099417 · has-indication-information · PDF-Seite 53

Adults Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack. Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients.) Paediatric population Treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children and adolescents aged less than 18 years and weighing from 30 kg to 50 kg after at least 5 days of initial parenteral anticoagulation treatment.

HOS-099411 · has-indication-information · PDF-Seite 29

Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery. Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients.)

HOS-099408 · has-interaction-information · PDF-Seite 8

CYP3A4 and P-gp inhibitors Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a day) led to a 2.6-fold / 2.5-fold increase in mean rivaroxaban AUC and a 1.7-fold / 1.6-fold increase in mean rivaroxaban Cmax, with significant increases in pharmacodynamic effects which may lead to an increased bleeding risk. Therefore, the use of rivaroxaban is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong inhibitors of both CYP3A4 and P-gp (see section 4.4). Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5-fold increase in mean rivaroxaban AUC and a 1.4-fold increase in Cmax. The interaction with clarithromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4). Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 1.3-fold increase in mean rivaroxaban AUC and Cmax. The interaction with erythromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8-fold increase in mean rivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects with normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0-fold increase in mean rivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects with normal renal function. The effect of erythromycin is additive to that of renal impairment (see section 4.4). Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4-fold increase in mean rivaroxaban AUC and a 1.3-fold increase in mean Cmax. The interaction with fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4). Given the limited clinical data available with dronedarone, co-administration with rivaroxa

Auszug; vollständigen Abschnitt im Original lesen.

HOS-099414 · has-interaction-information · PDF-Seite 35

CYP3A4 and P-gp inhibitors Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a day) led to a 2.6-fold / 2.5-fold increase in mean rivaroxaban AUC and a 1.7-fold / 1.6-fold increase in mean rivaroxaban Cmax, with significant increases in pharmacodynamic effects which may lead to an increased bleeding risk. Therefore, the use of rivaroxaban is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong inhibitors of both CYP3A4 and P-gp (see section 4.4). Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5-fold increase in mean rivaroxaban AUC and a 1.4-fold increase in Cmax. The interaction with clarithromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4). Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 1.3-fold increase in mean rivaroxaban AUC and Cmax. The interaction with erythromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8-fold increase in mean rivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects with normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0-fold increase in mean rivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects with normal renal function. The effect of erythromycin is additive to that of renal impairment (see section 4.4). Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4-fold increase in mean rivaroxaban AUC and a 1.3-fold increase in mean Cmax. The interaction with fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4). Given the limited clinical data available with dronedarone, co-administration with rivaroxa

Auszug; vollständigen Abschnitt im Original lesen.

HOS-099426 · has-interaction-information · PDF-Seite 94

The extent of interactions in the paediatric population is not known. The below mentioned interaction data was obtained in adults and the warnings in section 4.4 should be taken into account for the paediatric population. CYP3A4 and P-gp inhibitors Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a day) led to a 2.6-fold / 2.5-fold increase in mean rivaroxaban AUC and a 1.7-fold / 1.6-fold increase in mean rivaroxaban Cmax, with significant increases in pharmacodynamic effects which may lead to an increased bleeding risk. Therefore, the use of rivaroxaban is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong inhibitors of both CYP3A4 and P-gp (see section 4.4). Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5-fold increase in mean rivaroxaban AUC and a 1.4-fold increase in Cmax. The interaction with clarithromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4). 94 Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 1.3-fold increase in mean rivaroxaban AUC and Cmax. The interaction with erythromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8-fold increase in mean rivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects with normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0-fold increase in mean rivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects with normal renal function. The effect of erythromycin is additive to that of renal impairment (see section 4.4). Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4-fold increase in mean rivaroxaban AUC and a 1.3-fold increase in mean Cmax. The interac

Auszug; vollständigen Abschnitt im Original lesen.

HOS-099432 · has-interaction-information · PDF-Seite 125

CYP3A4 and P-gp inhibitors Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a day) led to a 2.6-fold / 2.5-fold increase in mean rivaroxaban AUC and a 1.7-fold / 1.6-fold increase in mean rivaroxaban Cmax, with significant increases in pharmacodynamic effects which may lead to an increased bleeding risk. Therefore, the use of rivaroxaban is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong inhibitors of both CYP3A4 and P-gp (see section 4.4). Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5-fold increase in mean rivaroxaban AUC and a 1.4-fold increase in Cmax. The interaction with clarithromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4). Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 1.3-fold increase in mean rivaroxaban AUC and Cmax. The interaction with erythromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8-fold increase in mean rivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects with normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0-fold increase in mean rivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects with normal renal function. The effect of erythromycin is additive to that of renal impairment (see section 4.4). Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4- fold increase in mean rivaroxaban AUC and a 1.3- fold increase in mean Cmax. The interaction with fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4). Given the limited clinical data available with dronedarone, co-administration with rivaro

Auszug; vollständigen Abschnitt im Original lesen.

HOS-099420 · has-interaction-information · PDF-Seite 61

The extent of interactions in the paediatric population is not known. The below mentioned interaction data was obtained in adults and the warnings in section 4.4 should be taken into account for the paediatric population. CYP3A4 and P-gp inhibitors Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a day) led to a 2.6-fold / 2.5-fold increase in mean rivaroxaban AUC and a 1.7-fold / 1.6-fold increase in mean rivaroxaban Cmax, with significant increases in pharmacodynamic effects which may lead to an increased bleeding risk. Therefore, the use of rivaroxaban is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong inhibitors of both CYP3A4 and P-gp (see section 4.4). Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5-fold increase in mean rivaroxaban AUC and a 1.4-fold increase in Cmax. The interaction with clarithromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4). Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 1.3-fold increase in mean rivaroxaban AUC and Cmax. The interaction with erythromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8-fold increase in mean rivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects with normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0-fold increase in mean rivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects with 61 normal renal function. The effect of erythromycin is additive to that of renal impairment (see section 4.4). Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4-fold increase in mean rivaroxaban AUC and a 1.3-fold increase in mean Cmax. The interac

Auszug; vollständigen Abschnitt im Original lesen.

HOS-099427 · has-pregnancy-information · PDF-Seite 96

Pregnancy Safety and efficacy of rivaroxaban have not been established in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, rivaroxaban is contraindicated during pregnancy (see section 4.3). Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban. Breast-feeding Safety and efficacy of rivaroxaban have not been established in breast-feeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore, rivaroxaban is contraindicated during breast-feeding (see section 4.3). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy. Fertility No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen (see section 5.3).

HOS-099433 · has-pregnancy-information · PDF-Seite 127

Pregnancy Safety and efficacy of rivaroxaban have not been established in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, rivaroxaban is contraindicated during pregnancy (see section 4.3). Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban. Breast-feeding Safety and efficacy of rivaroxaban have not been established in breast-feeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore, rivaroxaban is contraindicated during breast-feeding (see section 4.3). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy. Fertility No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen (see section 5.3).

HOS-099421 · has-pregnancy-information · PDF-Seite 63

Pregnancy Safety and efficacy of rivaroxaban have not been established in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, Rivaroxaban Accord is contraindicated during pregnancy (see section 4.3). Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban. Breast-feeding Safety and efficacy of rivaroxaban have not been established in breast-feeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore, Rivaroxaban Accord is contraindicated during breast-feeding (see section 4.3). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy. Fertility No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen (see section 5.3).

HOS-099409 · has-pregnancy-information · PDF-Seite 10

Pregnancy Safety and efficacy of rivaroxaban have not been established in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, rivaroxaban is contraindicated during pregnancy (see section 4.3). Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban. Breast-feeding Safety and efficacy of rivaroxaban have not been established in breast-feeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore, rivaroxaban is contraindicated during breast-feeding (see section 4.3). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy. Fertility No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen (see section 5.3).

HOS-099415 · has-pregnancy-information · PDF-Seite 36

Pregnancy Safety and efficacy of rivaroxaban have not been established in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, rivaroxaban is contraindicated during pregnancy (see section 4.3). Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban. Breast-feeding Safety and efficacy of rivaroxaban have not been established in breast-feeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore, rivaroxaban is contraindicated during breast-feeding (see section 4.3). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy. Fertility No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen (see section 5.3).

HOS-099407 · has-warning-information · PDF-Seite 5

In ACS patients, efficacy and safety of rivaroxaban 2.5 mg twice daily have been investigated in combination with the antiplatelet agents ASA alone or ASA plus clopidogrel/ticlopidine. In patients at high risk of ischaemic events with CAD/PAD, efficacy and safety of rivaroxaban 2.5 mg twice daily have been investigated in combination with ASA. In patients after recent revascularisation procedure of the lower limb due to symptomatic PAD, efficacy and safety of rivaroxaban 2.5 mg twice daily have been investigated in combination with the antiplatelet agent ASA alone or ASA plus short-term clopidogrel. If required, dual antiplatelet therapy with clopidogrel should be short-term; long-term dual antiplatelet therapy should be avoided (see section 5.1). Treatment in combination with other antiplatelet agents, e.g. prasugrel or ticagrelor, has not been studied and is not recommended. Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period. Haemorrhagic risk As with other anticoagulants, patients taking Rivaroxaban Accord are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Rivaroxaban Accord administration should be discontinued if severe haemorrhage occurs (see section 4.9). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban treatment on top of single or dual anti-platelet therapy. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate. Several sub-groups of patients, as detailed below, are at increased risk of bleeding. Therefore, the use of rivaroxaban in combination with dual antiplatelet therapy in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events. In addition these patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment (see section 4.8). Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site. Although treatment with rivaroxaban does not require routine monitoring of exp

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HOS-099431 · has-warning-information · PDF-Seite 122

Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period. Haemorrhagic risk As with other anticoagulants, patients taking Rivaroxaban Accord are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Rivaroxaban Accord administration should be discontinued if severe haemorrhage occurs. (see section 4.9) In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate. Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment (see section 4.8). Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site. Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. overdose and emergency surgery (see sections 5.1 and 5.2). 122 Renal impairment In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels may be significantly increased (1.6-fold on average) which may lead to an increased bleeding risk. Rivaroxaban Accord is to be used with caution in patients with creatinine clearance 15-29 ml/min. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2). Rivaroxaban Accord should be used with caution in patients with renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations (see section 4.5). Interaction with other medicinal products The use of Rivaroxaban Accord is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics (such as ketoconazole, itraco

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HOS-099425 · has-warning-information · PDF-Seite 91

Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period. Haemorrhagic risk As with other anticoagulants, patients taking Rivaroxaban Accord are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Rivaroxaban Accord administration should be discontinued if severe haemorrhage occurs. (see section 4.9) In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate. Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment (see section 4.8). Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site. Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. overdose and emergency surgery (see sections 5.1 and 5.2). Paediatric population There is limited data in children with cerebral vein and sinus thrombosis who have a CNS infection (see section 5.1). The risk of bleeding should be carefully evaluated before and during therapy with rivaroxaban. Renal impairment 91 In adult patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels may be significantly increased (1.6-fold on average) which may lead to an increased bleeding risk. Rivaroxaban Accord is to be used with caution in patients with creatinine clearance 15-29 ml/min. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2). Rivaroxaban Accord should be used with caution in patients with renal impairment concomitantly receiving other medicinal products which increase rivaroxaban

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HOS-099419 · has-warning-information · PDF-Seite 58

Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period. Haemorrhagic risk As with other anticoagulants, patients taking Rivaroxaban Accord are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Rivaroxaban Accord administration should be discontinued if severe haemorrhage occurs (see section 4.9). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate. Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment (see section 4.8). Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site. Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. overdose and emergency surgery (see sections 5.1 and 5.2). Paediatric population There is limited data in children with cerebral vein and sinus thrombosis who have a CNS infection (see section 5.1). The risk of bleeding should be carefully evaluated before and during therapy with rivaroxaban. Renal impairment In adult patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels may be significantly increased (1.6-fold on average) which may lead to an increased bleeding risk. Rivaroxaban Accord is to be used with caution in patients with creatinine clearance 15-29 ml/min. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2). 58 Rivaroxaban Accord should be used with caution in patients with renal impairment concomitantly receiving other medicinal products which increase rivaroxaba

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HOS-099413 · has-warning-information · PDF-Seite 32

Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period. Haemorrhagic risk As with other anticoagulants, patients taking Rivaroxaban Accord are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Rivaroxaban Accord administration should be discontinued if severe haemorrhage occurs (see section 4.9). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate. Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment (see section 4.8). In patients receiving rivaroxaban for VTE prevention following elective hip or knee replacement surgery, this may be done by regular physical examination of the patients, close observation of the surgical wound drainage and periodic measurements of haemoglobin. Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site. Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. overdose and emergency surgery (see sections 5.1 and 5.2). Renal impairment In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels may be significantly increased (1.6-fold on average) which may lead to an increased bleeding risk. Rivaroxaban Accord is to be used with caution in patients with creatinine clearance 15-29 ml/min. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2). In patients with moderate renal impairment (creatinine clearance 30-49 ml/min) concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations Rivaroxaban Ac

Auszug; vollständigen Abschnitt im Original lesen.