Pradaxa · 4.5 Interaction with other medicinal products and other forms of interaction · 2

HOS-094862 · has-adverse-reaction-information · PDF-Seite 15

Summary of the safety profile Dabigatran etexilate has been evaluated in clinical trials overall in approximately 64 000 patients; thereof approximately 35 000 patients were treated with dabigatran etexilate. In actively controlled VTE prevention trials 6 684 patients were treated with 150 mg or 220 mg dabigatran etexilate daily. The most commonly reported events are bleedings occurring in approximately 14 % of patients; the frequency of major bleeds (including wound site bleedings) is less than 2 %. Although rare in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes. 15 Tabulated list of adverse reactions Table 10 shows the adverse reactions ranked under headings of System Organ Classes (SOC) and frequency using the following convention: very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1 000 to < 1/100), rare ( 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the available data). Table 10: Adverse reactions SOC / Preferred term Frequency Blood and lymphatic system disorders Haemoglobin decreased Common Anaemia Uncommon Haematocrit decreased Uncommon Thrombocytopenia Rare Neutropenia Not known Agranulocytosis Not known Immune system disorder Drug hypersensitivity Uncommon Anaphylactic reaction Rare Angioedema Rare Urticaria Rare Rash Rare Pruritus Rare Bronchospasm Not known Nervous system disorders Intracranial haemorrhage Rare Vascular disorders Haematoma

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HOS-094868 · has-adverse-reaction-information · PDF-Seite 48

Summary of the safety profile Dabigatran etexilate has been evaluated in clinical trials overall in approximately 64 000 patients; thereof approximately 35 000 patients were treated with dabigatran etexilate. In total, about 9 % of patients treated for elective hip or knee surgery (short-term treatment for up to 42 days), 22 % of patients with atrial fibrillation treated for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years), 14 % of patients treated for DVT/PE and 15 % of patients treated for DVT/PE prevention experienced adverse reactions. The most commonly reported events are bleedings occurring in approximately 14 % of patients treated short-term for elective hip or knee replacement surgery, 16.6 % in patients with atrial fibrillation treated long-term for the prevention of stroke and systemic embolism, and in 14.4 % of adult patients treated for DVT/PE. Furthermore, bleeding occurred in 19.4 % of patients in the DVT/PE prevention trial RE-MEDY (adult patients) and in 10.5 % of patients in the DVT/PE prevention trial RE-SONATE (adult patients). Since the patient populations treated in the three indications are not comparable and bleeding events are distributed over several System Organ Classes (SOC), a summary description of major and any bleeding are broken down by indication and provided in tables 13-17 below. 48 Although low in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes. Tabulated list of adverse reactions Table 12 shows the adverse reactions identified from studies and post-marketing data in the indications primary VTE prevention after hip or knee replacement surgery, prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation, DVT/PE treatment and DVT/PE prevention. They are ranked under headings of System Organ Class (SOC) and frequency using the following convention: very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1 000 to < 1/100), rare ( 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the available data). Table 12: Adverse reactions Frequency SOC / Preferred term. Primary VTE Stroke and systemic DVT/PE prevention after hi

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HOS-094880 · has-adverse-reaction-information · PDF-Seite 122

Summary of the safety profile Dabigatran etexilate has been evaluated in clinical trials overall in approximately 64 000 patients; thereof approximately 35 000 patients were treated with dabigatran etexilate. The safety of dabigatran etexilate in the treatment of VTE and prevention of recurrent VTE in paediatric patients was studied in two phase III trials (DIVERSITY and 1160.108). In total, 328 paediatric patients had been treated with dabigatran etexilate. The patients received age and weight adjusted doses of an age-appropriate formulation of dabigatran etexilate. Overall, the safety profile in children is expected to be the same as in adults. In total, 26 % of paediatric patients treated with dabigatran etexilate for VTE and for prevention of recurrent VTE experienced adverse reactions. Tabulated list of adverse reactions Table 8 shows the adverse reactions identified from the studies in the treatment of VTE and prevention of recurrent VTE in paediatric patients. They are ranked under headings of System Organ Class (SOC) and frequency using the following convention: very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1 000 to < 1/100), rare ( 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the available data). Table 8: Adverse reactions Frequency SOC / Preferred term. treatment of VTE and prevention of recurrent VTE in paediatric patients Blood and lymphatic system disorders Anaemia Common Haemoglobin decreased Uncommon Thrombocytopenia Common Haematocrit decreased Uncommon Neutropenia Uncommon Agranulocytosis Not known Immune system disorder Drug hypersensitivity Uncommon Rash Common Pruritus Uncommon Anaphylactic reaction Not known Angioedema

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HOS-094874 · has-adverse-reaction-information · PDF-Seite 88

Summary of the safety profile Dabigatran etexilate has been evaluated in clinical trials overall in approximately 64 000 patients; thereof approximately 35 000 patients were treated with dabigatran etexilate. In total, 22 % of patients with atrial fibrillation treated for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years), 14 % of patients treated for DVT/PE and 15 % of patients treated for DVT/PE prevention experienced adverse reactions. The most commonly reported events are bleedings occurring in approximately 16.6 % in patients with atrial fibrillation treated long-term for the prevention of stroke and systemic embolism and in 14.4 % of adult patients treated for DVT/PE. Furthermore, bleeding occurred in 19.4 % of patients in the DVT/PE prevention trial RE-MEDY (adult patients) and in 10.5 % of patients in the DVT/PE prevention trial RE-SONATE (adult patients). Since the patient populations treated in the three indications are not comparable and bleeding events are distributed over several System Organ Classes (SOC), a summary description of major and any bleeding are broken down by indication and are provided in tables 12-15 below. Although low in frequency in clinical trials, major or severe bleeding may occur and, regardless of 88 location, may lead to disabling, life-threatening or even fatal outcomes. Tabulated list of adverse reactions Table 11 shows the adverse reactions identified studies and post-marketing data in the indications prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation, DVT/PE treatment and DVT/PE prevention. They are ranked under headings of System Organ Class (SOC) and frequency using the following convention.very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1 000 to < 1/100), rare ( 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the available data). Table 11: Adverse reactions Frequency SOC / Preferred term. Stroke and systemic embolism DVT/PE treatment prevention in patients with atrial and DVT/PE fibrillation prevention Blood and lymphatic system disorders Anaemia Common

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HOS-094870 · has-contraindication-information · PDF-Seite 78

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 • Severe renal impairment (CrCL < 30 mL/min) in adult patients • eGFR < 50 mL/min/1.73 m2 in paediatric patients • Active clinically significant bleeding • Lesion or condition, if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of 78  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, rivaroxaban, apixaban etc) except under specific circumstances. These are switching anticoagulant therapy (see section 4.2), when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see section 4.5) • Hepatic impairment or liver disease expected to have any impact on survival • Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole, dronedarone and the fixed-dose combination glecaprevir/pibrentasvir (see section 4.5) • Prosthetic heart valves requiring anticoagulant treatment (see section 5.1).

HOS-094858 · has-contraindication-information · PDF-Seite 6

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 • Severe renal impairment (CrCL < 30 mL/min) in adult patients • eGFR < 50 mL/min/1.73 m2 in paediatric patients • Active clinically significant bleeding • Lesion or condition, if considered a significant risk factor 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, rivaroxaban, apixaban etc) except under specific circumstances. These are switching anticoagulant therapy (see section 4.2), when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see section 4.5) • Hepatic impairment or liver disease expected to have any impact on survival • Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole, dronedarone and the fixed-dose combination glecaprevir/pibrentasvir (see section 4.5) • Prosthetic heart valves requiring anticoagulant treatment (see section 5.1). 6

HOS-094876 · has-contraindication-information · PDF-Seite 113

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 • eGFR < 50 mL/min/1.73 m2 in paediatric patients • Active clinically significant bleeding • Lesion or condition, if considered a significant risk factor 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 113  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, rivaroxaban, apixaban etc) except under specific circumstances. These are 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 impairment or liver disease expected to have any impact on survival • Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole, dronedarone and the fixed-dose combination glecaprevir/pibrentasvir (see section 4.5) • Prosthetic heart valves requiring anticoagulant treatment (see section 5.1).

HOS-094864 · has-contraindication-information · PDF-Seite 38

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 • Severe renal impairment (CrCL < 30 mL/min) in adult patients • eGFR < 50 mL/min/1.73 m2 in paediatric patients • Active clinically significant bleeding • Lesion or condition, if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of 38  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, rivaroxaban, apixaban etc) except under specific circumstances. These are switching anticoagulant therapy (see section 4.2), when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see section 4.5) • Hepatic impairment or liver disease expected to have any impact on survival • Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole, dronedarone and the fixed-dose combination glecaprevir/pibrentasvir (see section 4.5) • Prosthetic heart valves requiring anticoagulant treatment (see section 5.1).

HOS-094869 · has-indication-information · PDF-Seite 73

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischemic attack (TIA); age ≥ 75 years; heart failure (NYHA Class ≥ II); diabetes mellitus; hypertension. Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults Treatment of venous thromboembolic events (VTE) and prevention of recurrent VTE in paediatric patients from the time the child is able to swallow soft food to less than 18 years of age. For age appropriate dose forms, see section 4.2.

HOS-094857 · has-indication-information · PDF-Seite 2

Primary prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery. Treatment of VTE and prevention of recurrent VTE in paediatric patients from the time the child is able to swallow soft food to less than 18 years of age. For age appropriate dose forms, see section 4.2.

HOS-094863 · has-indication-information · PDF-Seite 31

Primary prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery. Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischemic attack (TIA); age ≥ 75 years; heart failure (NYHA Class ≥ II); diabetes mellitus; hypertension. Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults Treatment of VTE and prevention of recurrent VTE in paediatric patients fromthe time the child is able to swallow soft food to less than 18 years of age. For age appropriate dose forms, see section 4.2.

HOS-094875 · has-indication-information · PDF-Seite 110

Treatment of venous thromboembolic events (VTE) and prevention of recurrent VTE in paediatric patients from the time the child is able to swallow soft food to less than 18 years of age. For age appropriate dose forms, see section 4.2.

HOS-094866 · has-interaction-information · PDF-Seite 44

Transporter interactions Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (see table 9) is expected to result in increased dabigatran plasma concentrations. If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. Dose reductions may be required in combination with some P-gp inhibitors (see sections 4.2, 4.3, 4.4 and 5.1). Table 9: Transporter interactions P-gp inhibitors Concomitant use contraindicated (see section 4.3) Ketoconazole Ketoconazole increased total dabigatran AUC0-∞ and Cmax values by 2.38-fold and 2.35-fold, respectively, after a single oral dose of 400 mg, and by 2.53-fold and 2.49-fold, respectively, after multiple oral dosing of 400 mg ketoconazole once daily. Dronedarone When dabigatran etexilate and dronedarone were given at the same time total dabigatran AUC0-∞ and Cmax values increased by about 2.4-fold and 2.3-fold, respectively, after multiple dosing of 400 mg dronedarone bid, and about 2.1-fold and 1.9-fold, respectively, after a single dose of 400 mg. Itraconazole, Based on in vitro results a similar effect as with ketoconazole may be expected. cyclosporine Glecaprevir / The concomitant use of dabigatran etexilate with the fixed-dose combination of pibrentasvir the P-gp inhibitors glecaprevir/pibrentasvir has been shown to increase exposure of dabigatran and may increase the risk of bleeding. Concomitant use not recommended Tacrolimus Tacrolimus has been found in vitro to have a similar level of inhibitory effect on P-gp as that seen with itraconazole and cyclosporine. Dabigatran etexilate has not been clinically studied together with tacrolimus. However, limited clinical data with another P-gp substrate (everolimus) suggest that the inhibition of P-gp with tacrolimus is weaker than that observed with strong P-gp inhibitors. 44 Cautions to be exercised in case concomitant use (see sections 4.2 and 4.4) Verapamil When dabigatran etexilate (150 mg) was co-administered with oral verapamil, the Cmax a

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HOS-094872 · has-interaction-information · PDF-Seite 84

Transporter interactions Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (see table 8) is expected to result in increased dabigatran plasma concentrations. If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. Dose reductions may be required in combination with some P-gp inhibitors (see sections 4.2, 4.3, 4.4 and 5.1). Table 8: Transporter interactions P-gp inhibitors Concomitant use contraindicated (see section 4.3) Ketoconazole Ketoconazole increased total dabigatran AUC0-∞ and Cmax values by 2.38-fold and 2.35-fold, respectively, after a single oral dose of 400 mg, and by 2.53-fold and 2.49-fold, respectively, after multiple oral dosing of 400 mg ketoconazole once daily. Dronedarone When dabigatran etexilate and dronedarone were given at the same time total dabigatran AUC0-∞ and Cmax values increased by about 2.4-fold and 2.3-fold, respectively, after multiple dosing of 400 mg dronedarone bid, and about 2.1-fold and 1.9-fold, respectively, after a single dose of 400 mg. Itraconazole, Based on in vitro results a similar effect as with ketoconazole may be expected. cyclosporine Glecaprevir / The concomitant use of dabigatran etexilate with the fixed-dose combination of pibrentasvir the P-gp inhibitors glecaprevir/pibrentasvir has been shown to increase exposure of dabigatran and may increase the risk of bleeding. Concomitant use not recommended Tacrolimus Tacrolimus has been found in vitro to have a similar level of inhibitory effect on P-gp as that seen with itraconazole and cyclosporine. Dabigatran etexilate has not been clinically studied together with tacrolimus. However, limited clinical data with another P-gp substrate (everolimus) suggest that the inhibition of P-gp with tacrolimus is weaker than that observed with strong P-gp inhibitors. Cautions to be exercised in case concomitant use (see sections 4.2 and 4.4) Verapamil When dabigatran etexilate (150 mg) was co-administered with oral verapamil, the Cmax and AUC of dabigatran were increased but the magnitud

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HOS-094878 · has-interaction-information · PDF-Seite 117

Interaction studies have only been performed in adults. Transporter interactions Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (see table 5) is expected to result in increased dabigatran plasma concentrations. If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. See also sections 4.3, 4.4 and 5.1). 117 Table 5: Transporter interactions P-gp inhibitors Concomitant use contraindicated (see section 4.3) Ketoconazole Ketoconazole increased total dabigatran AUC0-∞ and Cmax values by 2.38-fold and 2.35-fold, respectively, after a single oral dose of 400 mg, and by 2.53-fold and 2.49-fold, respectively, after multiple oral dosing of 400 mg ketoconazole once daily. Dronedarone When dabigatran etexilate and dronedarone were given at the same time total dabigatran AUC0-∞ and Cmax values increased by about 2.4-fold and 2.3-fold, respectively, after multiple dosing of 400 mg dronedarone bid, and about 2.1-fold and 1.9-fold, respectively, after a single dose of 400 mg. Itraconazole, Based on in vitro results a similar effect as with ketoconazole may be expected. cyclosporine Glecaprevir / The concomitant use of dabigatran etexilate with the fixed-dose combination of pibrentasvir the P-gp inhibitors glecaprevir/pibrentasvir has been shown to increase exposure of dabigatran and may increase the risk of bleeding. Concomitant use not recommended Tacrolimus Tacrolimus has been found in vitro to have a similar level of inhibitory effect on P-gp as that seen with itraconazole and cyclosporine. Dabigatran etexilate has not been clinically studied together with tacrolimus. However, limited clinical data with another P-gp substrate (everolimus) suggest that the inhibition of P-gp with tacrolimus is weaker than that observed with strong P-gp inhibitors. Cautions to be exercised in case concomitant use (see section 4.4) Verapamil When dabigatran etexilate (150 mg) was co-administered with oral verapamil, the Cmax and AUC of dabigat

Auszug; vollständigen Abschnitt im Original lesen.

HOS-094860 · has-interaction-information · PDF-Seite 11

Transporter interactions Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (see table 7) is expected to result in increased dabigatran plasma concentrations. If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. Dose reductions may be required in combination with some P-gp inhibitors (see sections 4.2, 4.3, 4.4 and 5.1). Table 7: Transporter interactions P-gp inhibitors Concomitant use contraindicated (see section 4.3) Ketoconazole Ketoconazole increased total dabigatran AUC0-∞ and Cmax values by 2.38-fold and 2.35-fold, respectively, after a single oral dose of 400 mg, and by 2.53-fold and 2.49-fold, respectively, after multiple oral dosing of 400 mg ketoconazole once daily. Dronedarone When dabigatran etexilate and dronedarone were given at the same time total dabigatran AUC0-∞ and Cmax values increased by about 2.4-fold and 2.3-fold, respectively, after multiple dosing of 400 mg dronedarone bid, and about 2.1-fold and 1.9-fold, respectively, after a single dose of 400 mg. Itraconazole, Based on in vitro results a similar effect as with ketoconazole may be expected. cyclosporine Glecaprevir / The concomitant use of dabigatran etexilate with the fixed-dose combination of pibrentasvir the P-gp inhibitors glecaprevir/pibrentasvir has been shown to increase exposure of dabigatran and may increase the risk of bleeding. 11 Concomitant use not recommended Tacrolimus Tacrolimus has been found in vitro to have a similar level of inhibitory effect on P-gp as that seen with itraconazole and cyclosporine. Dabigatran etexilate has not been clinically studied together with tacrolimus. However, limited clinical data with another P-gp substrate (everolimus) suggest that the inhibition of P-gp with tacrolimus is weaker than that observed with strong P-gp inhibitors. Cautions to be exercised in case concomitant use (see sections 4.2 and 4.4) Verapamil When dabigatran etexilate (150 mg) was co-administered with oral verapamil, the

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HOS-094879 · has-pregnancy-information · PDF-Seite 121

Women of childbearing potential Women of childbearing potential should avoid pregnancy during treatment with Pradaxa. Pregnancy There is limited amount of data from the use of Pradaxa in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Pradaxa should not be used during pregnancy unless clearly necessary. Breast-feeding There are no clinical data of the effect of dabigatran on infants during breast-feeding. Breast-feeding should be discontinued during treatment with Pradaxa. Fertility No human data available. In animal studies an effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (representing a 5-fold higher plasma exposure level compared to patients). No other effects on female fertility were observed. There was no influence on male fertility (see section 5.3). 121

HOS-094873 · has-pregnancy-information · PDF-Seite 88

Women of childbearing potential Women of childbearing potential should avoid pregnancy during treatment with Pradaxa. Pregnancy There is limited amount of data from the use of Pradaxa in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Pradaxa should not be used during pregnancy unless clearly necessary. Breast-feeding There are no clinical data of the effect of dabigatran on infants during breast-feeding. Breast-feeding should be discontinued during treatment with Pradaxa. Fertility No human data available. In animal studies an effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (representing a 5-fold higher plasma exposure level compared to patients). No other effects on female fertility were observed. There was no influence on male fertility. At doses that were toxic to the mothers (representing a 5- to 10-fold higher plasma exposure level to patients), a decrease in foetal body weight and embryofoetal viability along with an increase in foetal variations were observed in rats and rabbits. In the pre- and post-natal study, an increase in foetal mortality was observed at doses that were toxic to the dams (a dose corresponding to a plasma exposure level 4-fold higher than observed in patients).

HOS-094861 · has-pregnancy-information · PDF-Seite 15

Women of childbearing potential Women of childbearing potential should avoid pregnancy during treatment with Pradaxa. Pregnancy There is limited amount of data from the use of Pradaxa in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Pradaxa should not be used during pregnancy unless clearly necessary. Breast-feeding There are no clinical data of the effect of dabigatran on infants during breast-feeding. Breast-feeding should be discontinued during treatment with Pradaxa. Fertility No human data available. In animal studies an effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (representing a 5-fold higher plasma exposure level compared to patients). No other effects on female fertility were observed. There was no influence on male fertility. At doses that were toxic to the mothers (representing a 5- to 10-fold higher plasma exposure level to patients), a decrease in foetal body weight and embryofoetal viability along with an increase in foetal variations were observed in rats and rabbits. In the pre- and post-natal study, an increase in foetal mortality was observed at doses that were toxic to the dams (a dose corresponding to a plasma exposure level 4-fold higher than observed in patients).

HOS-094867 · has-pregnancy-information · PDF-Seite 48

Women of childbearing potential Women of childbearing potential should avoid pregnancy during treatment with Pradaxa. Pregnancy There is limited amount of data from the use of Pradaxa in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Pradaxa should not be used during pregnancy unless clearly necessary. Breast-feeding There are no clinical data of the effect of dabigatran on infants during breast-feeding. Breast-feeding should be discontinued during treatment with Pradaxa. Fertility No human data available. In animal studies an effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (representing a 5-fold higher plasma exposure level compared to patients). No other effects on female fertility were observed. There was no influence on male fertility. At doses that were toxic to the mothers (representing a 5- to 10-fold higher plasma exposure level to patients), a decrease in foetal body weight and embryofoetal viability along with an increase in foetal variations were observed in rats and rabbits. In the pre- and post-natal study, an increase in foetal mortality was observed at doses that were toxic to the dams (a dose corresponding to a plasma exposure level 4-fold higher than observed in patients).

HOS-094871 · has-warning-information · PDF-Seite 79

Haemorrhagic risk Dabigatran etexilate should be used with caution in conditions with an increased risk of bleeding or with concomitant use of medicinal products affecting haemostasis by inhibition of platelet aggregation. Bleeding can occur at any site during therapy. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site. For adult patients in situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effect of dabigatran is required, the specific reversal agent idarucizumab is available. The efficacy and safety of idarucizumab have not been established in paediatric patients. Haemodialysis can remove dabigatran. For adult patients, fresh whole blood or fresh frozen plasma, coagulation factor concentration (activated or non-activated), recombinant factor VIIa or platelet concentrates are other possible options (see also section 4.9). In clinical trials, dabigatran etexilate was associated with higher rates of major gastrointestinal (GI) bleeding. An increased risk was seen in the elderly (≥ 75 years) for the 150 mg twice daily dose regimen. Further risk factors (see also table 4) comprise co-medication with platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA) or non steroidal antiinflammatory drugs (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux. Risk factors Table 4 summarises factors which may increase the haemorrhagic risk. 79 Table 4: Factors which may increase the haemorrhagic risk. Risk factor Pharmacodynamic and kinetic factors Age ≥ 75 years Factors increasing dabigatran plasma Major: levels • Moderate renal impairment in adult patients (30-50 mL/min CrCL) • Strong P-gp inhibitors (see section 4.3 and 4.5) • Mild to moderate P-gp inhibitor co-medication (e.g. amiodarone, verapamil, quinidine and ticagrelor; see section 4.5) Minor: • Low body weight (< 50 kg) in adult patients Pharmacodynamic int

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HOS-094859 · has-warning-information · PDF-Seite 7

Haemorrhagic risk Dabigatran etexilate should be used with caution in conditions with an increased risk of bleeding or with concomitant use of medicinal products affecting haemostasis by inhibition of platelet aggregation. Bleeding can occur at any site during therapy. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site. For adult patients in situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effect of dabigatran is required, the specific reversal agent idarucizumab is available. The efficacy and safety of idarucizumab have not been established in paediatric patients. Haemodialysis can remove dabigatran. For adult patients, fresh whole blood or fresh frozen plasma, coagulation factor concentration (activated or non-activated), recombinant factor VIIa or platelet concentrates are other possible options (see also section 4.9). Use of platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA) or non steroidal antiinflammatory drugs (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux increase the risk of GI bleeding. Risk factors Table 3 summarises factors which may increase the haemorrhagic risk. Table 3: Factors which may increase the haemorrhagic risk. Risk factor Pharmacodynamic and kinetic factors Age ≥ 75 years Factors increasing dabigatran plasma Major: levels • Moderate renal impairment in adult patients (30-50 mL/min CrCL) • Strong P-gp inhibitors (see section 4.3 and 4.5) • Mild to moderate P-gp inhibitor co-medication (e.g. amiodarone, verapamil, quinidine and ticagrelor; see section 4.5) Minor: • Low body weight (< 50 kg) in adult patients Pharmacodynamic interactions (see • ASA and other platelet aggregation inhibitors such as section 4.5) clopidogrel • NSAIDs • SSRIs or SNRIs

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HOS-094865 · has-warning-information · PDF-Seite 39

Haemorrhagic risk Dabigatran etexilate should be used with caution in conditions with an increased risk of bleeding or with concomitant use of medicinal products affecting haemostasis by inhibition of platelet aggregation. Bleeding can occur at any site during therapy. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site. For adult patients in situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effect of dabigatran is required, the specific reversal agent idarucizumab is available. The efficacy and safety of idarucizumab have not been established in paediatric patients. Haemodialysis can remove dabigatran. For adult patients, fresh whole blood or fresh frozen plasma, coagulation factor concentration (activated or non-activated), recombinant factor VIIa or platelet concentrates are other possible options (see also section 4.9). In clinical trials, dabigatran etexilate was associated with higher rates of major gastrointestinal (GI) bleeding. An increased risk was seen in the elderly (≥ 75 years) for the 150 mg twice daily dose regimen. Further risk factors (see also table 5) comprise co-medication with platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA) or non steroidal antiinflammatory drugs (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux. Risk factors Table 5 summarises factors which may increase the haemorrhagic risk. 39 Table 5: Factors which may increase the haemorrhagic risk. Risk factor Pharmacodynamic and kinetic factors Age ≥ 75 years Factors increasing dabigatran plasma Major: levels • Moderate renal impairment in adult patients (30-50 mL/min CrCL) • Strong P-gp inhibitors (see section 4.3 and 4.5) • Mild to moderate P-gp inhibitor co-medication (e.g. amiodarone, verapamil, quinidine and ticagrelor; see section 4.5) Minor: • Low body

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HOS-094877 · has-warning-information · PDF-Seite 114

Haemorrhagic risk Dabigatran etexilate should be used with caution in conditions with an increased risk of bleeding or with concomitant use of medicinal products affecting haemostasis by inhibition of platelet aggregation. Bleeding can occur at any site during therapy. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site. The efficacy and safety of the specific reversal agent idarucizumab used for adult patients in situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effect of dabigatran is required, have not been established in paediatric patients. Haemodialysis can remove dabigatran. For adult patients, fresh whole blood or fresh frozen plasma, coagulation factor concentration (activated or non-activated), recombinant factor VIIa or platelet concentrates are other possible options (see also section 4.9). Use of platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA) or non steroidal antiinflammatory drugs (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux increase the risk of GI bleeding. Risk factors Table 3 summarises factors which may increase the haemorrhagic risk. Table 3: Risk factors which may increase the haemorrhagic risk. Risk factor Factors increasing dabigatran Major: plasma levels • Strong P-gp inhibitors (see section 4.3 and 4.5) • Mild to moderate P-gp inhibitor co-medication (e.g. amiodarone, verapamil, quinidine and ticagrelor; see section 4.5) Pharmacodynamic interactions • ASA and other platelet aggregation inhibitors such as (see section 4.5) clopidogrel • NSAIDs • SSRIs or SNRIs • Other medicinal products which may impair haemostasis Diseases / procedures with special • Congenital or acquired coagulation disorders haemorrhagic risks • Thrombocytopenia or functional platelet defects • Recent biopsy, major trauma

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