Leitlinien & Arzneimittelsicherheit

HOS-096672 · has-adverse-reaction-information · PDF-Seite 33

Summary of the safety profile The safety of riociguat in adults has been evaluated in phase III studies of 650 patients patients with CTEPH and PAH receiving at least one dose of riociguat (see section 5.1). With longer observation in uncontrolled long term extension studies the safety profile was similar to that observed in the placebo controlled phase III trials. Most of the adverse reactions are caused by relaxation of smooth muscle cells in vasculature or the gastrointestinal tract. The most commonly reported adverse reactions, occurring in ≥ 10% of patients under riociguat treatment (up to 2.5 mg 3 times daily), were headache, dizziness, dyspepsia, peripheral oedema, nausea, diarrhoea and vomiting. 33 Serious haemoptysis and pulmonary haemorrhage, including cases with fatal outcome have been observed in patients with CTEPH or PAH treated with riociguat (see section 4.4). The safety profile of riociguat in patients with CTEPH and PAH appeared to be similar, therefore adverse reactions identified from placebo controlled 12 and 16 weeks clinical studies are presented as pooled frequency in the table listed below (see table 3). Tabulated list of adverse reactions The adverse reactions reported with riociguat are listed in the table below by MedDRA system organ class and by frequency. Frequencies are defined as: 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) and not known (cannot be estimated from the available data). Table 3: Adverse reactions reported with riociguat in adult patients in phase III studies (pooled CHEST 1 and PATENT 1 data) MedDRA Very common Common Uncommon System Organ Class Infections and infestations Gastroenteritis Blood and lymphatic Anaemia (incl. respective system disorders laboratory parameters) Nervous system disorders Dizziness, Headache Cardiac disorders Palpitations Vascular disorders Hypotension Respiratory, thoracic and Haemoptysis, Pulmonary mediastinal disorders Epistaxis, haemorrhage*

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HOS-096666 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The safety of riociguat in adults has been evaluated in phase III studies of 650 patients with CTEPH and PAH receiving at least one dose of riociguat (see section 5.1). With longer observation in 10 uncontrolled long term extension studies the safety profile was similar to that observed in the placebo controlled phase III trials. Most of the adverse reactions are caused by relaxation of smooth muscle cells in vasculature or the gastrointestinal tract. The most commonly reported adverse reactions, occurring in ≥ 10% of patients under riociguat treatment (up to 2.5 mg 3 times daily), were headache, dizziness, dyspepsia, peripheral oedema, nausea, diarrhoea and vomiting. Serious haemoptysis and pulmonary haemorrhage, including cases with fatal outcome have been observed in patients with CTEPH or PAH treated with riociguat (see section 4.4). The safety profile of riociguat in patients with CTEPH and PAH appeared to be similar, therefore adverse reactions identified from placebo controlled 12 and 16 weeks clinical studies are presented as pooled frequency in the table listed below (see table 1). Tabulated list of adverse reactions The adverse reactions reported with riociguat are listed in the table below by MedDRA system organ class and by frequency. Frequencies are defined as: 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) and not known (cannot be estimated from the available data). Table 1: Adverse reactions reported with riociguat in adult patients in phase III studies (pooled CHEST 1 and PATENT 1 data) MedDRA Very common Common Uncommon System Organ Class Infections and infestations Gastroenteritis Blood and lymphatic Anaemia (incl. respective system disorders laboratory parameters) Nervous system disorders Dizziness, Headache Cardiac disorders Palpitations Vascular disorders Hypotension Respiratory, thoracic and Haemoptysis, Pulmonary mediastinal disorders Epistaxis, haemorrhage*

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HOS-096668 · has-contraindication-information · PDF-Seite 29

- Co-administration with PDE5 inhibitors (such as sildenafil, tadalafil, vardenafil) (see sections 4.2 and 4.5). - Severe hepatic impairment (Child Pugh C). - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Pregnancy (see sections 4.4; 4.5 and 4.6). - Co-administration with nitrates or nitric oxide donors (such as amyl nitrite) in any form including recreational drugs called ‘poppers’ (see section 4.5). - Concomitant use with other soluble guanylate cyclase stimulators. - Treatment initiation for o children aged 6 to < 12 years with systolic blood pressure < 90 mmHg, o patients ≥ 12 to < 18 years with systolic blood pressure < 95 mmHg. - Patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH- IIP) (see section 5.1).

HOS-096662 · has-contraindication-information · PDF-Seite 6

- Co-administration with PDE5 inhibitors (such as sildenafil, tadalafil, vardenafil) (see sections 4.2 and 4.5). - Severe hepatic impairment (Child Pugh C). - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Pregnancy (see sections 4.4; 4.5 and 4.6). - Co-administration with nitrates or nitric oxide donors (such as amyl nitrite) in any form including recreational drugs called ‘poppers’ (see section 4.5). - Concomitant use with other soluble guanylate cyclase stimulators. - Treatment initiation for o children aged 6 to < 12 years with systolic blood pressure < 90 mmHg, o patients ≥ 12 years with systolic blood pressure < 95 mmHg. - Patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH- IIP) (see section 5.1).

HOS-096667 · has-indication-information · PDF-Seite 25

Adempas is indicated for the treatment of pulmonary arterial hypertension (PAH) in paediatric patients aged 6 to less than 18 years with WHO Functional Class (FC) II to III in combination with endothelin receptor antagonists (see section 5.1).

HOS-096661 · has-indication-information · PDF-Seite 3

Chronic thromboembolic pulmonary hypertension (CTEPH) Adempas is indicated for the treatment of adult patients with WHO Functional Class (FC) II to III with • inoperable CTEPH, • persistent or recurrent CTEPH after surgical treatment, to improve exercise capacity (see section 5.1). Pulmonary arterial hypertension (PAH) Adults Adempas, as monotherapy or in combination with endothelin receptor antagonists, is indicated for the treatment of adult patients with pulmonary arterial hypertension (PAH) with WHO Functional Class (FC) II to III to improve exercise capacity (see section 5.1). Paediatrics Adempas is indicated for the treatment of PAH in paediatric patients aged 6 to less than 18 years with WHO Functional Class (FC) II to III in combination with endothelin receptor antagonists (see section 5.1).

HOS-096664 · has-interaction-information · PDF-Seite 7

Interaction studies have been performed only in adults. Therefore, the absolute extent of interactions in the paediatric population is not known. The interaction data obtained in adults and the warnings in section 4.4 should be taken into account for the paediatric population. 7 Pharmacodynamic interactions Nitrates In a clinical study the highest dose of riociguat (2.5 mg tablets 3 times daily) potentiated the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) taken 4 and 8 hours after intake. Therefore co-administration of riociguat with nitrates or nitric oxide donors (such as amyl nitrite) in any form, including recreational drugs called ‘poppers’, is contraindicated (see section 4.3). PDE5 inhibitors Preclinical studies in animal models showed additive systemic blood pressure lowering effect when riociguat was combined with either sildenafil or vardenafil. With increased doses, over additive effects on systemic blood pressure were observed in some cases. In an exploratory interaction study in 7 patients with PAH on stable sildenafil treatment (20 mg 3 times daily) single doses of riociguat (0.5 mg and 1 mg sequentially) showed additive haemodynamic effects. Doses above 1 mg riociguat were not investigated in this study. A 12 week combination study in 18 patients with PAH on stable sildenafil treatment (20 mg 3 times daily) and riociguat (1.0 mg to 2.5 mg 3 times daily) compared to sildenafil alone was performed. In the long term extension part of this study (non controlled) the concomitant use of sildenafil and riociguat resulted in a high rate of discontinuation, predominately due to hypotension. There was no evidence of a favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors (such as sildenafil, tadalafil, vardenafil) is contraindicated (see sections 4.2 and 4.3). RESPITE was a 24-week, uncontrolled study to investigate switching from PDE5 inhibitors to riociguat, in 61 adult PAH patients on stable PDE5 inhibitors. All patients were WHO Functional Class III and 82% received background therapy with an endothelin receptor antagonist (ERA). For the transition from PDE5 inhibitors to riociguat, median treatment-free time for sildenafil was 1 day and for tadalafil 3 days. Overall, the safety profile observed in the study was comparable with that observed in the pivotal trials, with no serious adverse reactions r

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HOS-096670 · has-interaction-information · PDF-Seite 30

Interaction studies have been performed only in adults. Therefore, the absolute extent of interactions in the paediatric population is not known. The interaction data obtained in adults and the warnings in section 4.4 should be taken into account for the paediatric population. Pharmacodynamic interactions Nitrates In a clinical study the highest dose of riociguat (2.5 mg tablets 3 times daily) potentiated the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) taken 4 and 8 hours after intake. Therefore co-administration of riociguat with nitrates or nitric oxide donors (such as amyl nitrite) in any form, including recreational drugs called ‘poppers’, is contraindicated (see section 4.3). 30 PDE5 inhibitors Preclinical studies in animal models showed additive systemic blood pressure lowering effect when riociguat was combined with either sildenafil or vardenafil. With increased doses, over additive effects on systemic blood pressure were observed in some cases. In an exploratory interaction study in 7 patients with PAH on stable sildenafil treatment (20 mg 3 times daily) single doses of riociguat (0.5 mg and 1 mg sequentially) showed additive haemodynamic effects. Doses above 1 mg riociguat were not investigated in this study. A 12 week combination study in 18 patients with PAH on stable sildenafil treatment (20 mg 3 times daily) and riociguat (1.0 mg to 2.5 mg 3 times daily) compared to sildenafil alone was performed. In the long term extension part of this study (non controlled) the concomitant use of sildenafil and riociguat resulted in a high rate of discontinuation, predominately due to hypotension. There was no evidence of a favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors (such as sildenafil, tadalafil, vardenafil) is contraindicated (see sections 4.2 and 4.3). RESPITE was a 24-week, uncontrolled study to investigate switching from PDE5 inhibitors to riociguat, in 61 adult PAH patients on stable PDE5 inhibitors. All patients were WHO Functional Class III and 82% received background therapy with an endothelin receptor antagonist (ERA). For the transition from PDE5 inhibitors to riociguat, median treatment-free time for sildenafil was 1 day and for tadalafil 3 days. Overall, the safety profile observed in the study was comparable with that observed in the pivotal trials, with no serious adverse reactions rep

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HOS-096665 · has-pregnancy-information · PDF-Seite 10

Women of childbearing potential / Contraception Women and female adolescents of childbearing potential must use effective contraception during treatment with riociguat. Pregnancy There are no data from the use of riociguat in pregnant women. Studies in animals have shown reproductive toxicity and placental transfer (see section 5.3). Therefore, riociguat is contraindicated during pregnancy (see section 4.3). Monthly pregnancy tests are recommended. Breast-feeding No data on the use of riociguat in breast-feeding women are available. Data from animals indicate that riociguat is excreted into milk. Due to the potential for serious adverse reactions in breast-fed infants riociguat should not be used during breast-feeding. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with this medicinal product. Fertility No specific studies with riociguat in humans have been conducted to evaluate effects on fertility. In a reproduction toxicity study in rats, decreased testes weights were seen, but there were no effects on fertility (see section 5.3). The relevance of this finding for humans is unknown.

HOS-096671 · has-pregnancy-information · PDF-Seite 33

Women of childbearing potential / Contraception Women and female adolescent of childbearing potential must use effective contraception during treatment with riociguat. Pregnancy There are no data from the use of riociguat in pregnant women. Studies in animals have shown reproductive toxicity and placental transfer (see section 5.3). Therefore, riociguat is contraindicated during pregnancy (see section 4.3). Monthly pregnancy tests are recommended. Breast-feeding No data on the use of riociguat in breast-feeding women are available. Data from animals indicate that riociguat is excreted into milk. Due to the potential for serious adverse reactions in breast-fed infants riociguat should not be used during breast-feeding. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with this medicinal product. Fertility No specific studies with riociguat in humans have been conducted to evaluate effects on fertility. In a reproduction toxicity study in rats, decreased testes weights were seen, but there were no effects on fertility (see section 5.3). The relevance of this finding for humans is unknown.

HOS-096663 · has-warning-information · PDF-Seite 6

In pulmonary arterial hypertension, studies with riociguat have been mainly performed in forms related to idiopathic or heritable PAH and PAH associated with connective tissue disease. The use of riociguat in other forms of PAH not studied is not recommended (see section 5.1). In chronic thromboembolic pulmonary hypertension, pulmonary endarterectomy is the treatment of choice as it is a potentially curative option. According to standard medical practice, expert assessment of operability should be done prior to treatment with riociguat. Pulmonary veno-occlusive disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of riociguat to such patients is not recommended. Should signs of pulmonary oedema occur, the possibility of associated PVOD should be considered and treatment with riociguat should be discontinued. Respiratory tract bleeding In pulmonary hypertension patients there is increased likelihood for respiratory tract bleeding, particularly among patients receiving anticoagulation therapy. A careful monitoring of patients taking anticoagulants according to common medical practice is recommended. The risk of serious and fatal respiratory tract bleeding may be further increased under treatment with riociguat, especially in the presence of risk factors, such as recent episodes of serious haemoptysis including those managed by bronchial arterial embolisation. Riociguat should be avoided in patients with a history of serious haemoptysis or who have previously undergone bronchial arterial embolisation. In case of respiratory tract bleeding, the prescriber should regularly assess the benefit- risk of treatment continuation. Serious bleeding occurred in 2.4% (12/490) of patients taking riociguat compared to 0/214 of placebo patients. Serious haemoptysis occurred in 1% (5/490) patients taking riociguat compared to 0/214 patients taking placebo, including one event with fatal outcome. Serious haemorrhagic events also included 2 patients with vaginal haemorrhage, 2 with catheter site haemorrhage, and 1 each with subdural haematoma, haematemesis, and intra-abdominal haemorrhage. Hypotension Riociguat has vasodilatory properties which may result in lowering of blood pressure. Before prescribing riociguat, physicians should carefully consider whether patients with certain underlying conditions, could be adversely affected by vasodilatory effects (e.

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HOS-096669 · has-warning-information · PDF-Seite 29

In pulmonary arterial hypertension, studies with riociguat have been mainly performed in forms related to idiopathic or heritable PAH and PAH associated with connective tissue disease. The use of riociguat in other forms of PAH not studied is not recommended (see section 5.1). Pulmonary veno-occlusive disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of riociguat to such patients is not recommended. Should signs of pulmonary oedema occur, the possibility of associated PVOD should be considered and treatment with riociguat should be discontinued. Respiratory tract bleeding In pulmonary hypertension patients there is increased likelihood for respiratory tract bleeding, particularly among patients receiving anticoagulation therapy. A careful monitoring of patients taking anticoagulants according to common medical practice is recommended. The risk of serious and fatal respiratory tract bleeding may be further increased under treatment with riociguat, especially in the presence of risk factors, such as recent episodes of serious haemoptysis including those managed by bronchial arterial embolisation. Riociguat should be avoided in patients with a history of serious haemoptysis or who have previously undergone bronchial arterial embolisation. In case of respiratory tract bleeding, the prescriber should regularly assess the benefit- risk of treatment continuation. Serious bleeding occurred in 2.4% (12/490) of patients taking riociguat compared to 0/214 of placebo patients. Serious haemoptysis occurred in 1% (5/490) patients taking riociguat compared to 0/214 patients taking placebo, including one event with fatal outcome. Serious haemorrhagic events also included 2 patients with vaginal haemorrhage, 2 with catheter site haemorrhage, and 1 each with subdural haematoma, haematemesis, and intra-abdominal haemorrhage. Hypotension Riociguat has vasodilatory properties which may result in lowering of blood pressure. Before prescribing riociguat, physicians should carefully consider whether patients with certain underlying conditions, could be adversely affected by vasodilatory effects (e.g. patients on antihypertensive therapy or with resting hypotension, hypovolaemia, severe left ventricular outflow obstruction or autonomic dysfunction). Riociguat must not be used in patients with a systolic blood pressure below 95 mmHg (see section 4.3).

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