Ventavis · 4.1 Therapeutic indications · 1

HOS-093556 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile In addition to local effects resulting from administration of iloprost by inhalation such as cough, adverse reactions with iloprost are related to the pharmacological properties of prostacyclins. The most frequently observed adverse reactions ( 20 %) in clinical trials include vasodilatation (including hypotension), headache and cough. The most serious adverse reactions were hypotension, bleeding events, and bronchospasm. Tabulated list of adverse reactions The adverse reactions reported below are based on pooled clinical trial data from phase II and III clinical trials involving 131 patients taking the medicinal product and on data from post-marketing surveillance. The frequencies of adverse reactions are defined as very common (≥1/10) and common (≥1/100 to <1/10). The adverse reactions identified only during post-marketing surveillance, and for which a frequency could not be estimated from clinical trial data, are listed under "Frequency not known". Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 9  System organ class Very common Common Not known (cannot (MedDRA) (1/10) (1/100 to <1/10) be estimated from the available data) Blood and lymphatic system Bleeding events*§ Thrombocytopenia disorders Immune system disorders Hypersensitivity Nervous system disorders Headache Dizziness Cardiac disorders Tachycardia Palpitations Vascular disorders Vasodilatation Syncope§ (see Flushing section 4.4) Hypotension* Respiratory, thoracic and Chest discomfort / Dyspnoea Bronchospasm* (see mediastinal disorders chest pain Pharyngolaryngeal section 4.4) / Cough pain Wheezing Throat irritation Gastrointestinal

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HOS-093552 · has-contraindication-information · PDF-Seite 6

− Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. − Conditions where the effects of Ventavis on platelets might increase the risk of haemorrhage (e.g. active peptic ulcers, trauma, intracranial haemorrhage). − Severe coronary heart disease or unstable angina. − Myocardial infarction within the last six months. − Decompensated cardiac failure if not under close medical supervision. − Severe arrhythmias. − Cerebrovascular events (e.g. transient ischaemic attack, stroke) within the last 3 months. − Pulmonary hypertension due to venous occlusive disease. − Congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to pulmonary hypertension.

HOS-093551 · has-indication-information · PDF-Seite 2

Treatment of adult patients with primary pulmonary hypertension, classified as NYHA functional class III, to improve exercise capacity and symptoms.

HOS-093554 · has-interaction-information · PDF-Seite 8

Iloprost may increase the effects of vasodilatators and antihypertensive agents and then favour the risk of hypotension (see section 4.4). Caution is recommended in case of co-administration of Ventavis with other antihypertensive or vasodilatating agents as dose adjustment might be required. Since iloprost inhibits platelet function its use with the following substances may enhance iloprost- mediated platelet inhibition, thereby increasing the risk of bleeding: • anticoagulants, such as - heparin, - oral anticoagulants (either coumarin-type or direct), • or other inhibitors of platelet aggregation, such as - acetylsalicylic acid, - non-steroidal anti-inflammatory medicinal products, - non-selective phosphodiesterase inhibitors like pentoxifylline, - selective phosphodiesterase 3 (PDE3) inhibitors like cilostazol or anagrelide, - ticlopidine, - clopidogrel, - glycoprotein IIb/IIIa antagonists, like o abciximab, o eptifibatide, o tirofiban, - defibrotide. A careful monitoring of the patients taking anticoagulants or other inhibitors of platelet aggregation according to common medical practice is recommended. Intravenous infusion of iloprost has no effect either on the pharmacokinetics of multiple oral doses of digoxin or on the pharmacokinetics of co-administered tissue plasminogen activator (t-PA) in patients. Although, clinical studies have not been conducted, in vitro studies investigating the inhibitory potential of iloprost on the activity of cytochrome P450 enzymes revealed that no relevant inhibition of drug metabolism via these enzymes by iloprost is to be expected.

HOS-093555 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential Women of childbearing potential should use effective contraceptive measures during treatment with Ventavis. 8 Pregnancy Women with pulmonary hypertension (PH) should avoid pregnancy as it may lead to life-threatening exacerbation of the disease. Animal studies have shown reproductive effects (see section 5.3). There is a limited amount of data from the use of iloprost in pregnant women. If a pregnancy occurs, taking into account the potential maternal benefit, the use of Ventavis during pregnancy may be considered, only following careful benefit-risk evaluation, in those women who choose to continue their pregnancy, despite the known risks of pulmonary hypertension during pregnancy. Breast-feeding It is not known whether iloprost/metabolites are excreted in human breast milk. Very low levels of iloprost into milk were observed in rats (see section 5.3). A potential risk to the breast-feeding child cannot be excluded and it is preferable to avoid breast-feeding during Ventavis therapy. Fertility Animal studies have not shown harmful effect of iloprost on fertility.

HOS-093553 · has-warning-information · PDF-Seite 6

The use of Ventavis is not recommended in patients with unstable pulmonary hypertension, with advanced right heart failure. In case of deterioration or worsening of right heart failure transfer to other medicinal products should be considered. Hypotension Blood pressure should be checked while initiating Ventavis. In patients with low systemic blood pressure and in patients with postural hypotension or receiving medicinal products known to reduce blood pressure levels, care should be taken to avoid further hypotension. Ventavis should not be initiated in patients with systolic blood pressure less than 85 mmHg. Physicians should be alerted to the presence of concomitant conditions or medicinal products that might increase the risk of hypotension and syncope (see section 4.5). Syncope The pulmonary vasodilatory effect of inhaled iloprost is of short duration (one to two hours). Syncope is a common symptom of the disease itself and can also occur under therapy. Patients who experience syncope in association with pulmonary hypertension should avoid any exceptional 6 straining, for example during physical exertion. Before physical exertion it might be useful to inhale. The increased occurrence of syncope can reflect therapeutic gaps, insufficient effectiveness and/or deterioration of the disease. The need to adapt and/or change the therapy should be considered (see section 4.8). Patients with diseases of the respiratory tract Ventavis inhalation might entail the risk of inducing bronchospasm, especially in patients with bronchial hyperactivity (see section 4.8). Moreover, the benefit of Ventavis has not been established in patients with concomitant Chronic Obstructive Pulmonary Disease (COPD) and severe asthma. Patients with concomitant acute pulmonary infections, COPD and severe asthma should be carefully monitored. Pulmonary veno-occlusive disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease. Should signs of pulmonary oedema occur, the possibility of associated pulmonary veno-occlusive disease should be considered and treatment with Ventavis should be discontinued. Interruption of therapy In case of interruption of Ventavis therapy, the risk of rebound effect is not formally excluded. Careful monitoring of the patient should be performed when inhaled iloprost therapy is stopped and an alternative treatment should be c

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