Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Bayer AG, 51368, Leverkusen, Germany
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.
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).
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 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).
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 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.
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 considered in critically ill patients.
Data with intravenously administered iloprost indicated that the elimination is reduced in patients with hepatic dysfunction and in patients with renal failure requiring dialysis (see section 5.2). A cautious initial dose titration using dosing intervals of 3-4 hours is recommended (see section 4.2).
Prolonged oral treatment with iloprost clathrate in dogs up to one year was associated with slightly increased fasted serum glucose levels. It cannot be excluded that this is also relevant to humans on prolonged Ventavis therapy.
To minimise accidental exposure, it is recommended to use Ventavis with nebulisers with inhalation- triggered systems (such as Breelib or I-Neb), and to keep the room well ventilated. Newborns, infants and pregnant women should not be subjected to Ventavis in the room air.
Ventavis nebuliser solution should not come into contact with skin and eyes; oral ingestion of Ventavis solution should be avoided. During nebulisation sessions a facial mask must be avoided and only a mouthpiece should be used.
This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per dose.
Limited data are available on the use of the Breelib nebuliser. For patients being switched from an alternative device to the Breelib nebuliser the first inhalation should be made with Ventavis 10 microgram/ml (1ml ampoule) delivering 2.5 microgram iloprost at the mouthpiece and under close medical supervision to ensure that the faster inhalation provided by Breelib is well tolerated. First dosing with 2.5 microgram should be done even if patients had already been stable on 5 microgram inhaled with an alternative device (see section 4.2).
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:
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.
Women of childbearing potential should use effective contraceptive measures during treatment with Ventavis.
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.
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.
Animal studies have not shown harmful effect of iloprost on fertility.
Ventavis has major influence on the ability to drive and use machines for patients experiencing hypotensive symptoms such as dizziness.
Care should be exercised during initiation of therapy until any effects on the individual have been determined.
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.
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.
Very common: Bleeding events*§
Not known: Thrombocytopenia
Not known: Hypersensitivity
Very common: Headache
Common: Dizziness
Common: Tachycardia, Palpitations
Very common: Vasodilatation, Flushing
Common: Syncope§ (see section 4.4), Hypotension*
Very common: Chest discomfort/chest pain, Cough
Common: Dyspnoea, Pharyngolaryngeal pain, Throat irritation
Not known: Bronchospasm* (see section 4.4)/Wheezing
Very common: Nausea
Common: Diarrhoea, Vomiting, Mouth and tongue irritation including pain
Not known: Dysgeusia
Common: Rash
Very common: Pain in jaw/trismus
Very common: Peripheral oedema§
* Life-threatening and/or fatal cases have been reported.
§ see section "Description of selected adverse reactions"
Bleeding events (mostly epistaxis and haemoptysis) were very common as expected in this patient population with a high proportion of patients taking anticoagulant co-medication. The risk of bleeding may be increased in patients when potential inhibitors of platelet aggregation or anticoagulants are given concomitantly (see section 4.5). Fatal cases included cerebral and intracranial haemorrhage.
Syncope is a common symptom of the disease itself, but can also occur under therapy. The increased occurrence of syncope can be related to the deterioration of the disease or insufficient effectiveness of the product (see section 4.4).
In clinical trials peripheral oedema was reported in 12.2% of patients on iloprost and 16.2% of patients on placebo. Peripheral oedema is a very common symptom of the disease itself, but can also occur under therapy. The occurrence of peripheral oedema can be related to the deterioration of the disease or insufficient effectiveness of the product.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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