1 ml solution contains 10 microgram iloprost (as iloprost trometamol). Each ampoule with 1 ml solution contains 10 microgram iloprost. Each ampoule with 2 ml solution contains 20 microgram iloprost.

PHARMACEUTICAL FORM

CLINICAL PARTICULARS

Posology and method of administration

Ventavis should only be initiated and monitored by a physician experienced in the treatment of pulmonary hypertension.

At initiation of Ventavis treatment the first inhaled dose should be 2.5 microgram iloprost (as delivered at the mouthpiece of the nebuliser). If this dose is well tolerated, dosing should be increased to 5 microgram and maintained at that dose. In case of poor tolerability of the 5 microgram dose, the dose should be reduced to 2.5 microgram.

The dose per inhalation session should be administered 6 to 9 times per day according to the individual need and tolerability.

The duration of treatment depends on clinical status and is left to the physician's discretion. Should patients deteriorate on this treatment intravenous prostacyclin treatment should be considered.

Iloprost elimination is reduced in patients with hepatic dysfunction (see section 5.2). To avoid undesired accumulation over the day, special caution has to be exercised with these patients during initial dose titration. Initially, doses of 2.5 microgram should be administered with dosing intervals of 3-4 hours (corresponds to administration of max. 6 times per day). Thereafter, dosing intervals may be shortened cautiously based on individual tolerability. If a dose up to 5 microgram is indicated, again dosing intervals of 3-4 hours should be chosen initially and shortened according to individual tolerability. An accumulation of iloprost following treatment over several days is not likely due to the overnight break in administration of the medicinal product.

here is no need for dose adaptation in patients with a creatinine clearance >30 ml/min (as determined from serum creatinine using the Cockroft and Gault formula). Patients with a creatinine clearance of

30 ml/min were not investigated in the clinical trials. Data with intravenously administered iloprost indicated that the elimination is reduced in patients with renal failure requiring dialysis. Therefore, the same dosing recommendations as in patients with hepatic impairment (see above) are to be applied.

The safety and efficacy of Ventavis in children aged up to 18 years have not been established. No data from controlled clinical trials are available.

Ventavis is intended for inhalation use by nebulisation. The ready-to-use Ventavis 10 microgram / ml nebulizer solution is administered with a suitable inhalation device (nebuliser) (see section 6.6). Two compressed air nebuliser systems, HaloLite and Prodose, have been shown to be suitable nebulisers for the administration of Ventavis. With both systems the mass median aerodynamic diameter of the aerosol droplet (MMAD) with iloprost was between 2.6 and 2.7 micrometres. For each inhalation session the content of one ampoule containing 2 ml of Ventavis nebuliser solution will be transferred into the nebuliser medication chamber immediately before use. HaloLite and Prodose are dosimetric systems. They stop automatically after the pre-set dose has been delivered. The inhalation time depends on the patient's breathing pattern.

For a dose of 5 microgram iloprost at mouthpiece it is recommended to complete two inhalation cycles with 2.5 microgram pre-set dose program with a filling of one ampoule containing 2 ml Ventavis nebuliser solution, which is marked with two coloured rings (white - pink).

a portable ultrasonic battery-powered nebuliser, has also been shown to be suitable for the administration of Ventavis. The measured MMAD of the aerosol droplets was 2.6 micrometres.

For each inhalation session, the content of one ampoule containing 2 ml Ventavis nebuliser solution and which is marked with two coloured rings (white - pink) will be transferred into the nebuliser medication chamber immediately before use. Two programs can be operated: P1 Program 1: 5 microgram active substance on the mouth piece 25 inhalation cycles. P2 Program 2: 2.5 microgram active substance on the mouth piece 10 inhalation cycles. The selection of the pre-set program is made by the physician. Venta-Neb prompts the patient to inhale by an optical and an acoustic signal. It stops after the pre-set dose has been administered. To obtain the optimal droplet size for the administration of Ventavis the green baffle plate should be used. For details refer to the instruction manual of the Venta-Neb nebuliser.

The I-Neb AAD System is a portable, hand-held, vibrating mesh technology nebuliser system. This system generates droplets by ultrasound, which forces the solution through a mesh. The I-Neb AAD nebuliser has also been shown to be suitable for the administration of Ventavis. The measured MMAD of the aerosol droplets was 2.1 micrometres. This nebuliser monitors the breathing pattern to determine the aerosol pulse time required to deliver the pre-set dose of 2.5 or 5 microgram iloprost. The pre-set dose provided by the I-Neb AAD system is controlled by the medication chamber in combination with a control disc. There are two different colour coded medication chambers. For each medication chamber there is a corresponding colour coded control disc: For the 2.5 microgram dose the medication chamber with the red latch is used together with the red control disc. For the 5 microgram dose the medication chamber with the purple coloured latch is used together with the purple control disc. For each inhalation session with the I-Neb AAD, the content of one 1-ml ampoule of Ventavis, showing two coloured rings (white-yellow), will be transferred into the appropriate nebuliser medication chamber immediately before use.

Since the I-Neb nebuliser has been shown to produce an aerosol with slightly different physical characteristics to those of HaloLite, Prodose and Venta-Neb devices and a faster delivery of the solution (see section 5.2), patients stabilised on one nebuliser should not switch to another nebuliser without supervision by the treating physician. The efficacy and tolerability of inhaled iloprost when administered with other nebulising systems, which provide different nebulisation characteristics of iloprost solution, have not been established.

Contraindications

Special warnings and precautions for use

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. Should signs of pulmonary oedema occur when inhaled iloprost is administered in patients with pulmonary hypertension, the possibility of associated pulmonary veno-occlusive disease should be considered. The treatment should be stopped.

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 HaloLite/Prodose, 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.

Ventavis contains small amounts of ethanol (alcohol) (less than 100 mg per dose).

Interaction with other medicinal products and other forms of interaction

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 anticoagulants (such as heparin, coumarin-type anticoagulants) or other inhibitors of platelet aggregation (such as acetylsalicylic acid, non-steroidal anti-inflammatory medicinal products, ticlopidine, clopidogrel, glycoprotein IIb/IIIa antagonists: abciximab, eptifibatide and tirofiban) may increase 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.

Fertility, pregnancy and lactation

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. Taking into account the potential maternal benefit, the use of Ventavis during pregnancy may be considered 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.

Effects on ability to drive and use machines

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.

Undesirable effects

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 Ventavis 10 microgram/ml and on data from post- marketing surveillance. The frequencies of ADRs are defined as very common (>=1/10) and common (>=1/100 to <1/10). The ADRs 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, undesirable effects are presented in order of decreasing seriousness.

System organ class (MedDRA)	Very common ( 1/10)	Common ( 1/100 to <1/10)	Frequency not known
Blood and lymphatic system disorders	Bleeding events * SS		Thrombocytopenia
Immune system disorders			Hypersensitivity
Nervous system disorders	Headache	Dizziness
Cardiac disorders		Tachycardia, Palpitations
Vascular disorders	Vasodilatation	Syncope SS (see section 4.4), Hypotension *
Respiratory, thoracic and mediastinal disorders	Chest discomfort / chest pain Cough	Dyspnoea Pharyngolaryngeal pain Throat irritation	Bronchospasm * (see section 4.4) / Wheezing
Gastrointestinal disorders	Nausea	Diarrhoea Vomiting Mouth and tongue irritation including pain	Dysgeusia
Skin and subcutaneous tissue disorders		Rash
Musculoskeletal and connective tissue disorders	Pain in jaw/trismus
General disorders and administration site condition	Peripheral oedema SS

* Life-threatening and/or fatal cases have been reported. SS see section "Description of selected adverse reactions" 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 syncopes can be related to the deterioration of the disease or insufficient effectiveness of the product (see section 4.4). 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 of suspected adverse reactions

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.

Overdose

In the case of an overdose hypotensive/vasovagal reaction might be anticipated as well as headache, flushing, nausea, vomiting, and diarrhoea. An increase of blood pressure, bradycardia or tachycardia and limb or back pain might be possible.

A specific antidote is not known. Interruption of the inhalation session, monitoring and symptomatic measures are recommended.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitors excluding heparin, ATC code: B01AC11 Iloprost, the active substance of Ventavis, is a synthetic prostacyclin analogue. The following pharmacological effects have been observed in vitro:

The pharmacological effects after inhalation of Ventavis are: Direct vasodilatation of the pulmonary arterial bed occur with consecutive significant improvement of pulmonary artery pressure, pulmonary vascular resistance and cardiac output as well as mixed venous oxygen saturation. In a small, randomised, 12-week double-blinded, placebo-controlled study (the STEP trial), 34 patients treated with bosentan 125 mg twice per day for at least 16 weeks who were in stable haemodynamic conditions before enrolment, tolerated the addition of inhaled iloprost at the concentration of 10 microgram/ml (up to 5 microgram 6 to 9 times per day during waking hours). The mean daily inhaled dose was 27 microgram and the mean number of inhalations per day was 5.6. The acute adverse effects in patients receiving concomitant bosentan and iloprost were consistent with those observed in the larger experience of the phase 3 study in patients receiving only iloprost. No reliable conclusion could be drawn on efficacy of the association as the sample size was limited and the study was of short duration. No clinical trial data are available comparing directly in intra-patient observations the acute haemodynamic response after intravenous to that after inhaled iloprost. The haemodynamics observed suggest an acute response with preferential effect of inhaled treatment on the pulmonary vessels. The pulmonary vasodilatory effect of each single inhalation levels off within one to two hours. However, the predictive value of these acute haemodynamic data are considered to be of limited value as acute response does not in all cases correlate with long-term benefit of treatment with inhaled iloprost.

A randomised, double-blind, multi-centre, placebo-controlled phase III trial (study RRA02997) has been conducted in 203 adult patients (inhaled iloprost at the concentration of 10 microgram/ml: N=101; placebo n=102) with stable pulmonary hypertension. Inhaled iloprost (or placebo) was added to patients' current therapy, which could include a combination of anticoagulants, vasodilators (e.g. calcium channel blockers), diuretics, oxygen, and digitalis, but not PGI2 (prostacyclin or its analogues). 108 of the patients included were diagnosed with primary pulmonary hypertension, 95 were diagnosed with secondary pulmonary hypertension of which 56 were associated with chronic thromboembolic disease, 34 with connective tissue disease (including CREST and scleroderma) and 4 were considered appetite suppressant medicinal product related. The baseline 6-minute walk test values reflected a moderate exercise limitation: in the iloprost group the mean was 332 metres (median value: 340 metres) and in the placebo group the mean was 315 metres (median value: 321 metres). In the iloprost group, the median daily inhaled dose was 30 microgram (range 12.5 to 45 microgram/day). The primary efficacy endpoint defined for this study, was a combined response criterion consisting of improvement in exercise capacity (6-minute walk test) at 12 weeks by at least 10% versus baseline, and improvement by at least one NYHA class at 12 weeks versus baseline, and no deterioration of pulmonary hypertension or death at any time before 12 weeks. The rate of responders to iloprost was 16.8% (17/101) and the rate of responders in the placebo group was 4.9% (5/102) (p=0.007). In the iloprost group, the mean change from baseline after 12 weeks of treatment in the 6-minute walking distance was an increase of 22 metres (-3.3 metres in the placebo group, no data imputation for death or missing values). In the iloprost group the NYHA class was improved in 26% of patients (placebo: 15%) (p = 0.032), unchanged in 67.7% of patients (placebo: 76%) and deteriorated in 6.3% of patients (placebo: 9%). Invasive haemodynamic parameters were assessed at baseline and after 12 weeks treatment. A subgroup analysis showed that no treatment effect was observed as compared to placebo on the 6-minute walk test in the subgroup of patients with secondary pulmonary hypertension. A mean increase in the 6-minute walk test of 44.7 metres from a baseline mean value of 329 metres vs. a change of -7.4 metres from a baseline mean value of 324 metres in the placebo group (no data imputation for death or missing values) was observed in the subgroup of 49 patients with primary pulmonary hypertension receiving treatment of inhaled iloprost for 12 weeks (46 patients in the placebo group). No study has been performed with Ventavis in children with pulmonary hypertension.

Pharmacokinetic properties

When iloprost at the concentration of 10 microgram/ml is administered via inhalation in patients with pulmonary hypertension (iloprost dose at the mouthpiece: 5 microgram: inhalation time in between 4.6 - 10.6 min), peak serum levels of 100 to 200 picograms/ml were observed at the end of inhalation session. These levels decline with half-lives between approximately 5 and 25 minutes. Within 30 minutes to 1 hour after the end of inhalation, iloprost is not detectable in the central compartment (limit of quantification 25 picograms/ml).

No studies performed following inhalation. Following intravenous infusion, the apparent steady-state volume of distribution was 0.6 to 0.8 l/kg in healthy subjects. Total plasma protein binding of iloprost is concentration-independent in the range of 30 to 3,000 picograms/ml and amounts to approximately 60%, of which 75% is due to albumin binding.

No studies to investigate the metabolism of iloprost were performed following inhalation of Ventavis. After intravenous administration, iloprost is extensively metabolised via ss-oxidation of the carboxyl side chain. No unchanged substance is eliminated. The main metabolite is tetranor-iloprost, which is found in the urine in free and conjugated form. Tetranor-iloprost is pharmacologically inactive as shown in animal experiments. Results of in vitro studies reveal that CYP 450-dependent metabolism plays only a minor role in the biotransformation of iloprost. Further in vitro studies suggest that metabolism of iloprost in the lungs is similar after intravenous administration or inhalation.

No studies performed following inhalation. In subjects with normal renal and hepatic function, the disposition of iloprost following intravenous infusion is characterised in most cases by a two-phase profile with mean half-lives of 3 to 5 minutes and 15 to 30 minutes. The total clearance of iloprost is about 20 ml/kg/min, which indicates extrahepatic contribution to the metabolism of iloprost. A mass-balance study was done using 3H-iloprost in healthy subjects. Following intravenous infusion, the recovery of total radioactivity is 81 %, and the respective recoveries in urine and faeces are 68% and 12%. The metabolites are eliminated from plasma and urine in 2 phases, for which half-lives of about 2 and 5 hours (plasma) and 2 and 18 hours (urine) have been calculated.

In a randomised, crossover study with 20 healthy adult men, pharmacokinetics was investigated following inhalation of Ventavis (5 microgram iloprost) by the I-Neb AAD in comparison to the Prodose (5 microgram disk). Higher maximum serum level (Cmax) and systemic exposure (AUC(0-tlast)) as well as a shorter time to reach maximum serum concentration (tmax) were found following Ventavis inhalation via the I-Neb AAD in comparison to the Prodose nebuliser. The pharmacokinetic results reflect the slightly different in vitro characteristics of these nebulisers (see section 4.2).

Device	Dose of iloprost at mouthpiece	Estimated inhalation time (frequency of 15 breaths per minute)
HaloLite and Prodose	2.5 microgram 5 microgram	4 to 5 min 8 to 10 min

Device	Dose of iloprost at mouthpiece	Estimated Inhalation time
Venta-Neb	2.5 microgram 5 microgram	4 min 8 min

Device	Dose of iloprost at mouthpiece	Estimated Inhalation time
I-Neb AAD	2.5 microgram 5 microgram	3.2 min 6.5 min

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION