Ventavis 10 microgram/ml nebuliser solution

1 ml solution contains 10 micrograms iloprost (as iloprost trometamol).

Each ampoule with 1 ml solution contains 10 micrograms iloprost.

Each ampoule with 2 ml solution contains 20 micrograms iloprost.

Excipient: Ethanol 96% 0,81 mg per ml.

For a full list of excipients, see section 6.1.

Nebuliser solution.

Clear, colourless solution.

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

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

Ventavis is intended for inhalation use by nebulisation (see section 6.6).

Concomitant therapy should be adjusted to individual needs (see section 4.5 Interaction with other medicaments and other forms of interaction).

Adults

• Dose per inhalation session:

The recommended dose is 2.5 micrograms or 5.0 micrograms of inhaled iloprost (as delivered at the mouthpiece of the nebuliser) , starting with the low dose of 2.5 microgram for the first inhalation, followed by 5.0 micrograms for the second inhalation. In case of poor tolerability of the 5.0 microgram dose, the dose should be reduced to 2.5 micrograms.

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

Venta-Neb, 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 showing two coloured rings (white – pink) will be transferred into the nebuliser medication chamber immediately before use.

Two programs can be operated:

P1 Program 1: 5.0 micrograms active substance on the mouth piece 25 inhalation cycles.

P2 Program 2: 2.5 micrograms 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 is forcing 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 micrograms 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 micrograms dose the medication chamber (350 microlitre) with the red latch is used together with the red control disc.

For the 5 micrograms dose the medication chamber (650 microlitre) 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 VentaNeb devices and a faster delivery of the solution (see section 5.2), patients stabilized 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.

• Daily dose:

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

• Duration of treatment:

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.

Patients with hepatic impairment

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 micrograms should be administered with dosing intervals of at least 3 hours (corresponds to administration of max. 6 times per day). Thereafter, dosing intervals may be shortened cautiously based on individual tolerability. If a further increase in the dose up to 5.0 micrograms is indicated, again dosing intervals of at least 3 hours should be chosen initially and shortened according to individual tolerability. A further undesired accumulation of the medicinal product following treatment over several days is not likely due to the overnight break in administration of the medicinal product.

Patients with renal impairment

There 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.

Paediatric population

There is no experience with Ventavis in children or adolescents.

− Hypersensitivity to the active substance or to any of the excipients.

− Pregnancy and lactation (see section 4.6).

− 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.

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 drugs 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 alert to the presence of concomitant conditions or drugs 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 syncopes 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 Undesirable effects). 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 admninistered 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 at least 3 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 man 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.

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.

Iloprost may increase the effects of vasodilatators and antihypertensive agents and then favour the risk of hypotension (see section 4.4). Should significant hypotension occur this can be corrected by dose reduction of iloprost.

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 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 have to be expected.

Women of child-bearing potential

The potential risk for humans is unknown. Therefore, women of child-bearing potential should use effective contraceptive measures during treatment.

Pregnancy

There are no adequate data from the use of Ventavis in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Iloprost must not be administered to pregnant women (see section 4.3 Contraindications).

Breast-feeding

It is not known whether iloprost/metabolites are excreted in human breast milk. The medicinal product must not be administered to breast feeding mothers (see section 4.3 Contraindications).

Care should be exercised during initiation of therapy until any effects on the individual have been determined. In patients experiencing hypotensive symptoms such as dizziness, the ability to drive or operate machines may be seriously affected.

In addition to local effects resulting from administration of iloprost by inhalation such as increased cough, adverse reactions with iloprost are related to the pharmacological properties of prostacyclins.

The most common adverse reactions seen in clinical trials include vasodilatation (including hypotension), headache and increased cough.

The adverse reactions reported below are based on pooled clinical trial data from phase II and III clinical trials involving 131 patients taking the medication. 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.

* Bleeding events were very common as expected in this patient population with a high proportion of patients taking anticoagulant co-medication (see section 4.5).

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.

• Symptoms

No case of overdose has been reported. 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.

• Therapy

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

Pharmacotherapeutic group: Platelet aggregation inhibitors excluding heparin, ATC code: B01AC11

This medicinal product has been authorised under “Exceptional Circumstances”.

This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.

The European Medicines Agency (EMA) will review any new information which may become available every year and this SPC will be updated as necessary.

Iloprost, the active substance of Ventavis, is a synthetic prostacyclin analogue. The following pharmacological effects have been observed in vitro:

• Inhibition of platelet aggregation, platelet adhesion and release reaction

• Dilatation of arterioles and venules

• Increase of capillary density and reduction of increased vascular permeability caused by mediators such as serotonin or histamine in the microcirculation

• Stimulation of endogenous fibrinolytic potential

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, randomized, 12-week double-blinded phase, 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 (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.

• Efficacy in adult patients with pulmonary hypertension

A randomised, double-blind, multi-centre, placebo-controlled phase III trial (study RRA02997) has been conducted in 203 adult patients (inhaled iloprost: 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 drug 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 micrograms (range 12.5 to 45 micrograms/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.

• Absorption

When iloprost is administered via inhalation in patients with pulmonary hypertension (iloprost dose at the mouthpiece: 5 micrograms), 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).

• Distribution

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 3000 picograms/ml and amounts to approximately 60 %, of which 75 % is due to albumin binding.

• Metabolism

No studies performed following inhalation.

Iloprost is extensively metabolised principally via β-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 in 4 diastereoisomers. 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.

• Elimination

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.

• Pharmacokinetics after use with different nebulisers

In a randomized, crossover study with 20 healthy adult men, pharmacokinetics was investigated following inhalation of Ventavis (5 mcg iloprost) by the I-Neb AAD in comparison to the ProDose (5 mcg 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 nebulizer. The pharmacokinetic results reflect the slightly different in vitro characteristics of these nebulizers (see Section 4.2).

Pharmacokinetic parameters of iloprost after inhalation of 5 mcg iloprost by I-Neb AAD vs. ProDose

AUC(0-tlast) = Area under the concentration time curve from 0h data point up to last measurable serum level

CV = coefficient of variation

• Characteristics in patients

Renal dysfunction:

In a study with intravenous infusion of iloprost, patients with end-stage renal failure undergoing intermittent dialysis treatment are shown to have a significantly lower clearance (mean CL = 5 ± 2 ml/minute/kg) than that observed in patients with renal failure not undergoing intermittent dialysis treatment (mean CL = 18 ± 2 ml/minute/kg).

Hepatic dysfunction:

Because iloprost is extensively metabolised by the liver, the plasma levels of the active substance are influenced by changes in hepatic function. In an intravenous study, results were obtained involving 8 patients suffering from liver cirrhosis. The mean clearance of iloprost is estimated to be 10 ml/minute/kg.

Age and gender:

Age and gender are not of clinical relevance to the pharmacokinetics of iloprost.

• Systemic toxicity

In acute toxicity studies, single intravenous and oral doses of iloprost caused severe symptoms of intoxication or death (IV) at doses about two orders of magnitude above the intravenous therapeutic dose. Considering the high pharmacological potency of iloprost and the absolute doses required for therapeutic purposes the results obtained in acute toxicity studies do not indicate a risk of acute adverse effects in humans. As expected for a prostacyclin, iloprost produced haemodynamic effects (vasodilatation, reddening of skin, hypotension, inhibition of platelet function, respiratory distress) and general signs of intoxication such as apathy, gait disturbances, and postural changes.

Continuous IV/SC infusion of iloprost up to 26 weeks in rodents and non-rodents did not cause any organ toxicity at dose levels which exceeded the human therapeutic systemic exposure between 14 and 47 times (based on plasma levels). Only expected pharmacological effects like hypotension, reddening of skin, dyspnoea, increased intestinal motility were observed.

Based on Cmax values in rats the systemic exposure in these parenteral studies was approximately 3.5 times higher than the maximum achievable exposure after inhalation. This highest achievable dose of 48.7 micrograms/kg/day was also the “no observed adverse effect level” (NOAEL) as evaluated in inhalation toxicity studies in rats up to 26 weeks. Following inhalation the systemic exposure based on AUC values in rats exceeded the corresponding therapeutic exposure in human patients by approximately 13 times.

• Genotoxic potential, tumorigenicity

In vitro (bacterial, mammalian cells, human lymphocytes) and in vivo studies (micronucleus test) for genotoxic effects have not produced any evidence for a mutagenic potential.

No tumorigenic potential of iloprost was observed in tumorigenicity studies in rats and mice.

• Reproduction toxicology

In embryo- and foetotoxicity studies in rats continuous intravenous administration of iloprost led to anomalies of single phalanges of the forepaws in a few foetuses/pups without dose dependence.

These alterations are not considered as true teratogenic effects, but are most likely related to iloprost induced growth retardation in late organogenesis due to haemodynamic alterations in the foetoplacental unit. In comparable embryotoxicity studies in rabbits and monkeys no such digit anomalies or other gross-structural abnormalities were observed.

In rats, passage of extremely low levels of iloprost into the milk was observed.

• Local tolerance, contact sensitising and antigenicity potential

In inhalation studies in rats, the administration of an iloprost formulation with a concentration of 20 micrograms/ml up to 26 weeks did not cause any local irritation of the upper and lower respiratory tract.

A dermal sensitisation (maximisation test) and an antigenicity study in guinea pigs showed no sensitising potential.

Trometamol,

Ethanol 96 %,

Sodium chloride,

Hydrochloric acid (for pH adjustment),

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

2 years.

This medicinal product does not require any special storage conditions.

1-ml ampoules, colourless, glass type I, containing 1 ml nebuliser solution, ring coded with two coloured rings (white - yellow).

3-ml ampoules, colourless, glass type I, containing 2 ml nebuliser solution, ring coded with two coloured rings (white – pink).

1 ml nebuliser solution:

Packages containing 30 or 168 ampoules.

2 ml nebuliser solution:

Packages containing 30, 90, 100 or 300 ampoules.

Not all pack sizes may be marketed.

For each inhalation session the contents of one opened ampoule of Ventavis has to be transferred completely into the nebuliser medication chamber immediately before use.

After each inhalation session, any solution remaining in the nebuliser should be discarded.

Any unused product or waste material should be disposed of in accordance with local requirements.

Bayer Pharma AG

D-13342 Berlin

Germany

EU/1/03/255/001

EU/1/03/255/002

EU/1/03/255/003

EU/1/03/255/004

EU/1/03/255/005

EU/1/03/255/006

EU/1/03/255/007

EU/1/03/255/008

Date of first authorisation: 16 September 2003

Date of last renewal: 16 September 2008

07/2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu/.

Distributed in the United Kingdom by:

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire

RG14 1JA