Ventavis 10 microgram/ml nebuliser solution

Excipients warning

manufacturer address update

date of revision

Excipients Warning

HPRA reporting details

Summary of changes

**part of this SPC update was the merging of the 20 mcg/ml and 10 mcg/ml SPC (merged information not tracked below). All other changes are tracked below****

[…]

4.2     Posology and method of administration

 

Drug product	Suitable inhalation device (nebuliser) to be used
Ventavis 10 microgram/ml	Breelib	I-Neb AAD	Venta-Neb
Ventavis 20 microgram/ml	Breelib	I-Neb AAD

 

[…]

Posology

Dose per inhalation session

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 iloprost and maintained at that dose. In case of poor tolerability of the 5 microgram dose, the dose should be reduced to 2.5 microgram iloprost.

[…]

Special populations

Patients with hHepatic 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 microgram iloprost should be administered using Ventavis 10 microgram/ml 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 iloprost 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.

 

[…]

Patients with rRenal impairment

[…]

Method of administration

Ventavis is intended for inhalation use by nebulisation. The ready to use Ventavis 10 microgram / ml nebuliser 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. To minimize accidental exposure it is recommended to keep the room well ventilated.

The ready-to-use Ventavis nebuliser solution is administered with a suitable inhalation device (nebuliser) (see below and section 6.6).

Patients stabilised on one nebuliser should not switch to another nebuliser without supervision by the treating physician as different nebulisers have been shown to produce aerosols with slightly different physical characteristics and delivery of the solution that may be faster (see section 5.2).

·                Breelib

Breelib is a small handheld, battery-powered, breath activated, vibrating mesh technology system.

Ventavis 10 microgram/ml (1 ml ampoule) and Ventavis 20 microgram/ml nebuliser solution

Ventavis 10 microgram/ml nebuliser solution (1 ml ampoule) delivers 2.5 microgram and Ventavis 20 microgram/ml nebuliser solution delivers 5 microgram at the mouthpiece of the Breelib nebuliser.

At initiation of Ventavis treatment or if the patient is switched from an alternative device, the first inhalation should be made with 1 ml ampoule of Ventavis 10 microgram/ml (see section 4.4). If inhalation with Ventavis 10 microgram/ml is well tolerated, the dose should be increased by using Ventavis 20 microgram/ml. This dose should be maintained. In case of poor tolerability of Ventavis 20 microgram/ml, the dose should be reduced by using 1 ml ampoule of Ventavis 10 microgram/ml (see section 4.4).

The duration of an inhalation session with Breelib nebuliser is approximately 3 minutes, which reflects the higher delivery rate of the Breelib compared to other nebulisers.

Patients initiating Ventavis treatment or switching from an alternative device to Breelib should be closely supervised by the treating physician to ensure that dose and speed of inhalation are well tolerated.

When using the Breelib nebuliser please follow the instructions for use provided with the device. Fill the medication chamber with Ventavis immediately before use.

·                I-Neb AAD

 

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 been shown to be suitable for the administration of Ventavis 10 microgram/ml (1 ml ampoule) and 20 microgram/ml nebuliser solution. The Mass Median Aerodynamic Diameter (MMAD) of the aerosol measured using I-Neb nebulising systems equipped with power level 10 disc was similar between Ventavis 20 microgram/ml (golden programme) and Ventavis 10 microgram/ml (purple programme) nebuliser solutions (i.e.: around 2 micrometres) but with faster delivery when using Ventavis 20 microgram/ml.

The dose delivered by the I-Neb AAD system is controlled by the medication chamber in combination with a control disc. Each medication chamber is colour coded and has a corresponding colour coded control disc.

Ventavis 10 microgram/ml nebuliser solution (1 ml ampoule)

At initiation of Ventavis treatment with I-Neb system the first inhaled dose should be 2.5 microgram iloprost as delivered at the mouthpiece of the nebuliser using 1 ml ampoule of Ventavis 10 microgram/ml. If this dose is well tolerated, dosing should be increased to 5 microgram iloprost using 1 ml ampoule of Ventavis 10 microgram/ml and maintained at that dose. In case of poor tolerability of the 5 microgram dose, the dose should be reduced to 2.5 microgram iloprost.

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.

For the 2.5 microgram dose of Ventavis 10 microgram/ml the medication chamber with the red coloured latch is used together with the red control disc.

For the 5 microgram dose of Ventavis 10 microgram/ml 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 containing 2 ml of Ventavis nebuliser solution will be 10 microgram/ml, with two coloured rings (white - yellow), is  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.

 

Drug product	Ampoule coloured ring	Dosage	I-Neb AAD		Estimated inhalation time
			Medication chamber latch	Control disc
Ventavis 10 mcg/ml	1 ml ampoule white ‑ yellow ring	2.5 mcg	red	red	3.2 min
		5 mcg	purple	purple	6.5 min

 

Ventavis 20 microgram/ml nebuliser solution

Only patients who are maintained at the 5 microgram dose and who have repeatedly experienced extended inhalation times with Ventavis 10 microgram/ml, which could result in incomplete inhalation, may be considered suitable for switching to Ventavis 20 microgram/ml.

 

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

 

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)

Close supervision by the treating physician is necessary if switching from Ventavis 10 microgram/ml to Ventavis 20 microgram/ml to control the acute tolerance relating to faster delivery rate of iloprost with the double concentration.

This nebuliser monitors the breathing pattern to determine the aerosol pulse time required to deliver the pre-set dose of 5 microgram iloprost.

For the 5 microgram dose of Ventavis 20 microgram/ml the medication chamber with the gold coloured latch is used together with the gold control disc.

For each inhalation session with the I-Neb AAD, the content of one 1 ml ampoule of Ventavis 20 microgram/ml with two coloured rings (yellow - red), is transferred into the medication chamber immediately before use.

 

Drug product	Ampoule coloured rings	Dosage	I-Neb AAD
			Medication chamber latch	Control disc
Ventavis 20 mcg/ml	1 ml ampoule yellow ‑ red ring	5 mcg	golden	golden

 

·                Venta-Neb

 

Venta-Neb, a portable ultrasonic battery-powered nebuliser, has also been shown to be suitable for the administration of Ventavis 10 microgram/ml nebuliser solution (2 ml ampoule). The measured MMAD of the aerosol droplets was 2.6 micrometres.

 

At initiation of Ventavis treatment with Venta-Neb the first inhaled dose should be 2.5 microgram iloprost as delivered at the mouthpiece of the nebuliser using 2 ml ampoule of Ventavis 10 microgram/ml. If this dose is well tolerated, dosing should be increased to 5 microgram iloprost using 2 ml ampoule of Ventavis 10 microgram/ml and maintained at that dose. In case of poor tolerability of the 5 microgram dose, the dose should be reduced to 2.5 microgram iloprost.

 

For each inhalation session with the Venta-Neb, the content of one 2 ml ampoule containing 2 ml of Ventavis 10 microgram/ml nebuliser solution and which is marked with two coloured rings (white – pink) will be is transferred into the nebuliser medication chamber immediately before use.

 

Two programmes can be operated:

P1 Programme 1: 5 microgram active substance on the mouth piece 25 inhalation cycles.

P2 Programme 2: 2.5 microgram active substance on the mouth piece 10 inhalation cycles.

The selection of the pre-set programme 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 10 microgram/ml nebuliser solution the green baffle plate should be used. For details refer to the instruction manual of the Venta-Neb nebuliser.

 

Drug product Device	Ampoule coloured ring	Dose of iloprost at mouthpiece	Estimated iInhalation time
Ventavis 10 mcg/ml Venta Neb	2 ml ampoule white ‑ pink ring	2.5 mcg micorgram 5 mcg micorgram	4 min 8 min

 

Other nebulising systems

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 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 5 microgram dose the medication chamber with the purple coloured latch is used together with the purple controlled 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.

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

 

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 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.

[..]

Undesirable exposure to Ventavis

To minimise accidental exposure, it is recommended to use Ventavis with nebulisers with inhalation-triggered systems (such as Breelib or 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 contains ethanol

 

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

 

Switching to the Breelib nebuliser

 

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).

 

4.5     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 the following substances may enhance iloprost-mediated platelet inhibition, thereby increasing the risk of bleeding:

·                anticoagulants, (such as

-                 heparin,

-                 coumarin type 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    and tirofiban,) may increase the risk of bleeding

-                 defibrotide.

 

A careful monitoring of the patients taking anticoagulants or other inhibitors of platelet aggregation according to common medical practice is recommended.

[…]

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

 

[..]

System organ class (MedDRA)	Very common (³1/10)	Common (³1/100 to <1/10)	Frequency nNot known (cannot be estimated from the available data)

[..]

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).

 

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.

[…]

Paediatric population

No study has been performed with Ventavis in children with pulmonary hypertension.

5.2     Pharmacokinetic properties

 

Absorption

 

When iloprost at the concentration of 10 microgram/ml is administered via inhalation in patients with pulmonary hypertension or healthy volunteers (iloprost dose at the mouthpiece: 5 microgram: inhalation time in between 4.6 – 10.6 min), mean peak serum concentrations levels of about 100 to 200 picograms/ml were observed at the end of inhalation session. These concentrations levelsdecline with half-lives between approximately 5 and 25 minutes. Within 30 minutes to 1 2 hours 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 3,000 picograms/ml and amounts to approximately 60%, of which 75% is due to albumin binding.

[…]

Breelib nebuliser:

Pharmacokinetics of iloprost were investigated in a randomised, crossover study with 27 patients, stable on Ventavis 10 microgram/ml inhaled with I-Neb, following inhalation of single doses of 2.5 or 5 microgram iloprost using the Breelib or the I-Neb AAD nebuliser. Following inhalation of these doses with the Breelib the maximum plasma concentrations (Cmax) and systemic exposures (AUC (0–tlast)) increased dose-proportionally.

Cmax and AUC (0–tlast) after inhalation of 5 microgram iloprost administered as Ventavis 20 microgram/ml using the Breelib were 77% and 42%, respectively higher compared to inhalation of the same dose using Ventavis 10 microgram/ml and the I-Neb AAD system. Cmax and AUC (0–tlast) of iloprost after inhalation with Breelib were, however, still in the range of values observed with Ventavis 10 microgram/ml using other inhalers across different studies.

 

I-Neb AAD nebuliser:

Pharmacokinetics under the specific study conditions of extended inhalation time, were investigated in a randomised, crossover study with 19 healthy adult men following inhalation of single doses of Ventavis 10 microgram/ml and Ventavis 20 microgram/ml (dose of 5 microgram iloprost at the mouthpiece) using the I-Neb. Comparable systemic exposures (AUC (0–tlast)) and approximately 30% higher maximum serum concentrations (Cmax) were found following inhalation of Ventavis 20 microgram/ml compared to Ventavis 10 microgram/ml which was in line with the observed shorter inhalation time using Ventavis 20 microgram/ml.

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).

Pharmacokinetic parameters of iloprost after inhalation of 5 micorgram iloprost by I-Neb AAD vs. Prodose

	Cmax (pg/mL) geometric mean (CV%)	t max (h), median (range)	AUC(0 tlast) (pg h/mL) geometric mean (CV%)
I Neb Prodose	119 (41.2%) 80.0 (46.7%)	0.147(0.086    0.268) 0.183(0.133    0.279)	28.9 (47.4%) 18.7 (50.5%)

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

CV- coefficient of variation.

Other special populations

 

Renal impairment 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 impairment 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 gGender

Gender is not of clinical relevance to the pharmacokinetics of iloprost. No pharmacokinetic data are available in elderly patients

Elderly

Pharmacokinetics in elderly patients have not been investigated.

 

5.3       Preclinical safety data

 

Systemic toxicity

 

In acute toxicity studies, single intravenous and oral doses of iloprost caused severe symptoms of intoxication or death (intravenous 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 intravenous/subcutaneous 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.

 

In a chronic inhalation study in rats over 26 weeks, the highest achievable dose of 48.7 microgram/kg/day was identified as ‘no observed adverse effect level’ (NOAEL). Systemic exposures exceeded human therapeutic exposures after inhalation by factors of more than 10 (C_max, cumulative AUC).

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. The highest achievable dose of 48.7 microgram/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, tumourigenicity

 

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 tumourigenic potential of iloprost was observed in tumourigenicity studies in rats and mice.

 

Reproduction Reproductive toxicology

[…]

6.5       Nature and contents of container

Ventavis 10 microgram/ml nebuliser solution

[…]

Ampoules with 1 ml nebuliser solution (for the use of Breelib or I-Neb AAD):

Packages containing 30,42 or 168 ampoules:

·                30 ampoules

·                42 ampoules.

 

Multipacks containing:

·                168 (4x42) ampoules

·                168 (4x42) ampoules co-packed with Breelib consumables set (containing 1 mouthpiece and 1 medication chamber).

 

Ampoules with 2 ml nebuliser solution (for the use of Venta-Neb):

 

Packages containing: 30, 90, 100 or 300 ampoules

·                30 ampoules

·                90 ampoules

·                100 ampoules

·                300 ampoules.

 

Multipacks containing:

·                90 (3x30) ampoules

·                300 (10x30) ampoules.

 

Ventavis 20 microgram/ml nebuliser solution

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

 

Ampoules with 1 ml nebuliser solution (for the use of Breelib or I-Neb AAD):

 

Packages containing:

·                30 ampoules

·                42 ampoules.

 

Multipacks containing:

·                168 (4x42) ampoules

·                168 (4x42) ampoules co-packed with Breelib consumables set (containing 1 mouthpiece and 1 medication chamber).

 

Not all pack sizes may be marketed.

6.6       Special precautions for disposal and other handling

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.

[…]

8.         MARKETING AUTHORISATION NUMBER(S)

Ventavis 10 microgram/ml nebuliser solution

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

EU/1/03/255/011

EU/1/03/255/013

 

Ventavis 20 microgram/ml nebuliser solution

 

EU/1/03/255/009

EU/1/03/255/010

EU/1/03/255/012

EU/1/03/255/014

 

****All other changes following this are deletions from what was previously the 20 mg SPC in order for the two SPCs to be combined****

6.5     Nature and contents of container

 

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, 42 or 168 ampoules.

 

2 ml nebuliser solution:

Packages containing 30, 90, 100 or 300 ampoules.

 

Not all pack sizes may be marketed.

 

 

8.       MARKETING AUTHORISATION NUMBER(S)

 

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

EU/1/03/255/011

 

 

10.         DATE OF REVISION OF THE TEXT

 

11/2014

 

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

 

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

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.

 

Excipient with known effect:

Each ml contains 0.81 mg ethanol 96% (equivalent to 0.75 mg ethanol) (as ethanol 96%).Ethanol 96% 0.81 mg per ml.

 

For the full list of excipients, see section 6.1.

 

4.2     Posology and method of administration

 

Posology

 

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.

 

4.4     Special warnings and precautions for use

 

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.

 

 

4.8     Undesirable effects

 

System organ class (MedDRA)	Very common (³1/10)	Common (³1/100 to <1/10)	Frequency not known
Vascular disorders	Vasodilatation, Fflushing	Syncope§ (see section 4.4), Hypotension*

* Life-threatening and/or fatal cases have been reported.

§ see section “Description of selected adverse reactions”

 

 

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 VHPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

 

 

 

5.2     Pharmacokinetic properties

 

Age and gender

Age and gGender are is not of clinical relevance to the pharmacokinetics of iloprost. No pharmacokinetic data are available in elderly patients.

 

10.        DATE OF REVISION OF THE TEXT

 

07/2014

 

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

 

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

(Removal of the black triangle and explanatory statement.)

10.          DATE OF REVISION OF THE TEXT

 November December 2013



4.2     Posology and method of administration

 

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 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 further increase in the 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.

 

 

Paediatric population

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 not recommended for use in this population.

 

Method of administration

 

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 (nebulizser) (see section 6.6).

 

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 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).

 

 

Undesirable Exposure exposure to Ventavis

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.

 

Skin and eye contact, oral ingestion

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.

 

Newborns, infants, and pregnant women should not be subjected to Ventavis in the room air.

 

 

4.8     Undesirable effects

 

 

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/mlthe medication 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 (³1/10)	Common (³1/100 to <1/10)	Frequency not known
Blood and lymphatic system disorders	Bleeding events*§		Thrombocytopenia
Immune system disorders			Hypersensitivity
Nervous system disorders	Headache	Dizziness
Cardiac disorders		Tachycardia, Palpitations
Vascular disorders	Vasodilatation	Syncope§ § (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 Nasal congestion
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§

* Life-threatening and/or fatal cases have been reported.

§ 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.

 

 

5.1     Pharmacodynamic properties

 

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.

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 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).

 

 

5.2     Pharmacokinetic properties

 

Absorption

 

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).

 

 

6.       PHARMACEUTICAL PARTICULARS

 

6.1     List of excipients

 

Trometamol

Ethanol 96 %

Sodium chloride

Hydrochloric acid (for pH adjustment)

Water for injections

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 16 September 2003

Date of latest renewal: 26 August 201316 September 2008

 

 

10.         DATE OF REVISION OF THE TEXT

 

August 2013December 2013

 

 

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

 

1.       NAME OF THE MEDICINAL PRODUCT

 

Ventavis 10 microgramsmicrogram/ml nebuliser solution

 

 

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

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

Each ampoule with 1 ml solution contains 10 microgramsmicrogram iloprost.

Each ampoule with 2 ml solution contains 20 microgramsmicrogram iloprost.

 

 

4.1     Therapeutic indications

 

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

 

 

4.2     Posology and method of administration

 

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).

Posology

 

Adults

 

Dose per inhalation session:

 

At initiation of Ventavis treatment the first inhaled dose should be 2.5 microgramsmicrogram iloprost (as delivered at the mouthpiece of the nebuliser). If this dose is well tolerated, dosing should be increased to 5.0 microgramsmicrogram and maintained at that dose. In case of poor tolerability of the 5.0 microgramsmicrogram dose, the dose should be reduced to 2.5 microgramsmicrogram.

 

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 microgramsmicrogram 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 further increase in the dose up to 5 microgramsmicrogram 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.

 

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

 

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 not recommended for use in this population.

 

Method of administration

 

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

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

 

For a dose of 5 microgramsmicrogram iloprost at mouthpiece it is recommended to complete two inhalation cycles with 2.5 microgramsmicrogram pre-set dose program with a filling of one ampoule containing 2 ml Ventavis nebuliser solution, which is marked withshows 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 which is marked withshowing 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 microgramsmicrogram active substance on the mouth piece 25 inhalation cycles.

P2 Program 2: 2.5 microgramsmicrogram 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.

 

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

 

The I-Neb AAD System is a portable, hand-held, vibrating mesh technology nebuliser system. This system generates droplets by ultrasound, which is forcinges 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 microgramsmicrogram 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 microgramsmicrogram dose the medication chamber with the red latch is used together with the red control disc.

For the 5 microgramsmicrogram 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.

 

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

 

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.

 

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 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 further increase in the dose up to 5.0 micrograms 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.

 

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

 

No specific paediatric control studies have been conducted with Ventavis.

4.3     Contraindications

 

-        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.;

4.4     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.

 

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 productsdrugs 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 medicinal productsdrugs 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 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).

 

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 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.

 

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 considered in critically ill patients.

 

Renal or hepatic impairment

 

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).

 

Serum glucose levels

 

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 humansman on prolonged Ventavis therapy.

 

Exposure to Ventavis

 

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.

 

Skin and eye contact, oral ingestion

 

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 ethanol

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

 

4.5     Interaction with other medicinal products and other forms of interaction

 

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 haveis to be expected

4.6     Fertility, pregnancy and lactation

 

Fertility

Animal studies have not shown harmful effect of iloprost on fertility.

 

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 suckling

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.

 

 

4.7     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. In patients experiencing hypotensive symptoms such as dizziness, the ability  to drive or operate machines may be seriously affected.               

4.8     Undesirable effects

System organ class (MedDRA)	Very common (³ 1/10)	Common (³ 1/100 to < 1/10)	Frequency not known
Blood and lymphatic system disorders	Bleeding events*§		Thrombocytopenia
Immune system disorders			Hypersensitivity
Nervous system disorders	Headache	Dizziness
Vascular disorders	Vasodilatation	Syncope§ (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	Dysgueusia
Skin and subcutaneous tissue skin disorders		Rash
Musculoskeletal and connective tissue disorders	Pain in jaw/trismus

* 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 (see section 4.5). Fatal cases included cerebral and intracranial haemorrhage.

 

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 (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

 

 

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

 

 

4.9     Overdose

 

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.

5.1     Pharmacodynamic properties

                  

Pharmacotherapeutic group: Antithrombotic agents, pPlatelet 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 SmPC 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, randomizsed, 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 (up to 5 microgramsmicrogram 6 to 9 times per day during waking hours). The mean daily inhaled dose was 27 microgramsmicrogram 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.

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 medicinal productdrug 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 microgramsmicrogram (range 12.5 to 45 microgramsmicrogram/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

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 SmPC will be updated as necessary.

 

5.2     Pharmacokinetic properties

Absorption

 

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

 

Pharmacokinetics after use with different nebulisers

 

In a randomizsed, crossover study with 20 healthy adult men, pharmacokinetics was investigated following inhalation of Ventavis (5 microgramsmicrogrammcg iloprost) by the I-Neb AAD in comparison to the Prodose (5 microgramsmicrogrammcg 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 Sectionsection 4.2).

 

Pharmacokinetic parameters of iloprost after inhalation of 5 microgramsmicrogramcg iloprost by I-Neb AAD vs. Prodose

 

5.3     Preclinical safety data

 

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 microgramsmicrogram/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.

 

Local tolerance, contact sensitising and antigenicity potential

 

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

 

7.       MARKETING AUTHORISATION HOLDER

 

Bayer Pharma AG

D-13342 Berlin

Germany

 

10.         DATE OF REVISION OF THE TEXT

 

 

August 2013

 

 

 

 

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

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 with known effect: Ethanol 96% 0,81 mg per ml.

For the a full list of excipients, see section 6.1.

  

4.2     Posology and method of administration

 

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).

 

Posology

 

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.

At initiation of Ventavis treatment the first inhaled dose should be 2.5 micrograms iloprost (as delivered at the mouthpiece of the nebulizer). If this dose is well tolerated, dosing should be increased to 5.0 microgram and maintained at that dose. In case of poor tolerability of the 5.0 microgram dose, the dose should be reduced to 2.5 micrograms.

 

Method of administration

…………………………………………………………………………………………………………………………………………………………...........

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 microliter) with the red latch is used together with the red control disc.

For the 5 micrograms dose the medication chamber (650 microliter) with the purple coloured latch is used together with the purple control disc.

………………………………………………………………………………………………………………

 

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 3-4 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 3-4 hours should be chosen initially and shortened according to individual tolerability. An further undesired accumulation of iloprost 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

 

No specific paediatric control studies have been conducted with Ventavis. There is no experience with Ventavis in children or adolescents.

 

4.3     Contraindications

 

-        Hypersensitivity to the active substance or  to any of the excipients listed in section 6.1.

-        Pregnancy and lactation (see section 4.6).

…………………………………………………………………………………………………………………………………………………

 

4.4          Special warnings and precautions for use

…………………………………………………………………………………………………………………………………………………..

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 3-4 hours is recommended (see section 4.2).

 

4.5     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). Should significant hypotension occur this can be corrected by dose reduction of iloprost. 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.

………………………………………………………………………………………………………………..

 

4.6          Fertility, pregnancy and lactation

 

Fertility

Animal studies have not shown harmful effect of iloprost on fertility.

 

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). 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.

 

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).

Very low levels of iloprost into milk were observed in rats (see section 5.3). A potential risk to the suckling child cannot be excluded and it is preferable to avoid breast-feeding during Ventavis therapy.

 

4.8     Undesirable effects

 

Summary of the safety profile

 

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 frequently observed adverse reactions (≥ 20 %)  seen in clinical trials include vasodilatation (including hypotension), headache and increased 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 medication 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 (³ 1/10)	Common (³ 1/100 to < 1/10)	Frequency not known
Blood and lymphatic system disorders	Bleeding events*§		Thrombocytopenia
Immune system disorders			Hypersensitivity
Nervous system disorders	Headache	Dizziness
Vascular disorders	Vasodilatation	Syncope (see section 4.4), Hypotension*
Blood and lymphatic system disorders	Bleeding events*
Respiratory, thoracic and mediastinal disorders	Chest discomfort / chest pain Cough increased	Dyspnoea Pharyngolaryngeal pain and Tthroat irritation	Bronchospasm * (see section 4.4) / Wheezing
Gastrointestinal disorders	Nausea	Diarrhoea Vomiting Mouth and tongue irritation including pain	Dysgueusia
Skin and subcutaneous skin disorders		Rash
Musculoskeletal and connective tissue disorders	Pain in jaw/trismus
Skin and subcutaneous skin disorders		Rash

* Life-threatening and/or fatal cases have been reported.

§ * 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 (see section 4.5). Fatal cases included cerebral and intracranial haemorrhage.

 

Description of selected adverse reactions

 

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.

 

4.9          Overdose

 

•              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.

 

•              Management Therapy

 

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

 

 

5.1          Pharmacodynamic properties

……………………………………………………………………………………………………………………………………………………………

 

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

…………………………………………………………………………………………………………………………………………………………….

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)……………………………………………………………………….

 

5.2          Pharmacokinetic properties

…………………………………………………………………………………………………………………………………………………………..

 

•              Distribution

………………………………………………………………………………………………………………………………………………………….

 

•              Metabolism Biotransformation

 

No studies to investigate the metabolism of iloprost were performed following inhalation of Ventavis.

 

After intravenous administration, iIloprost is extensively metabolised principally 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 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.

………………………………………………………………………………………………………………………………………………………

 

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.

 

5.3          Preclinical safety data

………………………………………………………………………………………………………………………………………………………

•              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. No disturbance of postnatal development and reproductive performance was seen in the offspring that were raised, indicating that the observed retardation in rats was compensated during the postnatal development. In comparable embryotoxicity studies in rabbits and monkeys no such digit anomalies or other gross-structural abnormalities were observed even after considerably higher dose levels which exceeded the human dose multiple times.

In rats, passage of extremely low levels of iloprost and/or metabolites into the milk was observed (less than 1% of iloprost dose given intravenously).  No disturbance of post-natal development and reproductive performance was seen in animals exposed during lactation.

 

6.6     Special precautions for disposal and other handling

 

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. In addition, instructions for hygiene and cleaning of the nebulizers provided by the device manufacturers should be followed carefully.

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

 

 

9.            DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 16 September 2003

Date of lastest renewal: 16 September 2008

 

 

10.          DATE OF REVISION OF THE TEXT

 

1^st July 2011 20th April 2012

 

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

The name of the Marketing Authorisation holder in section 7 has changed from "Bayer Schering Pharma AG" to "Bayer Pharma AG"

The date of revision of the text (section 10) has been updated to "1st July 2011"

 

Changes for EMEA/H/C/474/II/33, approved February 2011

New text indicated by: underlined text

Deleted text: indicated by: strikethrough

 

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

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.

 

 

4.2     Posology and method of administration

 

Addition of text:

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

 

Subsection Patients with Renal Impairment addition of:

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.

 

 

4.3     Contraindications

 

Change of position of the text “- Pregnancy and Lactation”, now listed second

 

4.4     Special warnings and precautions for use

 

Superceded text

Newly approved text

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.   The pulmonary vasodilatory effect of inhaled iloprost is of short duration (one to two hours). 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 occurrence of a nocturnal or exertional syncope reflects therapeutic gaps and/or insufficient efficiency, and 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.   In patients with low systemic blood pressure, care should be taken to avoid further hypotension. Ventavis should not be initiated in patients with systolic arterial hypotension less than 85 mmHg.   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.   Iloprost 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 (HaloLite/Prodose), 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.

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.

 

 

4.5     Interaction with other medicinal products and other forms of interaction

 

Iloprost may increase the the effect of vasodilatators and antihypertensive agents 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.

 

4.6     Fertility, pregnancy and lactation

 

Under subsetcion “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. Ventavis is contra-indicated during pregnancy (see section 4.3).  Iloprost must not be administered to pregnant women (see section 4.3 Contraindications).

 

Under subsection “Breast-feeding”

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

 

 

 

4.7     Effects on ability to drive and use machines

 

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.

 

4.8     Undesirable effects

Superceded text

Newly approved text

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, hypotension, headache and increased cough.   Frequencies of  adverse reactions are reported as follows: very common  ≥  1/10; common ≥  1/100 to <  1/10; uncommon ≥ 1/1,000 and <  1/100; rare ≥  1/10,000 to < 1/1,000; very rare <  1/10,000.   The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs). The incidences are based on clinical trial data.   Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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.

 

Updated table

 

System organ class	Very common (³ 1/10)	Common (³ 1/100 to < 1/10)	Frequency not known
Immune system disorders			Hypersensitivity
Nervous system disorders	Headache	Dizziness
Vascular disorders	Vasodilatation Hypotension	Syncope (see section 4.4), Dizziness related to Hypotension
Blood and lymphatic system disorders	Bleeding events*
Respiratory, thoracic and mediastinal disorders	Chest discomfort / chest pain Cough increased	Dyspnoea Pharyngolaryngeal pain and throat irritation	Bronchospasm (see section 4.4) / Wheezing
Gastrointestinal disorder	Nausea	Diarrhoea Vomiting Mouth and tongue irritation	Dysgueusia
Musculoskeletal and connective tissue disorders	Pain in jaw/trismus	Pain in jaw/trismus
Skin and subcutaneous skin disorders		Rash

 

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.   Bleeding events (mostly haematoma) were common as expected in this patient population with a high proportion of patients taking anticoagulant co-medication. The frequency of bleeding events did not differ between iloprost and placebo-treated patients.   Post marketing experience   Vomiting, nausea, diarrhoea and dyspnoea have been reported in association with Ventavis inhalation.   Bronchospasm and wheezing have also been reported in patients treated with Ventavis inhalation (see section 4.4 Special warnings and precautions for use).   Adverse events in healthy volunteers   In a randomized placebo-controlled study in 160 healthy volunteers, inhaled doses of iloprost solution were given either with a fixed dose of 2.5 micrograms iloprost 6 times daily (total daily dose of 15 micrograms), or beginning with 5.0 microgram and increasing up to 20 micrograms, or the highest tolerated dose for a total of 6 dose inhalations (total daily dose of 70 micrograms).   In the fixed dose group of 2.5 micrograms per inhalation chest pain, or chest discomfort (32.5 %), pharyngolaryngeal pain, or throat irritation (22.5 %) and nausea (7.5 %) – (all non-serious and mild in intensity) – occurred more frequently in comparison with the adverse events obtained from the placebo controlled phase II and III studies in patients with doses of 2.5 micrograms or 5 micrograms per inhalation.   Five volunteers were unable to increase the dose up to 20 micrograms per inhalation because of mild to moderate transient chest pain or chest discomfort, usually accompanied by headache, dizziness and nausea.

* 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.

 

 

4.9     Overdose

 

·         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.

 

 

5.1     Pharmacodynamic properties

 

Insertion of:

 

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.

 

 

5.2     Pharmacokinetic properties

 

Under subsection “Elimination” insertion of:

 

“The total clearance of iloprost is about 20 ml/kg/min, which indicates extrahepatic contribution to the metabolism of iloprost.”

 

 

5.3     Preclinical safety data

 

Under subsection: “Genotoxic potential, tumorigenicity”

 

Iloprost is not a gene mutagen in bacterial and mammalian cells in vitro and is not clastogenic in human lymphocytes up to cytotoxic concentrations and in the micronucleus test in vivo. 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.

 

 

Under subsection “Reproduction toxicology”

 

In comparable embryotoxicity studies in rabbits and monkeys no such digit anomalies or other gross-structural abnormalities were observed in the foetuses/pups up to the highest tested dose.

 

 

6.6     Special precautions for disposal and other handling

 

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.

 

10.         DATE OF REVISION OF THE TEXT

 

February 2011