ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Ventavis 10 microgram/ml nebuliser solution
2.
1 ml solution contains 10 micrograms iloprost (as iloprost trometamol).
Each ampoule with 1 ml contains 10 micrograms iloprost.
Each ampoule with 2 ml contains 20 micrograms iloprost.
Excipient: Ethanol 96% 0,81 mg per ml.
For a full list of excipients, see section 6.1.
3.
Nebuliser solution.
Clear, colourless solution.
4.
Treatment of patients with primary pulmonary hypertension, classified as NYHA functional class III,
to improve exercise capacity and symptoms.
Ventavis should only be initiated and monitored by a physician experienced in the treatment of
pulmonary hypertension.
Ventavis is intended for inhalation use by nebulisation (see section 6.6).
Adults
Dose per inhalation session:
The recommended dose is 2.5 micrograms or 5.0 micrograms of inhaled iloprost (as delivered at the
mouthpiece of the nebuliser) , starting with the low dose of 2.5 microgram for the first inhalation,
followed by 5.0 micrograms for the second inhalation. In case of poor tolerability of the
5.0 microgram dose, the dose should be reduced to 2.5 micrograms.
Two compressed air nebuliser systems,
HaloLite and Prodose
, have been shown to be suitable
nebulisers for the administration of Ventavis. With both systems the mass median aerodynamic
diameter of the aerosol droplet (MMAD) with iloprost was between 2.6 and 2.7 micrometres. For each
inhalation session the content of one ampoule containing 2 ml of Ventavis nebuliser solution will be
transferred into the nebuliser medication chamber immediately before use. HaloLite and Prodose are
dosimetric systems. They stop automatically after the pre-set dose has been delivered. The inhalation
time depends on the patient’s breathing pattern.
2
Device
Dose of iloprost at
mouthpiece
Estimated inhalation time
(frequency of 15 breaths per minute)
HaloLite
2.5 micrograms
5 micrograms
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 micrograms iloprost at mouthpiece it is recommended to complete two inhalation
cycles with 2.5 micrograms pre-set dose program with a filling of one ampoule containing 2 ml
Ventavis nebuliser solution, which shows two coloured rings (white – pink).
Venta-Neb
, a portable ultrasonic battery-powered nebuliser, has also been shown to be suitable for the
administration of Ventavis. The measured MMAD of the aerosol droplets was 2.6 micrometres.
For each inhalation session, the content of one ampoule containing 2 ml Ventavis nebuliser solution
and showing two coloured rings (white – pink) will be transferred into the nebuliser medication
chamber immediately before use.
Two programs can be operated:
P1 Program 1: 5.0 micrograms active substance on the mouth piece 25 inhalation cycles.
P2 Program 2: 2.5 micrograms active substance on the mouth piece 10 inhalation cycles.
The selection of the pre set program is made by the physician.
Venta-Neb prompts the patient to inhale by an optical and an acoustic signal. It stops after the pre-set
dose has been administered.
To obtain the optimal droplet size for the administration of Ventavis the green baffle plate should be
used. For details refer to the instruction manual of the Venta-Neb nebuliser.
Device
Dose of iloprost at
mouthpiece
Estimated Inhalation time
Venta-Neb
2.5 micrograms
5 micrograms
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 forcing the solution through a mesh. The I-Neb
AAD nebuliser has also been shown to be suitable for the administration of Ventavis. The measured
MMAD of the aerosol droplets was 2.1 micrometres.
This nebuliser monitors the breathing pattern to determine the aerosol pulse time required to deliver
the pre-set dose of 2.5 or 5 micrograms iloprost.
The pre-set dose provided by the I-Neb AAD system is controlled by the medication chamber in
combination with a control disc. There are two different colour coded medication chambers. For each
medication chamber there is a corresponding colour coded control disc:
For the 2.5 micrograms dose the medication chamber (350 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.
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.
3
Device
Dose of iloprost at
mouthpiece
Estimated Inhalation time
I-Neb AAD
2.5 micrograms
5 micrograms
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 VentaNeb devices and a faster delivery of the
solution (see section 5.2), patients stabilized on one nebuliser should not switch to another nebuliser
without supervision by the treating physician.
The efficacy and tolerability of inhaled iloprost when administered with other nebulising systems,
which provide different nebulisation characteristics of iloprost solution, have not been established.
Daily dose:
The dose per inhalation session should be administered 6 to 9 times per day according to the
individual need and tolerability.
Duration of treatment:
The duration of treatment depends on clinical status and is left to the physician’s discretion. Should
patients deteriorate on this treatment intravenous prostacyclin treatment should be considered.
Patients with hepatic impairment
Iloprost elimination is reduced in patients with hepatic dysfunction (see section 5.2).
To avoid undesired accumulation over the day, special caution has to be exercised with these patients
during initial dose titration. Initially, doses of 2.5 micrograms should be administered with dosing
intervals of at least 3 hours (corresponds to administration of max. 6 times per day). Thereafter, dosing
intervals may be shortened cautiously based on individual tolerability. If a further increase in the dose
up to 5.0 micrograms is indicated, again dosing intervals of at least 3 hours should be chosen initially
and shortened according to individual tolerability. A further undesired accumulation of the medicinal
product following treatment over several days is not likely due to the overnight break in administration
of the medicinal product.
Patients with renal impairment
There is no need for dose adaptation in patients with a creatinine clearance > 30 ml/min (as determined
from serum creatinine using the Cockroft and Gault formula). Patients with a creatinine clearance of
≤
30 ml/min were not investigated in the clinical trials.
Paediatric population
There is no experience with Ventavis in children or adolescents.
Hypersensitivity to the active substance or to any of the excipients.
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;
4
Severe arrhythmias;
Cerebrovascular events (e.g. transient ischaemic attack, stroke) within the last 3 months.
Pulmonary hypertension due to venous occlusive disease.
Congenital or acquired valvular defects with clinically relevant myocardial function disorders not
related to pulmonary hypertension.
The use of Ventavis is not recommended in patients with unstable pulmonary hypertension, with
advanced right heart failure. In case of deterioration or worsening of right heart failure transfer to
other medicinal products should be considered.
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.
Iloprost may increase the effect of vasodilatators and antihypertensive agents.
5
Iloprost can inhibit platelet function and 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 and glycoprotein IIb/IIIa antagonists:
abciximab, eptifibatide and tirofiban) may increase the risk of bleeding. A careful monitoring of the
patients taking anticoagulants according to common medical practice is recommended. The
concomitant use of other platelet inhibitors should be avoided in patients taking anticoagulants.
Intravenous infusion of iloprost has no effect either on the pharmacokinetics of multiple oral doses of
digoxin or on the pharmacokinetics of co-administered tissue plasminogen activator (t-PA) in patients.
Although, clinical studies have not been conducted,
in vitro
studies investigating the inhibitory
potential of iloprost on the activity of cytochrome P450 enzymes revealed that no relevant inhibition
of drug metabolism via these enzymes by iloprost have to be expected.
Women of child-bearing potential
The potential risk for humans is unknown. Therefore, women of child-bearing potential should use
effective contraceptive measures during treatment.
Pregnancy
There are no adequate data from the use of Ventavis in pregnant women. Animal studies have shown
reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Ventavis is contra-
indicated during pregnancy (see section 4.3).
Breast-feeding
It is not known whether Ventavis enters the breast milk. The medicinal product must not be
administered to breast feeding mothers (see section 4.3).
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 abilityto drive or
operate machines may be affected.
In addition to local effects resulting from administration of iloprost by inhalation such as increased
cough, adverse reactions with iloprost are related to the pharmacological properties of prostacyclins.
The most common adverse reactions seen in clinical trials include vasodilatation, 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.
6
System organ class
Very common
Common
Frequency not known
Immune system
disorders
Hypersensitivity
Nervous system
disorders
Headache
Vascular disorders
Vasodilatation,
Hypotension
Syncope,
Dizziness related to
hypotension
Respiratory, thoracic
and mediastinal
disorders
Cough increased
Pharyngolaryngeal pain and
throat irritation
Gastrointestinal
disorder
Mouth and tongue irritation
Dysgeusia
Musculoskeletal and
connective tissue
disorders
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
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
7
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.
Symptoms
No case of overdose has been reported. Hypotensive/vasovagal reaction might be anticipated as well
as headache, flushing, nausea, vomiting, and diarrhoea.
Therapy
A specific antidote is not known. Interruption of the inhalation session, monitoring and symptomatic
measures are recommended.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Platelet aggregation inhibitors excluding heparin, ATC code: B01AC11
This medicinal product has been authorised under “Exceptional Circumstances”.
This means that due to the rarity of the disease it has not been possible to obtain complete information
on this medicinal product.
The European Medicines Agency (EMEA) will review any new information which may become
available every year and this SPC will be updated as necessary.
Iloprost, the active substance of Ventavis, is a synthetic prostacyclin analogue. The following
pharmacological effects have been observed
in vitro
:
Inhibition of platelet aggregation, platelet adhesion and release reaction
Dilatation of arterioles and venules
Increase of capillary density and reduction of increased vascular permeability caused by
mediators such as serotonin or histamine in the microcirculation
Stimulation of endogenous fibrinolytic potential
The pharmacological effects after inhalation of Ventavis are:
Direct vasodilatation of the pulmonary arterial bed occur with consecutive significant improvement of
pulmonary artery pressure, pulmonary vascular resistance and cardiac output as well as mixed venous
oxygen saturation.
No clinical trial data are available comparing directly in intra-patient observations the acute
haemodynamic response after intravenous to that after inhaled iloprost. The haemodynamics observed
suggest an acute response with preferential effect of inhaled treatment on the pulmonary vessels. The
pulmonary vasodilatory effect of each single inhalation levels off within one to two hours.
8
However, the predictive value of these acute haemodynamic data are considered to be of limited value
as acute response does not in all cases correlate with long-term benefit of treatment with inhaled
iloprost.
Efficacy in adult patients with pulmonary hypertension
A randomised, double-blind, multi-centre, placebo-controlled phase III trial (study RRA02997) has
been conducted in 203 adult patients (inhaled iloprost: N=101; placebo n=102) with stable pulmonary
hypertension. Inhaled iloprost (or placebo) was added to patients' current therapy, which could include
a combination of anticoagulants, vasodilators (e.g. calcium channel blockers), diuretics, oxygen, and
digitalis, but not PGI2 (prostacyclin or its analogues). 108 of the patients included were diagnosed
with primary pulmonary hypertension, 95 were diagnosed with secondary pulmonary hypertension of
which 56 were associated with chronic thromboembolic disease, 34 with connective tissue disease
(including CREST and scleroderma) and 4 were considered appetite suppressant drug related. The
baseline 6-minute walk test values reflected a moderate exercise limitation: in the iloprost group the
mean was 332 meters (median value: 340 meters) and in the placebo group the mean was 315 meters
(median value: 321 meters). In the iloprost group, the median daily inhaled dose was 30 micrograms
(range 12.5 to 45 micrograms/day). The primary efficacy endpoint defined for this study, was a
combined response criterion consisting of improvement in exercise capacity (6 minute walk test) at 12
weeks by at least 10% versus baseline,
and
improvement by at least one NYHA class at 12 weeks
versus baseline,
and
no deterioration of pulmonary hypertension or death at any time before 12 weeks.
The rate of responders to iloprost was 16.8% (17/101) and the rate of responders in the placebo group
was 4.9% (5/102) (p=0.007).
In the iloprost group, the mean change from baseline after 12 weeks of treatment in the 6 minute
walking distance was an increase of 22 meters (-3.3 meters in the placebo group, no data imputation
for death or missing values).
In the iloprost group the NYHA class was improved in 26% of patients (placebo: 15%) (p = 0.032),
unchanged in 67.7% of patients (placebo: 76%) and deteriorated in 6.3% of patients (placebo: 9%).
Invasive haemodynamic parameters were assessed at baseline and after 12 weeks treatment.
A subgroup analysis showed that no treatment effect was observed as compared to placebo on the
6-minute walk test in the subgroup of patients with secondary pulmonary hypertension.
A mean increase in the 6-minute walk test of 44.7 meters from a baseline mean value of 329 meters vs.
a change of -7.4 meters from a baseline mean value of 324 meters in the placebo group (no data
imputation for death or missing values) was observed in the subgroup of 49 patients with primary
pulmonary hypertension receiving treatment of inhaled iloprost for 12 weeks (46 patients in the
placebo group).
No study has been performed with Ventavis in children with pulmonary hypertension.
5.2 Pharmacokinetic properties
Absorption
When iloprost is administered via inhalation in patients with pulmonary hypertension (iloprost dose at
the mouthpiece: 5 micrograms), peak serum levels of 100 to 200 picograms/ml were observed at the
end of inhalation session. These levels decline with half-lives between approximately 5 and
25 minutes. Within 30 minutes to 1 hour after the end of inhalation, iloprost is not detectable in the
central compartment (limit of quantification 25 picograms/ml).
Distribution
No studies performed following inhalation.
9
Following intravenous infusion, the apparent steady-state volume of distribution was 0.6 to 0.8 l/kg in
healthy subjects. Total plasma protein binding of iloprost is concentration-independent in the range of
30 to 3000 picograms/ml and amounts to approximately 60 %, of which 75 % is due to albumin
binding.
Metabolism
No studies performed following inhalation.
Iloprost is extensively metabolised principally via 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.
Elimination
No studies performed following inhalation.
In subjects with normal renal and hepatic function, the disposition of iloprost following intravenous
infusion is characterised in most cases by a two-phase profile with mean half-lives of 3 to 5 minutes
and 15 to 30 minutes.
A mass-balance study was done using
3
H-iloprost in healthy subjects. Following intravenous infusion,
the recovery of total radioactivity is 81 %, and the respective recoveries in urine and faeces are 68 %
and 12 %. The metabolites are eliminated from plasma and urine in 2 phases, for which half-lives of
about 2 and 5 hours (plasma) and 2 and 18 hours (urine) have been calculated
.
Pharmacokinetics after use with different nebulisers
In a randomized, crossover study with 20 healthy adult men, pharmacokinetics was investigated
following inhalation of Ventavis (5 mcg iloprost) by the I-Neb AAD in comparison to the ProDose
(5 mcg disk).
Higher maximum serum level (Cmax) and systemic exposure (AUC(0-tlast)) as well as a shorter time
to reach maximum serum concentration (tmax) were found following Ventavis inhalation via the
I-Neb AAD in comparison to the ProDose nebulizer. The pharmacokinetic results reflect the slightly
different
in vitro
characteristics of these nebulizers (see Section 4.2).
Pharmacokinetic parameters of iloprost after inhalation of 5 mcg iloprost by I-Neb AAD vs.
ProDose
AUC(0-tlast)
(pg·h/mL)
geometric
mean (CV%)
I-Neb 119 (41.2%) 0.147 (0.086 – 0.268) 28.9 (47.4%)
ProDose 80.0 (46.7%) 0.183 (0.133 – 0.279) 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
Cmax
(pg/mL)
geometric
mean (CV%)
t max
(h),
median (range)
10
Characteristics in patients
Renal dysfunction:
In a study with intravenous infusion of iloprost, patients with end-stage renal failure undergoing
intermittent dialysis treatment are shown to have a significantly lower clearance
(mean CL = 5 ± 2 ml/minute/kg) than that observed in patients with renal failure not undergoing
intermittent dialysis treatment (mean CL = 18 ± 2 ml/minute/kg).
Hepatic dysfunction:
Because iloprost is extensively metabolised by the liver, the plasma levels of the active substance are
influenced by changes in hepatic function. In an intravenous study, results were obtained involving 8
patients suffering from liver cirrhosis. The mean clearance of iloprost is estimated to be
10 ml/minute/kg
.
Age and gender:
Age and gender are not of clinical relevance to the pharmacokinetics of iloprost.
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 micrograms/kg/day was also the “no observed adverse effect level” (NOAEL) as evaluated in
inhalation toxicity studies in rats up to 26 weeks. Following inhalation the systemic exposure based on
AUC values in rats exceeded the corresponding therapeutic exposure in human patients by
approximately 13 times.
Genotoxic potential, tumorigenicity
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
.
No tumorigenic potential of iloprost could be demonstrated in tumorigenicity studies in rats and mice.
Reproduction toxicology
In embryo- and foetotoxicity studies in rats continuous intravenous administration of iloprost led to
anomalies of single phalanges of the forepaws in a few foetuses/pups without dose dependence.
11
These alterations are not considered as true teratogenic effects, but are most likely related to iloprost
induced growth retardation in late organogenesis due to haemodynamic alterations in the
foetoplacental unit. In comparable embryotoxicity studies in rabbits and monkeys no such digit
anomalies or other gross-structural abnormalities were observed in the foetuses/pups up to the highest
tested dose.
In rats, passage of extremely low levels of iloprost into the milk was observed.
Local tolerance, contact sensitising and antigenicity potential
In inhalation studies in rats, the administration of an iloprost formulation with a concentration of
20 micrograms/ml up to 26 weeks did not cause any local irritation of the upper and lower respiratory
tract.
A dermal sensitisation (maximisation test) and an antigenicity study in guinea pigs showed no
sensitising potential.
6.
6.1 List of excipients
Trometamol,
Ethanol 96 %,
Sodium chloride,
Hydrochloric acid (for pH adjustment),
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
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 or 168 ampoules.
2 ml nebuliser solution:
Packages containing 30, 90, 100 or 300 ampoules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
12
For each inhalation session the contents of one opened ampoule of Ventavis has to be transferred into
the nebuliser medication chamber immediately before use.
After each inhalation session, any solution remaining in the nebuliser should be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Bayer Schering Pharma AG
D-13342 Berlin
Germany
8.
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
9.
Date of first authorisation: 16 September 2003
Date of last renewal: 16 September 2008
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu
/.
13
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
14
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Berlimed. S.A., Poligono Industrial Santa Rosa s/n, 28806 Alcalá de Henares, Madrid, Spain
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2)
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
OTHER CONDITIONS
The Marketing Authorisation Holder will submit yearly PSURs unless otherwise specified by the
CHMP.
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
The Marketing Authorisation Holder shall complete the following programme of studies within the
specified time frame, the results of which shall form the basis of the annual reassessment of the
benefit/risk profile.
Clinical aspects:
In July 2004, the CHMP and MAH agreed on a protocol for an observational study 308120 to
gather longer-term data on the safety and efficacy of Ventavis (iloprost). The first patient will be
enrolled by April 2005 the latest. Progress reports will be provided together with the submission of
the PSURs. A final study report will be provided within 6 months after last patient completed and
forwarded for review by CHMP, estimated dated of 4Q 2012.
15
ANNEX III
LABELLING AND PACKAGE LEAFLET
16
A. LABELLING
17
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
(PACK WITH 30 AMPOULES IN A CARTON WITH 90 (3 x 30) AMPOULES WITH 2 ML)
(PACK WITH 30 AMPOULES IN A CARTON WITH 300 (10 x 30) AMPOULES WITH 2 ML)
1.
Ventavis 10 microgram/ml, Nebuliser solution
Iloprost
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ampoule with 2 ml contains 20 micrograms iloprost (as iloprost trometamol) .
3.
LIST OF EXCIPIENTS
Excipients:
trometamol, ethanol 96 %, sodium chloride, hydrochloric acid (for pH adjustment), water for
injections.
4.
Nebuliser solution.
30 ampoules with 2 ml.
Part of a box containing 90 ampoules with 2 ml. No individual sale of single packs.
Part of a box containing 300 ampoules with 2 ml. No individual sale of single packs.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Inhalation use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
18
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Bayer Schering Pharma AG
D-13342 Berlin
Germany
EU/1/03/255/007
[90 (3 x 30) x 2 ml]
EU/1/03/255/008
[300 (10 x 30) x 2 ml]
13. BATCH NUMBER
Lot {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Ventavis 2 ml
19
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
(OUTER CARTON /
30 AMPOULES WITH 2 ML
90 AMPOULES WITH 2 ML
90 (3 x 30) AMPOULES WITH 2 ML
100 AMPOULES WITH 2 ML
300 AMPOULES WITH 2 ML
300 (10 x 30) AMPOULES WITH 2 ML)
1.
Ventavis 10 microgram/ml nebuliser solution
Iloprost
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 ml solution contains 10 micrograms iloprost (as iloprost trometamol).
Each ampoule with 2 ml contains 20 micrograms iloprost.
3.
LIST OF EXCIPIENTS
Excipients:
trometamol, ethanol 96 %, sodium chloride, hydrochloric acid (for pH adjustment), water for
injections
4.
Nebuliser solution.
30 ampoules with 2 ml.
90 ampoules with 2 ml.
90 (3 x 30) ampoules with 2 ml.
100 ampoules with 2 ml.
300 ampoules with 2 ml.
300 (10 x 30) ampoules with 2 ml.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Inhalation use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
20
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Bayer Schering Pharma AG
D-13342 Berlin
Germany
EU/1/03/255/001
[ 30 x 2 ml]
EU/1/03/255/006
[ 90 (3 x 30) x 2 ml]
EU/1/03/255/002
[100 x 2 ml]
EU/1/03/255/003
[300 x 2 ml]
EU/1/03/255/008
[300 (10 x 30) x 2 ml]
13. BATCH NUMBER
Lot {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Ventavis 2 ml
21
EU/1/03/255/007
[ 90 x 2 ml]
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
(PACK WITH 42 AMPOULES IN A CARTON WITH 168 (4 x 42) AMPOULES WITH 1 ML)
1.
Ventavis 10 microgram/ml, Nebuliser solution
Iloprost
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ampoule with 1 ml contains 10 micrograms iloprost (as iloprost trometamol) .
3.
LIST OF EXCIPIENTS
Excipients:
trometamol, ethanol 96 %, sodium chloride, hydrochloric acid (for pH adjustment), water for
injections.
4.
Nebuliser solution.
42 ampoules with 1 ml.
Part of a box containing 168 ampoules with 1 ml. No individual sale of single packs.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Inhalation use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
22
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Bayer Schering Pharma AG
D-13342 Berlin
Germany
EU/1/03/255/005
13. BATCH NUMBER
Lot {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Ventavis 1 ml
23
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
(OUTER CARTON /
30 AMPOULES WITH 1 ML
168 AMPOULES WITH 1 ML)
1.
Ventavis 10 microgram/ml, Nebuliser solution
Iloprost
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ampoule with 1 ml contains 10 micrograms iloprost (as iloprost trometamol) .
3.
LIST OF EXCIPIENTS
Excipients:
trometamol, ethanol 96 %, sodium chloride, hydrochloric acid (for pH adjustment), water for
injections
4.
Nebuliser solution.
30 ampoules with 1 ml.
168 ampoules with 1 ml.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Inhalation use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
24
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Bayer Schering Pharma AG
D-13342 Berlin
Germany
EU/1/03/255/004
[ 30 x 1 ml]
EU/1/03/255/005
[168 x 1 ml]
13. BATCH NUMBER
Lot {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
For the administration with the I-Neb nebuliser.
16. INFORMATION IN BRAILLE
Ventavis 1 ml
25
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
(AMPOULE WITH 2 ML)
1.
Ventavis 10 microgram/ml nebuliser solution
Iloprost
Inhalation use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Lot {number}
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
2 ml
6.
OTHER
26
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
(AMPOULE WITH 1 ML)
1.
Ventavis 10 microgram/ml nebuliser solution
Iloprost
Inhalation use
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Lot {number}
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
1 ml
6.
OTHER
27
B. PACKAGE LEAFLET
28
PACKAGE LEAFLET: INFORMATION FOR THE USER
Ventavis 10 microgram/ml nebuliser solution
Iloprost
Read all of this leaflet carefully before you start using this medicine.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if
their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Ventavis is and what it is used for
2.
Before you use Ventavis
3.
How to use Ventavis
5
How to store Ventavis
6.
Further information
1.
WHAT VENTAVIS IS AND WHAT IT IS USED FOR
What Ventavis is:
Ventavis is a nebuliser solution. The solution is changed into an aerosol mist by a special machine
called a nebuliser. Breathing in the mist carries Ventavis to the lungs, where it can work most
effectively in the artery between heart and lungs.
How Ventavis works:
Ventavis imitates a natural substance in the body called prostacyclin. Ventavis and prostacyclin inhibit
unwanted blocking or narrowing of blood vessels and allow more blood to flow through the arteries.
What Ventavis is used for:
Ventavis is used to treat moderate cases of primary pulmonary hypertension (PPH). This is a condition
where blood pressure is too high in the blood vessels between the heart and the lungs.
Ventavis tends to lower blood pressure within the pulmonary artery, by improving blood flow. This
means less work for the heart. Improved blood flow leads to an improved supply of oxygen to the
body and reduced strain on the heart. The heart can function more effectively.
29
4.
Possible side effects
2.
BEFORE YOU USE VENTAVIS
Do not use Ventavis:
If you think any of the following may apply to you,
please tell your doctor:
If you are allergic
(hypersensitive)
to iloprost or any of the other ingredients of Ventavis.
If you are at risk of bleeding
– for example, active ulcers, of the stomach or of the first part of
the small intestine
(duodenal ulcers),
injuries, bleeding within the skull.
If your disease is due to a blocked or narrowed vein
(venous occlusive disease)
..
If you have had a stroke
within the last 3 months,
or any other event reducing the blood
supply to the brain (e.g.
transient ischemic attack).
If you have a heart problem
, such as:
- a heart attack within the last six months
- severe changes in heart rate
- poor blood flow to the heart muscles (
severe coronary heart disease
or
unstable angina
).
Symptoms can be chest pain.
- a weak heart
(decompensated cardiac failure)
which is
not under close medical
observation.
-
a defect of the heart valves that causes the heart to work poorly (not related to
pulmonary hypertension).
If you are pregnant or breast-feeding
(see section 2., Take special care, ‘Pregnancy,
‘Breast-feeding’).
Take special care with Ventavis:
- If you have infection of the lungs,
severe asthma
, or other lung disease. Inhaling Ventavis
might trigger breathing difficulties.
If your blood pressure is too low
(less than 85 mmHg) you should not start the therapy with
Ventavis.
You will need special medical observation in some cases:
-
In general, you will need to
take special care to try and avoid fainting
or other effects of low
blood pressure, such as dizziness:
Stand up slowly when you get out of chairs or bed. You will help your body get used to the
change in position and blood pressure
If you tend to faint as soon as you get out of bed, it may be helpful to take your first dose of
the day while you’re still lying down.
Avoid any exceptional straining, for example physical exertion; it might be useful to inhale
Ventavis before. such physical exertion
Have someone on standby to watch you, if possible. Warn them to
call a doctor if you faint
.
The doctor will give advice on what to do and possibly prescribe treatment
If fainting episodes get worse because of the underlying disease, tell your doctor. The doctor
may consider a change of treatment.
-
If you suffer from a weak heart such as a right heart failure, and have the impression that
your disease is worsening,
tell your doctor. Symptoms can be swelling of feet and ankles,
shortness of breath, palpitations, urinating more frequently at night. Your doctor will consider
changing your treatment.
-
If you experience difficulty breathing, cough up blood, sweat excessively these may be signs
of a lung oedema.
Stop using Ventavis and tell your doctor immediately. He/she will check for
the cause and take appropriate measures.
-
If you have liver problems,
you may be prescribed a lower dose of Ventavis than for other
patients
-
If you have severe kidney problems requiring dialysis,
, see your doctor.
30
If you are under 18 years
, please make your doctor aware of your age.
Ventavis has not yet
been tested in children and adolescents.
Taking other medicines
Please tell your doctor or pharmacist if you are
taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Ventavis and certain other medicines may influence each other in the way they work in your body. Be
specially careful to mention any of these:
Medicines used to treat high blood pressure or heart disease
Medicines which inhibit blood clotting
(this includes acetylsalicylic acid a substance present
in many medicines that lower fever and relieve pain, as well as others)
Your doctor or pharmacist has more information on medicines to be careful with or avoid when using
Ventavis, so always tell them if you are taking other medicines.
Pregnancy:
• If you are pregnant, or think you might be
, tell your doctor straight away. Ventavis must not
be used by pregnant women (see section 2. Do not use Ventavis).
• If you could get pregnant,
use reliable contraception from the time you start treatment and
during treatment (ask your doctor).
Breast-feeding:
Stop breast-feeding when you start Ventavis treatment. Ventavis must not be given to women who are
breast-feeding, since it is not known whether the active substance is passed on through breast milk.
Ask your doctor or pharmacist for advice before taking any medicine.
Newborns, infants, and pregnant women should not be subjected to Ventavis in the room air.
These persons should not remain in a closed room where Ventavis is being administered to a patient.
Driving and using machines:
Ventavis brings down blood pressure and may cause dizziness or light-headedness in some people.
Do not drive or operate any tools or machines if you feel these effects of low blood pressure.
Important information about some of the ingredients of Ventavis:
This medicinal product contains small amounts (less than 100 mg per dose) of ethanol (alcohol).
3.
HOW TO USE VENTAVIS
How to use Ventavis:
Always take Ventavis exactly as your doctor has told you. Ventavis nebuliser solution is
inhaled
using the nebulisers your doctor prescribed (either the HaloLite, the Prodose, the
Venta-Neb or the I-Neb AAD system). The nebuliser turns Ventavis solution into a mist which
you breathe in through your mouth.
Follow carefully any extra instructions that come with the nebuliser. Check with your doctor or
pharmacist if you are unsure.
Ventavis solution that you do not use
in one inhalation session has to be thrown away.
31
How much to inhale:
The dose of Ventavis that is right for you depends on your individual condition and will be worked out
by your doctor.
Most people will have 6 to 9 inhalation sessions
spread throughout the day. One inhalation session
will usually last about 4 to 10 minutes depending on the prescribed dose. In case of liver problems,
your doctor will introduce you to Ventavis gradually and possibly prescribe fewer daily inhalations. In
case of severe kidney problems requiring dialysis, see your doctor.
If you have the impression that the effect of Ventavis is too strong or too weak,
talk to your doctor or
pharmacist
.
For HaloLite and ProDose systems:
Just before you start to inhale,
break open the glass container containing 2 ml solution, which shows
two coloured rings (white-pink), and transfer the complete contents into the nebuliser medication
chamber.
You should run the inhalation cycle twice if you require a high dose (5 micrograms) and once if you
require a low dose (2.5 micrograms). Independent of the dose the filling volume is always the contents
of one glass container.
The inhalation time depends on your breathing pattern.
Device
Dose of iloprost at mouthpiece
Estimated Inhalation time
(frequency of 15 breaths per minute)
HaloLite
2.5 micrograms
5 micrograms
4 to 5 min
8 to 10 min
Prodose
2.5 micrograms
5 micrograms
4 to 5 min
8 to 10 min
For the Venta-Neb system:
Just before you start to inhale,
break open the glass container and transfer the complete contents into
the nebuliser medication chamber.
Two programs can be operated:
Your doctor will adjust Venta-Neb to the program you need to receive the dose prescribed for you.
P1 Program 1 : 5.0 micrograms active substance on the mouth piece 25 inhalation cycles.
P2 Program 2 : 2.5 micrograms active substance on the mouth piece 10 inhalation cycles.
You should use the green baffle plate to obtain the optimal droplet size for the administration of
Ventavis.
Device
Dose of iloprost at mouthpiece
Estimated Inhalation time
Venta-Neb
2.5 micrograms
5 micrograms
4 min
8 min
For the I-Neb AAD system:
Just before you start to inhale,
break open the glass container containing 1 ml solution, which shows
two coloured rings (white - yellow), and transfer the complete contents into the nebuliser medication
chamber.
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.
32
For the 5 micrograms dose the medication chamber (650 microliter) with the purple coloured latch is
used together with the purple control disc.
You should make sure that you use the medication chamber with the red latch for the 2.5 micrograms
dose or the medication chamber with the purple latch for the 5 micrograms dose.
You should make also sure that the colour of the medication chamber latch fits with the colour of the
control disc used in order to receive the prescribed dose.
Device
Dose of iloprost at mouthpiece
Estimated Inhalation time
I-Neb AAD
2.5 micrograms
5 micrograms
3.2 min
6.5 min
For further details please refer to the instruction manual of the nebuliser device or ask your doctor.
Ask your doctor to have someone help you become thoroughly familiar with the use of the
nebuliser.
You should not switch to another nebuliser without consulting your treating doctor.
Caution:
Do not let Ventavis solution come into contact with your skin or eyes.
If it does, rinse the skin or
your eyes immediately with water. Do not drink Ventavis solution. If drinking accidentally occurs,
drink plenty of water and talk to a doctor. Drinking Ventavis could also lead to a temporary overdose
– see “
If you take more Ventavis than you should
”.
If you use more Ventavis than you should:
Using more Ventavis than you should may lead to a decrease in blood pressure with symptoms like
dizziness or fainting.
You may also experience headache, reddening of the face
(flushing)
, feeling sick
(nausea)
, vomiting or diarrhoea. If this happens:
Stop the inhalation session
Talk to your doctor
See also section 2, Take special care with Ventavis, for advice on what you have to do if you have
low blood pressure or fainting episodes.
If you forget to take a dose:
You should not take a double dose to make up for a forgotten dose. Please ask your doctor what you
should do.
If you stop taking Ventavis:
If you stop or wish to stop treatment, you should discuss this with your doctor first.
Room ventilation:
Be sure to ventilate or air the room in which you have taken your Ventavis treatment. Other persons
might accidentally be exposed to Ventavis through the room air.
In particular, newborns, infants, and
pregnant women should not be subjected to Ventavis.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
33
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Ventavis can cause side effects, although not everybody gets them. Below we list
possible side effects by how likely they are:
Very common: affects more than 1 user in 10.
Common:
affects 1 to 10 users in 100.
Very common side effects
-
Widening of the blood vessels
(vasodilatation)
. Symptoms can be flushing or reddening of the face.
- Increase in coughing
- Low blood pressure (hypotension).
Swelling, mainly of the ankles and legs, due to fluid retention
(
peripheral oedema) is a very
common symptom of the illness itself but can also occur during treatment with Ventavis.
Common effects
-
Headaches
- Pain in jaw/spasm of the jaw muscles
(trismus)
- Dizziness, which is related to low blood pressure
(hypotension)
- Fainting
(syncope)
-
Mouth and tongue irritation
-
Pain when swallowing
(pharyngolaryngeal pain)
and throat irritation
-
Rash
Fainting
(syncope)
is a common symptom of the illness itself but can also occur during
treatment with Ventavis.
See also section 2, Take special care with Ventavis, for advice on
what you can do to try and avoid this.
Side effects for which frequency is not known
- Hypersensitivity (i.e. allergy)
-
Disturbed sense of taste (
dysgeusia
)
Other possible effects
If you are also taking blood-thinning medicines
(anticoagulants)
, minor bleeding events are
likely to occur commonly. In this case ask your doctor.
Vomiting, nausea, diarrhoea and dyspnoea have been reported in patients using Ventavis.
Breathing difficulties and wheezing have been reported after Ventavis use, particularly in
patients with an infection of the lungs, severe asthma, or other lung disease.
Adverse events in healthy volunteers
Pain, discomfort in the breast (32.5 %), pain when swallowing
(pharyngolaryngeal pain, throat
irritation (22.5 %))
and nausea (7.5 %) were adverse events that occurred in healthy volunteers
in a special study, when they received fixed 2.5 microgram 6 times daily. All these adverse
events were non-serious and mild.
34
o
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
tell your doctor or pharmacist
.
5.
HOW TO STORE VENTAVIS
Keep out of the reach and sight of children.
Do not use Ventavis after the expiry date which is stated on the pack.
There are no special storage instructions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Ventavis contains:
The active substance
is iloprost.
1 ml solution contains 10 micrograms iloprost (as iloprost trometamol).
Each ampoule with 1 ml contains 10 micrograms iloprost.
Each ampoule with 2 ml contains 20 micrograms iloprost.
The other ingredients
are trometamol, ethanol 96%, sodium chloride, hydrochloric acid for pH
adjustment, and water for injections.
Ventavis is provided in colourless ampoules (type I glass), containing either 1 ml or 2 ml nebuliser
solution.
What Ventavis looks like and content of the pack:
Ventavis is a clear, colourless nebuliser solution for inhalation.
Ventavis is available in packs containing:
- 30, 90, 100, or 300 ampoules with 2 ml for the use with HaloLite, Prodose and Venta-Neb. The
ampoules containing 2 ml show two coloured rings (white – pink).
- or 30 or 168 ampoules with 1 ml for use with the I-Neb nebuliser. The ampoules containing 1 ml
show two coloured rings (white - yellow).
Not all pack-sizes may be marketed.
Marketing Authorisation Holder:
Bayer Schering Pharma AG, D-13342 Berlin, Germany
Manufacturer:
Berlimed S.A., Poligono Industrial Santa Rosa s/n, 28806 Alcalá de Henares, Madrid, Spain
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
Bayer SA-NV
Tél/Tel: +32-(0)2-535 63 11
Luxembourg/Luxemburg
Bayer SA-NV
Tél/Tel: +32-(0)2-535 63 11
България
Байер България ЕООД
Magyarország
Bayer Hungária KFT
35
тел. +359-(0)2-81 401 01
Tel.: +36-1-487 4100
Česká republika
Bayer s.r.o.
Tel: +420-266 101 111
Malta
.
Alfred Gera and Sons Ltd.
Tel: +35-621 44 62 05
Danmark
Bayer A/S
Tlf: +45-45 235 000
Nederland
Bayer B.V., Bayer Schering Pharma
Tel: +31-(0)297-28 06 66
Deutschland
Bayer Vital GmbH
Tel: +49-(0)214-30 513 48
Norge
Bayer AS
Tlf: +47-24 11 18 00
Eesti
Bayer OÜ
Tel: +372-655 85 65
Österreich
Bayer Austria Ges.m.b.H.
Tel: +43-(0)1-711 460
Ελλάδα
Bayer Ελλάς ΑΒΕΕ
Τηλ: +30-210-618 75 00
Polska
Bayer Sp. z o.o.
Tel.: +48-22-572 35 00
España
Química Farmacéutica Bayer S.L.
Tel: +34-93-495 65 00
Portugal
Bayer Portugal S.A.
Tel: +351-21-416 42 00
France
Bayer Santé
Tél.: +33-(0)3-28 16 34 00
Romania
SC Bayer SRL
Tel.: +40-(0)21-528 59 00
Ireland
Bayer Limited
Tel: + 353-(0)1-2999 313
Slovenija
Bayer d.o.o.
Tel: +386-(0)1-58 14 400
Ísland
Icepharma hf.
Sími: +354-540 8000
Slovenská republika
Bayer, spol. s r.o.
Tel. +421-(0)2-59 21 31 11
Italia
Italfarmaco S.p.A.
Tel: +39-02-644 31
Suomi/Finland
Bayer Oy, Bayer Schering Pharma
Puh/Tel: +358-(0)20-78521
Κύπρος
NOVAGEM Limited
Τηλ: +357-22-747 747
Sverige
Bayer AB
Tel: +46-(0)8-580 223 00
Latvija
SIA Bayer
Tel: +371-67 84 55 63
United Kingdom
Bayer plc
Tel: +44-(0)1635-56 30 00
Lietuva
UAB Bayer
Tel. +370-5-23 36 868
This leaflet was last approved in
36
This medicine has been authorised under “exceptional circumstances”.
This means that because of the rarity of this disease it has been impossible to get complete
information on this medicine.
The European Medicines Agency (EMEA) will review any new information on the medicine every
year and this leaflet will be updated as necessary.
------------------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only:
Instructions for use and handling
Two compressed air nebuliser systems,
HaloLite and Prodose
, have been shown to be suitable
nebulisers for the administration of Ventavis. For each inhalation session the content of one ampoule
containing 2 ml of Ventavis nebuliser solution will be transferred into the nebuliser medication
chamber immediately before use. HaloLite and Prodose are dosimetric systems. They stop
automatically after the pre-set dose has been delivered. The inhalation time depends on the patient’s
breathing pattern.
Device
Dose of iloprost at mouthpiece
Estimated Inhalation time
(frequency of 15 breaths per minute)
HaloLite
2.5 micrograms
5 micrograms
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 micrograms iloprost at mouthpiece it is recommended to complete two inhalation
cycles with 2.5 micrograms pre-set dose program with a filling of one ampoule containing 2 ml
Ventavis nebuliser solution, which shows two coloured rings (white – pink).
For details refer to the instruction manuals of the HaloLite and Prodose nebuliser.
VentaNeb
, 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 of Ventavis nebuliser solution
and showing two coloured rings (white – pink) will be transferred into the nebuliser medication
chamber immediately before use.
Two programs can be operated:
P1 Program 1: 5,0 micrograms active substance on the mouth piece 25 inhalation cycles.
P2 Program 2: 2,5 micrograms active substance on the mouth piece 10 inhalation cycles.
The selection of the pre set program is made by the physician.
VentaNeb 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
VentaNeb
2.5 micrograms
5 micrograms
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 forcing the solution through a mesh. The I-Neb
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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 and 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.
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 micrograms
5 micrograms
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 VentaNeb devices and a faster delivery of the
solution, patients stabilized on one nebuliser should not switch to another nebuliser without
supervision by the treating physician.
The efficacy and tolerability of inhaled iloprost when administered with other nebulising systems,
which provide different nebulisation characteristics of iloprost solution, have not been established.
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Source: European Medicines Agency
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