Consumer medicine information

Ventavis

Iloprost

BRAND INFORMATION

Brand name

Ventavis

Active ingredient

Iloprost

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ventavis.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Ventavis. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Ventavis against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

WHAT VENTAVIS IS USED FOR

Ventavis is used to treat:

  • Moderate or severe stages of pulmonary hypertension, caused by some defect of the vessel walls, connective tissue disease or other medications
  • Moderate and severe cases of secondary pulmonary hypertension that may have been caused by blood clots in the lungs, where surgery is not possible

Pulmonary hypertension is a condition where blood pressure is too high in the vessels which transport blood from the heart to the lungs.

Ventavis widens blood vessels, allowing more blood to reach the lungs and receive oxygen. This widening results in a decreased work load on the heart, which in turn allows the heart to function more effectively, leading to an improved supply of oxygen to the body and reduced strain on the heart.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

BEFORE YOU USE VENTAVIS

When you must not take it

Do not take Ventavis if you have an allergy to:

  • iloprost, the active ingredient of Ventavis
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take Ventavis if you have any of the following conditions:

  • increased risk of bleeding (for example active stomach ulcers, injuries, haemorrhaging or other bleeding)
  • Severe coronary heart disease or unstable angina (chest pain), heart attack within the last six months
  • Heart failure, severe irregular heart rate, suspected fluid build-up in the lungs
  • Stroke or other interruption of blood supply to the brain within the last 3 months
  • pulmonary hypertension due to the blockage of the veins
  • Congenital or acquired valvular defects with heart function which are not related to your disease

If you suffer from pulmonary hypertension, avoid getting pregnant as pregnancy may lead to a worsening of your condition and may even endanger your life.

If there is the possibility that you may become pregnant, use reliable contraception from the time you start treatment and during treatment.

Tell your doctor straight away if you are pregnant, or think you might be. The medicine should only be used during pregnancy if you doctor decides that the potential benefit outweighs the potential risk to the foetus.

Do not breast-feed if you are taking this medicine. It is not known whether the medicine passes into human milk.

Do not use this medicine after the expiry date printed on the pack and blister. The expiry date is printed on the carton and on each blister after “EXP” (e.g. 1118 refers to November 2018). The expiry date refers to the last day of that month. If it has expired return it to your pharmacist for disposal.

Do not use this medicine if the packaging is torn or shows signs of tampering. If the packaging is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • heart failure
  • low blood pressure
  • lung infections or other lung disease including Chronic Obstructive Pulmonary Disease (COPD) and severe asthma
  • liver function problems, or problems with your kidneys that require dialysis

If you have a history of fainting in association with pulmonary hypertension; you should avoid any unusual straining, for example during exercise; if fainting occur when you get out of bed, it may be helpful to take the first dose of the day while you are still in bed; if fainting gets worse, tell your doctor.

If you have not told your doctor about any of the above, tell him/her before you start using Ventavis.

Ventavis is not recommended for use in children under 18 years of age.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Ventavis may interfere with each other. These include:

  • Medicines used to treat high blood pressure or heart disease
  • Medicines which inhibit blood clotting or platelet aggregation [this includes Aspirin® or acetylsalicylic acid, warfarin, heparin, clopidogrel, NSAIDs, e.g. ibuprofen (Nurofen®), diclofenac (Voltaren®), as well as others]

These medicines may be affected by Ventavis or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

HOW TO USE VENTAVIS

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions printed on the pharmacist label, ask your doctor or pharmacist for help.

Caution: Ventavis solution should not come in contact with your skin or eyes; oral ingestion of Ventavis solution should be avoided. During nebulisation sessions a facial mask must not be used. Only a mouthpiece should be used.

How much to use

The usual dose per inhalation that is right for you depends on your individual condition and will be worked out by your doctor.

How to use it

Ventavis is taken as inhalation therapy using a special device (a nebuliser).

At the beginning of each inhalation session, a new ampoule of Ventavis should be used. Break the ampoule and transfer the contents of one ampoule of Ventavis completely into the nebuliser immediately before use.

In patients with liver problems, severe kidney problems and require dialysis, your doctor may consider different initial doses and dosing intervals depending on how you tolerate the treatment.

Depending on your individual condition, you will have 6 to 9 inhalation sessions per day. The duration of one inhalation session is about 4 to 10 minutes.

The pulmonary vessel widening effect of Ventavis is of short duration (one or two hours).

To minimise accidental exposure, it is recommended to use Ventavis with nebulisers with a filter or inhalation-triggered systems, and to keep the room well ventilated. Your doctor will advise you on the appropriate nebuliser to be used. Any additional instructions from the manufacturer of the nebulising device should also be followed carefully.

Ventavis solution that is not used in one inhalation session has to be discarded.

If the effect of Ventavis seems too strong or too weak, talk to your doctor or pharmacist.

How long to take it for

The duration of your treatment will be determined by your specialist.

If you take too much (overdose)

This may lead to dizziness, headache, flushing (reddening of the face), nausea (feeling sick), jaw pain or back pain. You may also experience an increase or decrease in blood pressure, slow heartbeat, fast heartbeat, vomiting, diarrhoea or limb pain.

Have someone contact a doctor immediately in these cases and mention that you are taking iloprost. Please be sure to tell your doctor if you have problems with these side effects. The doctor will need to monitor your condition and possibly administer appropriate therapy.

Interruption of inhalation is recommended in this case.

It is also advisable to telephone the Poisons Information Centre (Australia: 13 11 26 or New Zealand: 0800 POISON or 0800 764 766) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Ventavis. Do this even if there are no signs of discomfort or poisoning.

WHILE YOU ARE USING VENTAVIS

Things you must do

Tell any other doctors, dentists or pharmacists who are treating you that you are taking Ventavis.

If you are about to be started on any new medicine tell your doctor, dentist or pharmacist that you are taking Ventavis.

If you become pregnant while taking this medicine, tell your doctor immediately.

Things you must not do

Do not take Ventavis to treat any other complaints unless your doctor tells you to.

Do not give Ventavis to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor. If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects.

Things to be careful of

Do not drive or operate any tools or machines if you sense low blood pressure or dizziness occurring; the ability to properly drive or operate machines might be seriously affected.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Ventavis.

This medicine helps most people, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you.

The list below includes the most common side effects of your medicine seen.

  • widening of blood vessels (this may cause flushing, that is, a reddening of the face)
  • bleeding (mostly nosebleed or coughing up of blood); some serious cases of bleeding have been reported
  • chest pain
  • headache
  • increased cough
  • nausea and vomiting
  • pain in jaw or spasm of the jaw muscles (difficulty in opening the mouth)
  • pain when swallowing
  • fast or irregular heartbeat
  • low blood pressure
  • dizziness
  • diarrhoea
  • rash
  • back pain
  • swelling, usually in the legs
  • mouth and tongue irritation (including pain)
  • throat irritation
  • breathlessness
  • nasal congestion (stuffy nose)
  • fainting is a common symptom of the illness itself, but can also occur under therapy

You should tell your doctor immediately if you have any of the following:

Hypersensitivity, shortness of breath, wheezing.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

AFTER USING VENTAVIS

Storage

Keep Ventavis in a cool dry place where the temperature stays below 30°C.

Keep it where children cannot reach it. A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Return any unused medicine to your pharmacist.

PRODUCT DESCRIPTION

What it looks like

It comes as a (liquid) solution in a 3-mL glass ampoule and is administered as an aerosol by using a special inhalation device.

Each Ventavis ampoule contains 2 mL of solution for one inhalation session. A pack of Ventavis contains 6 or 30 ampoules.

Ingredients

Active ingredient:

  • Ventavis - 20 µg iloprost (as trometamol) per 2 mL solution

It also contains:

  • trometamol
  • 96% ethanol
  • sodium chloride
  • hydrochloric acid
  • water for injections

Australian Registration Number

Ventavis - AUST R 97219

Supplier

Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073

Bayer New Zealand Limited
3 Argus Place, Hillcrest,
North Shore
Auckland 0627

Date of preparation

March-2020

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

See MEDSAFE website (www.medsafe.govt.nz) for latest New Zealand Consumer Medicine Information.

® Registered Trademark of Bayer AG, Germany

© Bayer Australia Ltd

All rights reserved.

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Ventavis

Active ingredient

Iloprost

Schedule

S4

 

1 Name of Medicine

Iloprost.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

CAS: 73873-87-7.
Chemical name: (E)-(3aS,4R,5R,6aS)-hexahydro -5-hydroxy -4((E)-(3S,4RS) -3-hydroxy -4methyl-1octen -6-ynyl)-Δ2(1H)δ-pentalenevaleric acid.
Molecular formula: C22H32O4.
Molecular weight: 360.48.

2 Qualitative and Quantitative Composition

Ventavis 10 microgram/mL nebuliser solution. One ampoule with 2 mL nebuliser solution contains 26.8 microgram iloprost trometamol equivalent to 20 microgram iloprost. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Nebuliser solution.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Iloprost, the active ingredient of Ventavis, is a synthetic prostacyclin analog.
The pharmacological effects after inhalation of Ventavis are:
Direct vasodilatation of the pulmonary arterial bed occurred with consecutive significant improvement of pulmonary artery pressure, pulmonary vascular resistance and cardiac output as well as mixed venous oxygen saturation. Effects on systemic vascular resistance and systemic arterial pressure were minor.
Laboratory Code ZK 36374.

Clinical trials.

Clinical studies on the efficacy and safety of Ventavis solution for inhalation have been conducted. A phase II study (A00794) and a phase III study (A02997) comprise the main efficacy and safety data.

Phase II study (A00794).

This was an open label randomised phase II multicentre study which included a three month controlled phase (with either inhaled iloprost added to conventional therapy or conventional therapy alone) before patients went on to an open label, long-term therapy with inhaled iloprost for up to two years.
Patients with NYHA functional class II, III or IV were included with a mPAP of about 30 or 40 mmHg, for PPH or SPH respectively.
Thirty patients were randomised to the iloprost group and 33 to the control group. Fifteen patients prematurely discontinued study medication (8 iloprost and 7 control patients). After the end of the three month phase, 52 patients entered the long-term treatment phase with inhaled iloprost for up to 24 months.
During the randomised phase the median nominal daily iloprost dose was 100 microgram (50 microgram-150 microgram). During the long-term study phase the median range daily dose was 100 microgram (range 50 microgram to 200 microgram).
The following results were obtained during the three month randomised phase.
Improvement in the physical condition of the patients receiving iloprost (all health related quality of life outcomes showed more frequent improvement with iloprost).
Significant improvement with iloprost in patients who improved by at least one NYHA class at month two (p = 0.013), improvement of the Mahler focal score at month two and the Mahler transition score at each time point.
Nonsignificant improvement in walking distance with iloprost (p = 0.620).
Mortality was similar in both treatment groups.
Statistically significant difference between treatment groups in favour of iloprost. At month 3, p = 0.046.
The following interim results were obtained from 9-12 months of the follow-up phase.
Patients remained stable or improved (NYHA class and Mahler dyspnoea index).
Preinhalation values of haemodynamics and gas exchange remained stable compared to baseline.
Peak haemodynamic effect improved significantly.
Acute response to iloprost inhalation maintained after long-term treatment. No development of drug effect tolerance.

Phase III study (A02997).

This was a multicentre double blind randomised placebo controlled efficacy and safety study of 12 weeks duration. The study included 203 patients belonging to class III or IV NYHA functional class. The median inhaled iloprost daily dose was 30 microgram divided into 6 inhalations (range 12.5 microgram to 45 microgram). There was no tolerance development.
The primary endpoint was a combined responder criterion consisting of improvement in exercise capacity at 12 weeks by at least 10% versus baseline and improvement by at least one NYHA class at 12 weeks via baseline and no deterioration of PHT or death at any time before 12 weeks.
Iloprost showed superior efficacy compared to placebo with 16.8% (17/101) iloprost patients meeting the combined responder endpoint while only 4.9% (5/102) of placebo patients reached the primary endpoint (p = 0.007).
Exercise capacity: at week 12, at least 10% increase in the six minute walking distance as compared to baseline was noted in 37.6% of the iloprost group and 25.5% of the control group (p = 0.059).
NYHA functional class: in the iloprost group 24.8% improved versus 12.7% in the placebo group (p = 0.032).
Death and defined criteria of deterioration: one patient in the iloprost group and four patients in the placebo group died (p = 0.369) during the 12 week observation period. One patient from the iloprost group died after discontinuing the study. During the follow-up period (up to week 16), 2 further patients originally randomised to the iloprost group and 3 placebo patients died. There was no statistically significant difference in the rate of death or deterioration in patients taking iloprost compared to placebo.
Mahler dyspnoea index: iloprost showed a significantly better improvement compared to placebo (p = 0.015).
The overall incidence of side effects reported up to 12 weeks were comparable between the treatment groups for both the phase I and phase II study. (See Table 2.)
The HaloLite nebuliser system was used to administer Ventavis in the clinical trial.

5.2 Pharmacokinetic Properties

Absorption.

When iloprost is administered via inhalation in patients with pulmonary hypertension (iloprost dose at the mouthpiece: 5 microgram), mean peak serum concentrations of 100 to 200 picogram/mL were observed at the end of inhalation. These concentrations 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 picogram/mL).

Distribution.

No studies performed following inhalation.
Following intravenous infusion, the apparent steady-state volume of distribution was 0.6 to 0.8 L/kg in healthy subjects. Total plasma protein binding of iloprost is concentration independent in the range of 30 to 3000 picogram/mL and amounts to approximately 60%, of which 75% is due to albumin binding.

Metabolism.

No studies to investigate the metabolism of iloprost were performed following inhalation of Ventavis.
Iloprost is extensively metabolised principally via β-oxidation of the carboxyl side chain. No unchanged substance is eliminated. The main metabolite is tetranor iloprost, which is found in the urine in free and conjugated form in 4 diastereoisomers. Tetranor iloprost is pharmacologically inactive as shown in animal experiments. In vitro studies suggest that metabolism of iloprost in the lungs is similar after intravenous administration or inhalation.

Excretion.

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

Characteristics in patients.

Renal dysfunction.

The pharmacokinetics of intravenous iloprost was investigated in an open label, comparative study in 21 patients with chronic renal failure (CRF) not on dialysis (group 1) and patients with CRF on dialysis (group 2).
Group 1 contained 10 patients with a mean creatinine clearance of 0.29 ± 0.12 mL/minute/kg and group 2 included 11 patients with a mean creatinine clearance of 0.16 ± 0.05 mL/minute/kg. Iloprost was administered as an intravenous infusion at a rate of 1 nanogram/kg/minute for 60 minutes. The mean results are shown in Table 3.
Patients with endstage renal failure undergoing intermittent dialysis treatment were 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). The half-lives were similar in the two groups.

Hepatic dysfunction.

The pharmacokinetics of intravenous iloprost was investigated in an open labelled, uncontrolled study of 8 patients with liver impairment. The cirrhosis was of alcoholic origin in all cases except one which was cryptogenic. Five of the eight patients were Child-Pugh class B, two were class C and one was class A. Iloprost was given as an intravenous infusion at a rate of 1 nanogram/kg/minute for 60 minutes. The mean pharmacokinetic results compared with historical controls are given in Table 4.
Because iloprost is extensively metabolised by the liver, the plasma levels of the drug are influenced by changes in hepatic function. The mean clearance of iloprost in the study was estimated to be 10 mL/minute/kg. The results indicate that clearance of iloprost was reduced by 50% in the group of cirrhotic patients compared to the historical control groups. There is no effect on t1/2.

Age and gender.

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

5.3 Preclinical Safety Data

Genotoxicity.

Iloprost is not a mutagen in bacterial and mammalian cells in vitro, and in the micronucleus test in vivo.

Carcinogenicity.

There have been no carcinogenicity studies by the inhalation route. No tumorigenic potential was demonstrated in carcinogenicity studies in mice and rats dosed orally with up to 16 mg/kg/day iloprost for 22-24 months (9-12 times the clinical exposure based on Cmax).

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of patients with primary pulmonary hypertension or secondary pulmonary hypertension due to connective tissue disease or drug induced, in moderate or severe stages of the disease. In addition, treatment of moderate or severe secondary pulmonary hypertension due to chronic pulmonary thromboembolism, where surgery is not possible.

4.3 Contraindications

Hypersensitivity to iloprost 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, severe arrhythmias, suspected pulmonary congestion, 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.

4.4 Special Warnings and Precautions for Use

Identified precautions.

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.
The pulmonary vasodilatory effect of inhaled iloprost is of short duration (one or two hours).

Risk of syncope.

Physicians should be alert to the presence of concomitant conditions or drugs that might increase the risk of syncope (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Syncope is also a common symptom of the disease itself. Patients who have a history of syncope in association with pulmonary hypertension should avoid any unusual straining, for example during exercise. Before exercise it might be useful to inhale Ventavis. The pulmonary vasodilatory effect of inhaled iloprost is short duration (one to two hours). The increased occurrence of syncopes can reflect insufficient therapeutic effect and/or deterioration of the underlying disease. The need to adapt and/or change the therapy should be considered. If syncope occurs on rising, it may be helpful to take the first dose of the day on waking, while still recumbent.

Hypotension.

Vital signs should be monitored while initiating Ventavis. 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 pressure less than 85 mmHg.

Bronchospasm.

Ventavis inhalation might entail the risk of inducing bronchospasm, especially in patients with bronchial hyper-reactivity (see Section 4.8 Adverse Effects (Undesirable Effects)). The benefit of Ventavis has not been established in patients with concomitant chronic obstructive pulmonary disease (COPD) and severe asthma. Patients with concomitant acute pulmonary infections, COPD, and severe asthma should be carefully monitored.

Pulmonary venous hypertension.

Ventavis should not be used as the first treatment option in thromboembolic pulmonary hypertension if surgery is feasible.
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.

Use in hepatic and renal impairment.

Based on data with intravenously administered iloprost the elimination is reduced in patients with hepatic dysfunction and in patients with renal failure requiring dialysis and a dose reduction may be considered. A cautious initial dose titration using dosing intervals of 3-4 hours is recommended (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties.

Paediatric use.

The experience in children and adolescents (patients below 18 years of age) is limited. Therefore Ventavis is not recommended for use in this population (see Section 4.2 Dose and Method of Administration).

Other.

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.
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.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Iloprost may increase the antihypertensive effect of vasodilating and antihypertensive agents. Caution is recommended in case of coadministration of Ventavis with vasodilating or antihypertensive agents as dose adjustment might be required.
Because iloprost inhibits platelet function, its use with anticoagulants (such as heparin, coumarin type anticoagulants), or other inhibitors of platelet aggregation (such as acetylsalicylic acid, nonsteroidal anti-inflammatory drugs, nonselective phosphodiesterase inhibitors [e.g. theophylline, pentoxifylline, dipyridamole], selective phosphodiesterase 3 [PDE3] inhibitors [e.g. milrinone, cilostazol, anagrelide] and nitrovasodilators) may enhance iloprost mediated platelet inhibition, thereby increasing the risk of bleeding (see Section 4.8 Adverse Effects (Undesirable Effects)). If bleeding occurs, iloprost administration should be stopped. Careful monitoring of the patients taking anticoagulants or inhibitors of platelet aggregation according to common medical practice is recommended.
Oral premedication with acetylsalicylic acid up to 300 mg/day over a period of 8 days had no impact on the pharmacokinetics of iloprost. The results of human studies show that iloprost infusions do not affect the pharmacokinetics of multiple oral doses of digoxin in patients and iloprost has no impact on the pharmacokinetics of coadministered t-PA. In an animal study, it was found that iloprost may result in a reduction in t-PA steady-state plasma concentration.
In animal experiments, the vasodilatory effect of iloprost is attenuated when the animals are pretreated with glucocorticoids, while the inhibitory effect on platelet aggregation remains unaffected. The significance of this finding for use of Ventavis in man is not yet known.
Although, clinical studies have not been conducted, in vitro studies investigating the inhibitory potential of iloprost on the activity of cytochrome P450 enzymes revealed that no relevant inhibition of drug metabolism via these enzymes by iloprost is expected.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility was not impaired in rats treated with up to 1 mg/kg/day IV and up to 34.4 mg/kg/day PO iloprost (approximately 600 times the clinical exposure based on AUC).
(Category B3)
Women with pulmonary hypertension (PH) must avoid pregnancy as it may lead to life threatening exacerbation of the disease.
There are no adequate data from the use of Ventavis in pregnant women. In embryo- and fetotoxicity studies in rats, continuous IV infusion of iloprost increased skeletal anomalies at 0.01-1 mg/kg/day (incomplete ossification and shortened digits of the forepaws) and embryofetal resorption at 1 mg/kg/day. Increased embryofetal resorption and/or incomplete ossification, but not shortened digits, were also observed in rats treated with 34.4 mg/kg/day iloprost by oral gavage (ca 600 times the clinical exposure based on AUC) or in rabbits treated with 0.5 mg/kg/day iloprost by continuous IV infusion or 5.6 mg/kg/day by oral gavage (ca 300 times the clinical exposure based on AUC). There was no evidence of embryofetal toxicity in a monkey study at up to 40 microgram/kg/day (9 fetuses examined at this dose) by continuous IV infusion (60 times the anticipated clinical exposure based on AUC). The gestation time in rats was also prolonged slightly at 1 mg/kg/day by continuous IV infusion.
The potential risk to humans is not known. There are no adequate and well controlled studies in pregnant women. The limited amount of data regarding safety of inhaled iloprost in pregnancy, to both the pregnant woman and the unborn child, is based on the experience of a small number of women exposed during pregnancy, and a small number of paediatric cases exposed in utero, reported to the sponsor and in the published literature. Therefore women of childbearing potential should use effective contraceptive measures during treatment with Ventavis. If pregnancy occurs, Ventavis should only be used following careful risk/ benefit evaluation.
Low levels of iloprost or its metabolites are excreted into milk by lactating rats. Pup viability was reduced when lactating rats were treated with 1 mg/kg/day iloprost by continuous IV infusion or 34.4 mg/kg/day by oral gavage, with no effects on postnatal development at 0.1 mg/kg/day IV (68 times the clinical exposure based on AUC) and 0.7 mg/kg/day PO (20 times the clinical exposure based on AUC). There are no human data on the excretion of iloprost/ metabolites into human breast milk or on the safety of Ventavis exposure in infants. There are no adequate and well controlled studies to support the efficacy and safety in lactating women. Therefore women should not breastfeed during treatment with Ventavis.

4.8 Adverse Effects (Undesirable Effects)

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 prostaglandins. The most frequently observed adverse reactions (≥ 20%) in clinical trials include vasodilatation, headache and cough. The most serious adverse reactions were hypotension, bleeding events and bronchospasm.
The adverse drug reactions (ADRs) reported below are based on clinical trial data involving 131 patients taking the medication. The frequencies of ADRs are defined as: very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1,000 to < 1/100; rare: ≥ 1/10,000 to < 1/1,000; very rare: < 1/10,000. See Table 1.
As expected in patients with pulmonary hypertension, syncopes were common, and did not differ significantly between the treatment groups in frequency (see Section 4.4 Special Warnings and Precautions for Use).
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 it may also be related to the therapy.

Postmarketing adverse events.

Hypersensitivity, bronchospasm#, dysgeusia, thrombocytopenia, wheezing and nasal congestion have also been reported in patients treated with Ventavis (see Section 4.4 Special Warnings and Precautions for Use, Bronchial hyper-reactivity).
# Life threatening and/or fatal cases have been reported.

Adverse reactions in healthy volunteers.

In a 4 arm equally randomised placebo controlled study in 160 healthy volunteers, inhaled doses of iloprost solution were given either with a fixed dose of 2.5 microgram iloprost 6 times daily (total daily dose of 15 microgram) or beginning with 5.0 microgram and increasing up to 20 microgram or the highest tolerated dose for a total of 6 dose inhalations (total cumulative dose of 70 microgram).
In the fixed dose group of 2.5 microgram per inhalation chest pain, discomfort (32.5%), pharyngolaryngeal pain, throat irritation (22.5%) and nausea (7.5%), all nonserious and mild in intensity, occurred more frequently in comparison with the adverse reactions obtained from the placebo controlled phase II and III studies in patients with doses of 2.5 microgram or 5 microgram per inhalation.
Five patients were unable to increase the dose up to 20 microgram per inhalation because of mild to moderate transient chest pain, discomfort, usually accompanied by headache, dizziness and nausea.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

The solution is administered with a suitable inhalation device (nebuliser) as recommended in instruction for use and handling). Previous therapy should be adjusted to individual needs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). In order for the correct dose of iloprost to be delivered to the patient a suitable nebuliser must be used. The HaloLite nebuliser described in the Clinical trials section is not currently available in Australia. Clinical data on the use of other similar nebulisers with Ventavis is not available.
Ventavis nebuliser solution should not come into contact with skin and eyes; oral ingestion of Ventavis solution should be avoided.

Recommended dose.

Adults.

At initiation of Ventavis treatment the first inhaled dose should be 2.5 microgram iloprost (as delivered at the mouthpiece). 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 microgram.
The dose per inhalation session should be administered 6 to 9 times per day during waking hours according to the individual need and tolerability.
Depending on the desired dose at the mouthpiece and on the nebuliser, the duration of an inhalation session is approximately 4 to 10 minutes.

Patients with hepatic impairment.

Iloprost elimination is reduced in patients with hepatic dysfunction. Caution should be used during therapy in patients with Child-Pugh class B or more severe hepatic impairment. It should also be used with caution in patients with mild to moderate hepatic impairment. 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 maximum 6 times per day during waking hours). Thereafter, dosing intervals may be shortened cautiously based on individual tolerability. If a further increase in the dose up to 5.0 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.

Patients with renal impairment.

There is no need for dose adaptation in patients with a creatinine clearance > 30 mL/minute (as determined from serum creatinine using the Cockroft and Gault formula). Patients with a creatinine clearance ≤ 30 mL/minute were not investigated in the clinical trials. Based on data with intravenously administered iloprost the elimination is reduced in patients with renal failure requiring dialysis. Caution should be exercised in treating patients with severe renal failure. Therefore, the same dosing recommendations as in patients with hepatic impairment are to be applied (for dosing recommendations, see Patients with hepatic impairment).

Paediatric patients/ children and adolescents (below 18 years of age).

The experience in children and adolescents (patients below 18 years of age) is limited. Therefore, Ventavis is not recommended for use in this population (see Section 4.4 Special Warnings and Precautions for Use).

Duration of treatment.

Long-term 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.

Instructions for use/ handling.

For each inhalation session a new ampoule of Ventavis should be used. The content of the opened ampoule has to be completely transferred into the nebuliser chamber immediately before use.
Nebuliser solution not used in one inhalation session has to be discarded. In addition, instructions for hygiene and cleaning of the nebulisers provided by the device manufacturers should be followed carefully.

Use with nebulisers.

In general, suitable nebulisers to be used for the inhalation therapy with Ventavis nebuliser solution are CE certified and work with compressed air.
Nebulisers suitable for inhalation of iloprost should deliver 2.5 microgram or 5 microgram iloprost at the mouthpiece in a time period of approximately 4 to 10 minutes. The Mass Median Aerodynamic Diameter (MMAD) of the aerosol is between 2 and 4 micrometers. The respirable range of particles is 1-5 micrometers. To minimise accidental exposure, it is recommended to use Ventavis with nebulisers with a filter or inhalation triggered systems, and to keep the room well ventilated.
Nebuliser systems should be checked with the manufacturer of the nebuliser to ensure compliance with the above requirements of MMAD before use with Ventavis.
If switching to a different type of nebuliser supervision by the treating physician is necessary.

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, ability to drive or operate machines may be seriously affected.

4.9 Overdose

Cases of overdose were reported. Frequently observed symptoms following overdose are dizziness, headache, flushing, nausea, jaw pain or back pain. Hypotension, an increase of blood pressure, bradycardia or tachycardia, vomiting, diarrhoea and limb pain might also be possible.

Therapy.

A specific antidote is not known. Interruption of iloprost administration, monitoring and symptomatic measures are recommended.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Trometamol, ethanol 96%, sodium chloride, hydrochloric acid and 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

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Container type: Ampoules of 3 mL, colourless, glass type I, containing 2 mL nebuliser solution. Each ampoule contains 20 microgram iloprost.
Pack sizes: Pack containing 6 or 30 ampoules.
Some strengths, pack sizes and/or pack types may not be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

Summary Table of Changes