VENTAVIS 10 micrograms/ml SOLUTION FOR NEBULIZER INHALATION

Introduction

Package Leaflet: Information for the User

Ventavis 10 micrograms/ml solution for inhalation by nebuliser

Iloprost

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

1. What Ventavis is and what it is used for
2. What you need to know before you use Ventavis
3. How to use Ventavis
4. Possible side effects
5. Storage of Ventavis
6. Contents of the pack and other information

1. What Ventavis is and what it is used for

What Ventavis is

The active substance of Ventavis is iloprost. Iloprost mimics a natural substance in the body called prostacyclin. Ventavis inhibits unwanted blockage or narrowing of blood vessels and allows more blood to flow through the blood vessels.

What Ventavis is used for

Ventavis is used to treat moderate cases of primary pulmonary hypertension (PPH) in adult patients. PPH is a type of pulmonary hypertension where the cause of the increased blood pressure is unknown.

This is a disease where the blood pressure is too high in the blood vessels between the heart and the lungs.

Ventavis is used to improve exercise capacity (i.e. the ability to perform physical activities) and symptoms of this disease.

How Ventavis works

When you inhale the aerosol, Ventavis reaches the lungs, where it works most effectively on the artery between the heart and the lungs. By improving blood flow, oxygen supply to the body is improved and the load on the heart is reduced.

2. What you need to know before you use Ventavis

Do not use Ventavis

• if you are allergicto iloprost or any of the other ingredients of this medicine (listed in section 6),
• if you are at risk of bleeding- for example, if you have an active stomach ulcer or ulcer in the first part of the small intestine (duodenal ulcers), if you have suffered a physical injury (trauma), if you are at risk of bleeding in the brain,

• if you have a heart problem, such as

• insufficient blood flow to the heart muscle (severe coronary artery disease or unstable angina). A symptom may include chest pain,

• a heart attack in the last six months,
• weak heart (decompensated heart failure) that is not under close medical supervision,
• severe heart rhythm disorders,
• a heart valve defect (congenital or acquired) that makes the heart not work properly (not related to pulmonary hypertension),
• if you have had a stroke or any other event that has reduced blood flow to the brain(e.g. transient ischaemic attack) in the last 3 months,

• if your pulmonary hypertension is due to a blocked or narrowed vein(veno-occlusive disease).

Warnings and precautions

Talk to your doctor, pharmacist or nurse before you start using Ventavis:

• Inhaling Ventavis may trigger breathing difficulties (see section 4), especially in patients with bronchospasm (a sudden narrowing of the muscle of the small airways) and wheezing. Tell your doctor if you have a lung infection, severe asthma or other chronic lung disease(chronic obstructive pulmonary disease). Your doctor will monitor you closely.

• Your blood pressure will be taken before treatment and if it is too low(less than 85 mmHg for the highest value) you should not start therapy with Ventavis.

• In general, you will need to take special care to avoid the effects of low blood pressure, such as fainting and dizziness:
• • Tell your doctor if you are taking other medicines, as the combination with Ventavis may lower your blood pressure even further (see also "Using Ventavis with other medicines").

• Get up slowly from a chair or bed.
• If you tend to faint when getting up from bed, it may be helpful to take the first dose of the day while still lying down.
• If you tend to have fainting episodes, avoid any exceptional effort, for example during physical exercise; it may be helpful to inhale Ventavis before doing so.
• Fainting episodes may be due to the underlying disease. Tell your doctor if they get worse, as he/she may consider adjusting the dose or changing the treatment.

• If you have a heart condition, such as right heart failure and notice that your condition is getting worse, tell your doctor. Symptoms may include swelling of feet and ankles, difficulty breathing, palpitations, need to urinate more frequently at night or oedema. Your doctor will consider whether to change the treatment.

• If you have difficulty breathing, cough up blood and/or sweat excessively, these may be signs that you have fluid in the lungs(pulmonary oedema). Stop using Ventavis and tell your doctor immediately. He/she will look for the cause and take appropriate measures.

• If you have liver or severe kidney problems that require dialysis, tell your doctor. He/she may gradually change you to the prescribed dose or prescribe a lower dose of Ventavis than for other patients (see section 3 "How to use Ventavis").

Ventavis contact with skin or ingestion of Ventavis

• Do not let the Ventavis solution come into contact with the skin or eyes. If this happens, wash the skin or eyes immediately with plenty of water.

• Do not drink or swallow the Ventavis solution.

If this happens accidentally, drink plenty of water and tell your doctor.

Children and adolescents

The safety and efficacy of Ventavis in children up to 18 years of age have not been established.

Other medicines and Ventavis

Tell your doctor or pharmacist if you areusing, have recently used or might use any other medicines. Ventavis may affect how other medicines work and vice versa.

Tell your doctor if you are taking:

• Medicines for the treatment of high blood pressure or heart disease, such as

• beta-blockers,
• vasodilators of the nitrate type,
• ACE inhibitors.

Your blood pressure may drop too low.

Your doctor may change your dose.

• Medicines that make the blood less thick or that inhibit its coagulation, such as

• acetylsalicylic acid (AAS, a compound present in many medicines that reduces fever and relieves pain),
• heparin,
• anticoagulants of the coumarin type, such as warfarin or phenprocoumon,
• non-steroidal anti-inflammatory drugs,
• non-selective phosphodiesterase inhibitors, such as pentoxifylline,
• selective phosphodiesterase 3 inhibitors (PDE 3), such as cilostazol or anagrelide,
• ticlopidine,
• clopidogrel,
• glycoprotein IIb/IIIa antagonists, such as
• • abciximab,
  • eptifibatide,
  • tirofiban

• defibrotide

Your doctor will keep you under close supervision.

Before taking any medicine, talk to your doctor or pharmacist, who has more information on medicines that you should be cautious with or avoid when using Ventavis.

Using Ventavis with food and drinks

It is unlikely that food or drinks will affect Ventavis. However, you should avoid eating or drinking during inhalation.

Pregnancy

• If you have pulmonary hypertension, avoid becoming pregnant, as pregnancy can worsen your disease and even put your life at risk.

• If you could become pregnant, use reliable contraceptives from the start of treatment and during treatment.
• If you are pregnant, think you may be pregnant or plan to become pregnant, tell your doctor immediately. Ventavis should only be used during pregnancy if your doctor decides that the potential benefit outweighs the possible risks to you and the fetus.

Breast-feeding

It is not known whether Ventavis passes into breast milk. The potential risk to breast-fed infants cannot be excluded and breast-feeding should be avoided during treatment with Ventavis.

Ask your doctor or pharmacist for advice before taking any medicine.

Newborns, infants and pregnant women should not be in the same room while you are inhaling Ventavis.

Driving and using machines

Ventavis lowers blood pressure and may cause dizziness or instability in some people.

Do not drive or use tools or machines if you notice these effects.

Ventavis contains ethanol

Ventavis 10 micrograms/ml contains 0.81 mg of alcohol (ethanol) in each ml, which is equivalent to 0.081% (v/v). The amount of 0.81 mg of alcohol in 1 ml of this medicine is equivalent to less than 1 ml of beer or wine.

The small amount of alcohol in this medicine does not produce any noticeable effect.

3. How to use Ventavis

Treatment with Ventavis should only be initiated by a doctor with experience in the treatment of pulmonary hypertension.

How much to inhale and for how long

Follow exactly the administration instructions of this medication as indicated by your doctor.

In case of doubt, consult your doctor again.

The dose of Ventavis you need and the duration of treatment you need depend on your condition. Your doctor will advise you. Do not change the recommended dose without consulting your doctor first.

Different nebulizer devices can be used to administer Ventavis. Depending on the type of device used and the prescribed dose, it is appropriate to use 1 ml or 2 ml of Ventavis 10 micrograms/ml.

• Breelib Nebulizer

When starting treatment with Ventavis or if you switch from an alternative device, the first inhalation should be done with Ventavis 10 micrograms/ml (1 ml ampoule with white and yellow rings). If you tolerate this dose well, your next inhalation will be with Ventavis 20 micrograms/ml (ampoule with yellow and red rings). You should continue with this dose.

If you cannot tolerate the inhalation of Ventavis 20 micrograms/ml, consult your doctor, who may decide that you should receive Ventavis 10 micrograms/ml (1 ml ampoule).

Most people will need to perform 6 to 9 inhalation sessionsspread throughout the day. The duration of each inhalation session with Breelib is usually 3 minutes.

Your doctor will monitor your treatment when you start using the Breelib nebulizer to ensure that you tolerate the dose and inhalation rate well.

• I-Neb AAD Nebulizer (1 ml ampoule with white and yellow rings)

In general, when starting treatment with Ventavis, the first inhaled dose should be

2.5 micrograms of iloprost released by the nebulizer mouthpiece. If you tolerate this dose well, the dose should be increased to 5 micrograms of iloprost and you should continue with this dose. If you cannot tolerate the 5 microgram dose, the dose should be reduced to 2.5 micrograms.

Most people will need to perform 6 to 9 inhalation sessionsspread throughout the day. The duration of each inhalation session with I-Neb AAD is usually 4 to 10 minutes, depending on the prescribed dose.

• Venta-Neb Nebulizer (2 ml ampoule with white and pink rings)

In general, when starting treatment with Ventavis, the first inhaled dose should be

2.5 micrograms of iloprost released by the nebulizer mouthpiece. If you tolerate this dose well, the dose should be increased to 5 micrograms and you should continue with this dose. If you cannot tolerate the 5 microgram dose, the dose should be reduced to 2.5 micrograms.

Most people will need to perform 6 to 9 inhalation sessionsspread throughout the day. The duration of each inhalation session with Venta-Neb is usually 4 to 10 minutes, depending on the prescribed dose.

Depending on your individual needs, Ventavis can be used for long-term treatment. If you have kidney or liver problems

No dose modification is necessary in patients with mild or moderate kidney problems (patients with a creatinine clearance > 30 ml/min).

If you have severe kidney problems and require dialysis or have liver problems, your doctor will introduce Ventavis gradually and may prescribe fewer inhalations per day. Start treatment by inhaling 2.5 micrograms of iloprost, using a 1 ml ampoule of Ventavis 10 micrograms/ml (with white and yellow rings). Use dosing intervals of 3 - 4 hours (which corresponds to a maximum of 6 administrations per day). From then on, your doctor may cautiously shorten the dosing intervals based on how well you tolerate the treatment. If your doctor decides to further increase the dose to 5 micrograms, the dosing intervals should be re-established at 3 - 4 hours and shortened based on how well you tolerate the treatment.

If you notice that the effect of Ventavis is too strong or too weak, consult your doctor or pharmacist.Ask your doctor to have someone help you get familiar with the use of the nebulizer. You should not switch to another nebulizer without consulting the doctor who is treating you.

How to inhale

In each inhalation session, you should use a new Ventavis ampoule. Just before starting to inhale, break the glass ampoule and pour the solution into the medication chamber following the nebulizer's instructions for use.

Follow the instructions that come with the nebulizer carefully, especially those related to hygiene and cleaning of the nebulizer.

Follow exactly the administration instructions of Ventavis as indicated by your doctor.

• Ventavis 10 micrograms/ml solution for inhalation by nebulizer is inhaled using the nebulizers prescribed by your doctor (Breelib, Venta-Neb, or I-Neb AAD).

• The nebulizer transforms the Ventavis solution into an aerosol that is inhaled through the mouth.
• For inhalation, you should use a mouthpiece to avoid Ventavis coming into contact with your skin. Do not use a mask.
• Follow the instructions that come with the nebulizer carefully. Consult your doctor or pharmacist if you have any doubts.

• Any remaining Ventavis solution in the nebulizer after inhalation should be discarded (see section 5).

Ventilation of the room

Make sure to ventilate or air the room where you have taken the Ventavis treatment. Other people may be accidentally exposed to Ventavis through the air in the room. In particular,

newborns, infants, and pregnant women should not be in the same room while you are inhaling Ventavis.

• Breelib

Fill the medication chamber with Ventavis immediately before use. Follow the nebulizer's instructions for use regarding filling.

• I-Neb AAD

1. Immediately before inhalation, break the glass ampoule containing 1 ml of solution, which has two color-coded rings (white-yellow), and pour all its contents into the nebulizer's medication chamber.

1. The pre-set dose administered by the I-Neb AAD system is controlled by the medication chamber, in combination with a control disc. There are two medication chambers with distinct color codes. For each medication chamber, there is a control disc with its corresponding color code:

• • For the 2.5 microgramdose, the medication chamber with the red latch is usedalong with the red control disc.
  • For the 5 microgramdose, the medication chamber with the purple latch is usedalong with the purple control disc.
• To ensure you receive the prescribed dose, check the color of the medication chamber and the color of the control disc. These should be the same, either red for the 2.5 microgram dose or purple for the 5 microgram dose.

2.5 micrograms

The following table includes a summary of the instructions for using the I-Neb:

• Venta-Neb

1. Immediately before inhalation, break the glass ampoule containing 2 ml of solution, which has two color-coded rings (white-pink), and pour all its contents into the nebulizer's medication chamber.

1. Two programs can be used:
2. Your doctor will adjust the Venta-Neb system program to your needs so that you receive the prescribed dose for you.

• Program 1: 5 micrograms of active ingredient at the mouthpiece, 25 inhalation cycles.

• • Program 2: 2.5 micrograms of active ingredient at the mouthpiece, 10 inhalation cycles.
• To obtain the optimal droplet size for the administration of Ventavis, the green deflector plate should be used.

For more details, consult the nebulizer device's instruction manual or consult your doctor.

If you use more Ventavis than you should

Using more Ventavis than you should may cause dizziness, headache, flushing (redness of the face), nausea (feeling of discomfort), jaw pain or back pain.

You may also experience a decrease or increase in blood pressure, bradycardia (decrease in heart rate), tachycardia (increase in heart rate), vomiting, diarrhea, or pain in the limbs. If any of these occur when you have used more Ventavis than you should:

• Interrupt the inhalation session.

• Consult your doctor.

Your doctor will monitor and treat any resulting symptoms. No specific antidote is known.

If you forget to use Ventavis

Do not take a double dose to make up for forgotten doses. Consult your doctor about what you should do.

If you interrupt treatment with Ventavis

If you interrupt or wish to interrupt treatment, consult your doctor first.

If you have any other questions about the use of this medication, ask your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medications, this medication can cause side effects, although not everyone will experience them.

The following serious side effectsmay occur. If they occur, consult your doctor immediately:

Very common(may affect more than 1 in 10 people):

• Bleeding episodes (mostly nosebleeds and coughing up blood) may occur very frequently, especially if you are taking treatment to thin your blood (anticoagulants). The risk of bleeding may increase in patients treated at the same time with platelet aggregation inhibitors or anticoagulants (see also section 2). In very rare cases, fatal cases have been reported, including bleeding in the brain (cerebral and intracranial hemorrhage).

Common(may affect up to 1 in 10 people):

• Fainting (syncope) is a symptom of the underlying disease, but it may also occur during treatment with Ventavis (see also section 2 "Warnings and precautions" for recommendations on what you can do to avoid these symptoms).

• Low blood pressure (hypotension)

Frequency not known(cannot be estimated from the available data):

• Bronchospasm (sudden narrowing of the airway muscles) and wheezing (see also section 2 "Warnings and precautions").

The following is a list of other possible side effects based on their likelihood of occurrence:

Very common:may affect more than 1 in 10 people

• vasodilation (dilation of blood vessels). Symptoms may include flushing or redness of the face
• chest discomfort / chest pain
• cough
• headache
• nausea
• jaw pain / jaw muscle spasm (trismus)
• swelling of the limbs (peripheral edema)

Common:may affect up to 1 in 10 people

• difficulty breathing (dyspnea)

• dizziness

• vomiting

• diarrhea

• pain when swallowing (pharyngolaryngeal irritation)

• throat irritation

• irritation in the mouth and tongue, including pain

• skin rash

• rapid heartbeat (tachycardia)

• awareness of rapid or intense heartbeat (palpitations)

Frequency not known:the frequency cannot be estimated from the available data.

• reduction in the number of platelets in the blood (thrombocytopenia)

• hypersensitivity (i.e., allergy)

• taste disturbances (dysgeusia)

Other possible side effects

• Swelling, mainly of the ankles and legs due to fluid retention (peripheral edema), is a very common symptom of the underlying disease, but it may also occur during treatment with Ventavis.

Reporting side effects

If you experience any side effects, consult your doctor, even if they are possible side effects not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting side effects, you can help provide more information on the safety of this medication.

5. Storage of Ventavis

Keep this medication out of sight and reach of children.

Do not use this medication after the expiration date stated on the packaging and ampoule.

No special storage conditions are required.

Any remaining Ventavis solution in the nebulizer after inhalation should be discarded.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and any unused medication. This will help protect the environment.

6. Container Contents and Additional Information

Ventavis Composition:

• The active ingredientis iloprost.

1 ml of solution contains 10 micrograms of iloprost (as iloprost tromethamine).

Each 1 ml ampoule contains 10 micrograms of iloprost.

Each 2 ml ampoule contains 20 micrograms of iloprost.

• The other components aretromethamine, ethanol, sodium chloride, hydrochloric acid for pH adjustment, and water for injectable preparations.

Product Appearance and Container Contents

Ventavis is a clear, colorless solution for inhalation by nebulizer with Breelib, I-Neb, or Venta-Neb nebulizers.

Ventavis 10 micrograms/ml is supplied in colorless ampoules, which contain 1 ml or 2 ml of solution for inhalation by nebulizer.

Ventavis 10 micrograms/ml is available in the following containers:

• Ampoules of 1 ml for use with Breelib or I-Neb nebulizers:
• • Container containing 30 or 42 ampoules for use with Breelib and I-Neb nebulizers.
  • Multiple container containing 168 (4 x 42) ampoules for use with Breelib and I-Neb nebulizers.

• Multiple container containing 168 (4 x 42) ampoules with Breelib nebulizer consumable kit (containing 1 mouthpiece and 1 medication chamber).

The 1 ml ampoules are marked with two color rings (white-yellow).

• Ampoules of 2 ml for use with Venta-Neb nebulizer:
• • Container containing 30, 90, 100, or 300 ampoules.
  • Multiple container containing 90 (3 x 30) or 300 (10 x 30) ampoules.

The 2 ml ampoules are marked with two color rings (white-pink).

Not all pack sizes may be marketed.

Marketing Authorization Holder:

Bayer AG

51368 Leverkusen

Germany

Manufacturer:

Berlimed S.A.

Francisco Alonso 7

Poligono Industrial Santa Rosa

28806 Alcala de Henares

Madrid

Spain

For further information on this medicinal product, please contact the local representative of the marketing authorization holder.

België / Belgique / BelgienLietuva

Bayer SA-NV UAB Bayer

Tél/Tel: +32-(0)2-535 63 11 Tel. +37 05 23 36 868

????????Luxembourg / Luxemburg

????? ???????? ???? Bayer SA-NV

???. +359 02-424 72 80 Tél/Tel: +32-(0)2-535 63 11

Ceská republikaMagyarország

Bayer s.r.o. Bayer Hungária KFT

Tel: +420 266 101 111 Tel.:+36 14 87-41 00

DanmarkMalta

Bayer A/S Alfred Gera and Sons Ltd.

Tlf: +45-45 23 50 00 Tel: +35 621 44 62 05

DeutschlandNederland

Bayer Vital GmbH Bayer B.V.

Tel: +49 (0)214-30 513 48 Tel: +31-(0)297-28 06 66

EestiNorge

Bayer OÜ Bayer AS

Tel: +372 655 8565 Tlf. +47 23 13 05 00

Ελλ?δαÖsterreich

Bayer Ελλ?ς ΑΒΕΕ Bayer Austria Ges. m. b. H.

Τηλ: +30 210 61 87 500 Tel: +43-(0)1-711 46-0

EspañaPolska

Bayer Hispania S.L. Bayer Sp. z o.o.

Tel: +34-93-495 65 00 Tel.: +48 22 572 35 00

FrancePortugal

Bayer HealthCare Bayer Portugal, Lda.

Tél(N° vert): +33-(0)800 87 54 54 Tel: +351 21 416 42 00

HrvatskaRomânia

Bayer d.o.o. SC Bayer SRL

Tel: + 385-(0)1-6599 900 Tel: +40 21 529 59 00

IrelandSlovenija

Bayer Limited Bayer d. o. o.

Tel: +353 1 216 3300 Tel.: +386 (0)1 58 14 400

ÍslandSlovenská republika

Icepharma hf. Bayer, spol. s r.o.

Sími: +354 540 8000 Tel: +421 2 59 21 31 11

ItaliaSuomi/Finland

Bayer S.p.A. Bayer Oy

Tel: +39 02 397 81 Puh/Tel: +358 20 785 21

Κ?προςSverige

NOVAGEM Limited Bayer AB

Τηλ: +357 22 48 38 58 Tel: +46 (0) 8 580 223 00

LatvijaUnited Kingdom

SIA Bayer Bayer plc

Tel: +371 67 84 55 63 Tel: +44 (0)118 206 3000

Date of Last Revision of this Leaflet

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

There are also links to other websites on rare diseases and orphan medicines.

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This information is intended for healthcare professionals only:

Instructions for Use and Handling

Patients stabilized with a nebulizer should not switch to another nebulizer without close medical supervision, as different nebulizers have been shown to produce aerosols with slightly different physical characteristics and may have a faster administration of the solution (see section 5.2 of the Summary of Product Characteristics).

To minimize accidental exposure, it is recommended to keep the room well ventilated.

• Breelib

If the Breelib nebulizer is used, the instructions for use accompanying the device should be followed.

Fill the medication chamber with Ventavis immediately before use.

• I-Neb AAD

The I-Neb AAD system is a portable, manual, and vibrating mesh nebulizer system. This system generates small droplets by ultrasonic waves, passing the solution through a mesh. The I-Neb AAD nebulizer has been shown to be suitable for the administration of Ventavis 10 micrograms/ml (1 ml ampoule with white and yellow color rings). The measured MMAD of the small droplets of aerosol was 2.1 micrometers.

This nebulizer controls the breathing pattern to determine the required inhalation time to administer the pre-set dose of 2.5 or 5 micrograms of iloprost.

The dose administered by the I-Neb AAD system is controlled by the medication chamber, in combination with a control disc. Each medication chamber has a color code and has a control disc with the corresponding color code.

• For a dose of 2.5 micrograms, the medication chamber with the red latch is used with thered control disc.
• For a dose of 5 micrograms, the medication chamber with the purple latch is used with thepurple control disc.

In each I-Neb AAD inhalation session, immediately before use, the contents of a 1 ml Ventavis ampoule, which has two color rings (white-yellow), will be poured into the medication chamber.

The following table includes a summary of the instructions for using the I-Neb for Ventavis:

• Venta-Neb

Venta-Neb, a portable ultrasonic nebulizer with battery, has also been shown to be suitable for the administration of Ventavis 10 micrograms/ml. The measured MMAD of the aerosol droplets was 2.6 micrometers. In each inhalation session, the contents of a 2 ml ampoule of Ventavis 10 micrograms/ml solution for inhalation by nebulizer, which is marked with two color rings (white-pink), will be poured into the medication chamber of the nebulizer immediately before use.

Two programs can be used:

• Program 1: 5 micrograms of active ingredient in the mouthpiece, 25 inhalation cycles.

• Program 2: 2.5 micrograms of active ingredient in the mouthpiece, 10 inhalation cycles. The doctor selects the pre-set program.

An optical and acoustic signal from the Venta-Neb system alerts the patient to inhale. It stops automatically after administering the pre-set dose. To obtain the optimal droplet size for the administration of Ventavis, the green deflector plate should be used. Refer to the Venta-Neb nebulizer instruction manual for details.

The efficacy and tolerability of inhaled iloprost have not been established when administered with other nebulizer systems that provide different nebulization characteristics of the iloprost solution.