Iloprost Rafarm

Package leaflet: Information for the user

Iloprost RAFARM 10 micrograms/ml solution for nebuliser

Iloprost
Generic medicine
Please 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 questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effect, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet

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

1. What Iloprost RAFARM is and what it is used for

What is Iloprost RAFARM
The active substance of Iloprost RAFARM is iloprost. It mimics the action of a natural substance called prostacyclin. Iloprost RAFARM inhibits the unwanted blockage or constriction of blood vessels and allows a greater amount of blood to flow through the vessels.

What Iloprost RAFARM is used for
Iloprost RAFARM is used to treat moderate cases of primary pulmonary hypertension (PPH) in adult patients. PPH is a type of pulmonary hypertension in which the cause of increased blood pressure is unknown.
This is a disease in which the blood pressure in the vessels carrying blood between the heart and the lungs is too high.
Iloprost RAFARM is used to improve the ability to perform physical activity and to relieve symptoms.

How Iloprost RAFARM works
By inhaling the nebulized solution, Iloprost RAFARM is delivered directly to the lungs, where it acts most effectively on the artery between the heart and the lungs. The improvement in blood flow promotes a better oxygen supply to the body and reduces the workload on the heart.

2. What you need to know before using Iloprost RAFARM

Do not use Iloprost RAFARM

• if you are allergic to 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 duodenal ulcer (in the first part of the small intestine), if you have recently suffered physical injury (trauma), or if you are at risk of intracranial bleeding,
• if you have had any heart problems, such as
  • inadequate blood flow to the heart (severe coronary artery disease or unstable angina). Symptoms may include chest pain,
  • a heart attack within the last six months,
  • heart failure (cardiac decompensation) not under close medical supervision,
  • significantly unstable heart rate,
  • a heart valve defect (congenital or acquired) causing heart failure (unrelated to pulmonary hypertension),
• if you have had a stroke within the last 3 months or any other event that reduced blood supply to the brain (e.g. transient ischemic attack),
• if your pulmonary hypertension is caused by a blockage or narrowing of the veins (veno-occlusive disease).

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Iloprost RAFARM:

• Inhalation of Iloprost RAFARM may cause breathing difficulties (see section 4), especially in patients with bronchospasm (sudden constriction of muscles in the walls of small airways) or wheezing. Inform your doctor if you have a lung infection, severe asthma, or chronic lung diseases (chronic obstructive pulmonary disease). Your doctor will monitor you closely.
• Your blood pressure will be measured before treatment, and if it is too low (systolic blood pressure below 85 mmHg), treatment with Iloprost RAFARM should not be started.
• In general, you should take special care to avoid effects of low blood pressure, such as fainting and dizziness:
  • Inform your doctor if you are taking any other medicines, as their combined effects with Iloprost RAFARM may further lower your blood pressure (see below “Other medicines and Iloprost RAFARM”).
  • Stand up slowly from sitting or lying positions.
  • If you tend to faint when getting up from bed, it may be helpful to take the first daily dose while still lying in bed.
  • If you are prone to fainting, avoid excessive exertion; for example, it may be helpful to inhale Iloprost RAFARM before physical exercise.
• Episodes of fainting may be due to your underlying disease. Inform your doctor if these episodes worsen. They may consider adjusting your dose or changing your therapy.
• If you have heart failure, such as right-sided heart failure, and feel that your condition is worsening, discuss this with your doctor. Symptoms of worsening may include swelling of feet and ankles, shortness of breath, palpitations, frequent need to urinate at night, or edema. Your doctor will assess whether your treatment should be changed.
• If you experience difficulty breathing, coughing up blood and/or excessive sweating, these may be signs of fluid in the lungs (pulmonary edema). Stop treatment with Iloprost RAFARM and contact your doctor immediately. Your doctor will investigate the cause of your symptoms and take appropriate measures.
• If you have liver problems or severe kidney problems requiring dialysis, talk to your doctor. You may be prescribed a gradually increased dose or a lower dose of Iloprost RAFARM than other patients (see section 3 “How to use Iloprost RAFARM”).

Contact of Iloprost RAFARM with skin or accidental ingestion

• DO NOT allow the Iloprost RAFARM solution to come into contact with your skin or eyes. If this occurs, rinse the skin or eyes immediately with plenty of water.
• DO NOT drink or swallow the Iloprost RAFARM solution. If you accidentally swallow it, drink plenty of water and inform your doctor.

Children and adolescents
The safety and efficacy of Iloprost RAFARM have not been established in children and adolescents under 18 years of age.

Other medicines and Iloprost RAFARM
Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines. Iloprost RAFARM and certain other medicines may affect each other’s actions in the body. Inform your doctor if you are taking:

• Medicines used to treat high blood pressure or heart conditions, such as
  • beta-blockers,
  • nitrovasodilators,
  • ACE inhibitors. Your blood pressure may drop too much. Your doctor may adjust the dosage.
• Medicines that thin the blood or inhibit blood clotting, including
  • acetylsalicylic acid (ASA – a substance found in many medicines that reduce fever and relieve pain),
  • heparin,
  • coumarin anticoagulants, such as warfarin or phenprocoumon,
  • non-steroidal anti-inflammatory drugs (NSAIDs),
  • non-selective phosphodiesterase inhibitors, such as pentoxifylline,
  • selective phosphodiesterase 3 (PDE 3) inhibitors, such as cilostazol or anagrelide,
  • ticlopidine,
  • clopidogrel,
  • glycoprotein IIb/IIIa antagonists, such as
  • abciximab,
  • eptifibatide,
  • tirofiban,
  • defibrotide.

Your doctor will monitor you closely.
Before taking any medicine, consult your doctor or pharmacist, who can provide further information about medicines you should be cautious with or avoid while using Iloprost RAFARM.

Iloprost RAFARM with food and drink
Food and drink are not expected to affect Iloprost RAFARM. However, you should avoid eating or drinking during inhalation.

Pregnancy

• If you have pulmonary hypertension, avoid pregnancy, as pregnancy can worsen your condition and may endanger your life.
• If there is any possibility you could become pregnant, use reliable contraception from the start of treatment and throughout its duration.
• If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, consult your doctor immediately before taking this medicine. Iloprost RAFARM should be used during pregnancy only if your doctor determines that the potential benefit outweighs the potential risk to you and the fetus.

Breast-feeding
It is not known whether Iloprost RAFARM passes into breast milk. A potential risk to breastfed infants cannot be ruled out; therefore, breast-feeding should be avoided during treatment with Iloprost RAFARM.
Consult your doctor or pharmacist before taking any medicine.

Newborns, children, and pregnant women must not be present in the same room while you are inhaling Iloprost RAFARM.

Driving and using machines
Iloprost RAFARM lowers blood pressure and may cause dizziness or lack of concentration in some people. Do not drive or operate machinery if you experience these effects.

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

3. How to use Iloprost RAFARM

Treatment with Iloprost RAFARM must be initiated exclusively by a physician experienced in the
management of pulmonary hypertension.
How much Iloprost RAFARM to inhale and for how long
Always use this medicine exactly as your doctor has told you. If you are unsure, consult your
doctor.
The dose of Iloprost RAFARM and the duration of treatment depend on individual circumstances. Your
doctor will advise you accordingly. Do not change the recommended dose without first consulting your
doctor.
Different nebulizing devices can be used to administer Iloprost RAFARM. Depending on the type of device used and the prescribed dose, 1 ml or 2 ml of Iloprost RAFARM 10 micrograms/ml may be appropriate.

• Breelib Nebulizer
  If you are starting treatment with Iloprost RAFARM or have previously used a different device, the first inhalation should be performed with Iloprost RAFARM 10 micrograms/ml (1 ml vial with white and yellow rings). If you tolerate this dose well, the next inhalation should be with Iloprost RAFARM 20 micrograms/ml (vial with yellow and red rings). You should then continue with this dose.

If you do not tolerate the inhalation of Iloprost RAFARM 20 micrograms/ml, consult your doctor, who may
prescribe Iloprost RAFARM 10 micrograms/ml (1 ml vial).
Most people will have 6 to 9 inhalation sessions spread throughout the day.
Each session with Breelib usually lasts about 3 minutes.
When you first start using the Breelib nebulizer, your doctor will supervise your treatment to ensure
you tolerate the dose and inhalation rate.

• I-Neb AAD Nebulizer (1 ml vial with a yellow round dot)

Typically, at the beginning of treatment with Iloprost RAFARM, the first inhaled dose should correspond to
2.5 micrograms of iloprost delivered at the mouthpiece. If you tolerate this dose well, the dose should be
increased to 5 micrograms of iloprost and maintained at this level. If you do not tolerate the 5 microgram dose,
it should be reduced to 2.5 micrograms.
Most people will have 6 to 9 inhalation sessions spread throughout the day.
The duration of each session with the I-Neb AAD ranges between 4 and 10 minutes, depending on the
prescribed dose.

• Venta-Neb Nebulizer (2 ml vial with a blue round dot)

Typically, at the beginning of treatment with Iloprost RAFARM, the first inhaled dose should correspond to
2.5 micrograms of iloprost delivered at the mouthpiece. If you tolerate this dose well, the dose should be
increased to 5 micrograms of iloprost and maintained at this level. If you do not tolerate the 5 microgram dose,
it should be reduced to 2.5 micrograms.
Most people will have 6 to 9 inhalation sessions spread throughout the day.
The duration of each inhalation session with the Venta-Neb ranges between 4 and 10 minutes, depending on the
prescribed dose.
Depending on individual needs, Iloprost RAFARM may be used for long-term treatment.
If you have kidney or liver problems
In patients with mild or moderate renal impairment (patients with creatinine clearance >30 ml/min),
dose adjustment is not necessary.
In cases of severe renal impairment requiring dialysis or in patients with liver disease, your doctor will
initiate Iloprost RAFARM therapy gradually and may prescribe fewer inhalations per day. Begin therapy with the inhalation of 2.5 micrograms of iloprost using a 1 ml vial of Iloprost RAFARM 10 micrograms/ml (with white and yellow rings). Allow intervals of 3–4 hours between inhalations (corresponding to a maximum of 6 administrations per day). Subsequently, your doctor may cautiously reduce the dosing intervals, depending on your tolerance to treatment. If your doctor decides to increase the dose up to a maximum of 5 micrograms, the 3–4 hour intervals should initially be maintained and may be reduced later depending on your tolerance.
If you feel that the effect of Iloprost RAFARM is too strong or too weak, consult your doctor or pharmacist.
Ask your doctor to have someone assist you in becoming familiar with the use of the nebulizer. Do not switch to another type of nebulizer without consulting your treating physician.
How to perform inhalation
For each inhalation session, a new vial of Iloprost RAFARM must be used.
Immediately before starting inhalation, break the glass vial and pour the solution into the nebulizer chamber, following the nebulizer’s instructions for use.
Strictly follow all instructions provided with the device, especially those relating to hygiene and cleaning of the nebulizer.
Always take Iloprost RAFARM exactly as your doctor has instructed.

• The nebulizing solution of Iloprost RAFARM 10 micrograms/ml must be inhaled through the nebulizers prescribed by your doctor (Breelib, Venta-Neb, or the I-Neb AAD system).
• The nebulizer converts the Iloprost RAFARM solution into an aerosol, which you inhale through your mouth.
• For inhalation, use a mouthpiece to prevent Iloprost RAFARM from coming into contact with your skin. Do not use a face mask.
• Carefully follow all instructions provided by the device manufacturer regarding the delivery system. Consult your doctor or pharmacist if you have any doubts.
• Any residual solution of Iloprost RAFARM remaining in the nebulizer after inhalation must be discarded (see section 5).

Room ventilation
Ensure that the room in which you take Iloprost RAFARM is well ventilated or aired. Other people
might accidentally inhale Iloprost RAFARM through the room air. In particular, newborns, children, and pregnant women must not be present in the same room while you are inhaling Iloprost RAFARM.

• Breelib

Pour Iloprost RAFARM into the nebulizer chamber immediately before use, following the
instructions for use of the nebulizer.

• I-Neb AAD
  1. Immediately before inhaling, break the glass vial containing 1 ml of solution and marked with a yellow dot, and pour the entire contents into the nebulizer chamber.
  2. The pre-set dose delivered by the I-Neb AAD system is controlled by the nebulizer chamber in combination with a control disc. There are two nebulizer chambers, each distinguished by a different color. Each nebulizer chamber corresponds to a colored control disc:
• To deliver a dose of 2.5 micrograms, use the nebulizer chamber with the red safety lock together with the red control disc.
• To deliver a dose of 5 micrograms, use the nebulizer chamber with the purple safety lock together with the purple control disc. 3. To ensure you receive the prescribed dose, check the color of the nebulizer chamber and control disc. They must be the same color—red for the 2.5 microgram dose or purple for the 5 microgram dose.

The following table provides a summary of instructions for the use of I-Neb:

• Venta-Neb
  1. Immediately before starting inhalation, break open the glass vial containing 2 ml of solution, marked with two colored rings (white - pink), and pour the entire contents into the nebulizer chamber.
  2. You can choose between two programs:
  3. Your doctor will adjust Venta-Neb to the program you need to receive the prescribed dose.
• P1 Program 1: 5 micrograms of active substance over 25 inhalation cycles via mouthpiece.
• P2 Program 2: 2.5 micrograms of active substance over 10 inhalation cycles via mouthpiece. 4. Use the green deflector to obtain droplets of optimal size for the administration of Iloprost RAFARM.

For further information, please read the instructions manual of the nebulizer or consult your doctor.
If you use more Iloprost RAFARM than you should
Using a larger amount of Iloprost RAFARM than prescribed may cause dizziness,
headache, flushing (reddening of the face), nausea (feeling of illness), jaw or
back pain.
An increase or decrease in blood pressure, bradycardia (slowing of the heartbeat), tachycardia (acceleration of the heartbeat), vomiting, diarrhoea, or limb pain may also occur. If any of these symptoms occur following an intake of Iloprost RAFARM higher than intended, you must stop the inhalation session and contact your doctor.
The doctor will monitor you and treat the symptoms observed. A specific antidote is not known.
If you forget to use Iloprost RAFARM
Do not take a double dose to make up for the forgotten dose. Contact your doctor, who will advise you on what to do.
If you stop treatment with Iloprost RAFARM
If you stop or wish to stop treatment, consult your doctor first.
If you have any doubts about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following serious side effects may occur. If this happens, consult your doctor immediately.
Very common (may affect more than 1 in 10 people):

• Bleeding events (especially nosebleeds (epistaxis) and coughing up blood (haemoptysis)) may occur very commonly, particularly if you are also taking blood-thinning medicines (anticoagulants). The risk of bleeding may increase in patients receiving antiplatelet agents or anticoagulants concomitantly (see also section 2).
• Fatal cases have been reported very rarely, including cases of bleeding in the brain (cerebral and intracranial haemorrhage).

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

• Fainting (syncope) is a symptom of your disease but may also occur during treatment with Iloprost RAFARM (see also section 2 “Warnings and precautions” for advice on how to avoid it).
• Reduction in blood pressure (hypotension)

Not known: (frequency cannot be estimated from the available data):

• Bronchospasm (sudden constriction of the muscles in the walls of the small airways) and wheezing (see also section 2 “Warnings and precautions”)

The following additional side effects are listed below by frequency:
Very common: may affect more than 1 in 10 people

• Dilation of blood vessels (vasodilation). Symptoms may include flushing or redness of the face.
• Chest discomfort or pain
• Cough
• Headache
• Nausea
• Jaw pain or spasm of the jaw muscles (trismus)
• Swelling of the limbs (peripheral oedema)

Common: may affect up to 1 in 10 people

• Breathing difficulties (dyspnoea)
• Dizziness
• Vomiting
• Diarrhoea
• Pain on swallowing (pharyngolaryngeal irritation)
• Throat irritation
• Irritation of the mouth and tongue, accompanied by pain
• Skin rashes
• Rapid heartbeat (tachycardia)
• Awareness of a fast or strong heartbeat (palpitations)

Not known: frequency cannot be estimated from the available data.

• Reduction in the number of platelets in the blood (thrombocytopenia)
• Hypersensitivity (e.g. allergy)
• Taste disturbances (dysgeusia)

Other possible side effects

• Swelling, especially in the ankles and legs, due to fluid retention (peripheral oedema) is a very common symptom of the disease itself, but may also occur during treatment with Iloprost RAFARM.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse.
You can also report side effects directly via the national reporting system available at:
www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Iloprost RAFARM

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and vial.
There are no special storage instructions.
Any residual solution of Iloprost RAFARM remaining in the nebulizer after inhalation must be discarded.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Iloprost RAFARM contains:
The active substance is iloprost.
1 ml of solution contains 10 micrograms of iloprost (as iloprost trometamol).
Each 1 ml vial contains 10 micrograms of iloprost.
The other components are trometamol, ethanol, sodium chloride, hydrochloric acid 1N (for pH adjustment), and water for injections.

Description of the appearance of Iloprost RAFARM and contents of the pack:
Iloprost RAFARM is a clear, colourless solution free from visible particles, for inhalation using the Breelib, I-Neb or Venta-Neb nebulizer.
Iloprost RAFARM is available in colourless cartridges containing 1 ml or 2 ml of solution for nebulization.

Iloprost RAFARM 10 micrograms/ml is available in the following packs:

• 1 ml vials for use with the Breelib or I-Neb nebulizer:
  • Pack containing 30 or 42 vials for use with the Breelib and I-Neb nebulizers.
  • Multipack containing 168 (4 x 42) vials.

The 1 ml vials are marked with a yellow round dot.

• 2 ml vials for use with the Venta-Neb nebulizer:
  • Pack containing 30 vials.
  • Multipack containing 300 (10 x 30) vials.

The 2 ml vials are marked with a blue round dot.
Not all pack sizes may be marketed.

Marketing Authorization Holder:
RAFARM S.A.
12 Korinthou str., Ν. Psihiko,
15451 Athens
Greece

Manufacturer:
RAFARM S.A.
Thesi Pousi –Xatzi
Agiou Louka
19002, Paiania Attiki
Greece

The following information is intended for healthcare professionals only:

Instructions for use and handling

Stable patients using one type of nebulizer must not switch to another nebulizer without
close supervision by their physician, as different nebulizers produce aerosols with
slightly different physical characteristics and may deliver the solution more rapidly (see
section 5.2 of the product characteristics summary).
To minimize accidental exposure, it is recommended to ensure adequate ventilation of the environment.

• Breelib

For use of the Breelib nebulizer, follow the instructions for use provided with the device.
Pour Iloprost RAFARM into the nebulizer chamber immediately before use.

• I-Neb AAD

The I-Neb AAD System is a portable, handheld nebulizer based on vibrating mesh technology.
To generate droplets, this system uses ultrasound to push the solution through a mesh. The I-Neb AAD
nebulizer is suitable for the administration of Iloprost RAFARM 10 micrograms/ml (1 ml vial with a yellow dot).
The mass median aerodynamic diameter (MMAD) of the aerosol droplets was 2.1 micrometers.
This nebulizer monitors the breathing pattern to determine the aerosol release intervals required to deliver the preset dose of 2.5 or 5 micrograms of iloprost.
The dose delivered by the I-Neb AAD system is controlled by the nebulizer chamber in combination with a control disc. Each nebulizer chamber is identified by a color, which corresponds to a colored control disc.

• To deliver a dose of 2.5 micrograms, use the nebulizer chamber with the red safety lock together with the red control disc.
• To deliver a dose of 5 micrograms, use the nebulizer chamber with the purple safety lock together with the purple control disc.

For each inhalation session with I-Neb AAD, transfer the contents of one 1 ml vial of Iloprost RAFARM, marked with a yellow dot, into the nebulizer chamber immediately before use.

The following table provides a summary of the instructions for use of I-Neb with Iloprost RAFARM:

• Venta-Neb

Venta-Neb, a portable, battery-powered ultrasonic nebulizer, has also proven suitable for the
administration of Iloprost RAFARM. The measured MMAD value of the aerosol droplets is
2.6 micrometers. For each inhalation session, the contents of one vial containing 2 ml of
Iloprost RAFARM nebulizer solution, marked with a blue dot, shall be transferred into the
nebulizer chamber immediately before use.
Two programs can be used:

• PI Program 1: 5 micrograms of active substance over 25 inhalation cycles via mouthpiece.
• P2 Program 2: 2.5 micrograms of active substance over 10 inhalation cycles via mouthpiece.

The preset program is selected by the physician.
Venta-Neb signals the patient to inhale with an optical and an acoustic signal. It stops automatically at the end of the administration of the preset dose. To obtain droplets of optimal size for the
administration of Iloprost RAFARM, use of the green deflector is recommended. For further
details, refer to the instruction manual of the Venta-Neb nebulizer.

The efficacy and tolerability of inhaled iloprost administered via other nebulization systems, which provide different nebulization characteristics to the iloprost solution, have not been established.

Package leaflet: Information for the user

Iloprost RAFARM 20 micrograms/ml solution for nebuliser

Iloprost
Generic medicine
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

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

1. What Iloprost RAFARM is and what it is used for

What Iloprost RAFARM is
The active substance in Iloprost RAFARM is iloprost. It mimics the action of a naturally occurring substance called prostacyclin. Iloprost RAFARM prevents unwanted blockage or constriction of blood vessels and allows increased blood flow through the vessels.

What Iloprost RAFARM is used for
Iloprost RAFARM is used to treat adult patients with moderate primary pulmonary hypertension (PPH). PPH is a type of pulmonary hypertension in which the cause of the increased blood pressure is unknown.
This is a disease in which the blood pressure in the vessels carrying blood between the heart and the lungs is too high.
Iloprost RAFARM is used to improve exercise capacity and symptoms.

How Iloprost RAFARM works
By inhaling the nebulized solution, Iloprost RAFARM is delivered directly to the lungs, where it acts most effectively on the artery between the heart and the lungs. Improving blood flow enhances oxygen delivery to the body and reduces the workload on the heart.

2. What you need to know before using Iloprost RAFARM

Do not use Iloprost RAFARM

• if you are allergic to iloprost or to 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 or duodenal ulcer, if you have sustained a physical injury (trauma), or if you are at risk of intracranial haemorrhage,
• if you have had any heart problems, such as
  • insufficient blood supply to the heart (severe coronary artery disease or unstable angina). Symptoms may include chest pain,
  • a heart attack within the last six months,
• heart failure (cardiac insufficiency) not under close medical supervision,
• markedly unstable heart rate,
• a heart valve defect (congenital or acquired) causing heart failure (not related to pulmonary hypertension),
  • if you have had a stroke within the last 3 months or any other event that reduced blood flow to the brain (e.g. transient ischaemic attack),
  • if your pulmonary hypertension is caused by blockage or narrowing of the veins (pulmonary veno-occlusive disease).

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Iloprost RAFARM:

• Inhalation of Iloprost RAFARM may cause breathing difficulties (see section 4), especially in patients with bronchospasm (sudden constriction of muscles in the walls of the small airways) or wheezing. Inform your doctor if you have a lung infection, severe asthma, or chronic lung diseases (chronic obstructive pulmonary disease). Your doctor will monitor you closely.
• Your blood pressure will be measured before treatment; if it is too low (systolic blood pressure below 85 mmHg), treatment with Iloprost RAFARM should not be started.
• In general, you should take special care to avoid effects of low blood pressure, such as fainting and dizziness:
  • Inform your doctor if you are taking any other medicines, as their combined effects with Iloprost RAFARM may further lower your blood pressure (see below “Other medicines and Iloprost RAFARM”).
  • Rise slowly from sitting or lying down.
  • If you tend to faint when getting up from bed, it may be helpful to take the first daily dose while still lying in bed.
  • If you tend to faint, avoid excessive exertion; for example, during physical exercise, it may be helpful to inhale Iloprost RAFARM before exercising.
• Episodes of fainting may be due to your underlying disease.
• Inform your doctor if these episodes worsen. Your doctor may consider adjusting the dose or changing your therapy.
• If you have heart failure, such as right-sided heart failure, and feel that your condition is worsening, discuss this with your doctor. Symptoms of worsening may include swelling of the feet and ankles, shortness of breath, palpitations, frequent need to urinate at night, or oedema.
• Your doctor will assess whether your therapy should be changed.
• If you experience difficulty breathing, coughing up blood and/or excessive sweating, these may be signs of fluid in the lungs (pulmonary oedema). Stop treatment with Iloprost RAFARM and contact your doctor immediately.
• Your doctor will investigate the cause of your symptoms and take appropriate measures.
• If you have liver problems or severe kidney problems requiring dialysis, talk to your doctor. You may be prescribed a lower or gradually adjusted dose of Iloprost RAFARM compared to other patients (see section 3 “How to use Iloprost RAFARM”).

Contact of Iloprost RAFARM with skin or ingestion of Iloprost RAFARM

• DO NOT allow the Iloprost RAFARM solution to come into contact with your skin or eyes. If this happens, rinse the skin or eyes immediately with plenty of water.
• DO NOT drink or swallow the Iloprost RAFARM solution. If you accidentally swallow it, drink plenty of water and inform your doctor.

Children and adolescents
The safety and efficacy of Iloprost RAFARM have not been established in children and adolescents under 18 years of age.

Other medicines and Iloprost RAFARM
Inform your doctor or pharmacist if you are currently taking, have recently taken, or might take any other medicines. Iloprost RAFARM and certain other medicines may interact and affect each other’s action in the body.
Inform your doctor if you are taking:

• Medicines used to treat high blood pressure or heart conditions, such as
  • beta-blockers,
  • nitrovasodilators,
  • ACE inhibitors. Your blood pressure may drop too much. Your doctor may adjust your dosage.
• Medicines that thin the blood or inhibit blood clotting, including
  • acetylsalicylic acid (ASA – a substance found in many medicines used to reduce fever and relieve pain),
  • heparin,
  • coumarin anticoagulants, such as warfarin or phenprocoumon,
  • non-steroidal anti-inflammatory drugs (NSAIDs),
  • non-selective phosphodiesterase inhibitors, such as pentoxifylline,
  • selective phosphodiesterase 3 (PDE 3) inhibitors, such as cilostazol or anagrelide,
  • ticlopidine,
  • clopidogrel,
  • glycoprotein IIb/IIIa antagonists, such as abciximab, eptifibatide, tirofiban,
  • defibrotide.

Your doctor will monitor you closely.
Before taking any medicine, consult your doctor or pharmacist. They can provide further information about medicines you should be cautious with or avoid while using Iloprost RAFARM.

Iloprost RAFARM with food and drinks
Eating or drinking should not affect Iloprost RAFARM. However, you should avoid eating or drinking during inhalation.

Pregnancy

• If you have pulmonary hypertension, avoid pregnancy, as pregnancy can worsen your condition and may endanger your life.
• If you could become pregnant, use reliable contraception from the start of treatment and throughout its duration.
• If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, consult your doctor immediately before taking this medicine. Iloprost RAFARM should be used during pregnancy only if your doctor decides that the potential benefit outweighs the potential risk to you and the foetus.

Breast-feeding
It is not known whether Iloprost RAFARM passes into breast milk. A potential risk to breastfed infants cannot be ruled out; therefore, breast-feeding should be avoided during treatment with Iloprost RAFARM.

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

Newborns, children, and pregnant women must not be present in the same room while you are inhaling Iloprost RAFARM.

Driving and using machines
Iloprost RAFARM lowers blood pressure and may cause dizziness or lack of concentration in some people. Do not drive or operate machinery if you experience these effects.

Iloprost RAFARM contains ethanol
Iloprost RAFARM contains a small amount of ethanol (alcohol) (less than 100 mg per dose).

3. How to use Iloprost RAFARM

Treatment with Iloprost RAFARM must be initiated exclusively by a physician experienced in the
treatment of pulmonary hypertension.
How much Iloprost RAFARM should be inhaled and for how long
Use this medicine exactly as directed by your doctor. If you have any doubts, consult your
physician.
The dose of Iloprost RAFARM and the duration of treatment depend on individual circumstances. Your
doctor will advise you accordingly. Do not change the recommended dose without first consulting your
doctor.
Different nebulizing devices may be used to administer Iloprost RAFARM 20 µg/ml.

• Breelib nebulizer

If you are starting treatment with Iloprost RAFARM 20 micrograms/ml or have previously used a
different device, the first inhalation should be performed with Iloprost RAFARM 10 micrograms/ml (1 ml vial with a yellow dot). If you tolerate this dose well, the next inhalation should be with Iloprost
RAFARM 20 micrograms/ml (vial with an orange circular dot). You should then continue with
this dose.
If you do not tolerate inhalation of Iloprost RAFARM 20 micrograms/ml, consult your doctor, who may
prescribe Iloprost RAFARM 10 micrograms/ml (1 ml vial).
Most people will require 6 to 9 inhalation sessions spread throughout the day.
Each session with Breelib typically lasts approximately 3 minutes.
When you begin using the Breelib nebulizer, your doctor will supervise your treatment to ensure that
you tolerate the dose and the inhalation rate.

• I-Neb nebulizer

Because your inhalation times with Iloprost RAFARM 10 micrograms/ml (1 ml vial with a yellow dot) have been repeatedly prolonged, your doctor has decided to switch to Iloprost RAFARM 20
micrograms/ml.
Iloprost RAFARM 20 micrograms/ml has double the concentration of Iloprost RAFARM 10
micrograms/ml. The active substance can thus be delivered more rapidly to the lungs.
The switch from Iloprost RAFARM 10 micrograms/ml to Iloprost RAFARM 20 micrograms/ml will be performed under medical supervision, during which your doctor will monitor your tolerance to the higher concentration.
The dose should be administered 6 to 9 times daily, depending on individual needs and tolerability.
Depending on individual requirements, Iloprost RAFARM may be used for long-term treatment.
If you have kidney or liver problems
In patients with mild or moderate renal impairment (patients with creatinine clearance >30 ml/min),
dose adjustment is not required.
In case of severe renal impairment requiring dialysis or in patients with liver disease, your doctor will initiate Iloprost RAFARM therapy gradually and may prescribe fewer inhalations per day. Begin therapy by inhaling 2.5 micrograms of iloprost using Iloprost
RAFARM 10 micrograms/ml (1 ml vial with white and yellow rings). Allow an interval of 3–4 hours between doses (corresponding to a maximum of 6 doses per day). Subsequently, your doctor may cautiously reduce the dosing intervals, depending on your tolerance to treatment. If your doctor decides to increase the dose up to a maximum of 5 micrograms, the initial 3–4 hour intervals should again be respected and may later be reduced depending on your tolerance.
If you feel that the effect of Iloprost RAFARM is too strong or too weak, consult your doctor or pharmacist.
Ask your doctor to have someone assist you in becoming familiar with the use of the nebulizer. Do not switch to another type of nebulizer without consulting your treating physician.
How to perform inhalation
A new vial of Iloprost RAFARM must be used for each inhalation session.
Immediately before starting inhalation, break open the glass vial and
pour the solution into the nebulizer chamber, following the nebulizer’s instructions for use.
Strictly follow all instructions provided with the device, particularly those concerning
hygiene and cleaning of the nebulizer.
Always take Iloprost RAFARM exactly as directed by your doctor.

• The Iloprost RAFARM 20 micrograms/ml nebulizer solution must be inhaled through the nebulizers prescribed by your doctor (Breelib or I-Neb AAD nebulizers).
• The nebulizer converts the Iloprost RAFARM solution into an aerosol which you inhale through your mouth.
• For inhalation, use a mouthpiece to prevent Iloprost RAFARM from coming into contact with the skin. Do not use a face mask.
• Carefully follow all instructions provided by the device manufacturer. Consult your doctor or pharmacist if you have any doubts.
• Any residual Iloprost RAFARM solution remaining in the nebulizer after inhalation must be discarded (see section 5).

Room ventilation
Ensure that the room where you have taken Iloprost RAFARM is well ventilated or aired. Other
individuals could accidentally inhale Iloprost RAFARM through the room air. In particular,
newborns, children, and pregnant women must not be present in the same room while you are inhaling Iloprost
RAFARM.
Breelib

• Pour Iloprost RAFARM into the nebulizer chamber immediately before use, following the nebulizer’s instructions for use.

• I-Neb AAD
  1. Immediately before inhaling, take the Iloprost RAFARM 20 microgram/ml vial marked with an orange dot, break the glass vial, and pour the entire contents of 1 ml into the gold-coloured chamber of the nebulizer.
  2. The predetermined dose delivered by the I-Neb AAD nebulizer is controlled by the nebulizer chamber in combination with a control disc. For Iloprost RAFARM 20 microgram/ml (5 microgram dose), use the nebulizer chamber with the gold safety stop together with the gold control disc.
  3. To ensure you receive the prescribed dose, check the colour of the nebulizer chamber and control disc. They must be the same colour.

Since the I-Neb AAD nebulizer can be used for both Iloprost RAFARM 10 microgram/ml and Iloprost RAFARM 20 microgram/ml, the following table provides a summary of user instructions for I-Neb for the two concentrations of Iloprost RAFARM:

For further information, read the instruction manual of the nebulizer or consult your doctor.
If you use more Iloprost RAFARM than you should
Using a larger amount of Iloprost RAFARM than prescribed may cause dizziness, headache, flushing (reddening of the face), nausea (feeling unwell), jaw or back pain.
An increase or decrease in blood pressure, bradycardia (slowing of the heartbeat), tachycardia (acceleration of the heartbeat), vomiting, diarrhoea, or limb pain may also occur. If any of these symptoms occur following inhalation of a higher dose of Iloprost RAFARM than intended, you must stop the inhalation session immediately and contact your doctor.
Your doctor will monitor and treat any symptoms experienced. A specific antidote is not known.
If you forget to use Iloprost RAFARM
Do not take a double dose to make up for a forgotten dose. Contact your doctor for advice on what to do.
If you stop using Iloprost RAFARM
If you stop or wish to stop treatment, consult your doctor first.
If you have any questions about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
The following serious side effects may occur. If you experience any of these, consult your doctor immediately.
Very common (may affect more than 1 in 10 people):

• Bleeding events (especially nosebleeds (epistaxis) and coughing up blood (haemoptysis)) may occur very commonly, particularly if you are also taking medicines that thin the blood (anticoagulants). The risk of bleeding may increase in patients receiving concomitant platelet aggregation inhibitors or anticoagulants (see also section 2).
• Fatal cases have been reported very rarely, including cases of bleeding in the brain (cerebral and intracranial haemorrhage).

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

• Fainting (syncope) is a symptom of your disease but may also occur during treatment with Iloprost RAFARM (see also section 2 “Warnings and precautions” for advice on how to avoid it).
• Reduction in blood pressure (hypotension)

Not known (frequency cannot be estimated from the available data):

• Bronchospasm (sudden constriction of the muscles in the walls of the small airways) and wheezing (see also section 2 “Warnings and precautions”)

The following is a list of other side effects, in order of frequency:
Very common: may affect more than 1 in 10 people

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

Common: may affect up to 1 in 10 people

• difficulty breathing (dyspnoea)
• dizziness
• vomiting
• diarrhoea
• pain on swallowing (pharyngolaryngeal irritation)
• throat irritation
• mouth and tongue irritation, accompanied by pain
• skin rashes
• rapid heartbeat (tachycardia)
• awareness of a fast or strong heartbeat (palpitations)

Not known: frequency cannot be estimated from the available data.

• reduction in the number of platelets in the blood (thrombocytopenia)
• hypersensitivity (e.g. allergy)
• taste disturbances (dysgeusia)

Other possible side effects

• Swelling, particularly in the ankles and legs, due to fluid retention (peripheral oedema) is a very common symptom of the disease itself, but may also occur during treatment with Iloprost RAFARM.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse.
You can also report side effects directly via the national reporting system available at:
www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Iloprost RAFARM

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and vial.
There are no special storage instructions.
Any residual solution of Iloprost RAFARM remaining in the nebulizer after inhalation must be discarded.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Iloprost RAFARM contains:
The active substance is iloprost.
1 ml of solution contains 20 micrograms of iloprost (as iloprost trometamol).
Each 1 ml vial contains 20 micrograms of iloprost.
The other components are trometamol, ethanol, sodium chloride, hydrochloric acid 1N (for pH adjustment) and water for injections.

Description of the appearance of Iloprost RAFARM and contents of the package:
Iloprost RAFARM is a clear, colourless solution for inhalation by the Breelib or I-Neb nebuliser.
Iloprost RAFARM is available in colourless cartridges containing 1 ml of solution for inhalation for use with a nebuliser.
Iloprost RAFARM is available in the following pack sizes:

• Pack containing 30 vials or 42 vials for use with the Breelib and I-Neb nebuliser.
• Multiple pack containing 168 (4 x 42) vials for use with the Breelib and I-Neb nebuliser.

The vials containing 1 ml are marked with an orange circular dot.

Marketing Authorisation Holder:
Farma Group S.r.l.
via Farfisa, 18
60021 Camerano (AN)
Italy

Manufacturer:
RAFARM S.A.
Thesi Pousi –Xatzi
Agiou Louka
19002, Paiania Attiki
Greece

The following information is intended exclusively for healthcare professionals:

Instructions for use and handling

Patients stabilised with one type of nebuliser must not switch to another nebuliser without
close supervision by their physician, since different nebulisers produce an aerosol with
slightly different physical characteristics and may deliver the solution more rapidly (see
section 5.2 of the product characteristics summary).
To minimise accidental exposure, it is recommended to ensure adequate ventilation of the environment.

• Breelib

For use of the Breelib nebuliser, follow the instructions for use provided with the device.
Pour Iloprost RAFARM into the nebuliser chamber immediately before use.

• I-Neb AAD

The I-Neb AAD System is a portable, handheld nebulizer based on vibrating mesh technology.
To generate droplets, this system uses ultrasound to push the solution through a mesh.
This nebulizer monitors the breathing pattern to determine the aerosol release intervals required to deliver the predetermined dose of 5 micrograms of iloprost from Iloprost RAFARM solution for nebulization (1 ml vial with an orange dot).
The nebulizer delivers 5 micrograms of iloprost at the mouthpiece. The mass median aerodynamic diameter (MMAD) of the aerosol ranges between 1 and 5 micrometers.
For use of the I-Neb AAD system, follow the instructions below.
The dose delivered by the I-Neb AAD system is controlled by the nebulizer chamber in combination with a control disc. Each nebulizer chamber is color-coded and corresponds to a colored control disc.
For each inhalation session with I-Neb AAD, immediately before use, transfer the contents of one 1 ml vial of Iloprost RAFARM, marked with an orange dot, into the appropriate nebulizer chamber, using the gold-colored safety lock with a gold control disc.
Since the I-Neb AAD system can be used with both Iloprost 10 micrograms/ml and Iloprost 20 micrograms/ml, the table below provides a summary of user instructions for I-Neb for both concentrations of Iloprost RAFARM.

The following table provides a summary of the instructions for use of I-Neb with Iloprost RAFARM:

• Venta-Neb

Venta-Neb, a portable, battery-operated, ultrasonic nebulizer, has also proven suitable for the
administration of Iloprost RAFARM. The measured MMAD value of the aerosol droplets is 2.6 micrometers.
For each inhalation session, the contents of one vial containing 2 ml of Iloprost RAFARM nebulizing solution, marked with a blue dot, shall be transferred into the nebulizer chamber immediately before use.
Two programs are available:

• PI Program 1: 5 micrograms of active substance over 25 inhalation cycles via mouthpiece.
• P2 Program 2: 2.5 micrograms of active substance over 10 inhalation cycles via mouthpiece.

The preset program is selected by the physician.
Venta-Neb signals the inhalation to the patient with an optical and an acoustic signal. It stops automatically at the end of the administration of the preset dose. To obtain droplets of optimal size for the administration of Iloprost RAFARM, the use of the green deflector is recommended. For further details, refer to the instruction manual of the Venta-Neb nebulizer.

The efficacy and tolerability of inhaled iloprost administered via other nebulization systems, which provide different nebulization characteristics to the iloprost solution, have not been established.