ILOPROST RAFARM 10 micrograms/ml SOLUTION FOR NEBULIZER INHALATION

Introduction

Package Leaflet: Information for the User

Iloprost Rafarm 10 micrograms/ml solution for inhalation by nebulizer

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

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

What is Iloprost Rafarm

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

What is Iloprost Rafarm used for

Iloprost 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 blood pressure is too high in the blood vessels between the heart and lungs.

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

How Iloprost Rafarm works

When you inhale the aerosol, iloprost reaches the lungs, where it acts more effectively on the artery between the heart and 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 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 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 intracranial bleeding,
• if you have a heart problem, such as
  • insufficient blood flow to the heart muscles (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 suffered a stroke or any other event that has reduced blood flow to the brain (e.g., transient ischemic attack) in the last 3 months,
• if your pulmonary hypertension is due to a blocked or narrowed vein (venous occlusive disease).

Warnings and precautions

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

• Inhaling iloprost 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 iloprost.
• In general, you will need to be careful 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 this medicine may lower your blood pressure even further (see "Other medicines and Iloprost Rafarm" below).
  • 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 iloprost before doing so.
• Fainting episodes may be due to the underlying disease. Tell your doctor if they worsen, as he/she may consider adjusting the dose or changing the treatment.
• If you have a heart condition, such as right heart failure, and you notice that your disease 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 edema. Your doctor will consider whether you need 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 edema). Stop using iloprost 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.

You may be gradually switched to the prescribed dose or prescribed a lower dose of iloprost than other patients (see section 3 "How to use Iloprost Rafarm").

Contact of Iloprost Rafarm with skin or ingestion of Iloprost Rafarm

• DO NOT let the iloprost 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 iloprost solution

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

Children and adolescents

The safety and efficacy of iloprost in children under 18 years of age have not been established.

Other medicines and Iloprost Rafarm

Tell your doctor or pharmacist if you areusing, have recently used, or might use any other medicines. Iloprost 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 inhibit its clotting, 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 Iloprost Rafarm.

Using Iloprost Rafarm with food and drinks

It is unlikely that food or drinks will affect iloprost. 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. Iloprost 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 iloprost passes into breast milk. The potential risk to breast-fed infants cannot be excluded, and it is recommended to avoid breast-feeding during treatment with iloprost

Talk to your doctor or pharmacist before using any medicine.

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

Driving and using machines

Iloprost 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.

Iloprost Rafarm contains ethanol

Iloprost Rafarm contains a small amount of ethanol (alcohol) (less than 100 mg per dose). This medicine contains 0.081% w/v of ethanol (alcohol), which corresponds to an amount of 0.81 mg/ml. The amount in 0.81 mg/ml of this medicine is equivalent to less than 0.0203 ml of beer or 0.0081 ml of wine. The small amount of alcohol in this medicine has no noticeable effects.

3. How to use Iloprost Rafarm

Treatment with iloprost 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 indicated by your doctor. In case of doubt, consult your doctor again.

The dose of iloprost you need and the duration of the 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 Iloprost Rafarm. Depending on the type of device used and the prescribed dose, it is appropriate to use 1 ml or 2 ml of Iloprost Rafarm 10 micrograms/ml.

• Breelib Nebulizer

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

If you cannot tolerate the inhalation of iloprost 20 micrograms/ml, consult your doctor, who may decide that you should receive iloprost 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 a yellow round dot)

In general, when starting treatment with iloprost, 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 a blue round dot)

In general, when starting treatment with iloprost, 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, iloprost 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 iloprost gradually and may prescribe fewer inhalations per day. Start treatment by inhaling 2.5 micrograms of iloprost, using a 1 ml ampoule of iloprost 10 micrograms/ml (with a yellow round dot). 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 iloprost 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 ampoule of iloprost. Just before starting to inhale, break the glass ampoule and pour the solution into the medication chamber of the nebulizer, 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 iloprost indicated by your doctor.

• Iloprost 10 micrograms/ml is inhaled using the nebulizers prescribed by your doctor (Breelib, Venta-Neb, or I-Neb AAD).
• The nebulizer transforms the iloprost solution into an aerosol that is inhaled through the mouth.
• For inhalation, you should use a mouthpiece to avoid iloprost 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 iloprost solution that is left 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 iloprost treatment. Other people may be accidentally exposed to iloprost through the air in the room. In particular, newborns, infants, and pregnant women should not be in the same room while you are inhaling iloprost.

• Breelib

Fill the medication chamber with iloprost 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 a yellow dot, and pour all its contents into the medication chamber of the nebulizer.
2. 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 microgram dose, the medication chamber with the red latch is used along with the red control disc.
   • For the 5 microgram dose, the medication chamber with the purple latch is used along with the purple control disc.
3. 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.

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 a blue dot, and pour all its contents into the medication chamber of the nebulizer.
2. Two programs can be used:
3. Your doctor will adjust the Venta-Neb system program to your needs so that you receive the prescribed dose for you.
   • P1 Program 1: 5 micrograms of active ingredient in the mouthpiece, 25 inhalation cycles.
   • P2 Program 2: 2.5 micrograms of active ingredient in the mouthpiece, 10 inhalation cycles.

1. To obtain the optimal droplet size for the administration of iloprost, 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 Iloprost Rafarm than you should

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

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, phone: 91 562 04 20, indicating the medication and the amount ingested.

You may also experiencea 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 iloprost than you should, interrupt the inhalation session and consult your doctor. Your doctor will monitor and treat any resulting symptoms.There is no known specific antidote.

If you forget to use Iloprost Rafarm

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 Iloprost Rafarm

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).

Frequent(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 Iloprost Rafarm 10 micrograms/ml solution for inhalation by nebulizer (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 muscle of the small airways) 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 (widening 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)

Frequent: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 iloprost.

Reporting side effects

If you experience any side effects, consult your doctor, pharmacist, or nurse, even if it is a possible side effect that is not listed in this leaflet. You can also report them directly through the Spanish Medicines Monitoring System for Human Use: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medication.

5. Storage of Iloprost Rafarm

Keep this medication out of sight and reach of children.

Do not use this medication after the expiration date that appears on the packaging and ampoule. No special storage conditions are required.

Any remaining Iloprost Rafarm solution that is left in the nebulizer after inhalation should be discarded.

Medications should not be thrown away in drains or trash. Deposit the packaging and medications you no longer need in the pharmacy's SIGRE point. Ask your pharmacist how to dispose of the packaging and medications you no longer need. This way, you will help protect the environment.

6. Packaging Content and Additional Information

Composition ofIloprost Rafarm:

The active ingredient is iloprost. 1 ml of solution contains 10 micrograms of iloprost (as iloprost tromethamine). Each 1 ml ampoule contains 10 micrograms of iloprost.

The other components are tromethamine, ethanol, sodium chloride, hydrochloric acid 1N (for pH adjustment), and water for injectable preparations.

Appearance ofthe Product and Packaging Content

Iloprost Rafarm 10 micrograms/ml solution for inhalation by nebulizer is a clear and colorless solution without visible particles for inhalation with the Breelib, I-Neb, or Venta-Neb nebulizer.

Iloprost Rafarm 10 micrograms/ml solution for inhalation by nebulizer is available in colorless ampoules containing 1 ml or 2 ml of nebulizer solution.

Iloprost Rafarm 10 micrograms/ml solution for inhalation by nebulizeris available inthefollowingpackages:

• Ampoules of 1 ml for use with the Breelib or I-Neb nebulizers:

• Package containing 30 or 42 ampoules for use with the Breelib and I-Neb nebulizers.
• Multiple package containing 168 (4 x 42) ampoules.

The ampoules containing 1 ml are marked with a yellow dot.

• Ampoules of 2 ml for use with the Venta-Neb nebulizer:

• Package containing 30 ampoules.
• Multiple package containing 300 (10 x 30) ampoules.

The ampoules containing 2 ml are marked with a blue dot.

Only some package sizes may be marketed.

Marketing Authorization Holder:

Rafarm S.A.

12 Korinthou str., N. Psihiko,

15451 Athens, Greece

Tel: +30 210 6776550-1

Fax: +30 210 6776552

Manufacturer:

Rafarm S.A.

Thesi Pousi –Xatzi

Agiou Louka

19002, Paiania Attiki

Greece

Tel. 210 6643835

Fax 210 6645813

E-mail: [email protected]

You can request more information about this medicinal product by contacting the local representative of the marketing authorization holder:

EVER Pharma Therapeutics Spain, S.L.

C/ Toledo 170

28005 Madrid

Spain

Date ofthelast revision ofthisleaflet June/2021

Detailed and updated information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/.

This information is intended only for healthcare professionals:

Instructions for use and handling

Patients stabilized with a nebulizer should not switch to another nebulizer without the close supervision of the treating physician, as it has been shown that different nebulizers 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 Iloprost Rafarm 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 ultrasonics, which pass the solution through a mesh. It has been shown that the I-Neb AAD nebulizer is suitable for the administration of Iloprost Rafarm 10 micrograms/ml (1 ml ampoule with one yellow dot).

The measured MMAD of the small aerosol droplets 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 disk. Each medication chamber has a color code and has a control disk with the corresponding color code.

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

In each I-Neb AAD inhalation session, immediately before use, the contents of a 1 ml ampoule of Iloprost Rafarm, which has a yellow color dot, will be poured into the medication chamber.

The following table includes a summary of the instructions for the use of the I-Neb for Iloprost Rafarm:

• Venta-Neb

Venta-Neb, a portable ultrasonic nebulizer with a battery, has also been shown to be suitable for the administration of Iloprost Rafarm 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 Iloprost Rafarm 10 micrograms/ml, which is marked with a blue dot, will be poured into the medication chamber of the nebulizer immediately before use.

Two programs can be used:

• P1 Program 1: 5 micrograms of active ingredient in the mouthpiece, 25 inhalation cycles.
• P2 Program 2: 2.5 micrograms of active ingredient in the mouthpiece, 10 inhalation cycles.

The physician selects the pre-set program.

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

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