Iloprost Rafarm 10 micrograms/ml solution for inhalation by nebulizer: detailed information

Package leaflet: Information for the user

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, as 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, and you should not give it to other people, even if they have the same symptoms as you, because it may harm them.

If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are adverse effects not listed in this leaflet. See section 4.

Contents of the leaflet

What Iloprost Rafarm is and what it is used for
What you need to know before using Iloprost Rafarm
How to use Iloprost Rafarm
Possible adverse effects
How to store Iloprost Rafarm
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 this medicine is iloprost. Iloprost mimics a natural substance in the body called prostacyclin. Iloprost prevents unwanted blockage or narrowing of blood vessels and allows more blood to flow through the blood vessels.

What Iloprost Rafarm is used for

Iloprost 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 the increased blood pressure is unknown.

It is a disease in which blood pressure is too high in the blood vessels between the heart and the lungs.

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

How Iloprost Rafarm works

When the aerosol is inhaled, iloprost reaches the lungs, where it acts most effectively on the artery between the heart and the lungs. By improving blood flow, oxygen delivery to the body is enhanced and the strain on the heart is reduced.

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 components of this medicine (listed in section 6),
if you have a risk of bleeding – for example, if you have an active ulcer in the stomach or in the first part of the small intestine (duodenal ulcers), if you have suffered a physical injury (trauma), or if you are at risk of intracranial bleeding,
if you have a heart condition, such as
- inadequate blood flow to the heart muscles (severe coronary artery disease or unstable angina). Chest pain may be a symptom,
- a heart attack within the last six months,
- weakened heart (decompensated heart failure) not under close medical supervision,
- serious heart rhythm disturbances,
- a heart valve defect (congenital or acquired) causing poor heart function (unrelated to pulmonary hypertension),
if you have had a stroke or any other event reducing blood flow to the brain (e.g., transient ischemic attack) within the last 3 months,
if your pulmonary hypertension is due to a blocked or narrowed vein (pulmonary veno-occlusive disease).

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before starting iloprost:

Inhaling iloprost may trigger breathing difficulties (see section 4), especially in patients with bronchospasm (a sudden narrowing of the muscles in the small airways) and wheezing. Inform your doctor if you have a lung infection, severe asthma, or another chronic lung disease (chronic obstructive pulmonary disease). Your doctor will monitor you closely.
Your blood pressure will be measured before treatment, and if it is too low (less than 85 mmHg for the systolic value), iloprost therapy 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 other medicines, as combining them with this medicine may lower your blood pressure further (see below “Other medicines and Iloprost Rafarm”).
- Rise slowly from a chair or bed.
- If you tend to faint when getting up from bed, it may be helpful to take your first daily dose while still lying down.
- If you are prone to fainting episodes, avoid excessive exertion, such as physical exercise; inhaling iloprost before exercise may be beneficial.
Fainting episodes may be due to the underlying disease. Inform your doctor if these worsen, as they may consider adjusting your dose or changing your treatment.
If you have a heart condition, such as right heart failure, and notice your condition worsening, tell your doctor. Symptoms may include swelling of feet and ankles, shortness of breath, palpitations, increased need to urinate at night, or edema. Your doctor will consider whether your treatment needs to be changed.
If you have difficulty breathing, cough up blood, and/or sweat excessively, these may be signs that you have fluid in your lungs (pulmonary edema). Stop using iloprost and inform your doctor immediately. They will investigate the cause and take appropriate measures.
If you have severe liver problems or severe kidney problems requiring dialysis, inform your doctor.

Your doctor may gradually increase you to the prescribed dose or prescribe a lower dose of iloprost than for 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 solution to come into contact with the skin or eyes.

If this occurs, immediately wash the skin or eyes with plenty of water.

DO NOT drink or swallow the iloprost solution.

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

Children and adolescents

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

Other medicines and Iloprost Rafarm

Tell your doctor or pharmacist if you are using, have recently used, or might need to use any other medicines. Iloprost may affect how other medicines work and vice versa.

Inform your doctor if you are taking:

Medicines for treating high blood pressure or heart conditions, such as
beta-blockers,
nitrate-type vasodilators,
ACE inhibitors.

Your blood pressure may drop excessively.

Your doctor may adjust your dose.

Medicines that thin the blood or inhibit its clotting, such as
acetylsalicylic acid (ASA, a compound found in many medicines that reduces fever and relieves pain),
heparin,
coumarin-type anticoagulants, such as warfarin or phenprocoumon,
non-steroidal anti-inflammatory drugs,
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 has more information about medicines you should use with caution or avoid while using Iloprost Rafarm.

Use of Iloprost Rafarm with food and drink

Food or drink are not expected to affect iloprost. However, you should avoid eating or drinking during inhalation.

Pregnancy

If you have pulmonary hypertension, avoid becoming pregnant, as pregnancy may worsen your condition and even endanger your life.
If you could become pregnant, use reliable contraception from the start of treatment and throughout the treatment period.
If you are pregnant, think you might be pregnant, or plan to become pregnant, inform 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 unknown whether iloprost passes into breast milk. A potential risk to breastfed infants cannot be excluded, and breastfeeding should preferably be avoided during treatment with iloprost.

Consult your doctor or pharmacist before using any medicine.

Newborns, infants, and pregnant women must 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 operate tools or 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). This medicine contains 0.081% w/v ethanol (alcohol), equivalent to 0.81 mg/ml. The amount of 0.81 mg/ml in this medicine corresponds to less than 0.0203 ml of beer or 0.0081 ml of wine. The small amount of alcohol in this medicine has no notable effects.

3. How to use Iloprost Rafarm

Treatment with iloprost should only be initiated by a physician experienced in the treatment of pulmonary hypertension.

How much to inhale and for how long

Always follow exactly the administration instructions for this medicine given by your doctor. If you are unsure, consult your doctor again.

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

Different nebulizing devices may be used to administer Iloprost Rafarm. Depending on the type of device used and the prescribed dose, either 1 ml or 2 ml of Iloprost Rafarm 10 micrograms/ml may be appropriate.

Breelib Nebulizer

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

If you cannot tolerate 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 sessions spread throughout the day. The duration of each inhalation session with Breelib is usually about 3 minutes.

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

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

In general, when starting iloprost treatment, the first inhaled dose should be 2.5 micrograms of iloprost delivered at the mouthpiece of the nebulizer. 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 sessions spread throughout the day. The duration of each inhalation session with I-Neb AAD usually ranges from 4 to 10 minutes, depending on the prescribed dose.

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

In general, when starting iloprost treatment, the first inhaled dose should be 2.5 micrograms of iloprost delivered at the mouthpiece of the nebulizer. 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 sessions spread throughout the day. The duration of each inhalation session with Venta-Neb usually ranges from 4 to 10 minutes, depending on the prescribed dose.

Depending on your individual needs, iloprost may be used for long-term treatment.

If you have kidney or liver problems

Dose adjustment is not necessary in patients with mild to moderate renal impairment (patients with creatinine clearance > 30 ml/min).

If you have severe renal impairment requiring dialysis or have liver problems, your doctor will initiate 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 (corresponding to a maximum of 6 administrations per day). Thereafter, your doctor may cautiously shorten the dosing intervals depending on how well you tolerate the treatment. If your doctor decides to further increase the dose to 5 micrograms, dosing intervals of 3–4 hours should initially be re-established and then shortened based on your tolerance to treatment.

If you notice that the effect of iloprost is too strong or too weak, consult your doctor or pharmacist. Ask your doctor to arrange for someone to help you become familiar with using the nebulizer. Do not switch to another nebulizer without consulting your treating doctor.

How to inhale

For each inhalation session, use a new ampoule of iloprost. Just before starting inhalation, break the glass ampoule and pour the solution into the medication chamber according to the nebulizer's instructions for use.

Carefully follow the instructions provided with the nebulizer, especially those relating to hygiene and cleaning.

Always follow exactly the administration instructions for iloprost given 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 converts the iloprost solution into an aerosol, which is inhaled through the mouth.
For inhalation, use a mouthpiece to prevent iloprost from contacting your skin. Do not use a face mask.
Carefully follow the instructions provided with the nebulizer. Consult your doctor or pharmacist if you have any doubts.
Any remaining iloprost solution left in the nebulizer after inhalation must be discarded (see section 5).

Room ventilation

Ensure that the room where you take iloprost treatment is well ventilated or aired. Other people could be accidentally exposed to iloprost through the room air. 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.

Device

Medicament

Iloprost dose

from the mouthpiece

Estimated

inhalation time

Breelib

Iloprost 10 micrograms/ml (one yellow dot)

2.5 micrograms

3 minutes

I-Neb AAD

Immediately before inhalation, break the glass ampoule containing 1 ml of solution, which has a yellow dot, and pour all of its contents into the medication chamber of the nebulizer.
The preset dose delivered by the I-Neb AAD system is controlled by the medication chamber in combination with a control disc. There are two medication chambers with different color codes. Each medication chamber is used with a corresponding colored control disc:
- For the 2.5 microgram dose, use the medication chamber with the red latch together with the red control disc.
- For the 5 microgram dose, use the medication chamber with the purple latch together with the purple control disc.
To ensure that you receive the prescribed dose, check the color of the medication chamber and the color of the control disc. These must be the same color, either red for the 2.5 microgram dose or purple for the 5 microgram dose.

Device

Dose of iloprost at the mouthpiece

Estimated inhalation time

I-Neb AAD

2.5 micrograms

5 micrograms

3.2 min

6.5 min

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

Medication	Round colored ampoule dot	Dose	I-Neb AAD
Medication chamber lock	Control disc
Iloprost 10 micrograms/ml	1 ml ampoule One yellow dot	2.5 micrograms	red red
5 micrograms	purple purple

Venta-Neb

Immediately before inhalation, break the glass ampoule containing 2 ml of solution, which has a blue dot, and pour all of its contents into the dosing chamber of the nebulizer.
Two programs can be used:
Your doctor will adjust the Venta-Neb system program to your needs so that you receive the prescribed dose.
- P1 Program 1: 5 micrograms of active substance at the mouthpiece, 25 inhalation cycles.
- P2 Program 2: 2.5 micrograms of active substance at the mouthpiece, 10 inhalation cycles.
To achieve the optimal droplet size for iloprost administration, the green deflector plate must be used.

Device

Ilomedin dose at the mouthpiece

Estimated inhalation time

Venta-Neb

2.5 micrograms

5 micrograms

4 min

8 min

For further details, refer to the nebulizer device instruction manual or consult your doctor.

If you use more Iloprost Rafarm than you should

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

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

You may also experience a decrease or increase in blood pressure, bradycardia (decreased heart rate), tachycardia (increased heart rate), vomiting, diarrhea, or pain in the extremities.

If any of these occur when you have used more iloprost than recommended, stop 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 missed doses. Consult your doctor to find out what you should do.

If you interrupt treatment with Iloprost Rafarm

If you stop or wish to stop treatment, discuss this first with your doctor.

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

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

The following serious adverse effects may occur. If you experience any of them, consult your doctor immediately:

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

Episodes of bleeding may very commonly occur (mostly nosebleeds [epistaxis] and coughing up blood [haemoptysis]), especially if you are taking treatment to thin the blood (anticoagulants). The risk of bleeding may increase in patients treated simultaneously 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 haemorrhage).

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

Fainting (syncope) is a symptom of the disease itself, but it may also occur during treatment with Iloprost Rafarm 10 micrograms/ml solution for inhalation by nebuliser (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 available data):

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

The following is a list of other possible adverse effects according to their likelihood of occurrence:

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 / chest pain
cough
headache
nausea
jaw pain / spasm of jaw muscles (trismus)
swelling of the limbs (peripheral oedema)

Common: may affect up to 1 in 10 people

difficulty breathing (dyspnoea)
dizziness
vomiting
diarrhoea
pain when swallowing (pharyngolaryngeal irritation)
throat irritation
irritation of mouth and tongue, including pain
skin rash
rapid heartbeat (tachycardia)
awareness of rapid or strong heartbeat (palpitations)

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

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

Other possible adverse effects

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

Reporting of adverse effects

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

5. Storage of 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 packaging and vial. No special storage conditions are required.

Any remaining solution of Iloprost Rafarm left in the nebulizer after inhalation must be discarded.

Medicines must not be disposed of via wastewater or household waste. Unused medicines and their containers should be returned to the SIGRE point at your pharmacy. Ask your pharmacist how to dispose of medicines and containers you no longer need. This will help protect the environment.

6. Contents of the pack and other information

Composition of Iloprost Rafarm:

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

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

Appearance of the product and contents of the pack

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

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

Iloprost Rafarm 10 micrograms/ml solution for inhalation by nebulizer is available in the following packs:

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

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

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

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

Only certain pack 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]

For further information about this medicinal product, please contact the local representative of the Marketing Authorization Holder:

EVER Pharma Therapeutics Spain, S.L.

C/ Toledo 170

28005 Madrid

Spain

Date of the most recent revision of this package leaflet: June 2021

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

This information is intended for healthcare professionals only:

Instructions for use and handling

Patients who are stabilized on 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 deliver the solution more rapidly (see section 5.2 of the Summary of Product Characteristics).

To minimize accidental exposure, it is recommended to ensure adequate room ventilation.

Breelib

If using the Breelib nebulizer, follow the instructions for use provided with the device.

Fill the medication chamber with Iloprost Rafarm immediately before use.

Device

Medication

Iloprost dose

from the nebulizer

Estimated

inhalation time

Breelib

Iloprost Rafarm 10 micrograms/ml (one yellow dot)

2.5 micrograms

3 minutes

I-Neb AAD

The I-Neb AAD system is a portable, handheld vibrating mesh nebulizer system. This system uses ultrasound to generate fine droplets by passing the solution through a mesh. The I-Neb AAD nebulizer has been shown to be suitable for the administration of Iloprost Rafarm 10 micrograms/ml (1 ml ampoule with a yellow dot).

The measured MMAD of the aerosol droplets is 2.1 micrometers.

This nebulizer monitors the breathing pattern to determine the required inhalation time for delivering the preset dose of 2.5 or 5 micrograms of iloprost.

The dose delivered by the I-Neb AAD system is controlled by the dosing chamber in combination with a control disc. Each dosing chamber has a color code and is used with a corresponding color-coded control disc.

For 2.5 microgram doses, the dosing chamber with the red latch is used together with the red control disc.
For 5 microgram doses, the dosing chamber with the purple latch is used together with the purple control disc.

In each inhalation session with the I-Neb AAD, immediately before use, the contents of one 1 ml ampoule of Iloprost Rafarm with a yellow dot will be dispensed into the dosing chamber.

Device

Ilomedin dose at the mouthpiece

Estimated inhalation time

I-Neb AAD

2.5 micrograms

5 micrograms

3.2 min

6.5 min

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

Medication	Round colored cap point	Dose	I-Neb AAD
Medication chamber lock	Control disc
Iloprost Rafarm 10 micrograms/ml	1 ml vial One yellow point	2.5 micrograms	red red
5 micrograms	purple purple

Venta-Neb

Venta-Neb, a portable ultrasonic nebulizer with battery, has also proven suitable for the administration of Iloprost Rafarm 10 micrograms/ml. The measured MMAD of the aerosol droplets was determined to be 2.6 micrometers. For each inhalation session, the contents of one ampoule containing 2 ml of Iloprost Rafarm 10 micrograms/ml, marked with a blue dot, shall be poured into the medication chamber of the nebulizer immediately before use.

Two programs may be used:

P1 Program 1: 5 micrograms of active substance at the mouthpiece, 25 inhalation cycles.
P2 Program 2: 2.5 micrograms of active substance at the mouthpiece, 10 inhalation cycles.

The physician selects the preset program.

An optical and acoustic signal from the Venta-Neb system alerts the patient to inhale. It stops automatically after the preset dose has been delivered. To achieve the optimal droplet size for the administration of Iloprost Rafarm, the green deflector plate must be used. Refer to the Venta-Neb nebulizer instruction manual for details.

Device

Ilomedin dose at the mouthpiece

Estimated inhalation time

Venta-Neb

2.5 micrograms

5 micrograms

4 min

8 min

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