Leaflet: information for the user

Iloprost Rafarm 10 micrograms/ml solution for inhalation by nebuliser

Read 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 must not give it to others even if they have the same symptoms as you, as it may harm them.

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

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

2. What you need to know before you start using Iloprost Rafarm

3. How to use Iloprost Rafarm

4. Possible side effects

5. Storage of Iloprost Rafarm

6. Contents of the pack and additional information

What is Iloprost Rafarm

The active ingredient of this medication is iloprost. Iloprost imitates a natural substance of 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 in which the cause of the increased blood pressure is unknown.

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

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

How Iloprost Rafarm works

When inhaling the aerosol, iloprost reaches the lungs, where it acts more effectively on the artery located between the heart and the lungs. By improving blood flow, oxygen supply to the body is improved and the heart load is reduced.

No useIloprost Rafarm:

•if you areallergictoiloprost or to any of the other ingredients of this medication (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 thin intestine (duodenal ulcers), if you have suffered a physical injury (trauma), if you are at risk of suffering a hemorrhage in the brain,

•if you have a heart problem, such as for example a poor blood flow to the heart muscles (severe coronary disease or unstable angina). A symptom may include chest pain,

•if you have had a heart attack in the last six months,

•if you have a weak heart (decompensated heart failure) that is not under close medical supervision,

•if you have severe heart rhythm disturbances,

•if you have a heart valve defect (congenital or acquired) that makes the heart not function properly (not related to pulmonary hypertension),

•if you have suffered in the last 3 months a stroke or any other event that has reduced blood flow to the brain (e.g., transient ischemic attack),

•if you have pulmonary hypertension that is due to a blocked or narrowed vein (venous occlusive disease).

Warnings and precautions

Consult your doctor, pharmacist or nurse before starting to use iloprost:

•The inhalation of iloprost may trigger respiratory difficulties (see section 4), especially in patients with bronchospasm (a sudden narrowing of the small airway muscles) and wheezing. Inform your doctor if you have a lung infection, severe asthma or any other chronic lung disease (chronic obstructive pulmonary disease).

•Your doctor will closely monitor you.

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

•In general, you will need to take special care to avoid the effects of low blood pressure, such as fainting and dizziness:

– Inform your doctor if you are taking other medications, as the combination with this medication may lower your blood pressure even further (see "Other medications 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 episodes of fainting, avoid any exceptional effort, for example during physical exercise; it may be helpful to inhale iloprost before doing so.

•Episodes of fainting may be due to the underlying disease. Inform your doctor if they worsen, as they may consider adjusting your dose or changing your treatment.

•If you have a heart disease, such as heart failure, and you notice that your condition is worsening, tell your doctor. Symptoms may include swelling of the feet and ankles, difficulty breathing, palpitations, and increased need to urinate at night or edema. Your doctor will consider changing your treatment.

•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 or kidney problems that require dialysis, inform your doctor.

Your doctor may gradually change your prescribed dose or prescribe a lower dose of iloprost than other patients (see section 3 "How to use Iloprost Rafarm").

Contact of Iloprost Rafarm with the skin or ingestion of Iloprost Rafarm

•DO NOT let the iloprost solution come into contact with the skin or eyes.

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

•DO NOT drink or swallow the iloprost solution.

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

Children and adolescents

Iloprost 1 has not been established for safety and efficacy in children up to 18 years.

Other medications and Iloprost Rafarm

Inform your doctor or pharmacist if you are using, have used recently or may need to use any other medication. Iloprost may affect the way other medications work and vice versa.

Inform your doctor if you are taking:

• Medications for the treatment of hypertension or heart disease, such as

- beta-blockers,

- nitrate vasodilators,

- ACE inhibitors.

Your blood pressure may drop too low.

Your doctor may adjust your dose.

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

- acetylsalicylic acid (AAS, a compound present in many medications that reduce fever and calm pain),

- heparin,

- anticoagulants of the type coumarin, 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 surveillance.

Before taking any medication, consult your doctor or pharmacist, who has more information about the medications with which you should be cautious or avoid when using Iloprost Rafarm.

Use of Iloprost Rafarm with food and drinks

No significant effects are expected from food or drinks on 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 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 intend 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 for you and the fetus.

Breastfeeding

The passage of iloprost into breast milk is unknown. It cannot be excluded that there is a potential risk in infants and it is preferable to avoid breastfeeding during treatment with iloprost.

Consult your doctor or pharmacist before using any medication.

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

Driving and using machines

Iloprost reduces blood pressure and may cause dizziness or instability in some people.

Do not drive or use tools or machines 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 medication contains 0.081% w/v of ethanol (alcohol), which corresponds to a quantity of 0.81 mg/ml.The amount in 0.81mg/ml of this medication is equivalent to less than 0.0203 ml of beer or 0.0081 ml of wine.The small amount of alcohol in this medication has no notable effects.

The 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 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
  

When starting treatment with iloprost or if you change from an alternative device, the first inhalation should be done with iloprost 10 micrograms/ml (1 ml ampoule with a round yellow dot). If you tolerate this dose well, your next inhalation will be with iloprost 20 micrograms/ml (ampoule with a round orange 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 should perform 6 to 9 inhalation sessionsspread throughout the day. The duration of each inhalation session with Breelib is usually 3 minutes.

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

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

Generally, when starting treatment with iloprost, the first dose inhaled 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 should 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 (2 ml ampoule with a round blue dot)

Generally, when starting treatment with iloprost, the first dose inhaled 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 should 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 adjustment is necessary in patients with mild or moderate renal impairment (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 round yellow dot). Use dosing intervals of 3-4 hours (corresponding to a maximum of 6 administrations per day). From then on, your doctor may shorten the dosing intervals as needed based on how well you tolerate the treatment. If your doctor decides to increase the dose to 5 micrograms, the dosing intervals should be established again at 3-4 hours and shortened as needed 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 familiarize yourself with the use of the nebulizer. Do not change to another nebulizerwithout consulting the doctor treating you.

How to inhale

Use a new iloprost ampoule for each inhalation session. Just before starting to inhale, break the glass ampoule and pour the solution into the medication chamber following the nebulizer usage instructions.

Follow the instructions accompanying the nebulizer, 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.

• To inhale, use a mouthpiece to avoid iloprost coming into contact with your skin. Do not use a mask.

• Follow the instructions accompanying the nebulizer carefully. Consult your doctor or pharmacist if you have any doubts.

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

Room ventilation

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

• Breelib

Fillthemedicationchamber with iloprost immediatelybefore use. Followthenebulizer usage instructionsregardingfilling.

• I-Neb AAD

1. Immediately before inhalation, break the glass ampoule containing 1 ml of solution, which has a round 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 different color codes. For each medication chamber, there is a control disc with its corresponding color code:

• For the 2.5 microgram dose, the medication chamberwith the red latch is usedtogether with the red control disc.

• For the 5 microgram dose, the medication chamberwith the purple latch is usedtogether with the purple control disc.

3. To ensure that you receive the prescribed dose, check the color of the medication chamber and the

color of the control disc. These should match, 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 round 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.

4. To obtain the optimal droplet size for iloprost administration, the green deflecting plate should be used.

Formoredetails, consult thenebulizerdevice manualor consult withyourdoctor.

If you use moreIloprost Rafarm than you should

Using moreiloprost thanyoushouldcancause dizziness,headache,flushing (rednessoftheface), nausea (feelingofunwellness), jaw or back pain.

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

You may also experience a decrease or an increasein blood pressure,bradycardia (decrease in heart rate), tachycardia(increase in heart rate), vomiting, diarrheaor pain in the extremities.

If any of these occur when you have used moreiloprost than you should,interrupt the inhalation session and consult your doctor.Your doctor will monitor and treat any resulting symptoms.No specific antidote is known.

If you forget to useIloprost Rafarm

Do not takeadosedoubledtocompensateforthedosesyouforgot.Consult your doctorwhatyoushoulddo.

If you interruptthe treatment with Iloprost Rafarm

If you interruptorwanttointerruptthetreatment,consultyourdoctorfirst.

If you haveanyotherdoubtsabouttheuseofthismedication, ask your doctor,pharmacistor nurse.

Like allmedicines,thismedicinecancausesideeffects,although noteveryonewillexperiencethem.

Thefollowingserioussideeffectsmayoccur:Iftheydooccur,consultyourdoctorimmediately:

Verycommon(mayaffectmorethan1 in10people):

• Episodesofbleeding(inmostcases,nasalbleeding[epistaxis]andhemoptysis)mayoccurfrequently,especiallyifyouaretakinganticoagulanttherapy.Theriskofbleedingmayincreaseinpatientstreatedwithinhibitorsofplateletaggregationoranticoagulants(seealsosection2).

• Inveryrarecases,fatalcaseshavebeenreportedthatincludedcerebralandintracranialhemorrhage.

Common(mayaffectupto1 in10people):

• Syncope(syncope)isasymptomoftheunderlyingdisease,butmayalsooccurduringtreatmentwithIloprostRafarm10micrograms/mlsolutionforinhalationbynebulizer(seealsosection2“Warningsandprecautions”forrecommendationsonwhatyoucandotoavoidthesesymptoms).
• Lowbloodpressure(hypotension)

Frequencynotknown(cannotbeestimatedfromavailabledata):

• Bronchospasm(suddenconstrictionofthemusculatureofthesmallairways)andsibilantbreathing(seealsosection2“Warningsandprecautions”).

Thefollowingisalistofotherpossiblesideeffectsbasedontheirprobabilityofoccurrence:

Verycommon:mayaffectmorethan1 in10people

• vasodilation(dilationofthebloodvessels)maycausesymptomssuchasflushingorrednessoftheface
• chestdiscomfort/chestpain
• cough
• headache
• nausea

• jawpain/mandibularmusclespasm(trismus)
• peripheraledema(swellingoftheextremities)

Common:mayaffectupto1 in10people

• shortnessofbreath(dyspnea)
• dizziness
• vomiting
• diarrhea
• difficultyswallowing(pharyngolaryngealirritation)
• throatirritation
• mouthandlipirritation,includingpain
• skineruption
• rapidheartrate(tachycardia)
• awarenessofrapidorintenseheartbeats(palpitations)

Frequencynotknown:thefrequencycannotbeestimatedfromavailabledata.

• thrombocytopenia(reductioninthenumberofplateletsintheblood)
• hypersensitivity(i.e.,allergy)
• alterationoftaste(dysgeusia)

Otherpossiblesideeffects:

• Swellingmainlyoftheanklesandlegsduetofluidretention(peripheraledema)isaverycommonsymptomofthesamedisease,butmayalsooccurduringtreatmentwithiloprost.

Reportingofsideeffects:

Ifyouexperienceanytypeofsideeffect,consultyourdoctor,pharmacist,ornurse,evenifitisapossiblesideeffectthatdoesnotappearinthisleaflet.YoucanalsoreportthemdirectlytotheSpanishSystemforPharmacovigilanceofHumanMedicines:https://www.notificaram.es.Byreportingsideeffects,youcancontributetoprovidingmoreinformationonthesafetyofthismedicine.

Keepthismedicationout of the sight and reachofchildren.

Do not usethismedicationafter the expiration date thatappearson thecontainerand ampoule.No special storage conditionsare required.

Dispose of any remaining solution of Iloprost Rafarm thatremainsin the nebulizerafter inhalation.

Medicinesshould not bethrown awaydown the drainsorin the trash.Deposit the containers and medicines that you no longer need at the SIGRE pointof the pharmacy.Ask your pharmacisthow to dispose of the containersand medicinesthat you no longer need.This way,you will helpto protect theenvironment.

Composition ofIloprost Rafarm:

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

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

Appearance of the product and contents of the package:

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

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 nebulizer is available in the following packaging:

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

- Package containing 30 or 42 ampoules for use with the nebulizers Breelib and I-Neb.

- Multi-pack 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 nebulizer Venta-Neb:

- Package containing 30 ampoules.

- Multi-pack containing 300 (10 x 30) ampoules.

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

Only some sizes of packaging may be commercially available.

Marketing Authorization Holder:

Rafarm S.A.

12 Korinthou str., N. Psihiko,

15451 Athens, Greece

Tel: +30 210 6776550-1

Fax: +30 210 6776552

Responsible for manufacturing:

Rafarm S.A.

Thesi Pousi –Xatzi

Agiou Louka

19002, Paiania Attiki

Greece

Tel. 210 6643835

Fax 210 6645813

E-mail: [email protected]

Further information about this medicinal product can be obtained by contacting the local representative of the marketing authorization holder:

EVER Pharma Therapeutics Spain, S.L.

C/ Toledo 170

28005 Madrid

Spain

Last update of this leaflet: June/2021

The detailed and updated information about this medicinal product is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) http://www.aemps.gob.es/.

This information is intended solely for healthcare professionals:

Instructions for use and handling:

Patients stabilized with a nebulizer should not change to another nebulizer without the close supervision of the treating physician, as it has been demonstrated 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 Technical Dossier).

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

• Breelib

If the Breelib nebulizer is used, the user should follow the instructions for use provided with the device.

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 technology nebulizer. This system generates small droplets by ultrasonic, which makes the solution pass through a mesh. It has been demonstrated that the I-Neb AAD nebulizer is suitable for the administration of Iloprost Rafarm 10 micrograms/ml (ampoule of 1 ml with a yellow dot).

The measured MMAD of the small droplets of aerosol was 2.1 micrometers.

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

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

• For doses of 2.5 micrograms, the medication chamber with the red peg is used with the red control disc.

• For doses of 5 micrograms, the medication chamber with the purple peg is used with the purple control disc.

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

A summary of the instructions for the use of I-Neb for Iloprost Rafarm is included in the following table:

• Venta-Neb

Venta-Neb, portable ultrasonic nebulizer with battery, has also been demonstrated to be suitable for the administration of Iloprost Rafarm 10 micrograms/ml. It was determined that 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 doctor selects the pre-adjusted program.

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

No efficacy and tolerability of inhaled iloprost have been established when administered with other nebulization systems that provide different nebulization characteristics of the iloprost solution.