Iloprost Zentiva 10 micrograms/ml solution for inhalation by nebulizer

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Iloprost Zentiva 10 micrograms/ml solution for inhalation by nebuliser

Read the entire 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.
• If you experience any side effects, talk to your doctor, pharmacist or nurse, even if they are side effects not listed in this leaflet. See section 4.

Contents of the leaflet

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

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

What Iloprost Zentiva is

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

What Iloprost Zentiva is used for

This medicine 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.

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

How Iloprost Zentiva Works

When inhaled as an aerosol, iloprost reaches the lungs, where it acts most effectively on the artery located 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 starting to use Iloprost Zentiva

Do not use this medicine

• 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 ulcer in the stomach or the first part of the small intestine (duodenal ulcers), if you have sustained 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). Symptoms may include chest pain,

• a heart attack within the last 6 months,

• weakened heart (decompensated heart failure) not under close medical supervision,

• severe disturbances in heart rhythm,

• a defect in the heart valves (congenital or acquired) causing poor heart function (unrelated 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 ischemic attack),

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

Warnings and precautions

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

• Inhalation of 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 checked before treatment begins, and if it is too low (less than 85 mmHg for the systolic value), therapy with this medicine should not be started.

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

• Inform your doctor if you are taking other medicines, as combining them with iloprost may lower your blood pressure even further (see below “Use of Iloprost Zentiva with other medicines”).

• 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 any unusual exertion, for example during physical exercise; inhaling iloprost before exercising may be beneficial. Fainting episodes may be due to the underlying disease. Inform your doctor if they worsen, as he or she may consider adjusting your dose or changing your treatment.

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

• If you experience difficulty breathing, cough up blood and/or sweat excessively, these may be signs of fluid in the lungs (pulmonary edema). Stop using this medicine and inform your doctor immediately. He or she will investigate the cause and take appropriate measures.

• If you have liver problems or very severe kidney problems requiring dialysis, inform your doctor. Your dose may be gradually increased to the prescribed level, or you may be prescribed a lower dose of iloprost than other patients (see section 3 “How to use Iloprost Zentiva”).

Contact with iloprost on skin or ingestion of iloprost

• DO NOT allow the iloprost solution to come into contact with the skin or eyes. If this occurs, immediately wash the skin or eyes thoroughly with plenty of water.
• DO NOT drink or swallow the iloprost solution. If this happens accidentally, drink plenty of water and inform your doctor immediately.

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 Zentiva

Tell your doctor or pharmacist if you are using, have recently used, or might need to use any other medicine. Iloprost may affect the way other medicines work and other medicines may affect the way Iloprost works.

Tell your doctor if you are taking:

?Medications for the treatment of hypertension or heart conditions, such as:

• Beta-blockers.
• Nitrate-type vasodilators.
• ACE inhibitors.

Your blood pressure may drop too much. Your doctor may adjust your dosage.

Medications that thin the blood or inhibit its coagulation, such as:

• Acetylsalicylic acid (ASA, a compound found in many medications 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 keep you under close surveillance.

Before taking any medication, consult your doctor or pharmacist, who has more information about the medications you should use with caution or avoid while using this medicine.

Use of Iloprost with Food and Beverages

Food or beverages 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 can worsen your condition and may 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, you must inform your doctor immediately. This medicine 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 this medicine is excreted in breast milk. A potential risk to the breast-fed infant cannot be excluded, and it is preferable to avoid breast-feeding during treatment with iloprost.

Consult your doctor or pharmacist before taking any medicine.

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

Driving and using machines

This medicine 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 Zentiva contains ethanol

Iloprost Zentiva 10 micrograms/ml contains 0.75 mg of alcohol (ethanol) in 1 ml of nebuliser solution, which is equivalent to 0.81 mg of 96% (v/v) ethanol.

The amount of alcohol in 1 ml of this medicine is equivalent to less than 1 ml of beer or 1 ml of wine.

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

3. How to use Iloprost Zentiva

Iloprost treatment must be initiated only by a physician experienced in the treatment of pulmonary hypertension.

How much to inhale and for how long

Follow exactly the administration instructions for this medicine as given by your doctor. If in doubt, consult your doctor again.

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

Different nebulizer devices can be used to administer iloprost 10 micrograms/ml.

Depending on the type of device used and the prescribed dose, it is appropriate to use either 1 ml or 2 ml of Iloprost Zentiva 10 micrograms/ml.

?Nebulizer Breelib

When starting treatment with iloprost or when switching from an alternative device, the first inhalation must be performed using iloprost 10 micrograms/ml. If you tolerate this dose well, your next inhalation should be with iloprost 20 micrograms/ml. You should then continue with this dose.

If you are unable to tolerate the inhalation of iloprost 20 micrograms/ml, consult your doctor, who may decide that you should continue receiving iloprost 10 micrograms/ml.

Most patients will need to perform 6 to 9 inhalation sessions per day, spaced throughout the day. The duration of each inhalation session with Breelib usually lasts about 3 minutes.

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

?I-Neb AAD Nebulizer

In general, when starting treatment with iloprost, the first inhaled dose should be 2.5 micrograms of iloprost delivered at the mouthpiece of the nebulizer. If this dose is well tolerated, the dose should be increased to 5 micrograms of iloprost, and treatment should continue at this dose. If the 5 microgram dose is not tolerated, the dose should be reduced to 2.5 micrograms.

Most patients will need to perform 6 to 9 inhalation sessions per day, distributed throughout the day. The duration of each inhalation session with the I-Neb AAD typically lasts between 4 and 10 minutes, depending on the prescribed dose.

Venta-Neb Nebulizer (2 ampoules of Iloprost Zentiva)

In general, when starting treatment with iloprost, the first inhaled dose should be 2.5 micrograms of iloprost delivered at the mouthpiece of the nebulizer. If this dose is well tolerated, the dose should be increased to 5 micrograms, and treatment should continue at this dose. If the 5 microgram dose is not tolerated, the dose should be reduced to 2.5 micrograms.

Most patients will need to perform 6 to 9 inhalation sessions per day, distributed throughout the day. The duration of each inhalation session with Venta-Neb typically ranges from 4 to 10 minutes, depending on the prescribed dose.

Depending on individual needs, this medicine may be used for long-term treatment.

If you have kidney or liver problems

It is not necessary to adjust the dose in patients with mild or moderate renal impairment (patients with a creatinine clearance > 30 ml/min).

If you have severe renal impairment and require dialysis, or if you have liver problems, your doctor will introduce iloprost gradually and may prescribe fewer inhalations per day. Begin treatment by inhaling 2.5 micrograms of iloprost, using one 1 ml ampoule of iloprost 10 micrograms/ml. 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 should initially be re-established at 3 – 4 hours and then shortened according to your tolerance to treatment.

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

How to inhale

For each inhalation session, you must use a new ampoule of iloprost. Immediately before starting inhalation, break open the glass ampoule and transfer the solution into the medication chamber, following the nebulizer's instructions for use.

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

Always follow exactly the administration instructions for this medicine as given by your doctor.

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

Ventilation of the room

Ensure that the room where you have taken iloprost treatment is well ventilated or aired. Other people could be accidentally exposed to iloprost through the air in the room. In particular, newborns, infants, and pregnant women should not be present 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	Medication	Iloprost dose at the mouthpiece	Estimated inhalation time
Breelib	Iloprost Zentiva 10 micrograms/ml	2.5 micrograms	3 minutes

I-Neb AAD

1. Immediately before starting to inhale, break the glass ampoule containing 1 ml of solution, and pour all of its contents into the medication chamber of the nebulizer.
2. 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 has a corresponding control disc with the matching color code:
   • For the 2.5 microgram dose, the medication chamber with the red latch must be used together with the red control disc.
   • For the 5 microgram dose, the medication chamber with the purple latch must be used together 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 must match—either red for the 2.5 microgram dose or purple for the 5 microgram dose.

Device	Iloprost 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:

Medication	Dose	I-Neb AAD
Medication chamber latch	Control disc
Iloprost Zentiva 10 micrograms/ml	2.5 micrograms	red	red
5 micrograms	purple	purple

?Venta-Neb

1. Immediately before inhalation, break open two glass ampoules containing 1 ml of solution, and pour the entire contents into the medication chamber of the nebulizer.
2. Two programs can be used:
3. Your doctor will adjust the Venta-Neb system program according 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.
4. To achieve the optimal droplet size for delivery of this medication, the green deflector plate must be used.

Device	Iloprost 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 physician.

If you use more Iloprost Zentiva than you should

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

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

• Stop the inhalation session immediately.
• Consult your doctor.

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

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 medicine and the amount ingested.

If you forget to use Iloprost Zentiva

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 Zentiva

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

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 any of these occur, 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 antiplatelet agents 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 (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):

• Widening 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 edema) is a very common symptom of the disease itself, but it may also occur during treatment with Iloprost Zentiva.

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Reporting of Adverse Reactions

If you experience any type of adverse reaction, consult your doctor, pharmacist, or nurse, even if it involves possible effects not listed in this leaflet. You may also report them directly through the Spanish Pharmacovigilance System for Human Medicinal Products: www.notificaRAM.es. By reporting adverse reactions, you can help provide more information on the safety of this medicine.

5. Storage of Iloprost Zentiva

Keep this medicine out of sight and reach of children.

Do not use this medicine after the expiry date stated on the label and packaging after EXP. The expiry date refers to the last day of that month.

No special storage conditions are required. Do not freeze.

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

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and packaging that you no longer need. This will help protect the environment.

6. Contents of the container and other information

Composition of Iloprost Zentiva

• The active substance is iloprost.

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

• The other components are tromethamine, ethanol 96%, sodium chloride, hydrochloric acid (for pH adjustment) and water for injections.

Appearance of the product and contents of the container

Iloprost Zentiva is a clear, colorless solution without visible particles for inhalation using the Breelib, I-Neb, or Venta-Neb nebulizers.

Iloprost Zentiva 10 micrograms/ml is supplied in a clear glass ampoule of hydrolytic class I with a blue identification ring containing 1.0 ml of solution, packaged in a blister and cardboard box.

Iloprost Zentiva 10 micrograms/ml is available in the following pack sizes:

10x1 ml (2 blisters with 5 ampoules), 30x1 ml (6 blisters with 5 ampoules or 5 blisters with 6 ampoules), 40x1 ml (8 blisters with 5 ampoules), 42x1 ml (8 blisters with 5 ampoules and 1 blister with 2 ampoules or 7 blisters with 6 ampoules), 168x1 ml (33 blisters with 5 ampoules and 1 blister with 3 ampoules or 28 blisters with 6 ampoules), multiple container pack containing 160 ampoules (4 inner boxes containing 8 blisters with 5 ampoules each).

Some pack sizes may not be marketed.

Marketing Authorization Holder and Manufacturing Licensee:

Zentiva k.s.

U Kabelovny 130

Dolní Mecholupy

102 37 Prague 10

Czech Republic

For further information regarding this medicinal product, please contact the local representative of the Marketing Authorization Holder: Zentiva Spain S.L.U.

Avenida de Europa, 19, Building 3, 1st Floor

28224 Pozuelo de Alarcón, Madrid, Spain

This medicinal product is authorized in the Member States of the European Economic Area under the following names:

Austria	Ilosprost Zentiva
Denmark	Ilosprost Zentiva
Finland	Ilosprost Zentiva
Iceland	Ilosprost Zentiva
Spain	Ilosprost Zentiva
Czech Republic	Ilosprost Zentiva k.s.
Romania	Ilosprost Zentiva
Sweden	Ilosprost Zentiva

Date of the most recent review of this leaflet: 06/2021

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

This information is intended for healthcare professionals only:

Instructions for use and handling

Stabilized patients using a nebulizer should not switch to another nebulizer without close supervision by the physician in charge of treatment, 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 keep the room well ventilated.

Breelib

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

Fill the medication chamber with Iloprost Zentiva immediately before use.

Device	Medicament	Iloprost dose in the mouthpiece	Estimated inhalation time
Breelib	Iloprost Zentiva 10 micrograms/ml	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 forcing the solution through a mesh. The I-Neb AAD nebulizer has been shown to be suitable for the administration of Iloprost Zentiva 10 micrograms/ml.

The measured MMAD of the aerosol droplets is 2.1 micrometers.

This nebulizer monitors the breathing pattern to determine the required inhalation time 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 medication chamber in combination with a control disc. Each medication chamber has a color code and is used with a corresponding colored control disc.

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

For each inhalation session with the I-Neb AAD, immediately before use, the contents of one 1 ml ampoule of Iloprost Zentiva are added to the medication chamber.

Device	Iloprost 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 Zentiva:

Medication	Dosage	I-Neb AAD
Medication chamber latch	Control disc
Iloprost Zentiva 10 micrograms/ml	2.5 micrograms	red	red
5 micrograms	purple	purple

?Venta-Neb

Venta-Neb, a portable battery-powered ultrasonic nebulizer, has also proven suitable for the administration of Iloprost Zentiva 10 micrograms/ml. The measured MMAD (Mass Median Aerodynamic Diameter) of the aerosol droplets was determined to be 2.6 micrometers. For each inhalation session, the contents of two ampoules containing 1 ml of Iloprost Zentiva 10 micrograms/ml solution for inhalation should be added directly into the medication chamber of the nebulizer immediately before use.

Two programs can 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 when to inhale. The device stops automatically after the preset dose has been delivered. To achieve the optimal droplet size for the administration of Iloprost Zentiva, the green deflector plate must be used. Refer to the Venta-Neb nebulizer instruction manual for further details.

Device	Iloprost 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.