ILOPROST ZENTIVA 20 micrograms/ml SOLUTION FOR NEBULIZER INHALATION

Introduction

Package Leaflet: Information for the User

Iloprost Zentiva 20 micrograms/ml solution for inhalation by nebuliser

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

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

What is Iloprost Zentiva

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 where the cause of the high blood pressure is unknown.

This is a disease where the blood pressure is too high in the blood vessels between the heart and the lungs.

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

How Iloprost Zentiva works

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

2. What you need to know before you use Iloprost Zentiva

Do not use this medicine

• If you are allergicto 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 the first part of the small intestine (duodenal ulcers), if you have suffered a physical injury (trauma), if you are at risk of suffering an intracranial haemorrhage,
• If you have a heart problem, such as:

• insufficient blood flow to the heart muscles (severe coronary artery disease or unstable angina). Symptoms may include chest pain,
• a heart attack in the last 6 months,
• weak heart (decompensated heart failure) that is not under close medical supervision,
• severe heart rhythm disturbances,
• a heart valve defect (congenital or acquired) that makes the heart not work properly (not related to pulmonary hypertension),

• If you have had a stroke in the last 3 monthsor any other event that has reduced blood flow to the brain (e.g. transient ischaemic attack),
• If your pulmonary hypertension is due to a blocked or narrowed vein(veno-occlusive disease).

Warnings and precautions

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

• 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 this medicine.
• In general, you will need to be particularly 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 iloprost may lower your blood pressure even further (see "Using Iloprost Zentiva with other medicines" 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 treatment.

• If you have heart disease, such as right heart failure and notice that yourillness 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 oedema. Your doctor will consider whether you need to change 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 oedema). Stop using this medicine and tell your doctor immediately. He/she will look for the cause and take appropriate measures.
• If you have severe liver or kidney problems that require dialysis, tell your doctor. You may need to be gradually switched to the prescribed dose or your doctor may prescribe a lower dose of iloprost than for other patients (see section 3 "How to use Iloprost Zentiva").

Contact of iloprost with skin or ingestion of iloprost

• 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 up to 18 years of age have not been established.

Other medicines and Iloprost Zentiva

Tell your doctor or pharmacistif you are using, 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:

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• Beta-blockers.
• Vasodilators of the nitrate type.
• ACE inhibitors.

Your blood pressure may drop too low. Your doctor may need to change your dose.

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• Acetylsalicylic acid (AAS, a compound found 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 (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 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 this medicine.

Using Iloprost 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. This medicine should only be used during pregnancy if your doctor decides that the potential benefit outweighs the possible risks to you and the foetus.

Breast-feeding

It is not known whether this medicine passes into breast milk. The potential risk to breast-fed infants cannot be excluded and breast-feeding should be avoided 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

This medicine 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 Zentiva contains ethanol

Iloprost Zentiva 20 micrograms/ml contains 1.5 mg of alcohol (ethanol) in each ampoule, which is equivalent to 1.62 mg/ml of ethanol 96 % (v/v).

The amount 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 in this medicine does not produce any noticeable effect.

3. How to use Iloprost Zentiva

Treatment with iloprost should only be started by a doctor with experience in the treatment of pulmonary hypertension.

How much to inhale and for how long

Follow the instructions for administration of this medicine exactly as told by your doctor. If you are unsure, talk to 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 talking to your doctor first.

Different nebuliser devices can be used to administer iloprost 20 micrograms/ml.

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When starting treatment with iloprost or if you switch from an alternative device, the first inhalation should be with iloprost 10 micrograms/ml. If you tolerate this dose well, your next inhalation will be with iloprost 20 micrograms/ml. You should continue with this dose.

If you cannot tolerate the inhalation of iloprost 20 micrograms/ml, talk to your doctor, who may decide that you should receive iloprost 10 micrograms/ml.

Most people will need to have 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 nebuliser to ensure that you tolerate the dose and inhalation rate well.

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Since you have experienced prolonged treatment inhalation times repeatedly with iloprost 10 micrograms/ml, your doctor has decided to switch to iloprost 20 micrograms/ml.

Iloprost 20 micrograms/ml has a double concentration than iloprost 10 micrograms/ml. The active ingredient may be released more quickly to your lungs. Your doctor will monitor the treatment if you switch from iloprost 10 micrograms/ml to iloprost 20 micrograms/ml to check how you tolerate this higher concentration.

The dose should be administered 6 to 9 times a day, depending on individual needs and tolerability.

Depending on your individual needs, this medicine 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 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 iloprost 10 micrograms/ml. Use dosing intervals of 3 to 4 hours (which corresponds to a maximum of 6 administrations per day). From then on, your doctor may cautiously shorten the dosing intervals depending on how you tolerate the treatment. If your doctor decides to increase the dose further to 5 micrograms, the dosing intervals should be re-established to 3 to 4 hours and shortened depending on how you tolerate the treatment.

If you notice that the effect of this medicine is too strong or too weak, talk to your doctor orpharmacist.Ask your doctor to have someone help you get used to using the nebuliser. You should not switch to another nebuliser without talking to the doctor who is treating you.

How to inhale

For each inhalation session, use a new ampoule of iloprost. Just before starting to inhale, break the glass ampoule and pour the contents of 1 ml into the medication chamber of the nebuliser, following the instructions for use of the nebuliser.

Follow the instructions that come with the nebuliser carefully, especially those relating to hygiene and cleaning of the nebuliser.

Follow the instructions for administration of this medicine exactly as told by your doctor.

• Iloprost Zentiva 20 micrograms/ml solution for inhalation by nebuliser is inhaled using the nebulisers prescribed by your doctor (the Breelib nebuliser or I-Neb AAD).
• The nebuliser turns the iloprost solution into an aerosol that is inhaled through the mouth.
• For inhalation, use a mouthpiece to avoid iloprost coming into contact with your skin. Do not use a mask.
• Follow the instructions that come with the nebuliser carefully. Talk to your doctor or pharmacist if you have any doubts.
• Any remaining iloprost solution left in the nebuliser 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.

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Fill the medication chamber with iloprost immediately before use. Follow the instructions for use of the nebuliser regarding filling.

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1. Immediately before starting to inhale,take the Iloprost Zentiva 20 micrograms/ml ampoule, break the glass ampoule and pour all the contents of 1 ml into the golden medication chamber of the nebuliser.
2. The pre-set dose administered by the I-Neb AAD nebuliser is controlled by the medication chamber, in combination with a control disc.

In the case of Iloprost 20 micrograms/ml (dose of 5 micrograms), the medication chamber with the golden latch is used together with the golden control disc.

1. To ensure that you receive the prescribed dose, check the colour of the medication chamber and the colour of the control disc. These should be the same.

Since the I-Neb AAD nebuliser can be used with Iloprost Zentiva 10 micrograms/ml and Iloprost Zentiva 20 micrograms/ml, the following table includes a summary of the I-Neb user instructions for the 2 concentrations of Iloprost Zentiva:

For more details, refer to the nebuliser instruction manual or talk to your doctor.

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 sick), jaw pain or back pain.

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

• Stop the inhalation session.
• Talk to your doctor.

Your doctor will monitor you and treat any symptoms that occur. There is no specific antidote known.

In case of overdose or accidental ingestion, talk to your doctor or pharmacist immediately or call the Toxicology Information Service, telephone: 91 562 04 20, stating the medicine and the amount taken.

If you forget to use Iloprost Zentiva

Do not take a double dose to make up for forgotten doses. Talk to your doctor about what to do.

If you stop using Iloprost Zentiva

If you stop or want to stop treatment, talk to your doctor first.

If you have any further questions on 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 all people suffer from them.

The following serious adverse effectsmay occur. If they occur, consult your doctor immediately:

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

• Very frequent episodes of bleeding (mostly nosebleeds [epistaxis] and coughing up blood [hemoptysis]) may occur, especially if you are taking treatment to thin the 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). In very rare cases, fatal cases have been reported, including bleeding in the brain (cerebral and intracranial hemorrhage).

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

• Fainting (syncope) is a symptom of the disease itself, but it can 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 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 adverse effects based on their likelihood of occurrence:

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

• Vasodilation (dilation of blood vessels). Symptoms may include flushing or redness of the face.
• Chest discomfort / chest pain.
• Cough.
• Headache.
• Nausea.
• Jaw pain / spasm of the jaw muscles (trismus).
• Swelling of the extremities (peripheral edema).

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

• Difficulty breathing (dyspnea).
• Dizziness.
• Vomiting.
• Diarrhea.
• Pain when swallowing (pharyngolaryngeal irritation).
• Sore throat.
• Irritation of the mouth and tongue, including pain.
• Rash.
• Fast heartbeat (tachycardia).
• Awareness of a fast or intense heartbeat (palpitations).

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

• Decrease in the number of platelets in the blood (thrombocytopenia).
• Hypersensitivity (i.e., allergy).
• Taste disorders (dysgeusia).

Other possible adverse effects

• Swelling, mainly of the ankles and legs, due to fluid retention (peripheral edema) is a very common symptom of the disease itself, but it can 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 effect that is not listed in this leaflet. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Iloprost Zentiva

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiration date stated on the label and carton after CAD. The expiration date refers to the last day of that month.

No special storage conditions are required. Do not freeze.

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

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

6. Package contents and additional information

Composition of Iloprost Zentiva

• The active ingredientis iloprost.

Each 1 ml ampoule contains 20 micrograms of iloprost (as iloprost tromethamine).

• The other ingredients aretromethamine, ethanol 96%, sodium chloride, hydrochloric acid (for pH adjustment), and water for injectable preparations.

Appearance of the product and package contents:

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

Iloprost Zentiva 20 micrograms/ml is supplied in a transparent glass ampoule (hydrolytic class I) with red and yellow identification rings, containing 1.0 ml of solution, packaged in a blister pack and cardboard box.

Iloprost Zentiva 20 micrograms/ml is available in the following packages:

30x1 ml (6 blisters with 5 ampoules or 5 blisters with 6 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 package containing 160 ampoules (4 inner boxes containing 8 blisters with 5 ampoules).

Not all pack sizes may be marketed.

Marketing authorization holder and manufacturer:

Zentiva k.s.

U Kabelovny 130

Dolní Mecholupy

102 37 Prague 10

Czech Republic

You can request more information about this medicine by contacting the local representative of the marketing authorization holder: Zentiva Spain S.L.U.

Avenida de Europa, 19, Edificio 3, Planta 1.

28224 Pozuelo de Alarcón, Madrid

This medicine is authorized in the member states of the European Economic Area under the following names:

Date of last revision of this leaflet:06/2021

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

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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 close supervision by the treating physician, as it has been shown that different nebulizers produce aerosols with slightly different physical characteristics and may have 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.

If the Breelib nebulizer is used, follow the instructions for use that come with the device.

Fill the medication chamber with Iloprost Zentiva immediately before use.

The I-Neb AAD system is a portable, manual nebulizer system with vibrating mesh technology. This system generates tiny droplets by ultrasonics, which pass the solution through a mesh. This nebulizer controls the breathing pattern to determine the inhalation time required to administer the pre-set dose of 5 micrograms of iloprost from Iloprost Zentiva 20 micrograms/ml solution for inhalation by nebulizer.

The nebulizer device administers 5 micrograms of iloprost in the mouthpiece. The median aerodynamic mass diameter (MMAD) of the aerosol is between 1 and 5 micrometers.

When using the I-Neb AAD system, follow these instructions.

The dose administered by the I-Neb AAD system is controlled by the medication chamber, in combination with a control disc. For each medication chamber, there is a control disc with its corresponding color code.

In each I-Neb AAD inhalation session, the contents of an ampoule containing 1 ml of Iloprost Zentiva 20 micrograms/ml will be transferred to the appropriate medication chamber of the nebulizer with the gold latch and gold discimmediately before use.

Since the I-Neb AAD system can be used with Iloprost Zentiva 10 micrograms/ml and Iloprost Zentiva 20 micrograms/ml, the following table summarizes the instructions for use of the I-Neb for the 2 concentrations of Iloprost Zentiva:

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