Leaflet: information for the user

Iloprost Zentiva 20 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, consult your doctor, pharmacist or nurse.
• 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 isIloprost Zentivaand what it is used for

2. What you need to know before you start usingIloprost Zentiva

3. How to useIloprost Zentiva

4. Possible side effects

5. Storage ofIloprost Zentiva

6. Contents of the pack and additional information

What is Iloprost Zentiva

The active ingredient of Iloprost Zentiva is iloprost. Iloprost imitates a natural substance of the organism called prostacyclin. This medication inhibits the unwanted blockage or narrowing of blood vessels and allows more blood to flow through the blood vessels.

What is Iloprost Zentiva used for

This medication 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.

This medication 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 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.

Do not use this medicine

• if you are allergicto iloprost or to any of the other ingredients 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 orinthe first part of the small intestine (duodenal ulcers), if you have suffered a physical injury (trauma), if you are at risk of intracranial bleeding,
• if you have a heart problem, such as for example:

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

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

Warnings and precautions

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

• The inhalation of iloprost could trigger breathing difficulties (seesection 4), especially in patients with bronchospasm (a sudden narrowing of the small airway muscles) and wheezing. Inform your doctorif 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) treatment with this medicine should not be started.
• You will generally have totake 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 the combination with iloprost may lower your blood pressure even further (see “Use of Iloprost Zentiva with other medicines” below).
• Get up slowly from a chair or bed.
• If you are prone to fainting when getting up from bed, it may be helpful to take the first dose of the day while still in bed.
• If you are prone to episodes of fainting, avoid any exceptional effort, for example during physical exercise; it may be helpful to inhale iloprost beforedoing so. Fainting episodes may be due to the underlying disease. Inform yourdoctor if they worsen, as they may consider adjusting your dose orchanging treatment.

• If you have heart disease, such as right heart failure and notice that yourdisease is worsening, tell your doctor. Symptoms may include swelling of the feet and ankles, difficulty breathing, palpitations, need to urinate more frequently at night or edema. Your doctor will consider whether to change your treatment.
• If you have difficulty breathing, coughing up blood and/or sweating excessively, these may be signs of fluid in the lungs(pulmonary edema).Stop using this medicine andinform your doctor immediately. They will investigate the cause and take appropriate action.
• If you have severe liver or kidney problems that require dialysis, inform your doctor. You may be gradually changed to the prescribed dose orprescribed a lower dose of iloprost than other patients (see section 3 “How to use Iloprost Zentiva”).

Contact of iloprost with the skin or ingestion of iloprost

• 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

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

Other medicines and Iloprost Zentiva

Inform your doctor or pharmacistif you are using, have used recently or may need to use any other medicine. Iloprost may affect the way other medicines work and vice versa.

Inform your doctor if you are taking:

?Medicines for the treatment of hypertension or heart disease, such as:

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

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

?Medicines that make the blood less thick or inhibit its coagulation,such as:

• Acetylsalicylic acid (ASA, a compound present in many medicines that reduce fever and relieve 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 inhibitors (PDE 3), such as cilostazol or anagrelide.
• Ticlopidine.
• Clopidogrel.
• Glucoprotein IIb/IIIa antagonists, such as
• • Abciximab.
  • Eptifibatide.
  • Tirofiban.
  • Defibrotide.

Your doctor will keep a close eye on you.

Before taking any medicine, consult your doctor or pharmacist, who has more information on the medicines you should be cautious with or avoid when using this medicine.

Use of Iloprost with food and drinks

No food or drinks are 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 disease and even put your life at risk.
• If you may become pregnant, use reliable contraception from the start oftreatment and during treatment.
• If you are pregnant, think you may be pregnant or intend to become pregnant, inform your doctor immediately. This medicine 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 safety of this medicine during breastfeeding has not been established. It is not possible to rule out the potential risk to infants and it is recommended to avoid breastfeeding during treatment with iloprost.

Consult 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 operating 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 experience these effects.

Iloprost Zentiva contains ethanol

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

The amount in 1 ml of this medicine isequivalent to less than 1 ml of beer or 1 ml of wine.

The small amount of alcohol in this medicine has no perceptible effect.

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 20 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. 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, consult your doctor, who may decide that you should receive iloprost 10 micrograms/ml.

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 monitor your treatment when you start using the Breelib nebulizer to ensure that you tolerate the dose and inhalation speed well.

?I-Neb AAD

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

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

You should administer the dose 6 to 9 times a day, depending on individual needs and tolerability.

Depending on your individual needs, this medication 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 iloprost 10 micrograms/ml. 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 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 you tolerate the treatment.

If you notice that the effect of this medication is too strong or too weak,consult your doctor orpharmacist.Ask your doctor to have someone help you familiarize yourself with the use of the nebulizer. Do not change to another nebulizer without consulting the doctor treating you.

How to inhale

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

Follow the usage instructions that accompany the nebulizer, especially those related to hygiene and cleaning of the nebulizer.

Follow exactly the administration instructions of this medication indicated by your doctor.

• Iloprost Zentiva 20 micrograms/ml solution for inhalation by nebulizer is inhaled using the nebulizers prescribed by your doctor (the Breelib or I-Neb AAD nebulizer).
• The nebulizer transforms the iloprost solution into an aerosol that is inhaled through the mouth.
• To inhale, you must use a mouthpiece to avoid iloprost coming into contact with your skin. Do not use a mask.
• Follow the usage instructions that accompany the nebulizer carefully. Consult your doctor or pharmacist if you have any doubts.
• Any remaining solution of iloprost in the nebulizer after inhalation should be discarded (see section 5).

Room ventilation

Make sure to ventilate or air the room in which you have taken the iloprost treatment. Other people may accidentally be exposed to iloprost through the room air. Especially, newborns, infants, and pregnant women should not be in the same room while inhaling iloprost.

?Breelib

Fill the medication chamber with iloprost immediately before use. Follow the nebulizer usage instructions for filling.

?I-Neb AAD

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

In the case ofIloprost 20 micrograms/ml (dose of 5 micrograms), the medication chamber with the golden knob is used together with the golden control disk.

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

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

For more details, see the nebulizer manual or consult 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 of discomfort), jaw or back pain.

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

• Interrupt the inhalation session.
• Consult your doctor.

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

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.

If you forgot to use Iloprost Zentiva

Do not take a double dose to compensate for the missed doses. Consult your doctor on what to do.

If you interrupt the treatment with Iloprost Zentiva

Consult your doctor before interrupting or stopping treatment.

If you have any other doubts about the use of this medication, ask your doctor, pharmacist, or nurse.

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

The followingserious side effectsmay occur. If they occur, consult your doctor immediately:

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

• Very frequent episodes of bleeding (mainly nosebleeds [epistaxis] and coughing up blood [hemoptysis]) may occur, especially if you are taking treatment to thin your blood (anticoagulants). The risk of bleeding may increase in patients treated at the same time with platelet aggregation inhibitors or anticoagulants (see also section 2). In very rare cases, fatal cases have been reported that included intracranial hemorrhage (intracranial hemorrhage and cerebral hemorrhage).

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

• Loss of consciousness (syncope) is a symptom of the underlying disease, 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 the available data):

• Bronchospasm (sudden constriction of the small airway muscles) and wheezing (see also section 2 “Warnings and precautions”).

The following is a list of other possible side effects based on their probability of occurrence:

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

• Widening of blood vessels (vasodilation). Symptoms may include flushing orredness of the face.
• Chest discomfort / chest pain.
• Coughing.
• Headache.
• Nausea.
• Jaw pain / jaw muscle spasm (trismus).
• Swelling of the extremities (peripheral edema).

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

• Difficulty breathing (dyspnea).
• Dizziness.
• Vomiting.
• Diarrhea.
• Difficulty swallowing (pharyngolaryngeal irritation).
• Throat irritation.
• Irritation in the mouth and tongue, including pain.
• Skin rash.
• Fast heart rate (tachycardia).
• Consciousness of fast or intense heart rate (palpitations).

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

• Reduction in the number of platelets in the blood (thrombocytopenia).
• Hypersensitivity (i.e., allergy).
• Alterations in taste (dysgeusia).

Other possible side effects

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

Reporting of side effects

If you experience any type of side effect, consult your doctor, pharmacist or nurse,even if it is a possible side effect that does not appear in this leaflet.You can also report them directly through the Spanish System for the Pharmacovigilance of Medicines for Human Use:www.notificaRAM.es.By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the label and the packaging after CAD. The expiration date refers to the last day of that month.

No special storage conditions are required.Do not freeze.

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

Medications should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the packaging and medications that you no longer need. This will help protect the environment.

Composition of Iloprost Zentiva

• The active ingredientis iloprost.

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

• The other components aretrometamol, ethanol 96 %, sodium chloride, hydrochloric acid (for pH adjustment) and water for injection preparations.

Appearance of the product and contents of the package:

Iloprost Zentiva is a transparent and colorless solution without visible particles for inhalationwith the nebulizers Breelib or I-Neb.

Iloprost Zentiva20 micrograms/mlis supplied in a transparent glass ampoule (hydrolytic class No. I) with red, yellow identification rings, containing 1.0 ml of solution, packaged in blister and cardboard box.

Iloprost Zentiva20 micrograms/ml is available in the following pack sizes:

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 pack containing 160 ampoules (4 inner boxes containing 8 blisters with 5 ampoules).

Only some pack sizes may be marketed.

Marketing Authorization Holder and Responsible Manufacturer:

Zentiva k.s.

U Kabelovny 130

Dolní Mecholupy

102 37 Prague 10

Czech Republic

For more information about this medicine, please contact 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 with the following names:

Last review date of this leaflet:06/2021

For detailed information about this medicine, please visit the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.es/.

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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 theclose supervision of the treating physician, as it has been demonstrated that different nebulizers produce aerosols with slightly different physical characteristics andmay 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, follow the instructions for use provided with the device.

Fill the medication chamber with Iloprost Zentiva immediately before use.

?I-Neb AAD

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

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

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

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

In each inhalation session with the I-Neb AAD, the contents of one ampoule containing 1ml of Iloprost Zentiva 20 micrograms/ml will be transferred to the appropriate medication chamber of the nebulizerwith the golden latch and the golden diskimmediately 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 includes a summary of the instructions for use of the I-Neb for the 2 concentrations of Iloprost Zentiva:

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.