Leaflet: information for the user

Iloprost Zentiva 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, 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 medication

• if you are allergicto iloprost 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 orinthe first part of the small intestine (duodenal ulcers), if you have suffered a physical injury (trauma), if you are at risk of intracranial hemorrhage,

• if you have a heart problem, such as:

• 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 not function 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 medication:

• 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 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) do not start the therapy with this medication.
• In general, you will 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 medications, as the combination withiloprost may lower your blood pressure even further (see “UseofIloprost Zentiva with other medications”).
• Get up slowly from a chair or bed.
• If you tend to faint when getting up from bed, it may be helpful to take thefirst dose of the day while still lying down.
• If you tend to have episodes of fainting, avoid any exceptional effort, forexample 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 your treatment.

• If you have heart failure, 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, frequent nighttime urination, or edema. Your doctor will consider whether to change your treatment.
• If you have difficulty breathing, coughing up blood, and/or excessive sweating, these may be signs of fluid in the lungs(pulmonary edema).Stop using this medication andinform 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. 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 medications and Iloprost Zentiva

Inform your doctor or pharmacist if you areusing, 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 thinner or inhibit its coagulation,such as:

• Acetylsalicylic acid (ASA, a compound present in many medications that reduce fever and relieve pain).
• Heparin.
• Coumarin anticoagulants, such as warfarin or phenprocoumon.
• Nonsteroidal 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 closely monitor you.

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

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 contraceptives 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 medication should only be used during pregnancy if your doctor decides that the potential benefit outweighs thepossible risks for you and the fetus.

Lactation

It is unknown whether this medication passes into breast milk. It is not possible to rule out the 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 operating machines

This medication 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 10 micrograms/ml contains 0.75 mg of alcohol (ethanol) in 1 ml ofsolution for inhalation by nebulizer, which is equivalent to 0.81 mg of ethanol 96 % (v/v).

Theamount of alcohol in 1 ml of this medication is equivalent to less than 1 ml of beer or wine.

The small amount of alcohol in this medication does not produce any noticeable 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 depends 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 10 micrograms/ml.

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

?Breelib

When starting treatment with iloprost or if you change to 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 overtheday. 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

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. Ifyou cannot tolerate the 5 microgram dose, the dose should be reduced to 2.5 micrograms.

Most people should perform 6 to 9 inhalation sessionsspread overtheday. The duration of each inhalation session with I-Neb AAD is usually 4 to 10 minutes depending on the prescribed dose.

?Venta-Neb (2 ampoules of Iloprost Zentiva)

Generally, when starting treatment with iloprost, the first dose inhaled should be2.5 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 overtheday. The duration of each inhalation session with Venta-Neb is usually 4 to 10 minutes depending on the prescribed dose.

This medication can be used for long-term treatment according to your individual needs.

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 suffer from 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 1ml ampoule of iloprost 10 micrograms/ml. Use dosing intervals of 3 – 4 hours (corresponding to a maximum of 6 administrations per day). Your doctor may then shorten the dosing intervals as needed based on how well you tolerate the treatment. If your doctor decides to increase the dose to 5micrograms, the initial dosing intervals should be re-established at 3 – 4 hours and shortened as needed based on how well 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 instructions accompanying the nebulizer, especially those related tohygiene and cleaning of the nebulizer.

Follow exactly the administration instructions of this medication indicated 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 transforms the iloprost solution into an aerosol that is inhaledthrough 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 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 in which you have taken the iloprost treatment. Other people may be accidentally exposed to iloprost through the room air. In particular, newborns, infants, and pregnant women should not be in the same room while you are inhaling iloprost.

?Breelib

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

?I-Neb AAD

1. Immediately before starting to inhale, break the glass ampoule containing 1 ml of solution, 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 a corresponding color code:
   • For the dose of2.5 micrograms, the medication chamberwith the red latch is used with the red control disc.
   • For the dose of5 micrograms, the medication chamberwith the purple latch is used 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 be the same color, 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 two glass ampoules containing 1 ml of solution, 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 administering this medication, youshould use the green deflecting plate.

For more details, see the nebulizer device 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. There is no known antidote.

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

If you forget to use Iloprost Zentiva

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

If you interrupt treatment with Iloprost Zentiva

Consult your doctor before interrupting or stopping treatment.

If you have any other questions about using this medication, ask your doctor, pharmacist, or nurse.

Like all medicines, this medicine may 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 Zentiva.

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 Medicinal Products 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 should be discarded after inhalation.

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 10 micrograms of iloprost (as iloprost trometamol).

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

Appearance of the product and contents of the pack

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

Iloprost Zentiva 10 micrograms/mlis supplied in a transparent glass ampoule of hydrolytic class No. I with a blue identification ring containing 1.0 ml of solution, packaged in a blister and a 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), a multiple pack containing 160 ampoules (4 inner boxes containing 8 blisters with 5 ampoules).

Only some pack sizes may be marketed.

Marketing Authorisation Holder and Responsible Person for Manufacturing:

Zentiva k.s.

U Kabelovny 130

Dolní Mecholupy

102 37 Prague 10

Czech Republic

Further information on this medicinal product can be obtained by contacting the local representative of the marketing authorisation holder:
Zentiva Spain S.L.U.

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

28224 Pozuelo de Alarcón, Madrid

This medicinal product is authorised in the Member States of the European Economic Area with the following names:

Last update of this leaflet:06/2021

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

This information is intended solely for healthcare professionals:

Instructions for use and handling

Patients stabilised with a nebuliser should not change to another nebuliser withoutthe close supervision of the treating physician, as it has been demonstrated that different nebulisers produce aerosols with slightly different physical characteristics andmay have a faster administration of the solution (see section 5.2 of the SmPC).

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

?Breelib

If the Breelib nebuliser is used, the user should follow the instructions for use provided with thedevice.

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 nebuliser. This system generates small droplets by ultrasonic means, which pass through a mesh. It has been demonstrated that the I-Neb AAD nebuliser is suitable for the administration of Iloprost Zentiva 10 micrograms/ml.

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

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

• For doses of2.5 micrograms, the medication chamber with thered plug is used with the red control disc.
• For doses of5 micrograms,the medication chamber with themagenta plug is used with the magenta control disc.

Before each inhalation session with the I-Neb AAD, the contents of one ampoule of 1 ml of Iloprost Zentiva will be poured into the medication chamber.

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

?Venta-Neb

Venta-Neb, a portable ultrasonic nebuliser with battery, has also been demonstrated to be suitable for the administration of Iloprost Zentiva 10 micrograms/ml. It was determined that the measured MMAD of the aerosol droplets was 2.6 micrometres. Before each inhalation session, the contents of two ampoules containing 1 ml of Iloprost Zentiva 10 micrograms/ml solution for inhalation by nebuliser will be poured into the medication chamber of the nebuliser.

Two programmes can be used:

• P1 Programme 1: 5 micrograms of active ingredient in the mouthpiece, 25 inhalation cycles.
• P2 Programme 2: 2.5 micrograms of active ingredient in the mouthpiece, 10 inhalation cycles. The physician selects the pre-adjusted programme.

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 Zentiva, the green deflecting plate should be used. Consult the details in the Venta-Neb nebuliser manual.

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