Iloprost Zentiva Italia

Package leaflet: Information for the patient

Iloprost Zentiva Italia 100 micrograms/ml concentrate for solution for infusion

Equivalent medicine
Please read all of this leaflet carefully before you start using this medicine, as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• If you get any side effects, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4. Contents of this leaflet
  1. What Iloprost Zentiva Italia is and what it is used for
  2. What you need to know before you are given Iloprost Zentiva Italia
  3. How to use Iloprost Zentiva Italia
  4. Possible side effects
  5. How to store Iloprost Zentiva Italia
  6. Contents of the pack and other information

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

Iloprost Zentiva Italia contains the active substance iloprost, a compound that mimics a natural substance called prostacyclin. Iloprost and prostacyclin exert several actions, including inhibition of blood coagulation when there is a risk of thrombosis and embolism in veins or arteries, dilation of small blood vessels, and stimulation of the physiological mechanisms that dissolve blood clots (thrombi).

Iloprost Zentiva Italia is used to treat:

• Advanced stage thromboangiitis obliterans (Buerger's disease – an inflammatory disease of the blood vessels causing obstruction of blood vessels and damage to the vessels in the extremities such as hands and feet), in cases where revascularization surgery is not possible;
• Raynaud's phenomenon (extreme constriction of blood vessels in the fingers of the hands and feet) in patients who do not respond to other therapeutic measures;
• Severe occlusive peripheral arterial disease (severe reduction in blood flow to the lower limbs), particularly in patients at risk of amputation in whom surgical intervention or angioplasty is not possible.

2. What you need to know before taking Iloprost Zentiva Italia

Do not take Iloprost Zentiva Italia:

• if you are allergic to iloprost or to any of the other ingredients of this medicine (listed in section 6);
• if you are pregnant or breastfeeding (see “Pregnancy, breastfeeding, fertility”);
• if you have a condition associated with an increased risk of bleeding – for example, if you have a gastric (stomach) or duodenal ulcer, trauma, or bleeding within the skull;
• if you suffer from reduced blood flow to the heart muscle (severe coronary artery disease or unstable angina), causing chest tightness due to lack of oxygen in the heart muscle;
• if you have had a heart attack within the last 6 months;
• if you suffer from weak heart function (heart failure) in NYHA classes II–IV;
• if you have irregular heartbeats (arrhythmias);
• if you suspect fluid accumulation in the lungs (pulmonary congestion) accompanied by breathing difficulties. Consult your doctor if you think any of the above conditions apply to you.

Warnings and precautions
Talk to your doctor before taking Iloprost Zentiva Italia.

• If urgent amputation is required (e.g., due to infected gangrene), surgical intervention must not be delayed.
• If you smoke, you are strongly advised to stop smoking.
• If you have liver or kidney problems, the dose of Iloprost Zentiva Italia may need to be reduced.
• If you have low blood pressure, you must be particularly cautious to avoid a further drop in blood pressure (hypotension).
• Be aware of the possibility of hypotension when rising from a lying to an upright position after the infusion has been completed. You should rise slowly to help your body adjust to the new position and blood pressure.
• If you have heart disease, you will be closely monitored.
• If you have had a stroke or interruption of blood flow to the brain (transient ischemic attack) within the last 3 months.
• If undiluted Iloprost Zentiva Italia is injected near a vein, it may cause local reactions at the injection site.

If Iloprost Zentiva Italia comes into contact with skin or eyes
Avoid contact of this medicine with skin and eyes. If contact occurs, iloprost may cause persistent skin redness (erythema). In case of contact, immediately rinse skin and eyes thoroughly with plenty of water or physiological saline solution.
Iloprost Zentiva Italia must not be ingested.

Children and adolescents
There are no data available on the use of iloprost in children.

Other medicines and Iloprost Zentiva Italia
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
Iloprost Zentiva Italia may affect how other medicines work and vice versa.
Inform your doctor if you are taking:

• Medicines used to treat high blood pressure or heart conditions (such as beta-blockers, calcium antagonists, ACE inhibitors, vasodilators). Your blood pressure may drop further. Your doctor may need to adjust the dose of Iloprost Zentiva Italia.
• Medicines that thin the blood or prevent blood clotting. The risk of bleeding may increase. These include: acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs), heparin, or coumarin-like anticoagulants, phosphodiesterase inhibitors, and nitrovasodilators. If bleeding occurs, treatment with Iloprost Zentiva Italia should be stopped.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
This medicine must not be administered during pregnancy or breastfeeding.
If you are of childbearing age, use appropriate contraceptive methods during treatment.

Iloprost Zentiva Italia contains ethanol and sodium
This medicine contains 7.66 mg of alcohol (ethanol) per ml of concentrate, equivalent to 8.1 mg of 96% ethanol. The amount of ethanol in this medicine is equivalent to less than 0.2 ml of beer or 0.08 ml of wine. The small amount of alcohol in this medicine will not have any significant effect.
This medicine contains 3.54 mg of sodium per 1 ml of concentrate, which is considered essentially “sodium-free”.

3. How to use Iloprost Zentiva Italia

Iloprost Zentiva Italia must be administered only in hospital settings or in adequately equipped outpatient clinics and under close medical supervision.
The infusion solution must be prepared immediately before each daily infusion to ensure sterility.
Iloprost Zentiva Italia must be administered only after dilution.
After dilution, Iloprost Zentiva Italia will be administered to you through a vein by infusion over approximately 6 hours per day, via a central venous catheter or a peripheral vein.
The dose will be adjusted according to individual tolerability within a range of 0.5 to 0.2 ng iloprost/kg/min.
The exact infusion rate will be calculated based on body weight.
For further information for the physician or healthcare professional regarding the preparation and dilution, see section 6 “The following information is intended exclusively for healthcare professionals” at the end of this leaflet.
During the first 2–3 days of treatment, the individually tolerated dose will be determined. For this purpose, your doctor will start treatment at a low dose. If you experience any side effects such as headache, nausea, or low blood pressure, inform your doctor immediately.
The infusion rate must be reduced until the tolerated dose is established. If side effects are severe, the infusion will be suspended. Treatment should then continue (usually for up to 4 weeks) using the dose identified as tolerable during the first 2–3 days.
Blood pressure and heart rate will be monitored at the beginning of the infusion and after each dose increase.
The duration of treatment is 4 weeks. In the treatment of Raynaud's phenomenon, shorter treatment periods (3–5 days) are often sufficient to achieve improvement lasting for several weeks.

Patients with renal or hepatic impairment
If you have renal problems requiring dialysis or hepatic cirrhosis, elimination of iloprost is reduced and a dose reduction will be necessary (e.g. half the recommended dose). Inform your doctor if you have any liver or kidney problems.

If you are given more Iloprost Zentiva Italia than you should
Symptoms of overdose may include: drop in blood pressure (hypotension), headache, flushing (sudden reddening of the face), nausea, vomiting, and diarrhea.
Other possible symptoms include increased blood pressure, slowed or rapid heartbeat, and pain in the limbs or back.
If you experience symptoms suggesting you have been given too much Iloprost Zentiva Italia, the infusion must be stopped immediately and symptoms should be treated. There is no known specific antidote.
In case of accidental ingestion, contact your doctor immediately.

If you have any further questions about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
In patients treated with iloprost, the most serious side effects reported with fatal or life-threatening outcomes are:

• Common (may affect up to 1 in 10 people):
  particularly low blood pressure (hypotension),
  fast heartbeat (tachycardia),
  chest pain or discomfort due to insufficient blood flow to the heart (angina pectoris) – especially in patients with heart failure,
  difficulty breathing (dyspnoea).

• Uncommon (may affect up to 1 in 100 people):
  Stroke (cerebrovascular accident), heart attack, breathing problems or chest pain caused by blood clots in the lungs (pulmonary embolism), heart failure, seizures (convulsions), asthma, breathing difficulties or coughing up blood due to fluid accumulation in the lungs (pulmonary oedema).
  Another group of side effects relates to local reactions at the infusion site. For example, redness and pain at the infusion site or cutaneous vasodilation may occur, which can lead to visible superficial streaked redness along the course of the vein.

Other possible side effects are listed below according to their frequency:
Very common (may affect more than 1 in 10 people)

• headache
• facial redness (flushing)
• nausea, vomiting
• excessive sweating (hyperhidrosis)

These side effects are likely to occur at the beginning of treatment, during dose adjustment, to identify the best tolerable dose for the individual patient. However, they usually disappear rapidly upon dose reduction.
Common (may affect up to 1 in 10 people)

• Loss of appetite
• Apathy, confusion
• Dizziness/vertigo, numbness or tingling (paraesthesia), palpitations, increased sensitivity to pain or touch (hyperaesthesia), burning sensation, restlessness/agitation, sedation, drowsiness
• Slow heartbeat
• High blood pressure
• Diarrhoea, abdominal discomfort, stomach ache
• Jaw pain, jaw spasm, locked jaw (trismus), muscle pain, joint pain
• Pain, fever, increased body temperature, feeling of warmth, weakness, general malaise (malaise), chills, fatigue, thirst, skin redness (erythema), pain and inflammation of the vein at the infusion site (phlebitis)

Uncommon (may affect up to 1 in 100 people)

• Bleeding disorders with bruising and easy bleeding (thrombocytopenia)
• Allergic reaction (hypersensitivity)
• Anxiety, depression, hallucinations
• Fainting (syncope), tremor, migraine
• Blurred vision, eye irritation, eye pain
• Irregular heartbeat (arrhythmia, extrasystoles)
• Leg pain caused by blood clots in a leg vein (deep vein thrombosis)
• Diarrhoea with blood in stools, rectal bleeding, heartburn or stomach pain, pain due to constipation, constipation, belching, difficulty swallowing, dry mouth, altered taste
• Yellowing of the skin or whites of the eyes and/or itching (jaundice)
• Itching
• Painful attack of muscle spasms, muscle spasms, muscle stiffness
• Kidney pain, persistent feeling of needing to urinate (vesical tenesmus), difficult or painful urination, urinary tract disorders

Rare (may affect up to 1 in 1,000 people)

• Dizziness caused by inner ear disorders
• Cough
• Inflammation of the rectal lining (proctitis)

The risk of bleeding is higher in patients who are also receiving antiplatelet agents, heparin, or coumarin-type anticoagulants concomitantly.

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor or nurse.
You can also report side effects directly via the national reporting system available at:
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Iloprost Zentiva Italia

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and on the carton. The expiry date refers to the last day of that month.
This medicine requires no special storage conditions. Do not freeze.
Storage conditions after dilution
Chemical and physical in-use stability has been demonstrated for 24 hours at 2–8°C.
From a microbiological standpoint, the medicine should be used immediately. If not used immediately, the duration and conditions of in-use storage are the responsibility of the user and normally should not exceed 24 hours at 2–8°C.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Iloprost Zentiva Italia contains

• The active substance is iloprost. Each 0.5 ml vial of concentrate for solution for infusion contains 50 micrograms of iloprost (as iloprost trometamol). Each ml of concentrate for solution for infusion contains 100 micrograms of iloprost (as iloprost trometamol).
• The other components are ethanol 96%, trometamol, sodium chloride, diluted hydrochloric acid (for pH adjustment), water for injections.

Description of the appearance of Iloprost Zentiva Italia and contents of the pack
Clear, colourless solution free from visible particles. Iloprost Zentiva Italia is supplied in transparent glass vials
of hydrolytic class I, with identifying coloured rings: red, green, in PVC blisters, paper carton.
Each pack contains 1 or 5 vials of 0.5 ml.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Zentiva Italia Srl
Viale Bodio 37/b
20158 Milan, Italy

Manufacturer
Zentiva k.s.
U kabelovny 130
102 37, Praha 10 – Dolní Měcholupy
Czech Republic

This medicinal product is authorised in the Member States of the European Economic Area under the following names:
Czech Republic: Calovat
Italy: Iloprost Zentiva Italia
Germany: Iloprost Zentiva 100 Mikrogramm/ml Konzentrat zur Herstellung einer Infusionslösung
France: Iloprost Zentiva 100 microgrammes/ml, solution à diluer pour perfusion

The following information is intended exclusively for healthcare professionals
Instructions for handling
The ready-to-use infusion solution must be prepared immediately before use under aseptic conditions. The ready-to-use infusion solution must be prepared daily to ensure sterility.
Iloprost Zentiva Italia 100 micrograms/ml must be administered after dilution.
Due to possible interactions, no other medicinal products should be added to the ready-to-use infusion solution.
The ready-to-use solution is intended for use in a single patient and for a single infusion only. Any unused portion of the vial and any unused infusion solution must be discarded. Any unused medicinal product or waste material must be disposed of in accordance with local regulations.
If the ready-to-use infusion solution is not used immediately, the duration and storage conditions during use are the responsibility of the user. Normally, storage should not exceed 24 hours at 2 – 8°C.
If Iloprost Zentiva Italia 100 micrograms/ml comes into contact with the skin, the affected area must be washed immediately with abundant water or physiological saline solution.
The procedure for preparing a ready-to-use infusion solution is described below, depending on the infusion system used.

Use with an infusion pump
In general, the ready-to-use infusion solution should be administered intravenously using an infusion pump.
The contents of one 0.5 ml vial of Iloprost Zentiva Italia 100 micrograms/ml (e.g. 50 μg of iloprost) should be diluted using 250 ml of physiological saline or 5% glucose solution. The contents of the vial and the diluent must be thoroughly mixed.
If dilution with 5% glucose solution is chosen, it must be performed only in a glass container.
The required infusion rate for this infusion solution (0.2 μg/mL) to achieve a dose within the range of 0.5 to 2.0 ng/kg/min, as described in section 3 of this leaflet, must be determined based on the patient's individual body weight, as shown in Table 1.

Table 1: Infusion rate [ml/h] for different doses using an infusion pump.
Dose [ng/kg/min]
Body weight
0.5  1.0  1.5  2.0
[kg]
Infusion rate [ml/h]
40  6.0  12  18.0  24
50  7.5  15  22.5  30
60  9.0  18  27.0  36
70  10.5  21  31.5  42
80  12.0  24  36.0  48
90  13.5  27  40.5  54
100  15.0  30  45.0  60
110  16.5  33  49.5  66

Use with a syringe pump
Alternatively, a syringe pump with a 50 ml syringe may also be used for infusion.
The contents of one 0.5 ml vial of Iloprost Zentiva Italia 100 micrograms/ml (e.g. 50 μg of iloprost) should be diluted using 25 ml of physiological saline or 5% glucose solution. The contents of the vial and the diluent must be thoroughly mixed.
The required infusion rate for this infusion solution (2.0 μg/mL) to achieve a dose within the range of 0.5 to 2.0 ng/kg/min, as described in section 3 of this leaflet, must be determined based on the patient's individual body weight, as shown in Table 2.

Table 2: Infusion rate [ml/hour] for different doses using a syringe pump.
Dose (ng/kg/min)
Body weight
0.5  1.0  1.5  2.0
(kg)
Infusion rate (ml/hour)
40  0.60  1.2  1.80  2.4
50  0.75  1.5  2.25  3.0
60  0.90  1.8  2.70  3.6
70  1.05  2.1  3.15  4.2
80  1.20  2.4  3.60  4.8
90  1.35  2.7  4.05  5.4
100  1.50  3.0  4.50  6.0
110  1.65  3.3  4.95  6.6