EPOPROSTENOL NORMON 1.5 mg POWDER FOR SOLUTION FOR INFUSION

2. What you need to know before you use Epoprostenol NORMON

Do not use Epoprostenol NORMON

• if you are allergic to epoprostenol or any of the other ingredients of this medicine (listed in section 6),
• if you have heart failure,
• if you start to develop fluid accumulation in your lungs causing difficulty breathing after starting treatment.

If you think any of these apply to you, do not use Epoprostenol NORMON until you have talked to your doctor.

Warnings and precautions

Tell your doctor before using Epoprostenol NORMON:

• if you have bleeding problems.
• if you are on a low-sodium diet.

Skin injury at the injection site:

Epoprostenol NORMON is injected into a vein. It is important that the medicine does not leak out of the vein into the surrounding tissues. If it does, it will damage the skin. The symptoms are:

• sensitivity,
• burning,
• itching,
• swelling,
• redness.

This can continue with blistering and peeling of the skin. It is important that you check the injection site while being treated with Epoprostenol NORMON.

Contact the hospital immediately if the injection site becomes painful, itchy, or swollen, or if you notice any blistering or peeling.

Effect of Epoprostenol NORMON on blood pressure and heart rate:

Epoprostenol NORMON may speed up or slow down your heart rate. Your blood pressure may also become very low. While being treated with Epoprostenol NORMON, your heart rate and blood pressure should be monitored. The symptoms of low blood pressure include dizziness and fainting.

Tell your doctor if you have any of these symptoms. It may be necessary to decrease your dose or stop the infusion.

Using Epoprostenol NORMON with other medicines

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines, including those bought without a prescription.

Some medicines may affect how Epoprostenol NORMON works, or make it more likely that you will get side effects. Epoprostenol NORMON may also affect how other medicines work if taken at the same time. These include:

• medicines used to treat high blood pressure,
• medicines used to prevent blood clots,
• medicines used to dissolve blood clots,
• medicines used to treat inflammation or pain (also called NSAIDs),
• digoxin (used to treat heart conditions).

Tell your doctor or pharmacist if you are taking any of these medicines.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine, as symptoms may worsen during pregnancy.

It is not known if the components of Epoprostenol NORMON can pass into breast milk. You should stop breastfeeding while being treated with Epoprostenol NORMON.

Driving and using machines

Treatment may affect your ability to drive and use machines.

Do not drive or use machines unless you feel well.

Epoprostenol NORMON contains sodium

This medicine contains less than 23 mg (1 mmol) of sodium per vial, so it is essentially "sodium-free".

3. How to use Epoprostenol NORMON

Follow exactly the administration instructions for this medicine given by your doctor or pharmacist. If you are unsure, consult your doctor or pharmacist again.

Your doctor will tell you how much Epoprostenol NORMON is suitable for you. The amount you are given is based on your body weight and the type of disease. Your dose may be increased or decreased depending on how well you respond to treatment.

Epoprostenol NORMON is given by slow infusion (drip) into a vein.

Pulmonary arterial hypertension

The first treatment will be given to you in a hospital. This is because your doctor needs to monitor you and identify the best dose for you.

You will start with an infusion of Epoprostenol NORMON. The dose will be increased until your symptoms are relieved and side effects are controlled. Once the best dose has been identified, a permanent catheter (line) will be placed in one of your veins. You can then be treated using an infusion pump.

Kidney dialysis

You will be given an infusion of Epoprostenol NORMON during your dialysis.

Using Epoprostenol NORMON at home (only for the treatment of pulmonary arterial hypertension)

If you are being treated at home, your doctor or nurse will teach you how to prepare and use Epoprostenol NORMON. They will also tell you how to stop treatment if necessary. Stopping Epoprostenol NORMON should be done gradually. It is important that you carefully follow all instructions.

Epoprostenol NORMON comes as a powder in a glass vial. Before use, the powder needs to be dissolved.

Catheter care

If a catheter has been placed in a vein, it is very important to keep the area clean, or it may become infected. Your doctor or nurse will teach you how to clean the catheter and the area around it. It is very important that you carefully follow all instructions.

If you use more Epoprostenol NORMON than you should

Seek medical attention immediately if you think you have used or been given too much Epoprostenol NORMON. In case of overdose or accidental injection, consult your doctor, nurse, or pharmacist immediately or call the Toxicology Information Service, phone: 91 562 04 20, stating the medicine and the amount injected. The symptoms of overdose may include headache, nausea, vomiting, fast heartbeat, heat, or tingling or feeling that you may faint (dizziness/vertigo).

If you forget to use Epoprostenol NORMON

Do not use a double dose to make up for forgotten doses.

If you stop treatment with Epoprostenol NORMON

Stopping Epoprostenol NORMON should be done gradually. If you stop treatment too quickly, you may have serious side effects, including dizziness, weakness, and difficulty breathing. If you have problems with the infusion pump or catheter because it stops or prevents treatment with Epoprostenol NORMON, contact your doctor, nurse, or hospital immediately.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor or nurse immediately, as these may be signs of infection of the blood or low blood pressure or severe bleeding:

• You feel that your heart is beating faster, or you have chest pain or difficulty breathing.
• You feel dizzy or faint, especially when standing up.
• You have a fever or chills.
• You bleed more often, or for longer periods.

Very common side effects

These may affect more than 1 in 10 people:

• headache,
• jaw pain,
• general pain,
• vomiting,
• nausea,
• diarrhea,
• flushing of the face

Common side effects

These may affect up to 1 in 10 people:

• blood infection (septicemia),
• fast heartbeat,
• slow heartbeat,
• low blood pressure,
• bleeding in various locations and increased tendency to bruise, for example nosebleeds or gum bleeding,
• stomach upset or pain,
• chest pain,
• joint pain,
• feeling anxious, feeling nervous,
• skin rash,
• pain at the injection site

Common side effects that may appear in your blood tests

• decrease in the number of platelets in the blood (cells that help blood clotting).

Uncommon side effects

These may affect up to 1 in 100 people:

• sweating,
• dry mouth

Rare side effects

These may affect up to 1 in 1,000 people:

• infection at the injection site

Very rare side effects

These may affect up to 1 in 10,000 people:

• feeling of pressure around the chest,
• fatigue, weakness,
• agitation,
• pallor,
• redness at the injection site,
• overactive thyroid gland,
• blockage of the intravenous catheter

Other side effects

Frequency not known:

• enlarged or overactive spleen,
• fluid accumulation in the lungs (pulmonary edema),
• increased blood sugar (glucose) levels
• swelling due to fluid accumulation around the stomach
• excessive blood pumping from the heart leading to difficulty breathing, fatigue, swelling of the legs and abdomen due to fluid accumulation, persistent cough.

Reporting of side effects:

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if it is possible that they are not listed in this leaflet. You can also report side effects directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Epoprostenol NORMON

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

Do not use this medicine after the expiry date which is stated on the carton after "EXP". The expiry date refers to the last day of the month shown.

Do not store above 25°C. Store in the original package to protect from light and moisture. Do not freeze.

Use after storage of the reconstituted solution:

Before use, the reconstituted solutions of Epoprostenol NORMON with 5 ml of water for injection or sodium chloride 0.9% should be protected from light and are chemically stable for 5 days if stored refrigerated at 2-8°C or for up to 48 hours if stored at 25°C. Do not freeze the reconstituted solutions of Epoprostenol NORMON; discard any reconstituted solution that has been frozen. Also, discard any reconstituted solution that has been refrigerated for more than 5 days or stored at 25°C for more than 48 hours.

Before administration, the reconstituted solutions of Epoprostenol NORMON should be further diluted to the final concentration with the same diluent used for reconstitution. During use, a diluted solution of Epoprostenol NORMON of 15,000 ng/ml or higher concentration can be administered for a period of 24 hours at room temperature (if lower concentrations are used, the pump reservoir should be changed every 12 hours when administered at room temperature). These solutions should be protected from light.

From a microbiological point of view:The product should be used immediately. If not used immediately, the in-use storage times and conditions are the responsibility of the user and should not exceed 24 hours at 2 to 8°C, unless the reconstitution has been carried out under aseptic controlled and validated conditions.

Use after reconstitution and immediate dilution to the final concentration:

Epoprostenol NORMON reconstituted with 5 ml of water for injection or sodium chloride 0.9% and immediately diluted to the final concentration in the drug administration reservoir can be administered according to the conditions of use indicated in the following table:

These solutions should be protected from light.

Disposal of unused medicine and all materials that have been in contact with it should be done in accordance with local regulations.

6. Container Content and Additional Information

Composition of Epoprostenol NORMON

The active ingredient is epoprostenol. Each vial contains 1.5 mg of epoprostenol (as sodium epoprostenol).

The other components are: mannitol, arginine, and sodium hydroxide (for pH adjustment).

Product Appearance and Container Content

Epoprostenol NORMON is presented in the form of powder for solution for infusion. Each container contains a vial of lyophilized powder.

Marketing Authorization Holder and Manufacturer

LABORATORIOS NORMON, S.A.

Ronda de Valdecarrizo, 6 – 28760 Tres Cantos – Madrid (SPAIN)

Date of Last Revision of this Leaflet: February 2023

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

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This information is intended exclusively for healthcare professionals:

Renal Dialysis

The reconstituted epoprostenol solution with solvent (pH 11.5-13.5) should not be used with any preparation or administration material containing polyethylene terephthalate (PET) or polyethylene terephthalate modified with glycol (PETG). Based on published literature, likely compatible preparation and administration materials include:

• Modified acrylic
• Acrylonitrile butadiene styrene (ABS)
• Cyclic olefin polymer
• Polyamide
• Polyethersulfone
• Polyethylene
• Polyisoprene
• Polyolefin
• Polypropylene
• Polytetrafluoroethylene (PTFE)
• Polyurethane
• Polyvinyl chloride (PVC) (plasticized with bis(2-ethylhexyl) phthalate (DEHP))
• Polyvinylidene fluoride (PVDF)
• Silicone

Reconstitution:

Inject with a sterile syringe 5 ml of water for injection or sodium chloride 0.9% into the vial containing 1.5 mg of Epoprostenol NORMON lyophilized and gently shake until the powder is dissolved. This solution is now called concentrated solution and contains 300,000 ng/ml of epoprostenol. Only this concentrated solution is suitable for subsequent dilutions before use.

Dilution:

To obtain a solution with a concentration of 30,000 ng/ml of epoprostenol: Withdraw the concentrated solution with the syringe and add it to a sufficient volume of the same diluent to obtain a final total volume of 50 ml. Mix thoroughly.

To obtain a solution with a concentration of 5,000 ng/ml of epoprostenol: Withdraw the concentrated solution with the syringe and add it to a sufficient volume of the same diluent to obtain a final total volume of 300 ml. Mix thoroughly.

If reconstituted and diluted as described above, the epoprostenol infusion solutions will maintain 90% of their initial potency.

Calculation of Infusion Rate:

The infusion rate can be calculated from the following formula:

dose (ng/kg/min) x body weight (kg)

Infusion rate (ml/min) = -----------------------------------------------------

concentration of the solution (ng/ml)

Infusion rate (ml/h) = infusion rate (ml/min) x 60

Pulmonary Arterial Hypertension

The reconstituted epoprostenol solution with solvent (pH 11.5-13.5) should not be used with any preparation or administration material containing polyethylene terephthalate (PET) or polyethylene terephthalate modified with glycol (PETG). Based on available data from published literature, compatible preparation and administration materials include:

• Modified acrylic
• Acrylonitrile butadiene styrene (ABS)
• Cyclic olefin polymer
• Polyamide
• Polyethersulfone
• Polyethylene
• Polyisoprene
• Polyolefin
• Polypropylene
• Polytetrafluoroethylene (PTFE)
• Polyurethane
• Polyvinyl chloride (PVC) (plasticized with bis(2-ethylhexyl) phthalate (DEHP))
• Polyvinylidene fluoride (PVDF)
• Silicone

Suitable portable pumps for use include:

• CADD- Legacy 1
• CADD- Legacy PLUS
• CADD-Solis VIP (variable infusion profile)

Manufactured by Smiths Medical.

Compatible pump accessories include:

• CADD medication cassette "reservoir" 50 ml; and 100 ml from Smiths Medical.
• CADD extension set with 0.2 micras in-line filter (CADD extension set with male luer; 0.2 micras air-eliminating filter, clamp and integral anti-siphon valve with male luer) from Smiths Medical.

The extension set and in-line filter should be changed at least every 48 hours.

Reconstitution:

This will be carried out according to the instructions described for renal dialysis.

Dilution:

The concentrated solution must be diluted for use in the treatment of pulmonary arterial hypertension.

The concentrations commonly used in the treatment of pulmonary arterial hypertension are as follows:

• 30,000 ng/ml: 1.5 mg of epoprostenol reconstituted with 5 ml water for injection or sodium chloride 0.9% and diluted to a total volume of 50 ml in the same solvent.
• 15,000 ng/ml: 1.5 mg of epoprostenol reconstituted with 5 ml water for injection or sodium chloride 0.9% and diluted to a total volume of 100 ml in the same solvent.

The maximum recommended concentration for administration in primary or secondary pulmonary hypertension is 60,000 ng/ml.

Epoprostenol NORMON should not be administered with other parenteral solutions or medications when administered for pulmonary arterial hypertension.

To dilute the concentrated solution, pass it to a syringe and dispense it directly into the pump cassette. Then, dispense the additional diluent into the Epoprostenol NORMON concentrated solution in the cassette. Mix well.

The portable pump used to administer Epoprostenol NORMON 1.5 mg must (1) be small and lightweight, (2) allow adjustment of infusion rates in increments of nanograms/kg/min, (3) have alarms for occlusion, end of infusion, and low battery, (4) provide an accuracy of ± 6% of the programmed rate, (5) operate with positive pressures (continuous or pulsatile) with pulse intervals not exceeding 3 minutes at the infusion rates used to administer Epoprostenol NORMON 1.5 mg. The reservoir should be made of polypropylene or glass.

Protect the infusion bags from light during infusion.

Calculation of Infusion Rate:

The infusion rate can be calculated from the formula described above for renal dialysis. In the long-term administration of Epoprostenol NORMON, higher infusion rates may be necessary, and therefore more concentrated solutions.