FLOLAN 0.5 mg POWDER AND SOLVENT FOR SOLUTION FOR INFUSION

2. What you need to know before you use Flolan

Do not use Flolan

• to epoprostenol or any of the other ingredients of this medicine (listed in section 6)

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

Warnings and precautions

Tell your doctor before using Flolan:

Skin lesion at the injection site

Flolan is injected into a vein. It is essential that the medicine does not leak or spill 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 crucial that you monitor the injection site while being treated with Flolan.

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

Effect of Flolan on blood pressure and heart rate

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

Tell your doctorif you have any of these symptoms. It may be necessary to reduce your dose or stop the infusion.

Using Flolan with other medicines

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those bought without a prescription.

Some medicines may affect how Flolan works or make it more likely that you will get side effects. Flolan 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 pharmacistif you are taking any of these medicines.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine. The symptoms may worsen during pregnancy.

It is not knownif the components of Flolan can pass into breast milk. You should stop breast-feeding while being treated with Flolan.

Driving and using machines

The treatment may affect your ability to drive and use machines.

Do not drive or use machinesunless you feel well.

Flolan contains sodium (main component of table/cooking salt)

Patients on low-sodium diets should note that this reconstituted medicine contains 73 mg of sodium per dose.

Reconstituted concentrated solution:this medicine contains 73 mg of sodium (main component of table/cooking salt) in each vial of concentrated solution. This is equivalent to 4% of the maximum recommended daily intake of sodium for an adult.

Powder for solution for infusion:this medicine contains 3 mg of sodium (main component of table/cooking salt) in each vial of powder for solution. This is equivalent to 0.2% of the maximum recommended daily intake of sodium for an adult.

Parenteral solvent:this medicine contains 70 mg of sodium (main component of table/cooking salt) in each vial of solvent. This is equivalent to 4% of the maximum recommended daily intake of sodium for an adult.

3. How to use Flolan

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

Your doctor will tell you how much Flolan is right 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.

Flolan 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 find the best dose for you.

You will start with an infusion of Flolan. The dose will be increased until your symptoms are relieved and side effects are controlled. Once the best dose is found, a permanent catheter (line) will be put into one of your veins. You can then be treated using an infusion pump.

Kidney dialysis

You will be given an infusion of Flolan during your dialysis.

Using Flolan 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 Flolan. They will also tell you how to stop treatment if necessary. Stopping Flolan should be done gradually. It is essential that you follow allthe instructions carefully.

Flolan comes as a powder in a glass vial. Before use, the powder needs to be mixed with the liquid provided. The liquid does not contain preservatives. You must throw away any liquid that you do not use.

Catheter care

If a catheter is put into a vein, it is very importantto keep the area clean, or you may get an infection. Your doctor or nurse will teach you how to clean the catheter and the area around it. It is crucial that you follow allthe instructions carefully.

If you use more Flolan than you should

Seek medical help immediatelyif you think you have used or been given too much Flolan. The symptoms of overdose may include headache, nausea, vomiting, fast heart rate, warmth, or tingling or feeling like you may faint (dizziness/lightheadedness).

If you forget to use Flolan

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

If you stop using Flolan

Stopping Flolan should be done gradually. If you stop treatment too quickly, you may get 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 Flolan, contact your doctor, nurse, or hospital immediately.

If you have any other questions about using 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 if you get any of these symptoms, as they can be signs of infection of the blood, low blood pressure, or severe bleeding:

• You feel your heart 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.

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.

Very common side effects

These may affect more than 1 in 10people:

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

Common side effects

These may affect up to 1 in 10people:

• blood infection (septicemia)

• fast heart rate
• slow heart rate
• low blood pressure

• bleeding in various locations and increased tendency to bruise; for example, nosebleeds or bleeding gums
• discomfort or stomach pain
• chest pain
• joint pain
• feeling anxious or 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 100people:

• sweating
• dry mouth

Rare side effects

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

• infection at the injection site

Very rare side effects

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

• feeling of tightness 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)
• increase in blood sugar levels
• swelling due to fluid accumulation around the stomach
• excessive pumping of blood from the heart leading to difficult breathing, fatigue, swelling of the legs and abdomen due to fluid retention, 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 to the Spanish Medicines Agency (AEMPS) at www.notificaRAM.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Flolan

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 label.

Do not store above 25°C.

Store Flolan in a dry place.

Keep Flolan in the original package to protect it from light.

Do not freeze.

Pulmonary arterial hypertension

For solutions ≤ 150,000 ng/ml:

The freshly prepared solution of Flolan (either as a concentrated solution or further diluted) can be administered immediately or stored for a maximum of 8 days in the refrigerator (between 2°C and 8°C), in the medication cassette, and used within a maximum of:

• 72 hours up to 25°C or
• 48 hours up to 30°C or
• 24 hours up to 35°C or
• 12 hours up to 40°C

For solutions > 150,000 ng/ml and ≤ 300,000 ng/ml:

The reconstituted solutions that have been stored at 2-8°C for up to 7 days can be administered for up to 24 hours at 25°C.

The freshly prepared or reconstituted solutions that have been stored at 2-8°C for no more than 5 days can be administered for:

• up to 48 hours at 25°C
• up to 24 hours at 35°C

Discard any unused solution after this time.

Kidney dialysis

Once Flolan has been dissolved and diluted, any unused solution can be stored at 25°C and used within the next 12 hours.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Container Contents and Additional Information

Flolan Composition

The active ingredient is sodium epoprostenol.

Each vial contains:

• 0.5 mg of sodium epoprostenol
• See section 2 for more important information about sodium.

The other components are mannitol, glycine, sodium chloride, sodium hydroxide, and water for injectable preparations.

Product Appearance and Container Contents

Injection:

Flolan is an injectable solution consisting of powder and solvent. The powder is white to off-white and the solution is clear and colorless.

There are three Flolan containers available for use in pulmonary arterial hypertension, each pack contains:

• A vial of 0.5 mg powder and a vial of solvent, a vial adapter, and a filter.
• A vial of 0.5 mg powder and two vials of solvent, two vial adapters, and a filter.
• A vial of 0.5 mg powder.

There is only one Flolan container available for use in renal dialysis, each pack contains:

• A vial of 0.5 mg powder and a vial of solvent, a vial adapter, and a filter.

Only some pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder:

GlaxoSmithKline, S.A.

P.T.M. C/ Severo Ochoa, 2

28760 Tres Cantos (Madrid)

Tel: +34 900 202 700

[email protected]

Manufacturer:

GlaxoSmithKline Manufacturing, S.p.A.

Strada Provinciale Asolana, 90

43056 San Polo di Torrile, Parma, Italy.

or

GlaxoSmithKline Pharmaceuticals S.A.

Ul. Grunwaldzka

60-322 Poznan

Poland.

or

Glaxo Wellcome GmbH & Co.KG

Industriestrasse 32-36

23843 Bad Oldesloe

Germany.

This medicinal product is authorized in the Member States of the European Economic Area under the following names:

Austria Flolan

Belgium Flolan

Czech Republic Flolan

Denmark Epoprostenol

Estonia Flolan

France Flolan

Ireland Flolan

Italy Flolan

Luxembourg Flolan

Malta Flolan

Netherlands Flolan

Norway Flolan

Spain Flolan

United Kingdom Flolan

Date of last revision of this leaflet: March 2021

Detailed and up-to-date information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

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This information is intended only for healthcare professionals:

1. INFORMATION FOR HEALTHCARE PROFESSIONALS

Pulmonary Arterial Hypertension

There are three containers available for use in pulmonary arterial hypertension:

• A vial of 0.5 mg powder, a vial of solvent, a vial adapter, and a filter.
• A vial of 0.5 mg powder, two vials of solvent, two vial adapters, and a filter.
• A vial of 0.5 mg powder.

Only some container sizes may be marketed.

Initially, a container containing solvent for parenteral use should be used. More concentrated solutions may be required during chronic treatment with Flolan. The final concentrated solution can be increased by adding another vial of 0.5 mg lyophilized Flolan powder.

To increase the final concentration of the solution, only vials of the same amount of Flolan lyophilized powder as those included in the initial container should be used.

Flolan prepared with solvent (pH 11.7-12.3) should not be used with any preparation or administration material containing polyethylene terephthalate (PET) or polyethylene terephthalate modified with glycol (PETG). Based on available internal analysis data and 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 ambulatory pumps for use include:

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

Manufactured by Smiths Medical.

Pump accessories that are compatible include:

• CADD medication cassette "reservoir" 50 ml; and 100 ml from Smiths Medical.
• CADD extension set with in-line filter of 0.2 micras (CADD extension set with male luer; air-eliminating filter of 0.2 micras, 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:

1. Use only the supplied solvent for reconstitution.
2. Remove approximately 10 ml of the solvent with a sterile syringe, through a vial adapter*.
3. Remove the syringe from the vial adapter. Connect the needle to the syringe, inject the 10 ml of solvent into the vial containing Flolan powder, and gently shake until the powder is dissolved.
4. Withdraw the resulting Flolan solution into the syringe, remove the needle, and reinject it into the remaining volume of solvent through the vial adapter* and mix well.

*Alternatively, a needle can be used instead of the vial adapter

This solution is now referred to as the concentrated solution and contains 10,000 nanograms per ml of Flolan (for the 0.5 mg concentration). Only concentrated solutions are suitable for further dilution before use. Use a new vial adapter for each additional vial of sterile solvent that is needed. When 0.5 mg of Flolan powder is reconstituted with 50 ml of solvent, the final injection will have a pH of approximately 12 and a sodium ion content of approximately 73 mg.

Dilution:

Flolan can be used in concentrated solution or diluted form for the treatment of pulmonary arterial hypertension. Only concentrated solutions are suitable for further dilution with sterile solvent before use. Only the supplied solvent can be used for further dilution of reconstituted Flolan, using a new vial adapter for each additional vial of sterile solvent that is needed.

The 0.9% w/v sodium chloride solution should not be used if Flolan is to be administered for the treatment of pulmonary arterial hypertension, as the necessary pH is not maintained. Flolan solutions are less stable at low pH.

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

The final solution to be administered to the patient should be filtered using a 0.22 or 0.20 micras filter. It is preferable to use an in-line filter as part of the perfusion equipment during administration. Alternatively, when in-line filtration is not possible, the final solution (either as a concentrated solution or more diluted) must be filtered with the provided sterile 0.22 micras filter before being stored in the medication cassette, exerting firm but not excessive pressure. The usual time for filtering 50 ml of solution is 70 seconds.

If an in-line filter has been used during administration, it should be discarded when changing the perfusion equipment.

If, on the other hand, a syringe filter has been used during preparation, it should only be used for preparation and discarded afterwards. The concentrations commonly used in the treatment of pulmonary arterial hypertension are as follows:

• 5,000 nanograms/ml – a vial containing 0.5 mg of Flolan reconstituted and diluted to a total volume of 100 ml in the solvent.
• 10,000 nanograms/ml - two vials containing 0.5 mg of Flolan reconstituted and diluted to a total volume of 100 ml in the solvent.

Perfusion Rate Calculation:

The perfusion rate can be calculated from the following formula:

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

Perfusion rate (ml/min) =

solution concentration (nanograms/ml)

Perfusion rate (ml/h) = perfusion rate (ml/min) x 60

In the long-term administration of Flolan, higher perfusion rates may be necessary, and therefore more concentrated solutions.

Special Precautions for Storage

Do not store above 25°C.

Keep the container in the carton to protect it from light.

Keep in a dry place.

Do not freeze.

For more details on stability after reconstitution, see section 5 (storage of Flolan).

The solvent does not contain preservatives; therefore, each vial should only be used once and discarded afterwards.

Renal Dialysis

There is only one container available for use in renal dialysis:

• A vial of 0.5 mg powder and a vial of solvent, a vial adapter, and a filter.

Flolan prepared with sterile solvent (pH 12) should not be used with any preparation or administration material containing polyethylene terephthalate (PET) or polyethylene terephthalate modified with glycol (PETG). Based on available internal analysis data and published literature, the probable 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:

1. Use only the supplied solvent for reconstitution.

1. Remove approximately 10 ml of solvent in a sterile syringe, through a vial adapter*.

1. Remove the syringe from the vial adapter. Connect the needle to the syringe, inject the 10 ml of solvent into the vial containing the 0.5 mg lyophilized Flolan powder, and gently shake until the powder is dissolved.

1. Withdraw the resulting Flolan solution into the syringe, remove the needle, and reinject it into the remaining volume of solvent, through the vial adapter*, and mix well.

*Alternatively, a needle can be used instead of the vial adapter.

This solution is now referred to as the concentrated solution and contains 10,000 nanograms per ml of Flolan. Only this concentrated solution is suitable for further dilution before use. When 0.5 mg of Flolan powder for intravenous perfusion is reconstituted with 50 ml of solvent, the final injection will have a pH of approximately 12 and a sodium ion content of approximately 73 mg.

Dilution:

Normally, the concentrated solution is diluted immediately before use. It can be diluted with a 0.9% w/v sodium chloride solution, in a ratio of 2.3 volumes of sodium chloride solution to 1 volume of concentrated solution; for example, 50 ml of concentrated solution diluted with 117 ml of sodium chloride solution.

Other common intravenous fluids are not suitable for diluting the concentrated solution, as the required pH would not be maintained. Flolan solutions are less stable at low pH.

To dilute the concentrated solution, withdraw it with a larger syringe and

administer the concentrated solution directly into the chosen perfusion solution. Mix well.

The final solution for perfusion (either as a concentrated solution or more diluted) must be transferred to a suitable container or administration system before administration. During transfer, a sterile 0.22 micras filter should be used, exerting firm but not excessive pressure. The usual time for filtering 50 ml of solution is 70 seconds.

The syringe filter should only be used during preparation and discarded afterwards.

If reconstituted and diluted as described above, Flolan perfusion solutions will maintain 90% of their initial potency for approximately 12 hours at 25°C.

Perfusion Rate Calculation:

The perfusion rate can be calculated from the following formula:

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

Perfusion rate (ml/min) =

solution concentration (nanograms/ml)

Perfusion rate (ml/h) = perfusion rate (ml/min) x 60

For administration via a pump capable of delivering constant small-volume perfusions, suitable aliquots of the concentrated solution can be diluted with a sterile 0.9% w/v sodium chloride solution.

Detailed and up-to-date information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

INSTRUCTIONS FOR USE

Flolan Solution

Instructions for use with a vial adapter and ambulatory perfusion pumps

Please read these instructions before starting to prepare your Flolan solution. If you have any questions or doubts, contact your doctor.

• Wash your hands thoroughly before touching the necessary items.
• Put on your gloves before preparing Flolan (Step 1).
• Keep your workspace and the necessary items for preparing Flolan clean and dry to ensure that you prepare Flolan hygienically.
• Always follow your doctor's instructions exactly. The information in these instructions serves as a reminder of the process.

Storage Information

• Keep out of sight and reach of children.

• Store Flolan in a cool and dry place.
• Protect from light by keeping Flolan in its carton until it is used.

Do notuse Flolan after the expiration date shown on the label.

Do notfreeze.