PROTAMINE SULFATE LEO PHARMA 1,400 IU ANTI-HEPARIN (10mg)/mL INJECTABLE SOLUTION AND PERFUSION SOLUTION

2. What you need to know before you start using Protamine sulfate LEO Pharma

Do not use Protamine sulfate LEO Pharma:

if you are allergic to protamine sulfate or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

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

• if you are a diabetic using insulin (particularly protamine insulin)
• if you are allergic to fish
• if you are an infertile man (cannot conceive a child) or if you have undergone a vasectomy (surgery to sterilize a man)
• if you have previously been treated with protamine sulfate, protamine insulin or protamine chloride

If you have already been given your injection, tell the healthcare staff if you are in any of the above situations. If you are not sure, discuss it with your doctor.

Children and adolescents

This medicine is not intended for use in children and adolescents.

Other medicines and Protamine sulfate LEO Pharma

Tell your doctor, nurse or pharmacist if you are taking, have recently taken or might take any other medicines.

Pregnancy and breastfeeding

Pregnancy

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor, nurse or pharmacist for advice before using this medicine.

There is no available information on the use of this medicine in pregnant women.

Protamine sulfate LEO Pharma should not be used during pregnancy unless clearly necessary.

Breastfeeding

If you are breastfeeding, ask your doctor, nurse or pharmacist for advice before using this medicine.

There is no available information on the use of this medicine in breastfeeding women.

Breastfeeding should be discontinued if treatment with Protamine sulfate LEO Pharma is necessary.

Driving and using machines

The influence of this medicine on the ability to drive and use machines is negligible.

Protamine sulfate LEO Pharma contains sodium

This medicine contains less than 1 mmol (23 mg) of sodium per 5 ml; this is essentially "sodium-free".

3. How to use Protamine sulfate LEO Pharma

Your doctor will decide the amount of Protamine sulfate LEO Pharma suitable for you. This depends on the results of blood tests to determine how much heparin needs to be neutralized.

Protamine sulfate LEO Pharma is for intravenous administration and can be administered as a slow injection (over about 10 minutes) into a vein or can be added to the solution in your "drip".

You may need additional doses, especially if you need to reverse a low molecular weight heparin or if your surgery is long.

No more than 5 ml of this medicine will be administered to you in each 10-minute treatment period.

If you have been given too much Protamine sulfate LEO Pharma

This can interfere with blood clotting processes, increasing the time it takes for blood to clot.

In case of overdose or accidental administration, consult the Toxicology Information Service. Phone 91 562 04 20, or go to the emergency department of the nearest hospital, accompanied by this leaflet.

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

4. Possible side effects

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

Serious side effects:

If you experience any of the following side effects, you should contact your doctor, nurse or local hospital immediately for emergency help:

• Severe allergic reaction. Symptoms include severe breathing difficulties, wheezing, swelling of the face and lips, heart problems, collapse (fainting due to low blood pressure)
• High blood pressure in the lungs. Symptoms include severe breathing difficulties.
• Severe and prolonged decrease in blood pressure. Symptoms include a low number of pulses, blue-tinged skin, feeling of fainting or collapse (especially if Protamine sulfate LEO Pharma is administered too quickly)

The following less serious side effects have been observed with the administration of Protamine sulfate LEO Pharma:

• Low blood pressure. Symptoms include dizziness
• Vomiting
• Back pain
• Bleeding
• Allergic reaction, similar to hives or other skin rashes. Symptoms include feeling of heat, redness of the skin, difficulty breathing and swelling of the deeper layers of the skin (occasionally with swelling of the tongue and airways).

Reporting of side effects

If you experience any side effects, ask your doctor, pharmacist or nurse, even if they are not listed in this leaflet. You can also report them to the Spanish Medicines and Healthcare Products 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 Protamine sulfate LEO Pharma

• 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 and label after EXP. The expiry date is the last day of the month stated.
• This medicine does not require any special storage conditions.

• Use immediately after opening the ampoule.
• Discard the remaining solution.
• Use only if the solution is clear and the ampoule is intact.
• When diluted for administration as a slow intravenous infusion, the mixture should be used immediately.

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

6. Contents of the pack and further information

Composition of Protamine sulfate LEO Pharma

• The active substance is protamine sulfate. 1 ml contains 1,400 UI anti-heparin protamine sulfate (equivalent to 10 mg), 5 ml contain 7,000 UI anti-heparin protamine sulfate (equivalent to 50 mg).

• The other ingredients are: sodium chloride, hydrochloric acid (for pH adjustment), sodium hydroxide (for pH adjustment) and water for injections.

Appearance of Protamine sulfate LEO Pharma and contents of the pack

This product is presented as an injectable and infusion solution, being a colorless and clear liquid.

Ampoules of 5 ml. Pack sizes of 5 or 50 ampoules.

Not all pack sizes may be marketed.

Marketing authorisation holder and manufacturer

Marketing authorisation holder

LEO Pharma A/S

55 Industriparken, DK-2750 Ballerup, Denmark.

Manufacturer

CENEXI SAS

52, rue Marcel et Jacques Gaucher, 94120 Fontenay-sous-Bois, France.

You can ask for more information about this medicine by contacting the local representative of the marketing authorisation holder:

Laboratorios LEO Pharma, S.A.

Via Laietana 33, 7th floor

08003 Barcelona

Spain

Date of last revision of this leaflet: 09/2014

Detailed information on this medicine is available on the website of the Spanish Agency for Medicines and Healthcare Products (AEMPS) (http://www.aemps.gob.es/).

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Please cut along this line and keep this part of the leaflet. Give the rest of the leaflet to the patient.

This information is intended only for healthcare professionals:

Protamine sulfate LEO Pharma 1,400 UI anti-heparin (10 mg)/ml injectable and infusion solution

1 ml contains 1,400 UI anti-heparin protamine sulfate (equivalent to 10 mg)

5 ml contain 7,000 UI anti-heparin protamine sulfate (equivalent to 50 mg)

For more information, see the full summary of product characteristics.

Therapeutic indications:This medicine may be used to neutralize the anticoagulant effect of heparin or low molecular weight heparin (see summary of product characteristics).

Posology and method of administration

This medicine is administered as a slow intravenous injection over a period of about 10 minutes or as a slow intravenous infusion. The maximum dose to be administered as a single injection (bolus dose) should not exceed 5 ml (7,000 UI anti-heparin/50 mg). The dose is usually determined based on the results of blood coagulation tests. For this purpose, the determination of activated partial thromboplastin time (APTT), activated clotting time (ACT), anti-Xa activity and protamine neutralization test are suitable. Coagulation tests are usually performed 5-15 minutes after administration of protamine sulfate. Additional doses may be necessary since protamine sulfate is eliminated from the blood more rapidly than heparin and especially more rapidly than low molecular weight heparin. Prolonged absorption after subcutaneous administration of heparin or low molecular weight heparin may also indicate that repeated doses should be administered.

Neutralization of Heparin

1 ml of Protamine sulfate LEO Pharma (10 mg of protamine sulfate) will neutralize approximately 1,400 UI of heparin. Since heparin has a relatively short half-life when administered intravenously (30 minutes - 2 hours), the dose of protamine sulfate should be adjusted based on the time elapsed since the discontinuation of intravenous heparin administration. The dose of protamine sulfate in relation to the amount administered of heparin should be reduced if more than 15 minutes have elapsed since the end of the intravenous heparin injection.

Neutralization of Low Molecular Weight Heparin (LMWH)

Generally, a dose of 1 ml of Protamine sulfate LEO Pharma (10 mg of protamine sulfate) is recommended for every 1,000 UI anti-Xa of LMWH. Protamine sulfate neutralizes different LMWHs to varying degrees; therefore, in case of overdose, the manufacturer's recommendations for the specific LMWH should be consulted. Protamine sulfate is only capable of partially neutralizing the anti-Xa activity of LMWH, and neutralization will not be more effective if higher doses of protamine sulfate are administered than recommended. There is a risk that neutralization may be incomplete with a single injection of protamine sulfate in the case of neutralization of subcutaneously administered LMWH. The absorption phase from the injection site will result in additional amounts of LMWH reaching the circulation (also called 'depot effect'). In these cases, repeated administrations of protamine sulfate or a continuous slow intravenous infusion may be necessary. When estimating the dose of protamine sulfate required in relation to the time elapsed since the administration of the last dose of LMWH, the half-life of LMWHs should also be taken into account.

Cardiopulmonary bypass procedures

The dose of protamine sulfate should be determined based on the results of blood coagulation tests. For this purpose, the determination of activated partial thromboplastin time (APTT), activated clotting time (ACT), anti-Xa activity and protamine neutralization test are suitable. Coagulation tests are usually performed 5-15 minutes after administration of protamine sulfate. Generally, a dose of 0.1 ml to 0.2 ml (1-2 mg) of Protamine sulfate LEO Pharma is administered intravenously for every 100 units of heparin administered.

Special precautions for disposal

Use immediately after opening the ampoule.

Discard the remaining solution.

Use only if the solution is clear, without visible particles, and the ampoule is intact. Disposal of unused medicine and all materials that have come into contact with it should be done in accordance with local regulations.

Protamine sulfate LEO Pharma can be administered as a slow intravenous infusion, in which case it should be used with a sodium chloride 9 mg/ml solution. Such mixtures should not be stored.