Rapilysin 10 U powder and solvent for solution forinjection

Rapilysin (a recombinant plasminogen activator) is a thrombolytic medicine used to dissolve blood clots that have formed in certain blood vessels and to restore the blood flow in these blocked vessels (=thrombolysis).
Rapilysin is used after an acute myocardial infarction (heart attack) in order to dissolve the blood clot causing the heart attack. It is given within 12 hours after the onset of symptoms.

The doctor will ask you questions before giving you Rapilysin, to find out if you have an increased risk of bleeding.

Do not use Rapilysin:
Before treatment with Rapilysin, make sure your doctor knows if you

• are allergic (hypersensitive) to reteplase or any of the other ingredients of Rapilysin
• have a bleeding disorder
• are taking medicine to thin your blood (oral anticoagulants, e.g. warfarin)
• have a brain tumour or a malformed blood vessel or a vessel wall dilatation (aneurysm) in the brain
• have other tumours associated with an increased risk of bleeding
• have had a stroke
• have had external heart massage within the past 10 days
• have severe uncontrolled high blood pressure (hypertension)
• have an ulcer in the stomach or small intestine
• have enlarged blood vessels in the gullet (oesophagus) (frequently caused by liver disease)
• have severe liver or kidney disease
• have acute inflammation of the pancreas or pericardium (the sac surrounding the heart), or an infection of the heart muscle (bacterial endocarditis)
• have in the past 3 months had severe bleeding, a major injury or major surgery (e.g. coronary artery bypass graft, or surgery or injury to the head or spine), given birth, or had an organ biopsy or other medical / surgical procedure.

Take special care with Rapilysin :

Bleeding

The most common side effect of Rapilysin is bleeding. Therefore Rapilysin must be given only in the presence and under the instructions of an emergency doctor.

Pay careful attention to all possible bleeding sites (e.g. injection sites). Heparin, which is given together with Rapilysin, may also increase bleeding.

The risks of Rapilysin treatment may be increased if you have any of the following conditions:

• diseases of the blood vessels in the brain
• systolic blood pressure higher than 160 mmHg
• bleeding in the gastrointestinal, urinary or genital tract within the past 10 days
• high likelihood of a blood clot in the heart (e.g. as a result of narrowing of a heart valve or atrial fibrillation)
• septic inflammation of a vein with blood clotting (septic thrombophlebitis) or blocked blood vessels at an infected site
• age over 75 years
• any other condition in which bleeding might be especially dangerous or might occur at a site where it would be difficult to control

At present, little data are available on the use of Rapilysin in patients with diastolic blood pressure higher than 100 mmHg

Abnormal heart beats (arrhythmias)

Thrombolytic treatment may cause the heart to beat irregularly. Therefore tell the medical staff immediately if you

• feel palpitations or an irregular heart beat

Repeated use

At present there is no experience with repeated use of Rapilysin. Therefore, repeated use is not recommended. Antibody formation to the reteplase molecule has not been seen.

Use in children

Safety and effectiveness of Rapilysin in children have not been established. Treatment of children with Rapilysin is not recommended.

Using other medicines:

Heparin and other medicines that thin the blood (anticoagulants) and acetylsalicylic acid (a substance used in many medicines used to relieve pain and lower fever) may increase the risk of bleeding.

Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines, even those not prescribed.
For information on medicines that should not be physically mixed with Rapilysin solution for injection see section 3.

Pregnancy

There is no experience with Rapilysin in pregnant women. Therefore it should not be used except in life-threatening situations. You must tell your doctor if you are pregnant or think you are pregnant. Your doctor can tell you the risks and benefits of using Rapilysin during pregnancy.

Breast-feeding

You should not breast-feed your baby during treatment with Rapilysin as it is not known whether Rapilysin is excreted into mother?s milk. Mother?s milk should be thrown away during the first 24 hours after thrombolytic treatment. Discuss with your doctor when you can take up breast-feeding again.

Rapilysin is usually given in a hospital. The medicine is supplied in vials as a powder for injection. Before use, the powder for injection must be dissolved in the water for injection supplied in the prefilled syringe that is in the package. Do not add any other medicines . The resulting solution must be used immediately. The solution must be examined to ensure that only clear, colourless solution is injected. If the solution is not clear and colourless it should be thrown away.

Treatment with Rapilysin 10 U should be started as soon as possible after the symptoms of heart attack begin.

Heparin and Rapilysin cannot be mixed in the same solution . Other medicines may also not mix well with Rapilysin. No other medicines should be added to the injection solution (see below). Rapilysin should be injected preferably through an intravenous line that is used only for the injection of Rapilysin. No other medicines should be injected through the line reserved for Rapilysin, either at the same time, or before or after Rapilysin injection. This applies to all medicines including heparin and acetylsalicylic acid, which are given before and after Rapilysin to reduce the risk of new blood clots forming.
If the same line has to be used, this line (including Y-line) must be flushed thoroughly with a 0.9 % sodium chloride or 5 % dextrose solution before and after the Rapilysin injection.

Dosage of Rapilysin

Rapilysin is given as a 10 U injection followed by a second 10 U injection 30 minutes later (double bolus).

Each injection should be given slowly within 2 minutes. The injection must not be given mistakenly outside the vein. Therefore, be sure to tell the medical staff if you experience pain during the injection.

Heparinand acetylsalicylicacid are given before and after Rapilysin to reduce the risk of new blood clots forming.

Dosage of Heparin

The recommended dose of heparin is 5000 I.U. given as a single injection before Rapilysin, followed by an infusion of 1000 I.U. per hour starting after the second Rapilysin injection. Heparin should be given for at least 24 hours, preferably for 48 - 72 hours, in order to keep aPTT values 1.5 to 2 times normal.

Dosage of Acetylsalicylic Acid

The dose of acetylsalicylic acid given before Rapilysin should be at least 250 mg ? 350 mg and should be followed by 75 ? 150 mg/day, at least until discharge from hospital.

Instructions for use/handling

Incompatibility of some prefilled glass syringes (including Rapilysin) with certain needle free connectors has been reported. Therefore, the compatibility of the glass syringe and intravenous access should be ensured before use. In case of incompatibility an adaptor can be used and removed together with the glass syringe immediately after administration

Use aseptic technique throughout.

1. Remove the protective flip-cap from the vial of Rapilysin 10 U and clean the rubber closure with an alcohol wipe.

2. Open the package containing the reconstitution spike, remove both protective caps from the reconstitution spike.

3. Insert the spike through the rubber closure into the vial of Rapilysin 10 U.

4. Take the 10 ml syringe out of the package. Remove the tip cap from the syringe. Connect the syringe to the reconstitution spike and transfer the 10 ml of solvent into the vial of Rapilysin 10 U.

5. With the reconstitution spike and syringe still attached to the vial, swirl the vial gently to dissolve the Rapilysin 10 U powder. DO NOT SHAKE.

6. The reconstituted preparation results in a clear, colourless solution. If the solution is not clear and colourless it should be discarded.

7. Withdraw 10 ml of Rapilysin 10 U solution back into the syringe. A small amount of solution may remain in the vial due to overfill.

8. Disconnect the syringe from the reconstitution spike. The dose is now ready for intravenous administration.

9. No other medicines should be injected through the line reserved for Rapilysin either at the same time, or prior to, or following Rapilysin injection. This applies to all products including heparin and acetylsalicylic acid, which should be administered before and following the administration of reteplase to reduce the risk of re-thrombosis.

10. In those patients where the same line has to be used, this line (including Y-line) must be flushed thoroughly with a 0.9 % sodium chloride or 5 % dextrose solution prior to and following the Rapilysin injection.

If more Rapilysin is used than recommended:

In the event of overdosage there may be an increased risk of bleeding.

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

The most common side effects of Rapilysin which may affect more than 10 % of the treated patients:

• Bleeding at the injection site, e.g. blood blister (haematoma)
• Chest Pain / angina, low blood pressure and heart failure /shortness of breath may reappear
• Burning sensation when Rapilysin is injected

Common side effects occurring in 1 to 10 % of the treated patients are:

• Bleeding in the digestive tract (e.g. bloody or black vomit, or stools) in the gums or in the urinary or genital tract
• Abnormal heart beats (arrhythmias), cardiac arrest, circulatory collapse or another heart attack may occur

Uncommon side effects occurring in 0,1 to 1 % of the treated patients are:

• Bleeding around the heart, in the abdomen, the brain or the eyes, under the skin, from the nose or as coughed up blood
• Damage to the heart or heart valves, or a blood clot in the lung, brain or other part of body may occur
• hypersensitivity (e.g.allergic reactions)

Other less common side effects occurring in less than 0.01 % of the treated patients are:

• Events related to the nervous system (e.g. epileptic seizure, convulsion, speech disorder, delirium, agitation, confusion, depression, psychosis)
• severe allergic reaction, causing shock or collapse

Cardiovascular events can be life-threatening or cause death.

Patients with systolic blood pressure over 160 mmHg have a greater risk of bleeding in the brain. The risk of intracranial bleeding and fatal intracranial bleeding increases with increasing age. Blood transfusions were rarely required. Death or permanent disability are not uncommon in patients who have a stroke (including bleeding in the brain) or other serious bleeding problem.

Be sure to tell hospital staff immediately if any of these symptoms appear. If you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

• Keep out of the reach and sight of children.
• Do not use Rapilysin after the expiry date stated on the carton and on the label of the vial.
• Do not store above 25 °C.
• Keep the vial in the outer carton in order to protect from light.
• After reconstitution (?when dissolved?), the solution must be used immediately.

What Rapilysin contains:

• The active substance of Rapilysin is reteplase 10U/10ml after reconstitution.
• The other ingredients in the vials are: Powder: Tranexamic acid di-potassium-hydrogen phosphate phosphoric acid sucrose polysorbate 80

Solvent:
10 ml Water for injection (prefilled syringe)

What Rapilysin looks like and content of the pack

Rapilysin is presented as a powder and a solvent for injection (0.56 g powder in a vial and 10 ml solvent in a pre-filled syringe with a reconstitution spike and a needle-pack of 2)

Marketing authorisation holder

Actavis Group PTC ehf
Reykjavíkurvegi 76-78
220 Hafnarfjordur
Iceland.

Manufacturer

Cenexi
52, Rue Marcel et Jacques Gaucher
94120 Fontenay-Sous-Bois
France

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

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