RAPILYSIN

Treatment with reteplase should be initiated as soon as possible after the onset of AMI symptoms. Rapilysin should be prescribed by physicians experienced in the use of thrombolytic treatment and with the facilities to monitor its use.

Posology Dosage of Rapilysin Rapilysin is administered as a 10 U bolus dose followed by a second 10 U bolus dose 30 minutes later (double bolus). Each bolus is administered as a slow intravenous injection within 2 minutes. Ensure that the injection is not mistakenly given paravenously.

Heparin and acetylsalicylic acid should be administered before and following the administration of Rapilysin to reduce the risk of re-thrombosis. U. U. per hour starting after the second reteplase bolus. 5 to 2 times normal. Dosage of Acetylsalicylic Acid The initial dose of acetylsalicylic acid prior to thrombolysis should be at least 250 mg (250 – 350 mg) followed by 75 – 150 mg/day at least until discharge.

Paediatric population No data are available. Method of administration Reteplase is supplied as a freeze-dried substance in vials. The lyophilisate is reconstituted with the contents of the accompanying syringe. 6. Rapilysin should be injected preferably through an intravenous line whose sole purpose is the injection of Rapilysin.

No other medicines should be injected through the line reserved for Rapilysin, neither at the same time, nor prior to, nor 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.

9 % sodium chloride or 5 % glucose solution prior to and following the Rapilysin injection.

Summary of the safety profile The most commonly reported adverse drug reaction associated with reteplase treatment is haemorrhage, predominantly at the injection site. Local reactions at injection site can also occur. As with other thrombolytic agents, recurrent ischaemia/angina, hypotension and heart failure/pulmonary oedema have been reported frequently as sequelae of myocardial infarction and/or thrombolytic administration.

Haemorrhage The most frequent adverse drug reaction associated with reteplase treatment is haemorrhage. Reports of intracranial bleeding, many of which are fatal, are of particular concern. Systolic blood pressure over 160 mmHg before thrombolysis with reteplase was associated with greater risk for cerebral bleeding.

The risk of intracranial bleeding and fatal intracranial bleeding increases with increasing age. Blood transfusions were rarely required. Death and permanent disability are not uncommonly reported in patients who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.

Tabulated list of adverse reactions The frequency of adverse reactions reported is listed in the following table. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).

g. g. g. g. haematoma), a local reaction at injection site, for example a burning sensation Injury, poisoning and procedural complications Not known Fat embolism, which may lead to corresponding consequences in the organs concerned4 1.

Available evidence on reteplase does not indicate an antibody-mediated origin of these hypersensitivity reactions. 2. Ischaemic or haemorrhagic cerebrovascular events may be contributing or underlying conditions. 3. As with other thrombolytic agents these cardiovascular events have been reported as sequelae of myocardial infarction and/or thrombolytic administration.

Each patient being considered for therapy with reteplase should be carefully evaluated. 2. Bleeding The most common complication encountered during reteplase therapy is bleeding. g. mitral stenosis with atrial fibrillation - septic thrombophlebitis or occluded arteriovenous cannula at seriously infected site - age over 75 years - any other condition in which bleeding constitutes a significant hazard or would be particularly difficult because of its location The concomitant use of heparin anticoagulation may contribute to bleeding.

As fibrin is lysed during reteplase therapy, bleeding from recent puncture sites may occur. Therefore, thrombolytic therapy requires careful attention to all possible bleeding sites (including catheter insertion sites, arterial and venous puncture sites, cut down sites and needle puncture sites).

The use of rigid catheter as well as intramuscular injections and nonessential handling of the patient should be avoided during treatment with reteplase. Caution should be employed when used with other medicinal products affecting haemostasis such as heparin, low-molecular-weight heparins, heparinoids, oral anticoagulants and antiplatelet agents other than acetylsalicylic acid, such as dipyridamole, ticlopidine, clopidogrel or glycoprotein IIb/IIIa receptor antagonists.

Should serious bleeding, in particular cerebral haemorrhage, occur any concomitant heparin should be terminated immediately. In addition, the second bolus of reteplase should not be given if the serious bleeding occurs before it is administered.

In general, however, it is not necessary to replace the coagulation factors because of the relatively short half-life of reteplase. Most patients who have bleeding can be managed by interruption of thrombolytic and anticoagulant therapy, volume replacement and manual pressure applied to an incompetent vessel.

Protamine should be considered if heparin has been administered within 4 hours of the onset of bleeding. In the patients who fail to respond to these conservative measures, judicious use of transfusion products may be indicated. Transfusions of cryoprecipitate, fibrinogen, fresh frozen plasma and platelets should be considered with clinical and laboratory reassessment after each administration.

1. g. g. coronary artery bypass graft, intracranial or intraspinal surgery or trauma), obstetrical delivery, organ biopsy, previous puncture of non- compressible vessels.