Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Actavis Group PTC ehf, Reykjavíkurvegi 76-78, 220 Hafnarfjordur, Iceland
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Because thrombolytic therapy increases the risk of bleeding, reteplase is contra-indicated in the following situations:
Each patient being considered for therapy with reteplase should be carefully evaluated. For information on product incompatibilities see section 6.2.
The most common complication encountered during reteplase therapy is bleeding. In the following conditions the risks of reteplase therapy may be increased and should be weighed against the anticipated benefits:
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. A target fibrinogen level of 1 g/l is desirable with cryoprecipitate or fibrinogen infusion.
At present, insufficient data in patients with a diastolic blood pressure >100 mmHg prior to thrombolytic therapy are available for reteplase.
Coronary thrombolysis may result in arrhythmias associated with reperfusion. It is strongly recommended that antiarrhythmic therapy for bradycardia and/or ventricular tachyarrhythmias (e.g. ventricular tachycardia or fibrillation) be available when reteplase is administered.
Since at present there is no experience with readministration of reteplase, the readministration is not recommended. However, no antibody formation to the reteplase molecule has been observed. If an anaphylactoid reaction occurs, the injection should be discontinued immediately and appropriate therapy should be initiated.
No interaction studies have been performed. Retrospective analyses of clinical studies did not reveal any clinically relevant interactions with medicinal product used concomitantly with reteplase in patients with acute myocardial infarction. Heparin, vitamin K antagonists and medicinal product that alter platelet function (such as acetylsalicylic acid, dipyridamole and abciximab) may increase the risk of bleeding if administered prior to, during or after reteplase therapy.
Attention should be paid to this effect especially during periods of low plasma fibrinogen (up to about 2 days after fibrinolytic therapy of AMI).
For information on product incompatibilities see section 4.2.
There are no adequate data on the use of reteplase in pregnant women. The only relevant available animal data refer to studies performed in rabbits, which showed vaginal bleedings associated with abortions (see section 5.3). The potential risk for humans is unknown. Except in life-threatening situations, Rapilysin should not be used in pregnant women.
It is not known whether reteplase is excreted into breast milk. Breast milk should be discarded within the first 24 hours after thrombolytic therapy.
Not relevant.
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.
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.
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).
Uncommon: Hypersensitivity reactions (e.g. allergic reactions)1
Very rare: Serious anaphylaxis/anaphylactoid reactions1
Uncommon: Cerebral haemorrhage2
Very rare: Events related to the nervous system (e.g. epileptic seizure, convulsion, aphasia, speech disorder, delirium, acute brain syndrome, agitation, confusion, depression, psychosis)
Very common: Recurrent ischaemia/angina, hypotension and heart failure/pulmonary oedema
Common: Arrhythmias (e.g. AV block, atrial fibrillation/flutter, ventricular tachycardia/fibrillation, electromechanical dissociation (EMD)), cardiac arrest, cardiogenic shock and reinfarction
Uncommon: Mitral regurgitation, pulmonary embolism, other systemic embolism/cerebral embolism and ventricular septal defect
Common: Gastrointestinal haemorrhage (haematemesis, melena), gingival or genitourinary bleeding
Uncommon: Haemopericardium, retroperitoneal bleeding, cerebral haemorrhage, epistaxis, haemoptysis, eye haemorrhage and ecchymosis
Very common: Haemorrhage at the injection site (e.g. haematoma), a local reaction at injection site, for example a burning sensation
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. These events can be life-threatening and may lead to death.
4 This event has been reported for the therapeutic class of thrombolytic agents.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
This medicinal product should not be mixed with Heparin and/or acetylsalicylic acid. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Heparin and Rapilysin are incompatible when combined in solution. Other incompatibilities may also exist. No other medicines should be added to the injection solution.
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