Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: Boehringer Ingelheim Limited Ellesfield Avenue Bracknell Berkshire RG12 8YS
Hypersensitivity to the active substance or to any of the excipients.
Actilyse is contraindicated in cases where there is a high risk of haemorrhage such as:
Actilyse is not indicated for the treatment of acute stroke in paediatric patients under 18 years.
Actilyse is not indicated for the treatment of acute stroke in adults over 80 years of age.
Thrombolytic/fibrinolytic treatment requires adequate monitoring. Actilyse should only be used by physicians trained and experienced in the use of thrombolytic treatments and with the facilities to monitor that use. It is recommended that when Actilyse is administered standard resuscitation equipment and pharmacotherapy be available in all circumstances.
The risk of intracranial haemorrhage is increased in elderly patients, therefore in these patients the risk/benefit evaluation should be carried out carefully.
As yet, there is only limited experience with the use of Actilyse in children and adolescents.
As with all thrombolytic agents, the expected therapeutic benefit should be weighed up particularly carefully against the possible risk, especially in patients with:
The use of rigid catheters should be avoided.
A dose exceeding 100 mg of alteplase must not be given because it has been associated with an additional increase in intracranial bleeding.
Therefore special care must be taken to ensure that the dose of alteplase infused is as described in section 4.2.
There is limited experience with readministration of Actilyse. Actilyse is not suspected to cause anaphylactic reactions. If an anaphylactoid reaction occurs, the infusion should be discontinued and appropriate treatment initiated.
The expected therapeutic benefit should be weighed up particularly carefully against the possible risk, especially in patients with systolic blood pressure > 160 mm Hg.
Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.
Same as for acute myocardial infarction (see above)
Special precautions for use: Treatment must only be performed under the responsibility and follow-up of a physician trained and experienced in neurovascular care.
Special warnings / conditions with a decreased benefit/risk ratio: Compared to other indications patients with acute ischaemic stroke treated with Actilyse have a markedly increased risk of intracranial haemorrhage as the bleeding occurs predominantly into the infarcted area.
This applies in particular in the following cases:
Blood pressure (BP) monitoring during treatment administration and up to 24 hours seems justified; an intravenous antihypertensive therapy is also recommended if systolic BP > 180 mm Hg or diastolic BP > 105 mm Hg.
The therapeutic benefit is reduced in patients that had a prior stroke or in those with known uncontrolled diabetes, thus the benefit/risk ratio is considered less favourable, but still positive in these patients.
In patients with very mild stroke, the risks outweigh the expected benefit (see section 4.3).
Patients with very severe stroke are at higher risk for intracerebral haemorrhage and death and should not be treated (see section 4.3).
Patients with extensive infarctions are at greater risk of poor outcome including severe haemorrhage and death. In such patients, the benefit/risk ratio should be thoroughly considered.
In stroke patients the likelihood of good outcomes decreases with increasing age, increasing stroke severity and increased levels of blood glucose on admission while the likelihood of severe disability and death or relevant intracranial bleedings increases, independently from treatment. Patients over 80, patients with severe stroke (as assessed clinically and/or by appropriate imaging techniques) and patients with blood glucose levels < 50 mg/dl or >400 mg/dl at baseline should not be treated with Actilyse (see section 4.3).
Data available from ECASS III and the pooled analysis indicate that the net clinical benefit becomes smaller in elderly with increasing age compared to younger patients as benefit from treatment with Actilyse appears to decrease and the risk of mortality appears to increase with increasing age.
Reperfusion of the ischaemic area may induce cerebral oedama in the infarcted zone.
Due to an increased haemorrhagic risk, treatment with platelet aggregation inhibitors should not be initiated within the first 24 hours following thrombolysis with alteplase.
No formal interaction studies with Actilyse and medicinal products commonly administered in patients with acute myocardial infarction have been performed.
The risk of haemorrhage is increased if coumarine derivatives, oral anticoagulants, platelet aggregation inhibitors, unfractionated heparin or LMWH or active substances which interfere with coagulation are administered (before, during or within the first 24 hours after treatment with Actilyse) (see section 4.3).
Concomitant treatment with ACE inhibitors may enhance the risk of suffering an anaphylactoid reaction, as in the cases describing such reactions a relatively larger proportion of patients were receiving ACE inhibitors concomitantly.
Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.
There is very limited experience with the use of alteplase during pregnancy and lactation. Studies in animals have shown reproductive toxicity (see section 5.3). In cases of an acute life-threatening disease the benefit has to be evaluated against the potential risk. It is not known if alteplase is excreted into breast milk.
Not relevant.
Adverse reactions listed below are classified according to frequency and system organ class. Frequency groupings are defined according to the following convention: 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), Not known (cannot be estimated from the available data).
Except for intracranial haemorrhage as adverse reaction in the indication stroke and reperfusion arrhythmias in the indication myocardial infarction, there is no medical reason to assume that the qualitative and quantitative adverse reaction profile of Actilyse in the indications pulmonary embolism and acute ischaemic stroke is different from the profile in the indication myocardial infarction.
The most frequent adverse reaction associated with Actilyse is bleeding resulting in a fall in haematocrit and/or haemoglobin values:
Very common: bleeding from damaged blood vessels (such as haematoma) injection site haemorrhage (puncture site haemorrhage, catheter site haematoma, catheter site haemorrhage)
Common: intracranial haemorrhage (such as cerebral haemorrhage, cerebral haematoma, haemorrhagic stroke, haemorrhagic transformation of stroke, intracranial haematoma, subarachnoid haemorrhage) in the treatment of acute ischaemic stroke. Symptomatic intracerebral haemorrhage represents the major adverse reaction in the treatment of acute ischaemic stroke (up to 10 % of patients without any increase of overall mortality and without any relevant increase in overall mortality and severe disability combined, i.e. mRS of 5 and 6). respiratory tract haemorrhage (such as pharyngeal haemorrhage, epistaxis, haemoptysis), gastrointestinal haemorrhage (such as gastric haemorrhage, gastric ulcer haemorrhage, haemorrhage rectum, haematemesis, melaena, mouth haemorrhage, gingival bleeding), ecchymosis, urogenital haemorrhage (such as haematuria, haemorrhage urinary tract), blood transfusion (necessary)
Uncommon: intracranial haemorrhage (such as cerebral haemorrhage, cerebral haematoma, haemorrhagic stroke, haemorrhagic transformation of stroke, intracranial haematoma, subarachnoid haemorrhage) in the treatment of acute myocardial infarction and acute pulmonary embolism, ear haemorrhage, haemopericardium, retroperitoneal haemorrhage (such as retroperitoneal haematoma)
Rare: bleeding in parenchymatous organs (such as hepatic haemorrhage, pulmonary haemorrhage)
Very rare: eye haemorrhage
Death and permanent disability are reported in patients who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.
If a potentially dangerous haemorrhage occurs in particular cerebral haemorrhage, the fibrinolytic therapy must be discontinued. In general, however, it is not necessary to replace the coagulation factors because of the short half-life and the minimal effect on the systemic coagulation factors. 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 few patients who fail to respond to these conservative measures, judicious use of transfusion products may be indicated. Transfusion of cryoprecipitate, 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 infusion. Antifibrinolytic agents are available as a last alternative.
Uncommon: hypersensitivity reactions / anaphylactoid reactions (e.g. allergic reactions including rash, urticaria, bronchospasm, angio-oedema, hypotension, shock or any other symptom associated with allergic reactions)
Very rare: serious anaphylaxis
Transient antibody formation to Actilyse has been observed in rare cases and with low titres, but a clinical relevance of this finding could not be established.
Very rare: events related to the nervous system (e.g. epileptic seizure, convulsion, aphasia, speech disorder, delirium, acute brain syndrome, agitation, confusion, depression, psychosis) often in association with concurrent ischaemic or haemorrhagic cerebrovascular events
As with other thrombolytic agents, the following events have been reported as sequelae of myocardial infarction and / or thrombolytic administration.
Very common: recurrent ischaemia / angina, hypotension and heart failure / pulmonary oedema, reperfusion arrhythmias (such as arrhythmia, extrasystoles, AV block I° to complete, atrial fibrillation / flutter, bradycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia / fibrillation, electromechanical dissociation [EMD])
Common: cardiac arrest, cardiogenic shock and reinfarction
Uncommon: mitral regurgitation, pulmonary embolism, other systemic embolism / cerebral embolism, ventricular septal defect
These cardiac events can be life-threatening and may lead to death.
Uncommon: embolism (thrombotic embolisation), which may lead to corresponding consequences in the organs concerned
Common: nausea, vomiting
Very common: blood pressure decreased
Common: body temperature increased
Rare: fat embolism (cholesterol crystal embolisation), which may lead to corresponding consequences in the organs concerned
The reconstituted solution may be diluted with sterile sodium chloride 9 mg/ml (0.9 %) solution for injection up to a minimal concentration of 0.2 mg alteplase per ml.
Further dilution, the use of water for injections for dilution or in general the use of carbohydrate infusion solutions, e.g. dextrose, is not recommended due to increasing formation of turbidity of the reconstituted solution.
Actilyse should not be mixed with other medicinal products neither in the same infusion vial nor the same catheter (not even with heparin).
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