The following special warnings and precautions apply for the treatment of acute myocardial infarction, acute massive pulmonary embolism and acute ischaemic stroke: ACTILYSE should be used by physicians experienced in the use of thrombolytic treatment and with the facilities to monitor that use. As with other thrombolytics, it is recommended that when ACTILYSE is administered standard resuscitation equipment and medication be available in all circumstances.
Hypersensitivity: Immune-mediated hypersensitivity reactions associated with the administration of ACTILYSE can be caused by the active substance alteplase, gentamicin (a trace residue from the manufacturing process), any of the excipients (see also Contraindications) or the stopper of the glass vial (ACTILYSE powder and sterile water for injection) which contains natural rubber (a derivative of latex).
No sustained antibody formation to the recombinant human tissue-type plasminogen activator molecule has been observed after treatment. There is no systematic experience with re-administration of ACTILYSE.
There is also a risk of hypersensitivity reactions mediated through a non-immunological mechanism.
Angio-oedema represents the most common hypersensitivity reaction reported with ACTILYSE. This risk may be enhanced in the indication acute ischaemic stroke and/or by concomitant treatment with ACE inhibitors (see Interactions).
Patients treated for any authorised indication should be monitored for angio-oedema during and for up to 24h after infusion.
If a severe hypersensitivity reaction (e.g. angio-oedema) occurs, the infusion should be discontinued and appropriate treatment promptly initiated. This may include intubation.
Bleeding: The most common complication encountered during ACTILYSE therapy is bleeding. The concomitant use of heparin anticoagulation may contribute to bleeding. As fibrin is lysed during ACTILYSE therapy, bleeding from recent puncture sites may occur. Therefore, thrombolytic therapy requires careful attention to all possible bleeding sites (including those following catheter insertion, arterial and venous puncture cutdown and needle puncture). The use of rigid catheters, intramuscular injections and non-essential handling of the patient should be avoided during treatment with ACTILYSE.
Should serious bleeding occur, in particular cerebral haemorrhage, the fibrinolytic therapy must be discontinued and concomitant heparin administration should be terminated immediately. Administration of protamine should be considered if heparin has been administered within 4 hours before 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 should also be considered.
A dose exceeding 100 mg of ACTILYSE should not be given in acute myocardial infarction as well as pulmonary embolism and 90 mg in acute ischaemic stroke because it has been associated with an increase in intracranial bleeding.
As with all thrombolytics, the use of ACTILYSE therapy has to be carefully evaluated in order to balance the potential risks of bleeding with expected benefits under the following conditions: Recent intramuscular injection or small recent traumas, such as biopsies, puncture of major vessels, cardiac massage for resuscitation; Conditions with an increased risk of haemorrhage, which are not mentioned under contraindications.
Patients receiving oral anticoagulants treatment: The use of ACTILYSE may be considered when appropriate test(s) of anticoagulant activity for the product(s) concerned show no clinically relevant activity.
For the treatment of acute myocardial infarction the following special warnings and precautions apply in addition: Systolic blood pressure > 160 mmHg, see also Contraindications; Advanced age, which may increase the risk of intracerebral haemorrhage. As the therapeutic benefit is also positive in elderly patients, the risk-benefit-evaluation should be carried out carefully.
Arrhythmias: Coronary thrombolysis may result in arrhythmia associated with reperfusion.
Reperfusion arrhythmias may lead to cardiac arrest, can be life threatening and may require the use of conventional antiarrhythmic therapies.
Glyco-Protein IIb/IIIa antagonists: The concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.
Thrombo-embolism: The use of thrombolytics can increase the risk of thrombo-embolic events in patients with left heart thrombus, e.g., mitral stenosis or atrial fibrillation.
For the treatment of acute pulmonary embolism the following special warnings and precautions apply in addition: Systolic blood pressure > 160 mmHg, see also Contraindications; Advanced age, which may increase the risk of intracerebral haemorrhage. As the therapeutic benefit is also positive in elderly patients, the risk-benefit-evaluation should be carried out carefully.
For the treatment of acute ischaemic stroke the following special warnings and precautions apply in addition: Treatment must be performed under the responsibility of a physician trained and experienced in neurological care. For the verification of treatment indication remote diagnostic measures may be considered as appropriate (see Thrombolytic treatment of acute ischaemic stroke under Indications).
Bleeding: Intracerebral haemorrhages represents the major adverse event (up to approximately 15% of patients). However, this had not shown an increased overall morbidity or mortality.
Compared to other indications patients with acute ischaemic stroke treated with ACTILYSE have a significantly increased risk of intracranial haemorrhage as the bleeding occurs predominantly into the infarcted area.
This applies in particular in the following cases: all situations listed in Contraindications and in general all situations involving a high risk of haemorrhage; late time-to-treatment onset; patients pre-treated with acetyl salicylic acid (ASA) may have a greater risk of intracerebral haemorrhage, particularly if ACTILYSE treatment is delayed; compared to younger patients, patients of advanced age (over 80 years) may have a somewhat poorer outcome independent of treatment and may have an increased risk of intracerebral haemorrhage when thrombolysed. In general, the benefit-risk of thrombolysis in patients of advanced age remains positive. Thrombolysis in AIS patients should be evaluated on individual benefit-risk basis.
Treatment must not be initiated later than 4.5 hours after the onset of symptoms because of unfavourable benefit/risk ratio mainly based on the following: positive treatment effects decrease over time; particularly in patients with prior ASA treatment the mortality rate increases; increased risk of symptomatic haemorrhage.
Blood pressure monitoring: Blood pressure (BP) monitoring during treatment administration and up to 24 hours is necessary; intravenous antihypertensive therapy is recommended if systolic BP > 180 mmHg or diastolic BP > 105 mmHg.
Special patient groups at reduced benefit-risk: The therapeutic benefit is reduced in patients who have had a prior stroke (see also Contraindications) or in whom uncontrolled diabetes exists. The benefit/risk ratio is considered less favourable, although still positive in these patients.
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 a favourable outcome decreases with longer time to treatment from onset of symptoms, increasing age, increasing stroke severity and increased levels of blood glucose on admission while the likelihood of severe disability and death or symptomatic intracranial bleeding increases, independently of treatment.
Cerebral oedema: Reperfusion of the ischaemic area may induce cerebral oedema in the infarcted zone.
Paediatric population: As yet, there is only limited experience with the use of ACTILYSE in children.
In children ≥ 16 years of age the benefit should be weighed carefully against the risks on an individual basis.
Children ≥ 16 years of age should be treated according to the treatment guidance for the adult population after confirmation of thromboembolic arterial ischaemic stroke (ruling out "stroke mimics").
Effects on ability to drive and use machines: Not applicable.