Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use

Traceability
In order to improve the traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded in the patient file.

Thrombolytic/ fibrinolytic treatment requires adequate monitoring. Actilyse should only be used under the responsibility and follow-up of 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 is 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), or any of the excipients . 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 section 4.5). 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.

Haemorrhages
The most common complication encountered during Actilyse therapy is bleeding. The concomitant use of other active substances affecting coagulation or platelet function may contribute to bleeding. As fibrin is Actilyse                                                                  Updated Prescribing Information  20 mg, 50 mg                                                                                     Feb 2023 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.
If a potentially dangerous haemorrhage occurs, in particular cerebral haemorrhage, the fibrinolytic therapy must be discontinued and concomitant heparin administration should be terminated immediately.. 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.

The risk of intracranial haemorrhage is increased in elderly patients, therefore in these patients the risk/benefit evaluation should be carried out carefully.
As with all thrombolytic agents, the expected therapeutic benefit should be weighed up particularly carefully against the possible risk, especially in patients with
 small recent traumas, such as biopsies, puncture of major vessels, intramuscular injections, cardiac massage for resuscitation
 conditions with an increased risk of haemorrhage which are not mentioned in section 4.3.

Patients receiving oral anticoagulant treatment:
The use of Actilyse may be considered when dosing or time since the last intake of anticoagulant treatment makes residual efficacy unlikely confirmed by appropriate test(s) of anticoagulant activity for the product(s) concerned showing no clinically relevant activity on the coagulation system (e.g. INR≤ 1.3 for vitamin K antagonists or other relevant test(s) for other oral anticoagulants are within the respective upper limit of normal).

Paediatric population As yet, there is only limited experience with the use of Actilyse in children and adolescents. When Actilyse is considered for the treatment of acute ischaemic stroke in carefully selected adolescents ≥ 16 years of age the benefit should be weighed carefully against the risks on an individual basis and discussed with the patient and parent/guardian as appropriate. Adolescents ≥ 16 years of age should be treated according to the instruction in the label for the adult population after imaging by appropriate techniques to rule out stroke mimics and confirming arterial occlusion corresponding to the neurological deficit (see section 5.1).

Additional special warnings and precautions in acute myocardial infarction and acute massive pulmonary embolism:
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.

The expected therapeutic benefit should be weighed up particularly carefully against the possible risk, especially in patients with systolic blood pressure > 160 mm Hg (see section 4.3) and with 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.
Actilyse                                                                Updated Prescribing Information  20 mg, 50 mg                                                                                   Feb 2023
GPIIb/IIIa antagonists:
Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.
Additional special warnings and precautions in acute myocardial infarction 
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.

Thromboembolism:
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.
Additional special warnings and precautions in acute ischaemic stroke: Special precautions for use:
Treatment must only be performed under the responsibility and follow-up of a physician trained and experienced in neurovascular care. For the verification of treatment indication remote diagnostic measures may be considered as appropriate (see section 4.1).

Special warnings / conditions with a decreased benefit/risk ratio:
Intracerebral haemorrhage represents the major adverse reaction in the treatment of acute ischaemic stroke (up to 15 % of patients without any increase of overall mortality and without any relevant increase in overall mortality and severe disability combined, i.e. modified Rankin scale [mRS] score of 5 and 6).

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:
 all situations listed in section 4.3. and in general all situations involving a high risk of haemorrhage
 as time to treatment from onset of stroke symptoms increases, net clinical benefit decreases.Therefore, the administration of Actilyse should not be delayed.
   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. They are also more likely to have more severe strokes which are associated with a higher absolute risk of intracerebral haemorrhage when thrombolysed compared with milder strokes when thrombolysed or with non-thrombolysed patients. Although available data indicate that the net benefit of Actilyse in patients over 80 years is smaller compared with younger patients, Actilyse can be used in patients over 80 years on an individual benefit-risk basis (see section 5.1). Patients of advanced age should be selected very carefully taking into account both the general health and the neurological status.
 The therapeutic benefit is reduced in patients that had a prior stroke (see also section 4.3) 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 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 bleedings increases, independently from treatment.
Actilyse                                                                Updated Prescribing Information     20 mg, 50 mg                                                                                   Feb 2023
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 seems justified; an intravenous antihypertensive therapy is also recommended if systolic BP > 180 mmHg or diastolic BP > 105 mmHg.

Other special warnings
Reperfusion of the ischaemic area may induce cerebral oedema 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.

Effects on Driving

4.7 Effects on ability to drive and use machines

Not relevant.
Actilyse                                                                   Updated Prescribing Information  20 mg, 50 mg                                                                                      Feb 2023