Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Boehringer Ingelheim Limited, Ellesfield Avenue, Bracknell, Berkshire RG12 8YS
Generally, in all indications Actilyse should not be administered to patients with known hypersensitivity to the active substance alteplase, gentamicin (a trace residue from the manufacturing process) or to any of the excipients listed in section 6.1.
Contraindications in acute myocardial infarction, acute massive pulmonary embolism and acute ischaemic stroke:
Actilyse is contraindicated in cases where there is a high risk of haemorrhage such as:
Additional contraindications in acute myocardial infarction:
Additional contraindications in acute massive pulmonary embolism:
Additional contraindications in acute ischaemic stroke:
Actilyse is not indicated for the treatment of acute ischaemic stroke in children under 16 years of age (for adolescents ≥16 years of age see section 4.4).
In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded in the patient file.
The appropriate presentation of alteplase product should be chosen carefully and in accordance with the intended use. The 2 mg presentation of alteplase is not indicated for use in acute myocardial infarction, acute massive pulmonary embolism or acute ischaemic stroke (due to risk of massive under dosing). Only 10 mg, 20 mg or 50 mg presentations are indicated for use in these indications.
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.
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, or the stopper of the glass vial with Actilyse powder 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 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.
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.
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
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).
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).
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.
Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.
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.
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.
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).
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:
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:
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.
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.
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 a hypersensitivity reaction (see section 4.4).
Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.
There is a limited amount of data from the use of Actilyse in pregnant women. Nonclinical studies performed with alteplase in doses higher than human doses exhibited fetal immaturity and/or embryotoxicity, secondary to the known pharmacological activity of the drug. Alteplase is not considered to be teratogenic (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 human milk.
Clinical data on fertility are not available for Actilyse. Nonclinical studies performed with alteplase showed no adverse effect on fertility (see section 5.3).
Not relevant.
The most frequent adverse reaction associated with Actilyse is bleeding in different forms resulting in a fall in haematocrit and/or haemoglobin values.
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 intracerebral/intracranial haemorrhage as adverse reaction in the indication stroke as well as for reperfusion arrhythmias in the indication acute myocardial infarction, there is no medical reason to assume that the qualitative and quantitative adverse reaction profile of Actilyse in the indications acute massive pulmonary embolism and acute ischaemic stroke is different from the profile in the indication acute myocardial infarction.
Table 1. Adverse reactions in acute myocardial infarction, acute massive pulmonary embolism and acute ischaemic stroke:
very common: intracerebral haemorrhage represents the major adverse reaction in the treatment of acute ischaemic stroke, all haemorrhages including those in this table, e.g. ICH and non-ICH
common: intracerebral 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 massive pulmonary embolism, pharyngeal haemorrhage, gastrointestinal haemorrhage (such as gastric haemorrhage, gastric ulcer haemorrhage, rectal haemorrhage, haematemesis, melaena, mouth haemorrhage, gingival bleeding), ecchymosis, urogenital haemorrhage (such as haematuria, haemorrhage urinary tract), injection site haemorrhage (puncture site haemorrhage, catheter site haematoma, catheter site haemorrhage)
uncommon: pulmonary haemorrhage (such as haemoptysis, hemothorax, respiratory tract haemorrhage), epistaxis, ear haemorrhage
rare: eye haemorrhage, pericardial haemorrhage, retroperitoneal bleeding (such as retroperitoneal haematoma)
not known***: bleeding in parenchymatous organs (such as hepatic haemorrhage)
rare: hypersensitivity reactions (e.g. rash, urticaria, bronchospasm, angio-oedema, hypotension, shock)*
very rare: serious anaphylaxis
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
very common: recurrent ischaemia/angina pectoris, hypotension and heart failure/pulmonary oedema
common: cardiogenic shock, cardiac arrest and reinfarction
uncommon: reperfusion arrhythmias (such as arrhythmia, extrasystoles, AV block first degree to atrioventricular block complete, atrial fibrillation/flutter, bradycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia/fibrillation, electromechanical dissociation [EMD]), mitral regurgitation, pulmonary embolism, other systemic embolism/cerebral embolism, ventricular septal defect
rare: Embolism which may lead to corresponding consequences in the organs concerned
rare: nausea
not known***: vomiting
uncommon: blood pressure decreased
not known***: body temperature increased
not known***: fat embolism (cholesterol crystal embolisation), which may lead to corresponding consequences in the organs concerned
not known***: Blood transfusions (necessary)
* See sections 4.4 and 4.5
** Cardiac disorders
As with other thrombolytic agents, the events described above under the respective section have been reported as sequelae of myocardial infarction and / or thrombolytic administration. These cardiac events can be life-threatening and may lead to death.
*** Frequency calculation
This adverse reaction has been observed in post-marketing experience. With 95 % certainty, the frequency category is not greater than “rare”, but might be lower. Precise frequency estimation is not possible as the adverse drug reaction did not occur in a clinical trial database of 8299 patients.
Death and permanent disability are reported in patients who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.
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 Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
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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