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  • Actilyse
    / Boehringer Ingelheim


    Active Ingredient
    Alteplase 20 mg/vial, 50 mg/Vial

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Vial

    1 X 20 mg

    not in the basket chart 47792 9710

    Vial

    1 X 50 mg

    not in the basket chart 47794 9711

    Dosage

    Actilyse should be given as early as possible after symptom onset. The following dose guidelines apply.
    Acute myocardial infarction
    a) 90 minutes (accelerated) dose regimen for patients with acute myocardial infarction, in whom treatment can be started within 6 hours after symptom onset.
    b) 3 h dose regimen for patients with acute myocardial infarction, in whom treatment can be started between 6 and 12 hours after symptom onset.
    For dosing tables please see the attached doctor’s leaflet.
    Adjunctive therapy: Antithrombotic adjunctive therapy is recommended according to the current international guidelines for the management of patients with ST-elevation myocardial infarction;
    Method of administration: The reconstituted solution should be administered intravenously and is for immediate use.
    Acute Massive pulmonary embolism
    In patients with a body weight ≥65 kg:
    A total dose of 100 mg of alteplase should be administered in 2 hours. Most experience is available with the following dose regimen: For dosing tables please see the attached doctor’s leaflet.
    Adjunctive therapy: After treatment with Actilyse heparin therapy should be initiated (or resumed) when aPTT values are less than twice the upper limit of normal. The infusion should be adjusted to maintain aPTT between 50-70 seconds (1.5 to 2.5 fold of the reference value).
    Method of administration: The reconstituted solution should be administered intravenously and is for immediate use.

    Acute ischaemic stroke
    Treatment must only be performed under the responsibility and follow-up of a physician trained and experienced in neurovascular care.
    Treatment with Actilyse must be started as early as possible within 4.5 hours of the onset of symptoms . Beyond 4.5 hours after onset of stroke symptoms there is a negative benefit risk ratio associated with Actilyse administration and so it should not be administered.
    The recommended total dose is 0.9 mg alteplase/kg body weight (maximum of 90 mg) starting with 10% of the total dose as an initial intravenous bolus, immediately followed by the remainder of the total dose infused intravenously over 60 minute.
    For dosing table for acute ischaemic stroke please see the attached doctor’s leaflet.
    Adjunctive therapy: The safety and efficacy of this regimen with concomitant administration of heparin and acetylsalicylic acid within the first 24 hours of onset of the symptoms have not been sufficiently investigated.
    Administration of acetylsalicylic acid or intravenous heparin should be avoided in the first 24 hours after treatment with Actilyse due to an increased haemorrhagic risk. If heparin is required for other indications (e.g. prevention of deep vein thrombosis) the dose should not exceed 10,000 IU per day, administered subcutaneously.
    Method of administration: The reconstituted solution should be administered intravenously and is for immediate use.
    Paediatric population: There is limited experience with the use of Actilyse in children and adolescents. Actilyse is contraindicated for the treatment of acute ischaemic stroke in children and adolescents under 16 years of age. The dose for adolescents 16-17 years old is the same as for adults.
    See prescribing information for full details.


    Indications

    Acute Myocardial Infarction: In adults for the lysis of thrombi obstructing coronary arteries, the reduction of infarct size, the improvement of ventricular function, the reduction of the incidence of congestive heart failure and the reduction of mortality associated with AMI. Treatment should be initiated as soon as possible after the onset of AMI symptoms.
    Acute Massive Pulmonary embolism with hemodynamic deprivation: Alteplase is indicated in the management of acute massive pulmonary embolism (PE) in adults: For the lysis of acute pulmonary emboli, defined as obstruction of blood flow to a lobe or multiple segments of the lung, For the lysis of pulmonary emboli accompanied by unstable hemodynamics e.g. failure to maintain blood pressure without supportive measures. The diagnosis should be confirmed by objective means, such as pulmonary angiography or noninvasive procedures such as lung scanning.
    For fibrinolytic treatment of acute ischaemic stroke: Treatment must be started as early as possible within 4.5 hours after onset of stroke symptoms and after exclusion of intracranial haemorrhage by appropriate imaging techniques (e.g. cranial computerised tomography or other diagnostic imaging method sensitive for the presence of haemorrhage). The treatment effect is time-dependent; therefore earlier treatment increases the probability of a favourable outcome. This treatment is restricted to a prescription by a specialist in neurology.


    Contra-Indications

    Generally in all indications this drug 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.
    Contraindications in acute myocardial infarction, acute massive pulmonary embolism and acute ischaemic stroke:
    Alteplase is contraindicated in cases where there is a high risk of haemorrhage such as: Significant bleeding disorder at present or within the past 6 months. Known haemorrhagic diathesis. Patients receiving effective oral anticoagulant treatment, e.g. warfarin sodium (INR>1.3). Manifest or recent severe or dangerous bleeding. Known history of or suspected intracranial haemorrhage. Suspected subarachnoid haemorrhage or condition after subarachnoid haemorrhage from aneurysm. Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery). Recent (less than 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a non-compressible blood-vessel (e.g. subclavian or jugular vein puncture). Severe uncontrolled arterial hypertension. Bacterial endocarditis, pericarditis. Acute pancreatitis. Documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial-aneurysm, arterial/venous malformations. Neoplasm with increased bleeding risk. Severe liver disease, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis. Major surgery or significant trauma in past 3 months.
    Additional contraindications in acute massive pulmonary embolism: Any known history of Haemorrhagic stroke or stroke of unknown origin. Known history of ischaemic stroke or transient ischaemic attack (TIA) in the preceding 6 months, except current acute ischaemic stroke within 4.5 hours.
    Additional contraindications in acute myocardial infarction: Any known history of haemorrhagic stroke or stroke of unknown origin.  Known history of ischaemic stroke or transient ischaemic attack (TIA) in the preceding 6 months, except current acute ischaemic stroke within 4.5 hours. Known history of ischaemic stroke or transient ischaemic attack (TIA) in the preceding 6 months, except current acute ischaemic stroke within 4.5 hours.
    Additional contraindications in acute ischaemic stroke: Symptoms of ischaemic attack beginning more than 4.5 hours prior to infusion start or symptoms for which the onset time is unknown and could potentially be more than 4.5 hours ago. Minor neurological deficit or symptoms rapidly improving before start of infusionSevere stroke as assessed clinically (e.g. Nihss>25) and/or by appropriate imaging techniques.  Seizure at onset of stroke. Evidence of intracranial haemorrhage (ich) on the ct-scan. Symptoms suggestive of subarachnoid haemorrhage, even if ct-scan is normal. Administration of heparin within the previous 48 hours and a thromboplastin time exceeding the upper limit of normal for laboratory. Patients with any history of prior stroke and concomitant diabetes. Prior stroke within the last 3 months.
    Platelet count of below 100,000/mm3. Systolic blood pressure > 185 mm Hg, or diastolic bp > 110 mm hg, or aggressive management (intravenous pharmacotherapy) necessary to reduce bp to these limits, Blood glucose < 50 mg/dl or > 400 mg/dl (<2.8mM or >22.2mM).
    Use in children and adolescents: Actilyse is not indicated for the treatment of acute ischaemic stroke in children under 16 years of age.


    Special Precautions

    Traceability: 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.
    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), 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. 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 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 nonessential 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 at the attached doctor’s leaflet.
    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 prescribing information for full details.


    Side Effects

    The most frequent adverse reaction associated with Actilyse is bleeding in different forms resulting in a fall in haematocrit and/or haemoglobin values.
    See prescribing information for full details.  


    Drug interactions

    No formal interaction studies with Actilyse and medicinal products commonly administered in patients with acute myocardial infarction have been performed.
    Drugs affecting coagulation/platelet function: 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).
    ACE inhibitors: Concomitant treatment with ACE inhibitors may enhance the risk of suffering a hypersensitivity reaction.
    Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.


    Pregnancy and Lactation

    Pregnancy: There is limited amount of data from the use of alteplase in pregnant women.
    Lactation: It is not known if alteplase is excreted into human milk.
    See prescribing information for full details.


    Overdose

    Symptoms: If the maximum recommended dose is exceeded the risk of intracranial bleeding increases.
    The relative fibrin specificity notwithstanding, a clinical significant reduction in fibrinogen and other blood coagulation components may occur after overdosage.
    Therapy: In most cases, it is sufficient to await the physiological regeneration of these factors after the Actilyse therapy has been terminated. If, however, severe bleeding results, the infusion of fresh frozen plasma is recommended and if necessary, synthetic antifibrinolytics may be administered.


    Important notes

    Storage: Store in the original package in order to protect from light. Do not store above 25°C.


    Manufacturer
    Boehringer Ingelheim GmbH
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