- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Thrombolytic treatment in acute myocardial infarction- 90 minutes (accelerated) dose regimen (see section 4.2): for patients in whom treatment can be started within 6 h after symptom onset- 3 h dose regimen (see section 4.2): for patients in whom treatment can be started between 6 - 12 h after symptom onset provided that the diagnosis has been clearly confirmed.Actilyse has proven to reduce 30-day-mortality in patients with acute myocardial infarction.
Thrombolytic treatment in acute massive pulmonary embolism with haemodynamic instabilityThe diagnosis should be confirmed whenever possible by objective means such as pulmonary angiography or non-invasive procedures such as lung scanning. There is no evidence for positive effects on mortality and late morbidity related to pulmonary embolism.
Fibrinolytic treatment of acute ischaemic strokeTreatment 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.
|Actilyse vial||10 mg||20 mg||50 mg|
|Volume of water for injections to be added to dry powder:|
|Final concentration (a) 1 mg alteplase/ml (ml)||10||20||50|
|(b) 2 mg alteplase/ml (ml)||5||10||25|
Myocardial infarctiona) 90 minutes (accelerated) dose regimen for patients with myocardial infarction, in whom treatment can be started within 6 hours after symptom onset:
|Concentration of alteplase|
|1 mg/ml||2 mg/ml|
|15 mg as an intravenous bolus||15||7.5|
|50 mg as an infusion over 30 minutes||50||25|
|followed by an infusion of 35 mg over 60 minutes until the maximal dose of 100 mg||35||17.5|
|Concentration of alteplase|
|1 mg/ml||2 mg/ml|
|15 mg as an intravenous bolus||15||7.5|
|ml/kg bw||ml/kg bw|
|and 0.75 mg/kg body weight (bw) over 30 minutes (maximum 50 mg)||0.75||0.375|
|followed by an infusion of 0.5 mg/kg body weight (bw) over 60 minutes (maximum 35 mg)||0.5||0.25|
|Concentration of alteplase|
|1 mg/ml||2 mg/ml|
|10 mg as an intravenous bolus||10||5|
|50 mg as an infusion over the first hour||50||25|
|ml/30 min||ml/ 30 min|
|followed by infusions of 10 mg over 30 minutes until the maximal dose of 100 mg over 3 hours||10||5|
Pulmonary embolismA total dose of 100 mg of alteplase should be administered in 2 hours. Most experience is available with the following dose regimen:
|Concentration of alteplase|
|1 mg/ml||2 mg/ml|
|10 mg as an intravenous bolus over 1 - 2 minutes||10||5|
|followed by an intravenous infusion of 90 mg over 2 hours||90||45|
Acute ischaemic strokeTreatment must only be performed under the responsibility and follow-up of a physician trained and experienced in neurovascular care, see sections 4.3 and 4.4. The recommended dose is 0.9 mg alteplase/kg body weight (maximum of 90 mg) infused intravenously over 60 minutes with 10% of the total dose administered as an initial intravenous bolus.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 (see section 5.1). 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. 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.
Additional contraindications in acute myocardial infarction, acute pulmonary embolism and acute ischaemic stroke:Actilyse 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 (see section 4.4)• 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 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 3 hours.
Additional contraindications in acute 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 3 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 (see section 5.1) • minor neurological deficit or symptoms rapidly improving before start of infusion• severe 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 or diastolic BP > 110 mm Hg, or aggressive management (intravenous pharmacotherapy) necessary to reduce BP to these limits• blood glucose < 50 or > 400 mg/dl.
Use in children and, adolescentsActilyse is not indicated for the treatment of acute stroke in paediatric patients under 18 years.
Use in elderly patientsActilyse is not indicated for the treatment of acute stroke in adults over 80 years of age.
Special warnings and precautions in acute myocardial infarction, acute pulmonary embolism and acute ischaemic stroke: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.
HypersensitivityNo sustained antibody formation to the recombinant human tissue-type plasminogen activator molecule has been observed after treatment. There is no systemic experience with re-administration of Actilyse. Anaphylactoid reactions associated with the administration of Actilyse are rare and can be caused by hypersensitivity to the active substance alteplase, gentamicin (a trace residue from the manufacturing process) or to any of the excipients. The stopper of the glass vial with Actilyse power contains natural rubber (a derivative of latex) which may cause allergic reactions. If an anaphylactoid reaction occurs, the infusion should be discontinued and appropriate treatment initiated.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• 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.The use of rigid catheters should be avoided.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).
Additional special warnings and precautions in acute myocardial infarction: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.GPIIb/IIIa antagonists:Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.
Additional special warnings and precautions in acute pulmonary embolism:same as for acute myocardial infarction (see above)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.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:• all situations listed in section 4.3. and in general all situations involving a high risk of haemorrhage• small asymptomatic aneurysms of the cerebral vessels• with later time-to-treatment from onset of stroke symptoms the net clinical benefit is reduced and may be associated with a higher risk of ICH and death compared to patients treated earlier. 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..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.Other special warnings: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.
HaemorrhageThe 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|
Immune system disorders
|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|
Nervous system disorders
|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|
Cardiac disordersAs 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|
|uncommon:||embolism (thrombotic embolisation), which may lead to corresponding consequences in the organs concerned|
|very common:||blood pressure decreased|
|common:||body temperature increased|
Injury and poisoning and procedural complications
|rare:||fat embolism (cholesterol crystal embolisation), which may lead to corresponding consequences in the organs concerned|
Myocardial infarctionA placebo controlled trial with 100 mg alteplase over 3 hours (LATE) showed a reduction of 30-day-mortality compared to placebo for patients treated within 6-12 hours after symptom onset. In cases, in which clear signs of myocardial infarction are present, treatment initiated up to 24 hours after symptom onset may still be beneficial.
Pulmonary embolismIn patients with acute massive pulmonary embolism with haemodynamic instability thrombolytic treatment with Actilyse leads to a fast reduction of the thrombus size and a reduction of pulmonary artery pressure. Mortality data are not available.
Acute strokeIn two USA studies (NINDS A/B) a significant higher proportion of patients, had a favourable outcome with alteplase, compared to placebo (no or minimal disability). These findings were confirmed in the ECASS III trial (see paragraph below), after in the meantime two European studies and an additional USA study had failed to provide the respective evidence in settings essentially not compliant with the current EU product information.The ECASS III trial was a placebo-controlled, double-blind trial conducted in patients with acute stroke in a time-window of 3 to 4.5 hours in Europe. Treatment administration in the ECASS III study was in line with the European SmPC for Actilyse in its stroke indication, except the upper end of the time of treatment window i.e. 4.5 hours. The primary end point was disability at 90 days, dichotomized for favourable (modified Rankin scale [mRS] 0 to 1) or unfavourable (mRS 2 to 6) outcome. A total of 821 patients (418 alteplase/403 placebo) were randomized. More patients achieved favourable outcome with alteplase (52.4%) vs. placebo (45.2%; odds ratio [OR] 1.34; 95% CI 1.02 - 1.76; P=0.038). The incidence of symptomatic intracranial haemorrhage was higher with alteplase vs. placebo (27.0% vs 17.6%, p=0.0012; Mortality was low and not significantly different between alteplase (7.7%) and placebo (8.4%; P=0.681). Subgroup results of ECASS III confirm that a longer OTT is associated with an increasing risk for mortality and symptomatic intracranial haemorrhage. The results of ECASS III show a positive net-clinical benefit for ACTILYSE® in the 3 to 4.5 hour time window, while pooled data demonstrate that the net-clinical benefit is no longer favourable for alteplase in the time window beyond 4.5 hours. The safety and efficacy of ACTILYSE® for acute ischaemic stroke treatment up to 4.5 hours time stroke onset time to start of treatment (OTT) has been assessed by an ongoing registry (SITS-ISTR: The Safe Implementation of Thrombolysis in Stroke registry). In this observational study safety outcome data of 21.566 treated patients in the 0 to 3 hour time window were compared with data from 2.376 patients treated between 3 to 4.5 hours after onset of AIS. The incidence of symptomatic intracranial haemorrhage (according to the SITS-MOST definition) was found to be higher in the 3 to 4.5 hour time window (2.2%) as compared with the up to 3 hour time window (1.7%). Mortality rates at 3 months were similar comparing the 3 to 4.5 hour time window (12.0%) with the 0 to 3.0 hours time window (12.3%) with an unadjusted OR 0.97 (95% CI: 0.84-1.13, p=0.70) and an adjusted OR 1.26 (95% CI: 1.07-1.49, p=0.005. The SITS observational data support clinical trial evidence of stroke onset time to start of treatment (OTT) as an important predictor of outcome following acute stroke treatment with alteplase.
Powder for solution:ArgininePhosphoric acid, dilutePolysorbate 80
Solvent:Water for injectionsThe pH of the reconstituted solution is 7.3 ± 0.5.
Powder for solution:10 ml, 20 ml or 50 ml sterilised glass vials, sealed with sterile siliconised grey butyl-type stoppers with aluminium/plastic flip-off caps.
Solvent:The water for injections is filled into either 10 ml, 20 ml or 50 ml vials, depending on the size of the powder vials. The water for injections vials are sealed with rubber stoppers and aluminium/plastic flip-off caps.Transfer cannulas (included with pack sizes of 20 mg and 50 mg only)
Pack sizes:10 mg:1 vial with 467 mg powder for solution for injection and infusion1 vial with 10 ml of water for injections20 mg:1 vial with 933 mg powder for solution for injection and infusion1 vial with 20 ml of water for injections1 transfer cannula50 mg:1 vial with 2333 mg powder for solution for injection and infusion1 vial with 50 ml of water for injections1 transfer cannulaNot all pack sizes may be marketed.
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