Actilyse

Alteplase (recombinant human tissue-type plasminogen activator).

Each pack contains 1 injection vial containing recombinant human tissue-type plasminogen activator 50 mg, 1 vial of solvent containing sterile water for injection 50 mL and 1 IV kit.
The reconstituted solution contains alteplase 1 mg/mL.
Each vial also contains L-arginine, phosphoric acid and polysorbate 80 as excipients.

Pharmacotherapeutic Group: Fibrinolytic.
Pharmacology: The active ingredient of Actilyse is alteplase, a recombinant human tissue-type plasminogen activator. It is a glycoprotein that activates plasminogen directly to plasmin. When administered IV, alteplase remains relatively inactive in the circulatory system. Once bound to fibrin, it is activated, inducing the conversion of plasminogen to plasmin leading to the dissolution of the fibrin clot.
Acute Myocardial Infarction (AMI) Patients: Two (2) Actilyse dose regimens have been studied in patients experiencing acute myocardial infarction. The comparative efficacy of these 2 regimens has not been evaluated.
Accelerated Infusion in AMI Patients: Accelerated infusion of Actilyse was studied in an international, multi-center trial (GUSTO) that randomized 41,021 patients with acute myocardial infarction to 4 thrombolytic regimens. Administration of Actilyse 100 mg over 90 min, with concomitant IV heparin infusion, led to a lower mortality after 30 days (6.3%) as compared to the administration of streptokinase, 1.5 million IU over 60 min, with SC or IV heparin (7.3%). The 1% absolute decrease in 30-day mortality for Actilyse compared to streptokinase was statistically significant (p=0.007).
Actilyse treated patients showed higher infarct related vessel patency rates at 60 and 90 min after thrombolysis than the streptokinase-treated patients. No differences in patency rates were noted at ≥180 min.
A large scale mortality trial (ASSENT 2) in approximately 17,000 patients showed that alteplase and tenecteplase are therapeutically equivalent in reducing mortality (6.2% for both treatments, at 30 days). The use of tenecteplase was associated with a significantly lower incidence of non-intracranial bleedings compared to alteplase (26.4% vs 28.9%, p=0.0003). The reduction of the risk of bleeding is likely to be related to the increased fibrin specificity of tenecteplase and to its weight adapted regimen.
Three-Hour Infusion in AMI Patients: In a double-blind, randomized trial (5013 patients) comparing Actilyse to placebo (ASSET study) patients infused with Actilyse within 5 hrs of the onset of symptoms of acute myocardial infarction experienced improved 30-day survival compared to those treated with placebo. At 1 month, the overall mortality rates were 7.2% for the Actilyse treated group and 9.8% for the placebo-treated group (p=0.001). This benefit was maintained at 6 months for Actilyse treated patients (10.4%) compared to those treated with placebo (13.1%, p=0.008).
In a double-blind, randomized trial (721 patients) comparing Actilyse to placebo, patients infused with Actilyse within 5 hrs of the onset of symptoms experienced improved ventricular function 10-22 days after treatment compared to the placebo group, when global ejection fraction was measured by contrast ventriculography (50.7% versus 48.5%, p=0.01). Patients treated with Actilyse had a 19% reduction in infarct size, as measured by cumulative release of HBD (α-hydroxybutyrate dehydrogenase) activity compared to placebo-treated patients (p=0.001). Patients treated with Actilyse had significantly fewer episodes of cardiogenic shock (p=0.02), ventricular fibrillation (p<0.04) and pericarditis (p=0.01) compared to patients treated with placebo. Mortality at 21 days in Actilyse treated patients was reduced to 3.7% compared to 6.3% in placebo-treated patients (1-sided, p=0.05). Although these data do not demonstrate unequivocally a significant reduction in mortality for this study, they do indicate a trend that is supported by the results of the ASSET study.
In a placebo controlled trial (LATE) in 5711 AMI patients with onset of symptoms between 6 and 24 hrs a 100-mg Actilyse over 3 hrs infusion was compared with placebo. A nonsignificant reduction of 14.1% (95% CI: 0-28.1%, p>0.05) in 30-day-mortality was observed with Actilyse. In a pre-specified survival analysis in patients treated within 12 hrs of symptom onset, a significant 25.6% reduction in mortality in favour of Actilyse (95% CI: 6.3-45%; p=0.023) was observed.
Pulmonary Embolism Patients: In a comparative randomized trial of alteplase versus urokinase in 63 patients with angiographically documented acute massive pulmonary embolism both treatment groups experienced a significant reduction in pulmonary embolism-induced pulmonary hypertension. Pulmonary haemodynamics improved significantly faster with Actilyse than with urokinase.
Acute Ischaemic Stroke Patients: Several studies have been carried out in the field of acute ischaemic stroke. The NINDS study is the only study without an upper age limit ie, which also included patients >80 years. All other randomized trials have excluded patients >80 years. Therefore, treatment decisions in this patient group require particular care on an individual patient basis.
Two (2) placebo-controlled, double-blind trials (NINDS t-PA Stroke Trial, Part 1 and Part 2) enrolled patients with measurable neurological deficit who could complete screening and begin study treatment within 3 hrs from symptom onset. A cranial computerized tomography (CT) scan was performed prior to treatment to rule out the presence of symptomatic intracranial haemorrhage (SICH). Patients were also excluded for the presence of conditions related to risks of bleeding, for minor neurological deficit, for rapidly improving symptoms prior to initiating study treatment, or for blood glucose of <50 mg/dL or >400 mg/dL. Patients were randomized to receive either Actilyse 0.9 mg/kg maximum of 90 mg, or placebo. Actilyse was administered as a 10% initial bolus >1 min followed by continuous IV infusion of the remainder over 60 min.
The initial study (NINDS-Part 1, n=291) evaluated neurological improvement at 24 hrs after stroke onset. The primary endpoint, the proportion of patients with a ≥4 point improvement in the National Institutes of Health Stroke Scale (NIHSS) score or complete recovery (NIHSS score=0), was not significantly different between treatment groups. A secondary analysis suggested improved 3-months outcome associated with Actilyse treatment using the following stroke assessment scales: Barthel Index, Modified Rankin Scale (mRS), Glasgow Outcome Scale, and the NIHSS. A second study (NINDS-Part 2, n=333) assessed clinical outcome at 3 months as the primary outcome. A favourable outcome was defined as minimal or no disability using the 4-stroke assessment scales: Barthel Index (score >95), Modified Rankin Scale (score <1), Glasgow Outcome Scale (score=1), and NIHSS (score <1). The odds ratio for favourable outcome in the Actilyse group was 1.7 (95% CI: 1.2-2.6). Compared to placebo there was 13% absolute increase in the number of patients with minimal or no disability (mRS 0-1) (OR 1.7; 95% CI: 1.1-2.6). There was also a consistent benefit seen with Actilyse on other neurologic and disability scales. Secondary analyses demonstrated consistent functional and neurological improvement within all four stroke scales as indicated by median scores. These results were highly consistent with the 3-months outcome treatment effects observed in the Part 1 study. The incidences of all-cause 90-day mortality, SICH, and new ischemic stroke following Actilyse treatment compared to placebo indicated a significant increase in symptomatic SICH (according to NINDS definition) following Actilyse treatment within 36 hrs (Actilyse 6.4%; Placebo 0.65%). In Actilyse treated patients, there were no increases compared to placebo in the incidences of 90-day mortality or severe disability (Actilyse 20.5%; Placebo 17.3%).
A pooled analysis of 2775 patients from 6 major randomized clinical trials (NINDS part 1 and 2, two ECASS trial and ATLANTIS part A and B), 104 evaluated the disability status of patients treated with Actilyse or placebo. In this analysis, the odds of a favourable outcome at 3 months increased as the time to treatment with Actilyse decreased. A SICH rate was seen in 5.9% of patients treated with Actilyse [(versus 1.1% of controls (p<0.0001)] which was associated with age but not with time to treatment. This analysis strongly confirms that rapid treatment with Actilyse is associated with better outcomes at 3 months. It also provides evidence that the therapeutic window may extend as far out as 4.5 hrs.
In a large observational study (SITS-MOST: The Safe Implementation of Thrombolysis in Stroke-Monitoring Study) the safety and efficacy of Actilyse for acute stroke treatment within 3 hrs in a routine clinical setting was assessed and compared with results from randomized clinical trials (RCTs). All patients had to be compliant with the European summary of the product characteristics of Actilyse treatment and outcome data of 6483 patients from 285 centres in 14 European countries were collected. Primary outcome were symptomatic intracranial haemorrhage within 24 hrs and mortality at 3 months. The rate of SICH found in SITS-MOST was comparable with the SICH rate as reported in randomized trials 7.3% (95% CI: 6.7-8) in SITS-MOST versus 8.6% (95% CI: 6.1-11.1) in RCTs. Mortality was 11.3% (95% CI: 10.5-12.1) in SITS-MOST vs 17% (95% CI: 13.9-20.7) in RCTs. The results of SITS-MOST indicate that, the routine clinical use of Actilyse within 3 hrs of stroke onset is as safe as reported in randomized clinical trials.
The ECASS III trial as a placebo-controlled, double-blind trial conducted in patients with acute stroke in a time-window of 3-4.5 hrs. The study enrolled patients with measurable neurological deficit compliant with the European summary of product characteristics (SPC) except the time-window. After exclusion of brain haemorrhage or major infarction by computed tomography, patients with acute ischemic stroke were randomized in a 1:1 double-blind fashion to intravenous alteplase (0.9 mg/kg bodyweight) or placebo. The primary end point was disability at 90 days, dichotomized for favourable [modified Rankin scale (mRS 0-1) or unfavourable (mRS 2-6)] outcome. The principal secondary end point was a global outcome analysis of 4 neurologic and disability scores combined. Safety endpoints included mortality, SICH and serious adverse events. A total of 821 patients were (418 alteplase/403 placebo) 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]. On the global analysis, outcome was also improved (OR, 1.28; 95% CI: 1-1.65; p=0.048). The incidence of SICH was higher with alteplase vs placebo (any SICH 27% vs 17.6%, p=0.0012; SICH by NINDS definition 7.9% vs 3.5%, p=0.006). Mortality was low and not significantly different between alteplase (7.7%) and placebo (8.4%; p=0.681). The results of ECASS III show that Actilyse between 3 and 4.5 hrs after symptom onset significantly improves clinical outcomes in patients with acute ischemic stroke.
The safety and efficacy of Actilyse for acute ischaemic stroke treatment up to 4.5 hrs time onset to treatment (OTT) has been assessed by an ongoing AIS registry (SITS-ISTR: The Safe Implementation of Thrombolysis in Stroke Registry). Primary outcome and mortality data of 15,294 patients in the 0-3 hrs time window were compared with data from 947 patients treated between 3-4.5 hrs after onset of AIS. At 3 months, the incidence of symptomatic intracerebral haemorrhage (according to the NINDS definition) was found to be slightly higher in the 3-4.5 hrs time window (9.13%; 95% CI: 7.38-11.24) as compared with the up to 3 hrs time window (7.49% CI: 7.07-7.93). Mortality rates were similar comparing the 3-4.5 hrs time window (12.4%) with the 0-3 hrs time window 12.3%.

Thrombolytic treatment in acute myocardial infarction: 90-min (accelerated) dose regimen (see Dosage & Administration): For patients in whom treatment can be started within 6 hrs of symptom onset; 3-hr dose regimen (see Dosage & Administration): For patients in whom treatment can be started between 6-12 hrs after symptom onset. Actilyse has proven to reduce 30-day-mortality in patients with acute myocardial infarction.
Thrombolytic treatment in acute massive pulmonary embolism with haemodynamic instability: The diagnosis should be confirmed whenever possible by objective means eg, pulmonary angiography or noninvasive procedures eg, lung scanning. There are no clinical trials on mortality and late morbidity related to pulmonary embolism.
Thrombolytic 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.

Actilyse should be given as soon as possible after symptom onset.
Myocardial Infarction: 90-minutes (accelerated) dose regimen in whom treatment can be started within 6 hours after symptom onset: 15 mg as an intravenous bolus, 50 mg as an infusion over the first 30 minutes, followed by an infusion of 35 mg over 60 minutes, until the maximal dose of 100 mg. In patients with a body weight below 65 kg, the total dose should be weight-adjusted with 15 mg as an intravenous bolus and 0.75 mg/kg body weight over 30 minutes (maximum of 50 mg), followed by an infusion of 0.5 mg/kg over 60 minutes (maximum of 35 mg).
3-hour dose regimen in whom treatment can be started between 6 and 12 hours after symptom onset: 10 mg as an intravenous bolus, 50 mg as an intravenous infusion over the first hour, followed by infusions of 10 mg over 30 minutes, until the maximal dose of 100 mg over 3 hours, in patients with a body weight below 65 kg the total dose should not exceed 1.5 mg/kg.
The accepted maximum dose in acute myocardial infarction is 100 mg alteplase.
Adjunctive Therapy: Antithrombotic adjunctive therapy is recommended according to the current international guidelines for the management of patients with ST-elevation myocardial infarction.
Pulmonary Embolism: A total dose of 100 mg should be administered in 2 hours. The most experience available is with the following dose regimen: 10 mg as an intravenous bolus over 1 - 2 minutes, 90 mg as an intravenous infusion over two hours, The total dose should not exceed 1.5 mg/kg in patients with a body weight below 65 kg
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).
Acute Ischaemic Stroke: The recommended dose is 0.9 mg/kg (maximum of 90 mg) infused over 60 minutes with 10% of the total dose administered as an initial intravenous bolus. Treatment should be initiated as early as possible within 4.5 hours of symptom onset. The treatment effect is time-dependent; therefore earlier treatment increases the probability of a favourable outcome.
Adjunctive Therapy: The safety and efficacy of this regimen with concomitant administration of heparin and acetylsalicylic acid during the first 24 hrs after the symptom onset has not been investigated sufficiently. Therefore, administration of acetylsalicylic acid or IV heparin should be avoided in the first 24 hrs after treatment with Actilyse. If heparin is required for other indications (eg, prevention of deep vein thrombosis) the dose should not exceed 10,000 IU/day administered SC.
Administration: Instructions for Use/Handling: Under aseptic conditions, the contents of an injection vial of Actilyse (50 mg) dry substance is dissolved with sterilised water for injection to obtain a final concentration of 1 mg alteplase per mL.
The 1 mg/mL reconstituted solution may be diluted further with sterile sodium chloride 9 mg/mL (0.9%) solution for injection up to a minimal concentration of 0.2 mg/mL.
A further dilution of the 1 mg/mL reconstituted solution with sterilised water for injections or in general, the use of carbohydrate infusion solutions, e.g. dextrose is not recommended. Actilyse must not be mixed with other drugs, neither in the same infusion-vial nor via the same venous line (not even with heparin).

The relative fibrin specificity not withstanding a clinically significant reduction in fibrinogen and other blood coagulation components may occur after overdosage. 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 or fresh blood is recommended and if necessary, synthetic antifibrinolytics may be administered.

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.
As with all thrombolytic agents, Actilyse should not be used in cases where there is a high risk of haemorrhage eg, significant bleeding disorder at present or within the past 6 months, known haemorrhagic diathesis; patients receiving oral anticoagulants eg, warfarin sodium (INR >1.3); any history of central nervous system damage (ie, neoplasm, aneurysm, intracranial or spinal surgery); history, evidence or suspicion of intracranial haemorrhage including sub-arachnoid haemorrhage; severe uncontrolled arterial hypertension; major surgery or significant trauma in the past 3 months (this includes any trauma associated with the current acute myocardial infarction), recent trauma of the head or cranium; prolonged or traumatic cardiopulmonary resuscitation (>2 min), obstetrical delivery within the past 10 days, recent puncture of a noncompressible blood vessel (eg, subclavian or jugular vein puncture); severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis; haemorrhagic retinopathy eg, in diabetes (vision disturbances may indicate haemorrhagic retinopathy) or other haemorrhagic ophthalmic conditions; bacterial endocarditis and pericarditis; acute pancreatitis; documented ulcerative gastrointestinal disease during the last 3 months; arterial aneurysms, arterial/venous malformations; neoplasm with increased bleeding risk.
The following contraindications apply where Actilyse is indicated: Acute Myocardial Infarction and Pulmonary Embolism: Haemorrhagic stroke or stroke of unknown origin at any time, ischaemic stroke or transient ischaemic attack (TIA) in the preceding 6 months, except current acute ischaemic stroke within 4.5 hours.
Acute Ischaemic Stroke: Symptoms of ischaemic attack which began >4.5 hrs prior to infusion or when the onset of symptom is unknown; symptoms of acute ischaemic stroke which were either rapidly improving or only minor prior to start of infusion; severe stroke assessed clinically (eg, NIHSS >25) and/or by appropriate imaging techniques; seizure at the onset of stroke; history of previous stroke or serious head trauma within three months; combination of previous stroke, seizure at the onset of stroke; history of previous stroke or serious head-trauma within three months; a combination of previous stroke and diabetes mellitus; administration of heparin within 48 hours preceding the onset of stroke with an elevated activated partial thromboplastin time (aPTT) at presentation; platelet count of less than 100,000 / mm3; systolic blood pressure > 185 or diastolic blood pressure > 110 mmHg, or aggressive management (IV medication) necessary to reduce blood pressure to these limits; blood glucose < 50 or > 400 mg/dL.
Actilyse is not indicated for the therapy of acute stroke in children and adolescents under 18 years. For use in patients above 80 years of age, see Precautions.

Actilyse should be used by physicians experienced in the use of thrombolytic treatment and with facilities to monitor the use. As with other thrombolytics, it is recommended that when Actilyse is administered, standard resuscitation equipment and medication be available in all circumstances.
General: Bleeding: The most common complication encountered during Actilyse therapy is bleeding. The concomitant use of heparin anticoagulant 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 cut down and needle puncture). The use of rigid catheters, IM 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 hrs 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 re-assessment after each administration. A target fibrinogen level of 1 g/L is desirable with cryoprecipitate infusion. Antifibrinolytic agents should also be considered.
A dose >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 and acute pulmonary embolism the following special warnings and precautions apply in addition: Systolic blood pressure > 160 mmHg; advanced age, which may increase the risk of intracerebral haemorrhage. As the therapeutic benefit is also increased in elderly patients, the risk-benefit-evaluation should be carried out carefully. For the treatment of acute myocardial infarction the following special warnings and precautions apply in addition: Arrhythmias: Coronary thrombolysis may result in arrhythmia associated with reperfusion. Referfusion arrhythmias may lead to cardiac arrest, can be life threatening and may require the use of the conventional antiarrhytmic therapies. Glyco-ProteinIIb/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 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). 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 Contraindications and in general all situations involving a high risk of haemorrhage; small asymptomatic aneurysms of the cerebral vessels; 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. Not more than 0.9 mg alteplase/kg bodyweight (max. of 90 mg) should be administered in view of the increased risk of cerebral haemorrhage; patients over 80 years of age may have an increased risk of intracerebral haemorrhage and a reduced net benefit from treatment compared to younger patients. Therefore, the use of ACTILYSE should be weighed carefully against anticipated risks on an individual patient basis. Treatment should 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 (BP) monitoring during treatment administration and up to 24 hours is necessary; i.v. antihypertensive therapy is recommended if systolic BP > 180 mmHg or diastolic BP > 105 mmHg. The therapeutic benefit is reduced in patients who have had a prior stroke or in whom uncontrolled diabetes exists. The benefit/risk ratio is considered less favourable, although still positive in these patients. In patients with very mild stroke, the risks outweigh the expected benefit and they should not be treated with ACTILYSE. Patients with very severe stroke are at higher risk of intracerebral haemorrhage and death and should not be treated with ACTILYSE. 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 increasing age, increasing stroke severity and increased levels of blood glucose on admission while the likelihood of severe disability and death or relevant intracranial bleeding increases, independently of 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. 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. As yet, there is only limited experience with the use of ACTILYSE in children.
Use in pregnancy & lactation: Pregnancy: There is 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 Pharmacology: Toxicology under Actions). In cases of an acute life-threatening disease the benefit has to be evaluated against the potential risk.
Lactation: It is not known if alteplase is excreted into human milk.
Fertility: Clinical data on fertility are not available for ACTILYSE. Nonclinical studies performed with alteplase showed no adverse effect on fertility (see Pharmacology: Toxicology under Actions).
Use in children: ACTILYSE is not indicated for the therapy of acute stroke in children and adolescents under 18 years.
Use in the elderly: For use in patients above 80 years of age, see previously mentioned.

Indications myocardial infarction, acute pulmonary embolism and acute ischaemic stroke: The most frequent adverse reaction associated with ACTILYSE is bleeding (> 1:100, ≤ 1:10: major bleeds; > 1:10: any haemorrhage) resulting in a fall in haematocrit and/or haemoglobin values. Haemorrhage at any site or body cavity can occur and may result in life-threatening situations, permanent disability or death. The type of bleeds associated with thrombolytic therapy can be divided into two broad categories: superficial bleeding, normally from punctures or damaged blood vessels; internal bleeding at any site or body cavity.
With intracranial haemorrhagic neurological symptoms such as somnolence, aphasia, hemiparesis, convulsion may be associated. The classification of fat embolism, which was not observed in the clinical trial population, was based on spontaneous reporting. The number of patients treated in clinical trials in the indications pulmonary embolism and stroke (within the 0 - 4.5 hours time window) is very small in comparison to the number in the trial for myocardial infarction described above. Therefore, small numerical differences observed in comparison with the number in myocardial infarction were presumably attributable to the small sample size. Except for intracranial haemorrhage as side effect in the indication stroke as well as for reperfusion arrhythmias in the indication myocardial infarction there is no medical reason to assume that the qualitative and quantitative side effect profile of ACTILYSE in the indications pulmonary embolism and acute ischaemic stroke is different from the profile in the indication myocardial infarction.
Immune system disorders: anaphylactoid reactions, which are usually mild, but can be life threatening in isolated cases. They may appear as: rash, urticarial, bronchospasm, angioedema, hypotension, shock or any other symptom associated with hypersensitivity.
If they occur, conventional anti-allergic therapy should be initiated. In such cases a relatively larger proportion of patients were receiving concomitant Angiotensin Converting Enzymes inhibitors. No definite anaphylactic (IgE mediated) reactions to ACTILYSE are known. Transient antibody formation to ACTILYSE has been observed in rare cases and with low titres, but a clinical relevance of this finding could not be established.
Eye disorders: eye haemorrhage.
Cardiac disorders: pericardial haemorrhage.
Vascular disorders: haemorrhage, such as haematoma; embolism which may lead to corresponding consequences in the organs concerned; bleeding of parenchymatous organs, such as: hepatic haemorrhage; pulmonary haemorrhage.
Respiratory, thoracic and mediastinal disorders: respiratory tract haemorrhage, such as: pharyngeal haemorrhage; haemoptysis; epistaxis.
Gastrointestinal disorders: gastrointestinal haemorrhage, such as: gastric haemorrhage; gastric ulcer haemorrhage; rectal haemorrhage; haematemesis; melaena; mouth haemorrhage; nausea; vomiting. Nausea and vomiting can also occur as symptoms of myocardial infarction: retroperitoneal haemorrhage, such as: retroperitoneal haematoma; gingival bleeding.
Skin and subcutaneous tissue disorders: ecchymosis.
Renal and urinary disorders: urogenital haemorrhage, such as: haematuria; haemorrhage urinary tract.
General disorders and administration site conditions: injection site haemorrhage, puncture site haemorrhage, such as: catheter site haematoma; catheter site haemorrhage.
Investigations: blood pressure decreased; body temperature increased. Injury and poisoning and procedural complications: fat embolism, which may lead to corresponding consequences in the organs concerned.
Surgical and medical procedures: transfusion.

No formal interaction studies with Actilyse and medicinal products commonly administered in patients with acute myocardial infarction have been performed.
Medicinal products that affect coagulation or those that alter platelet function may increase the risk of bleeding prior to, during or after Actilyse therapy.
Concomitant treatment with ACE inhibitors may enhance the risk of suffering an anaphylactoid reaction, as in the cases describing such reactions a relatively larger proportion of patients were receiving ACE inhibitors concomitantly.

Store below 30°C.
Chemical and physical in-use stability: The reconstituted solution has been demonstrated to be stable for 24 hours at 2-8°C and for 8 hours at 30°C.
Microbiological in-use stability: From a microbiological point of view, the product should be used immediately after reconstitution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 - 8°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AD02 - alteplase ; Belongs to the class of enzymes. Used in the treatment of thrombosis.

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