ACTILYSE 20 Mg Powder and solvent for injectable solution and Boîte perfusion of 1 powder Bottle + solvent bottle (+ nozzle) of 20 ml

ACTILYSE 20 Mg Powder and solvent for injectable solution and Boîte perfusion of 1 powder Bottle + solvent bottle (+ nozzle) of 20 ml
Therapeutic class:   Hémostase and blood
Active ingredients:   Altéplase
Statute:   Drug subjected to medical regulation
Laboratory:   Boehringer Ingelheim

Indications

1. Treatment thrombolytic the acute phase of the myocardial infarction:
- Therapeutic Diagram called “accelerated” (90 minutes) (see heading posology and mode of administration) intended for the patients among whom the treatment can be begun in the 6 hours following the appearance of the symptoms.
- Therapeutic Diagram called “3 hours” (see heading posology and mode of administration): intended for the patients among whom the treatment can be begun between 6 and 12 hours after the appearance of the symptoms, provided that the indication is obvious.
The alteplase makes it possible to reduce death rate to 30 days after myocardial infarction.
2. Treatment thrombolytic after massive acute pulmonary embolism with hemodynamic instability:
The diagnosis will have to be confirmed as far as possible by objective methods (angiography, scanner).
There does not exist proof of a benefit in term of morbi-mortality in this indication.
3. Fibrinolytic treatment of the ischemic cerebral vascular accident to the acute phase:
The treatment must be founded in the 3 hours following the appearance of the symptoms of cerebral vascular accident and after having excluded the diagnosis from intracranial hemorrhage by suitable techniques from imagery.

Posology

The treatment by the altéplase will have to be founded as soon as possible after the appearance of the symptoms. The following recommendations concerning posology must be applied:
- Before the administration and under rigorous conditions of asepsis, to dissolve the altéplase (10, 20 or 50 Mg) in a volume of water for injectable preparations in accordance with the following table, in order to obtain a final concentration either of 1 Mg of altéplase/ml, or of 2 Mg of altéplase/ml:
Bottle of ACTILYSE 10 Mg/20 Mg/50 Mg.
Volume of water for injectable preparations to add to the dry powder:
Final concentration:
a) 1 Mg of altéplase/ml: 10 ml/20 ml/50 ml.
b) 2 Mg of altéplase/ml: 5 ml/10 ml/25 ml.
- The reconstituted solution must then be managed by intravenous way. It can be diluted more with a sterile injectable sodium chloride solution to 9 mg/ml (0,9%) until the minimal concentration of 0,2 mg/ml. It is not recommended to dilute the solution reconstituted by means of water for injectable preparations or of a sweetened aqueous solution (dextrose for example). ACTILYSE should not be mixed with other drugs (of which heparin) in the same bottle of perfusion or the same catheter. For other practical instructions for the preparation and handling, to see headings incompatibilities and instructions for the use, handling and elimination.
- The experiment is limited at the child and the teenager. ACTILYSE is contra-indicated for the treatment of the acute vascular accident at the child and the teenager (see heading counter-indications).
1. Myocardial infarction:
a) Posological diagram called “accelerated” (90 minutes) adapted to the patients being able to be treated in the 6 hours following the appearance of the symptoms:
Concentration of altéplase 1 mg/ml // 2 mg/ml:
. Intravenous Bolus of 15 Mg: 15 ml // 7,5 ml.
. Perfusion of 50 Mg over 30 minutes: 50 ml // 25 ml.
. Followed by a perfusion of 35 Mg over 60 minutes without exceeding the maximum amount of 100 Mg: 35 ml // 17,5 ml.
- Among patients of body weight lower than 65 kg, the amount must be adapted according to the weight according to the diagram of administration according to:
. Intravenous Bolus of 15 Mg: 15 ml // 7,5 ml.
. Perfusion of 0,75 mg/kg of body weight (pc) over 30 minutes (to the maximum 50 Mg): 0,75 ml/kg (PC) // 0,375 ml/kg (PC).
. Followed by a perfusion of 0,5 mg/kg of body weight (pc) over 60 minutes (to the maximum 35 Mg): 0,5 ml/kg (PC) // 0,25 ml/kg (PC).
b) Posological diagram called “3 hours” adapted to the patients among whom the treatment is implemented between 6th and 12th hour following the appearance of the symptoms:
Concentration of altéplase 1 mg/ml // 2 mg/ml:
. Intravenous Bolus of 10 Mg: 10 ml // 5 ml.
. Perfusion of 50 Mg over the first 60 minutes: 50 ml // 25 ml.
. Followed successive perfusions of 10 Mg over 30 minutes until a maximum amount of 100 Mg over 3 a.m.: 10 ml/30 min // 5 ml/30 min.
- Among patients of body weight lower than 65 kg, the total amount should not exceed 1,5 mg/kg.
- The total amount of altéplase should not exceed 100 Mg.
TREATMENTS ASSOCIATE:
An auxiliary treatment antithrombotic is recommended in accordance with the current international recommendations concerning the assumption of responsibility of the patients presenting a myocardial infarction with know-shift of the segment ST a treatment by the acetylsalicylic acid must be founded as soon as possible after the appearance of the symptoms and continued to the long course, except if it is contra-indicated.
2. Pulmonary embolism:
A total amount of 100 Mg of altéplase must be managed in 2 hours. The gained experience relates primarily to the following posological diagram:
Concentration of altéplase 1 mg/ml // 2 mg/ml:
- Intravenous Bolus of 10 Mg out of 1 to 2 minutes: 10 ml // 5 ml.
- Follow-up of a perfusion of 90 Mg over 2 a.m.: 90 ml // 45 ml.
For the patients weighing less than 65 kg, the total amount should not exceed 1,5 mg/kg.
TREATMENT ASSOCIATES:
After the treatment by ACTILYSE, a héparinothérapie must be founded (or begun again) if the value of the TCA is lower than twice the higher limit of the normal. The perfusion must be adjusted in order to maintain a TCA from 50 to 70 seconds (1,5 and 2,5 times the value of reference).
3. Ischemic cerebral vascular accident with the acute phase:
- The treatment must be managed by a specialist physician in neurology (see headings counter-indications and warning statements and precautions for use).
- Posology is of 0,9 Mg of altéplase/kg of body weight (maximum amount of 90 Mg) in intravenous perfusion over 60 minutes, 10% of the total amount having to be managed initially by intravenous bolus.
- The treatment by ACTILYSE must be initiated in the 3 hours following the appearance of the symptoms.
TREATMENT ASSOCIATES:
The tolerance and the effectiveness of this protocol of administration in partnership with heparin and the acetylsalicylic acid during the first 24 hours following the appearance of the symptoms were not sufficiently studied. The administration of acetylsalicylic acid or heparin per intravenous way must be avoided during the first 24 hours following the administration of ACTILYSE. If the heparin administration is made necessary for other indications (for example in prevention of major venous thrombosis), posology should not exceed 10000 UI per day, by subcutaneous way.

Against indications

CONTRA-INDICATE:
- Over-sensitiveness with the active substance or the one of the excipients.
- Like all the agents thrombolytic, ACTILYSE is contra-indicated in all the cases associated at the high hemorrhagic risk:
. current significant hemorrhagic disorder or during the last six months,
. diathèse hemorrhagic known,
- concomitant treatment by oral anticoagulants (for example warfarin),
- hemorrhage severe or potentially dangerous, manifest or recent,
- antecedents or suspicion of intracranial hemorrhage,
- suspicion of hemorrhage under-arachnoïdienne or antecedents of hemorrhage under-arachnoïdienne related to an aneurism,
- antecedents of severe lesion of the central nervous system (for example neoplasy, aneurism, intracerebral surgical operation or intrarachidienne),
- recent traumatic external cardiac massage (less than 10 days), childbirth, recent puncture of a vessel nonaccessible to compression (for example, puncture of the vein subclavian or chin-strap),
- severe arterial hypertension not controlled,
- bacterial endocarditis, péricardite,
- pancréatite acute,
- gastro-intestinal ulcers documented during the last 3 months, varixes oesophagiennes, aneurism arterial, malformations arterial or venous,
- neoplasy raising the hemorrhagic risk,
- severe hepatopathy including hepatic insufficiency, cirrhosis, hypertension portale (varixes oesophagiennes) and evolutionary hepatitis,
- important surgical operation or traumatisms during the last 3 months.
1. Counter-indication complementary in the indication of myocardial infarction to the acute phase:
- any known antecedent of hemorrhagic cerebral vascular accident or unknown origin,
- known antecedents of ischemic cerebral vascular accident or transitory ischemic accident (AIT) during the six previous months, except if the ischemic cerebral vascular accident with the acute phase occurred in the three previous hours.
2. Complementary counter-indication in the indication of acute pulmonary embolism:
- any known antecedent of hemorrhagic cerebral vascular accident or unknown origin,
- known antecedents of ischemic cerebral vascular accident or transitory ischemic accident (AIT) during the six previous months, except if the acute ischemic cerebral vascular accident occurred in the three previous hours.
3. Counter-indications complementary in the ischemic indication of cerebral vascular accident to the acute phase:
- symptoms of ischemic cerebral vascular accident appeared more than 3 hours before the initiation of the treatment or of which the hour of appearance is unknown,
- minor neurological deficit or symptoms quickly improving before initiation of the treatment,
- cerebral vascular accident considered to be severe clinically (for example NIHSS > 25) and/or by imagery,
- convulsive crisis at the beginning of the cerebral vascular accident,
- signs of intracranial hemorrhage (HIC) to the scanner,
- symptoms suggesting a hemorrhage under-arachnoïdienne, even in the absence of anomaly with the scanner,
- heparin administration during the 48 previous hours with a time of thromboplastine exceeding the higher limit of the normal,
- patient diabetic presenting of the antecedents of cerebral vascular accident,
- antecedent of cerebral vascular accident during the last 3 months,
- plates lower than 100000/mm3,
- systolic blood pressure > 185 mmHg or diastolic blood pressure > 110 mmHg, or treatment of attack (by intravenous way) necessary to reduce the blood pressure to these values thresholds,
- glycemia lower than 50 or higher than 400 mg/dl.
USE AT the CHILD, the TEENAGER AND the OLD PATIENT:
ACTILYSE is not indicated for the treatment of the cerebral vascular accident to the acute phase among patients of less than 18 years or more than 80 years.
BREAST FEEDING: the experiment of the administration of altéplase during breast feeding is very limited. It is not known if the alteplase is excreted in the mother’s milk.
DISADVISE:
- At present, the experiment of the use of ACTILYSE at the child and the teenager is limited.
- Pregnancy: the experiment of the administration of altéplase during the pregnancy is very limited. Studies carried out in the animal revealed a toxicity on the reproduction. In the event of threat of the vital prognosis, it is necessary to take into account the awaited benefit and the possible risks.

Undesirable effects

- The frequency of the undesirable effects is given by using MedDRA convention:
. Very frequent: > 1/10.
. Frequent: > 1/100 and < = 1/10.
. Not very frequent: > 1/1000 and < = 1/100.
. Rare: > 1/10000 and < = 1/1000.
. Very rare: < = 1/10000, including the isolated cases.
- Except for the cases of intracranial hemorrhages like undesirable effect for the treatment of the cerebrovascular accident and the cases of arrhythmias of reperfusion for the treatment of the myocardial infarction, no medical reason lets suppose that the qualitative and quantitative profile undesirable effects of ACTILYSE can be different within the framework from the treatment of the pulmonary embolism and the stroke or within the framework of the treatment of the myocardial infarction.
HEMORRHAGES:
The hemorrhagic disorders associated with a fall of the hématocrite and hemoglobinemy constitute the undesirable effects most frequently associated with the administration of ACTILYSE:
- Very frequent:
Bleeding on the level of damaged vessels (such as hématome), hemorrhage with the site of injection (hemorrhage to the site of puncture, hématome to the site of the catheter, hemorrhage to the site of the catheter).
- Frequent:
. Intracranial hemorrhage (such as brain hemorrhage, hématome cerebral, hemorrhagic cerebral vascular accident, hemorrhagic transformation of an cerebral vascular accident, hématome intracranial, hemorrhage under-arachnoïdienne) in the event of treatment of one cerebral vascular accident to the acute phase. The symptomatic intracerebral hemorrhage represents the principal undesirable effect in the treatment of the acute ischemic cerebral vascular accident (up to 10% of the patients without increase in mortality or total morbidity).
. Hemorrhage of the respiratory tracts (such as pharyngée hemorrhage, épistaxis, hemoptysy).
. Gastro-intestinal hemorrhage (such as gastric hemorrhage, gastric ulcerous hemorrhage, hemorrhage of the rectum, hématémèse, méléna, oral hemorrhage, bleedings of the gums).
. Bruises.
. Urogenital hemorrhage (such as hématurie, hemorrhage of the urinary tracts).
. Need for a blood transfusion.
- Not very frequent:
. Intracranial hemorrhage (such as brain hemorrhage, hématome cerebral, hemorrhagic vascular accident, hemorrhagic transformation of an vascular accident, hématome intracranial, hemorrhage under-arachnoïdienne) in the event of treatment of an acute myocardial infarction or an acute pulmonary embolism.
. Hémopéricarde.
. Hemorrhage rétropéritonéale (such as hématome rétropéritonéal).
- Rare:
Bleedings of the parenchymatous bodies (such as hepatic hemorrhage, pulmonary hemorrhage).
- Very rare:
Ocular bleedings.
- Irreversible deaths and handicaps were reported among patients having presented an cerebral vascular accident (including intracranial bleedings) or other episodes of serious bleedings.
- The fibrinolytic treatment must be stopped in the event of occurred of a potentially dangerous hemorrhage, in particular of a brain hemorrhage. In general, it is however not necessary to manage factors of coagulation because of the short half-life of the altéplase and of its weak effects on these systemic factors of coagulation. In the majority of the cases, the bleedings can be controlled by an interruption of the treatments thrombolytic and anticoagulant, by the administration of a vascular solution of filling or by a manual pressure on the injured vessel. One can plan to resort to the protamine in the event of heparin administration in the 4 hours preceding occurred by the hemorrhage. Among rare patients not answering these preserving measurements, the suitable use of products of transfusion can be considered. A transfusion of cryoprecipity, frozen fresh plasma or plates can be under consideration by supervising the clinical and biological parameters after each administration. The fibrinogen rate to be reached in the event of perfusion of cryoprecipity is of 1 g/L. The antifibrinolytiques ones constitute the last therapeutic alternative.
DISORDERS OF THE IMMUNE SYSTEM:
- Not very frequent:
Reactions of over-sensitiveness/reactions anaphylactoïdes (for example allergic reactions such as cutaneous eruption, urticaria, bronchospasme, edema of Quincke, hypotension, shock or any other symptom associated with an allergic reaction).
- Very rare:
Serious Anaphylaxie.
- In rare cases, one could observe a transitory formation of low levels of antibodies directed against ACTILYSE, but the clinical relevance of these observations was not established.
DISORDERS OF THE NERVOUS SYSTEM:
Very rare:
Events of central origin (for example epileptic fit, convulsions, aphasia, disorders of the word, delirium, neuropsychiatric disorders acute, agitation, confusion, depression, psychosis), often associated with events cérébrovasculaires of ischemic or hemorrhagic origin.
CARDIAC DISORDERS:
As with the other agents thrombolytic, the following events were reported as after-effects of a myocardial infarction or a treatment thrombolytic:
- Very frequent:
Recurring myocardic ischaemia/angor, hypotension and pulmonary impaired renal function/edema, arrhythmias of reperfusion (such as arrhythmia, extrasystole, block auriculoventriculaire of the 1st degree to the complete block, auricular fibrillation, auricular flutter, bradycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia, fibrillation, electromagnetic dissociation).
- Frequent:
Cardiac arrest, shock cardiogenic and repetition of infarction.
- Not very frequent:
Mitral Régurgitation, pulmonary embolism or another systemic embolism, cerebral emboli, anomalies of the ventricular septum.
- These cardiac disorders can threaten the vital prognosis and involve the death.
VASCULAR DISORDERS:
Not very frequent:
Embolism (thrombotic embolisation) being able to have consequences in the affected bodies.
DISORDERS GASTRO-INTESTINAUX:
Frequent:
Nauseas, vomiting.
INVESTIGATIONS:
- Very frequent:
Arterial pressure decrease.
- Frequent:
. Increase in the body temperature.
. Lesions, intoxications and complications related to the procedures.
- Rare:
Lubricating embolism (embolism by cholesterol crystals) being able to have consequences in the affected bodies.