ACTILYSE 20 mg pdre/solv p sol inj
SYNTHESIS
Hemostasis - Hematopoiesis - Hemoglobinopathies - Antithrombotics : Thrombolytics ( Alteplase )
ATC classification:
BLOOD AND HEMATOPOIETIC ORGANS : ANTITHROMBOTICS - ANTITHROMBOTICS : ENZYMES ( ALTEPLASE )
Substance
alteplase
Excipients:
arginine , phosphoric acid , polysorbate 80
solvent excipient: water for injection
Excipients with known effect :
EEN without threshold dose: natural rubber
Presentation
ACTILYSE 20 mg Pdre/solv p sol inj Fl pdre+Fl solv/20ml
Cip: 3400955852933
Storage conditions: Before opening: < 25° for 36 months (Store away from light, Store in its packaging)
List 1
Approved for Communities
SHAPES AND PRESENTATIONS
Powder (white to pale yellow freeze-dried cake) and solvent for solution for IV injection and infusion:
10 mg vial of powder + 10 ml vial of solvent, unit box.
20 mg vial of powder + 20 ml vial of solvent + transfer cannula, unit box.
50 mg vial of powder + 50 ml vial of solvent + transfer cannula, unit box.
The reconstituted preparation is a clear, colorless to pale yellow solution.
COMPOSITION
Powder: per vial
Alteplase * (INN)
10 mg (5.8 MIU)
Where 20 mg (11.6 MIU)
Where 50 mg (29 MIU)
Excipients: arginine, phosphoric acid (for pH adjustment), polysorbate 80.
Solvent: water for injections.
* Alteplase is produced by recombinant DNA technology in a Chinese hamster ovary cell line.
The specific activity of the internal reference substance is 580,000 IU/mg, this value being confirmed by comparison with the second WHO international standard for tPA. The specification for the specific activity of alteplase is 522,000 to 696,000 IU/mg.
DC
DIRECTIONS
Thrombolytic treatment in the acute phase of myocardial infarction:
Therapeutic regimen known as “accelerated” (90 minutes) ( see Dosage and Method of administration ): intended for patients in whom treatment can be started within 6 hours of the onset of symptoms.
Therapeutic regimen known as "3 hours" ( see Dosage and Method of administration ): intended for patients in whom treatment can be started between 6 and 12 hours after the onset of symptoms, provided that the indication is obvious.
Alteplase reduces the 30-day mortality rate after myocardial infarction.
Thrombolytic treatment after massive pulmonary embolism in the acute phase with haemodynamic instability:
The diagnosis should be confirmed, as far as possible, by objective methods (angiography, scanner).
There is no proof of a benefit in terms of morbidity and mortality in this indication.
Fibrinolytic treatment of ischemic stroke in the acute phase:
Treatment should be initiated as soon as possible within 4.5 hours of the onset of stroke symptoms and after excluding intracranial hemorrhage by appropriate imaging techniques (e.g., CT scan or other diagnostic method). sensitive imaging for the diagnosis of hemorrhage). The treatment effect is time-dependent; therefore, the earlier treatment is given, the greater the likelihood of a favorable clinical outcome.
DC
DOSAGE AND METHOD OF ADMINISTRATION
Login to access this content
DC
CONTRAINDICATIONS
Login to access this content
DC
WARNINGS AND PRECAUTIONS FOR USE
Traceability: In order to improve the traceability of biological medicinal products, the name and batch number of the product administered must be clearly recorded.
The appropriate presentation of Actilyse should be chosen carefully and in accordance with the intended use. The 2 mg vial of alteplase is not suitable for use in the acute phase of myocardial infarction, acute massive pulmonary embolism or ischemic stroke (due to a risk of significant under-dosing). Only 10 mg, 20 mg and 50 mg vials are indicated for these uses.
Any thrombolytic/fibrinolytic treatment requires appropriate management. Actilyse should only be used under the responsibility and supervision of physicians who are trained and experienced in the use of thrombolytic agents and who have adequate means of monitoring. It is recommended that Actilyse be administered in facilities that have resuscitation equipment and treatment available at all times.
Hypersensitivity:
Immune-mediated hypersensitivity reactions associated with the administration of Actilyse may be induced by the active substance alteplase or one of the excipients.
No lasting formation of antibodies against recombinant human tissue plasminogen activator molecule was observed after treatment. There are no data relating to re-administration of Actilyse.
There is also a risk of hypersensitivity reactions, mediated by a non-immunological mechanism.
The most frequently reported hypersensitivity reaction with Actilyse is angioedema. The risk may be increased in the case of ischemic stroke in the acute phase and/or by taking concomitant treatment with angiotensin-converting enzyme inhibitors ( see Interactions ). The risk of angioedema should be monitored in patients treated for any authorized indication, during the infusion and within 24 hours after the infusion.
If a severe hypersensitivity reaction (eg angioedema) occurs, the infusion should be discontinued and appropriate treatment instituted immediately. This may include intubation.
Hemorrhages:
The most common complication encountered during treatment with Actilyse is bleeding. Concomitant use of heparin may contribute to bleeding. During treatment with Actilyse, fibrin is lysed, which may cause bleeding at recent puncture sites. Thus, any thrombolytic treatment requires special attention to all potential bleeding sites (including those following the insertion of a catheter, arterial or venous puncture sites, incision sites and needle stick sites). The use of rigid catheters, intramuscular injections and non-essential procedures should be avoided during treatment with Actilyse.
Fibrinolytic therapy and concomitant heparin therapy should be discontinued immediately if potentially dangerous haemorrhage, particularly cerebral haemorrhage, occurs. In general, however, it is not necessary to administer coagulation factors due to the short half-life of alteplase and its weak effects on these systemic coagulation factors. In most cases, bleeding can be controlled by discontinuation of thrombolytic and anticoagulant therapy, administration of fluid replacement therapy, or manual pressure on the injured vessel. Consideration may be given to using protamine if heparin is administered within 4 hours before the onset of haemorrhage. In the rare patients who do not respond to these conservative measures, the appropriate use of transfusion products can be considered. Transfusion of cryoprecipitate, fresh frozen plasma or platelets may be considered by monitoring clinical and biological parameters after each administration. The fibrinogen level to be achieved in the event of cryoprecipitate infusion is 1 g/l. Antifibrinolytics are the last therapeutic alternative. The fibrinogen level to be achieved in the event of cryoprecipitate infusion is 1 g/l. Antifibrinolytics are the last therapeutic alternative. The fibrinogen level to be achieved in the event of cryoprecipitate infusion is 1 g/l. Antifibrinolytics are the last therapeutic alternative.
The risk of intracranial hemorrhage is increased in the elderly; therefore, the benefit/risk ratio should be carefully assessed in this type of patient.
As with all thrombolytic agents, the use of alteplase should carefully consider the possible risks and the expected therapeutic benefit, particularly in the following cases:
Recent minor trauma, such as biopsies, puncture of large vessels, intramuscular injections, cardiac massage during resuscitation.
Pathology likely to increase a hemorrhagic risk and not listed in the Contraindications section .
In case of concomitant treatment with oral anticoagulants:
The use of Actilyse may be considered when the dose or the time since the last dose of anticoagulant treatment makes a residual effect unlikely and this is confirmed by an appropriate test(s) of anticoagulant activity. for the product(s) concerned not showing clinically significant activity on the coagulation system (for example INR ≤ 1.3 for vitamin K antagonists, or if the other( s) appropriate test(s) for other oral anticoagulants do not exceed the upper limit of normal).
Pediatric population:
There is little experience with the use of Actilyse in children and adolescents.
When Actilyse is considered for the treatment of acute ischemic stroke in carefully selected adolescents aged 16 years or older, the benefit of treatment should be carefully weighed against the risks on an individual basis. This choice should be discussed with the patient and the parents or guardian if applicable. Adolescents 16 years of age or older should be treated as instructed in this monograph given for adult patients, after appropriate imaging technique to exclude conditions mimicking stroke and confirming arterial occlusion, corresponding neurological deficit ( see Pharmacodynamics ).
Additional special warnings and special precautions for use in the indications of myocardial infarction in the acute phase and massive pulmonary embolism in the acute phase:
Do not administer a dose of alteplase greater than 100 mg, due to the increased risk of intracranial haemorrhage.
Special care should be taken to ensure that the dose of alteplase administered is as described in the Dosage and Method of Administration section .
The use of alteplase must carefully take into account the possible risks and the expected therapeutic benefit, in particular in patients whose systolic blood pressure is greater than 160 mm Hg ( see Contraindications ) and in people with a advanced age as this may increase the risk of intracerebral hemorrhage. As the therapeutic benefit is still positive for elderly patients, an assessment of the benefit/risk ratio must be carried out carefully.
GPIIb/IIIa receptor antagonists: Concomitant administration of a GPIIb/IIIa receptor antagonist increases the risk of bleeding.
Special warnings and special precautions for use in acute myocardial infarction:
Arrhythmias:
Coronary thrombolysis can lead to reperfusion arrhythmia.
Reperfusion arrhythmia can cause cardiac arrest, be life-threatening and require the use of conventional antiarrhythmic therapies.
Thromboembolism:
The use of thrombolytics may increase the risk of thromboembolic events in patients with left heart thrombus, such as mitral valve stenosis or atrial fibrillation.
Additional special warnings and special precautions for use in case of ischemic stroke in the acute phase:
Special precautions for use:
The initiation and monitoring of treatment must be carried out under the responsibility of a doctor trained and experienced in neurovascular pathology. For verification of treatment choice, remote diagnostic measures (telemedicine) may be considered appropriate ( see Indications ).
Special warnings/Populations with a reduced benefit/risk ratio:
Intracerebral hemorrhage represents the major adverse effect of the treatment of ischemic stroke in the acute phase (up to 15% of patients without an increase in overall mortality and without a significant increase in the combined endpoint overall mortality + major handicap, i.e. presenting a score on the modified Rankin scale (mRS) of 5 and 6).
Compared to other indications, patients treated with Actilyse in the context of acute ischemic stroke show a marked increase in the risk of intracranial haemorrhage, with haemorrhage occurring preferentially in the area of the infarction.
This warning applies in particular to the following cases:
Any situation mentioned in the Contraindications paragraph and, more generally, any situation involving a significant risk of bleeding.
As the time to treatment after onset of stroke symptoms increases, the net clinical benefit decreases. Therefore the administration of Actilyse should not be delayed.
Patients who have previously received treatment with acetylsalicylic acid (ASA) may be at increased risk of intracerebral haemorrhage, particularly if treatment with Actilyse is started late.
Compared to younger patients, patients with advanced age (over 80 years of age) may have poorer clinical outcomes regardless of treatment. They are also likely to have more severe stroke associated with a higher absolute risk of intracerebral hemorrhage when treated with thrombolysis compared to moderate stroke treated with thrombolysis or compared to patients not treated with thrombolysis. thrombolysis. Although the available data show that the net benefit of Actilyse in patients over 80 years of age is lower than in younger patients. Actilyse can be used in patients over 80 years of age on the basis of individual benefit and risk ( see Pharmacodynamics). Patients of advanced age should be selected carefully taking into account both general health and neurological status.
The therapeutic benefit is diminished in patients with a history of stroke (see also Contraindications section ) or with uncontrolled diabetes. In these patients, the benefit-risk ratio is considered less favourable, but remains positive.
In patients with a very mild form of stroke, the risks associated with the treatment outweigh the expected benefit ( see Contraindications ).
Patients who have had a very severe stroke present a greater risk of intracranial haemorrhage and death and should not be treated with Actilyse.
Patients with extensive infarctions have an increased risk of adverse outcome (including severe bleeding and death). The benefit/risk ratio should be carefully assessed in these patients.
In patients presenting with a cerebrovascular accident, the probability of favorable evolution decreases with the increase in the time of treatment since the appearance of the symptoms, with the age, with the degree of severity of the attack and with the high rates blood glucose on admission, while the risk of severe disability, death or intracranial hemorrhage increases, regardless of treatment.
Treatment should not be initiated later than 4.5 hours after the onset of symptoms, the benefit/risk balance becoming unfavorable due to:
a decrease in the positive effect of the treatment over time;
an increased mortality rate, particularly in patients previously treated with acetylsalicylic acid;
an increased risk of symptomatic bleeding.
Blood pressure monitoring:
Blood pressure monitoring should be instituted when treatment is administered and should be maintained for 24 hours. If systolic blood pressure is greater than 180 mm Hg or diastolic blood pressure is greater than 105 mm Hg, intravenous antihypertensive therapy is recommended.
Other special warnings:
Reperfusion of the area of ischemia can lead to cerebral edema in the area of infarction. Due to an increased haemorrhagic risk, no antiplatelet treatment should be initiated within the first 24 hours following thrombolytic treatment with alteplase.
DC
INTERACTIONS
Login to access this content
DC
FERTILITY / PREGNANCY / BREASTFEEDING
Pregnancy :
Data on the administration of Actilyse to pregnant women are limited. Nonclinical studies performed with alteplase at doses higher than those used in humans have revealed fetal immaturity and/or embryotoxicity secondary to the known pharmacological activity of the product. Alteplase is not considered teratogenic ( see Preclinical Safety ). In the event of a life-threatening threat, the expected benefits and the possible risks must be taken into account.
Feeding with milk :
It is unknown whether alteplase is excreted in human milk.
Fertility:
There are no clinical fertility data available for Actilyse. Non-clinical studies carried out with alteplase did not show any adverse effect on fertility ( see Preclinical safety ).
Symptoms :
If the maximum recommended dose is exceeded, the risk of intracranial hemorrhage increases.
Despite the relative specificity of alteplase for fibrin, overdosage may lead to clinically significant decreases in fibrinogen and other coagulation factors.
Treatment :
In most cases, it suffices to wait for the physiological regeneration of these elements after the end of treatment with Actilyse.
However, if severe bleeding occurs, the transfusion of fresh frozen plasma is recommended, as well as, if necessary, the administration of synthetic antifibrinolytics.
Subchronic toxicity tests in rats and monkeys did not reveal any unexpected effects.
Mutagenesis tests did not show any mutagenic potential.
No teratogenic effect was observed after intravenous infusion of pharmacologically active doses in pregnant females. Administration of more than 3 mg/kg/day induced embryotoxicity (embryonic death, growth retardation) in rabbits. No effects on peri and postnatal development and on fertility parameters were observed at doses up to 10 mg/kg/day in rats.
DP
INCOMPATIBILITIES
The reconstituted solution can be diluted in sterile 0.9% sodium chloride solution to a minimum concentration of 0.2 mg alteplase per ml.
In case of further dilution, the use of water for injections or in general the use of glucose solutions for infusion, eg dextrose, is not recommended due to increased formation of turbidity in the reconstituted solution.
Actilyse must not be mixed with other medicinal products (including heparin), either in the same infusion bottle or in the same catheter.
DP
STORAGE CONDITIONS
Unopened vials:
The duration of the conversation :
3 years.
Store in the original packaging, protected from light.
Store at a temperature not exceeding +25°C.
Reconstituted solution:
Stability of the reconstituted solution has been demonstrated for 24 hours at 2°C to 8°C and for 8 hours at 25°C.
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°C to 8°C.
DP
HANDLING/DISPOSAL PROCEDURES
In order to obtain a final concentration of 1 mg of alteplase per ml, the total volume of solvent supplied must be added to the vial containing the Actilyse powder. A transfer cannula is provided for this purpose with the 20 and 50 mg presentations. For the 10 mg vial, a syringe should be used.
In order to obtain a final concentration of 2 mg alteplase per ml, only half of the solvent volume supplied should be used (see table below). In this case, a syringe should always be used to introduce the required volume of solvent into the vial containing the Actilyse lyophilisate.
Under strict aseptic conditions, dissolve alteplase (10, 20 or 50 mg) in a volume of water for injections in accordance with the following table, in order to obtain a final concentration of 1 mg of alteplase/ml , i.e. 2 mg of alteplase/ml:
Actilyse powder quantity 10mg 20mg 50mg
(a) Volume of sterile water for injections to be added to the powder 10mL 20mL 50mL
Final concentration: 1 mg alteplase/ml 1 mg alteplase/ml 1 mg alteplase/ml
(b) Volume of sterile water for injections to be added to the powder 5mL 10mL 25mL
Final concentration: 2 mg alteplase/ml 2 mg alteplase/ml 2 mg alteplase/ml
The reconstituted solution should then be administered intravenously. The reconstituted 1 mg/ml solution may be further diluted with sterile sodium chloride 9 mg/ml (0.9%) solution for injection to a minimum concentration of 0.2 mg/ml as it cannot be excluded the appearance of turbidity in the reconstituted solution. Further dilution of the reconstituted 1 mg/ml solution with water for injections or a sugar solution (e.g. dextrose) is not recommended due to increased turbidity formation in the reconstituted solution. . Actilyse must not be mixed with other medicinal products (including heparin) in the same infusion bottle.
For incompatibilities, see Incompatibilities .
The reconstituted solution is for single use only. Any unused solution or waste should be disposed of in accordance with applicable regulations.
Instructions for reconstitution of Actilyse:
Reconstitute immediately before administration.
Remove the protective cap from the two vials containing the water for injections and the Actilyse powder, by lifting the caps off with your thumb.
Wipe the rubber top of each vial with an alcohol swab.
Remove the transfer cannula * from its case. Do not disinfect or sterilize the transfer cannula, it is sterile. Remove one of its caps.
* (if a transfer cannula is included in the box. Reconstitution can also be done with a syringe and a needle.)
Hold the vial containing the water for injections upright and on a stable surface. On the top of the vial, pierce the rubber stopper with the transfer cannula, vertically and well in the center of the stopper, pressing gently but firmly, without turning.
Hold the vial containing the water for injections and the transfer cannula firmly with one hand, using the two flaps on either side of the cannula.
Remove the remaining cap on top of the transfer cannula.
Hold the vial containing the water for injections and the transfer cannula firmly with one hand, using the two flaps on either side of the cannula.
Take the vial of Actilyse containing the powder and hold it above the transfer cannula, positioning the pointed end of the transfer cannula well in the center of the stopper.
Push the vial containing the powder vertically onto the transfer cannula, gently but firmly and without turning, until the rubber stopper is perforated.
Turn both vials upside down so that the water for injections can completely fill the vial with the powder.
Remove the empty vial that contained the water for injections together with the transfer cannula.
They can be thrown away.
Take the bottle containing the reconstituted solution of Actilyse and shake gently until any powder remains dissolved, but do not stir, this will produce foam.
If any bubbles remain, allow the solution to stand for a few minutes and wait for the bubbles to disappear.
The solution represents 1 mg/ml of Actilyse. It must be clear and colorless or even pale yellow and must not contain particles.
Withdraw the amount needed using a needle and syringe.
Do not use the same puncture hole as the transfer cannula to avoid leakage.
Use immediately.
Do not store unused solution.
PRESCRIPTION/ISSUE/CARE
LIST I
Medicinal product reserved for hospital use and for use in emergency situations according to article R.5121-96 of the Public Health Code.
MA 3400955718420 (1991, SPC rev 11.08.2022) 10 mg.
3400955852933 (1987, SPC rev 11.08.2022) 20 mg.
3400955853015 (1987, SPC rev 11.08.2022) 50 mg.
Collect.