Medicinal Products

ACTILYSIS 10 mg

Generic drug of the therapeutic class: Haemostasis and blood
active ingredients: Alteplase
laboratory: Boehringer Ingelheim

Powder and solvent for solution for injection or IV infusion
Box of 1 Bottle of powder + 10 ml solvent bottle
All forms

Indication

1 Thrombolytic therapy in the acute phase of myocardial infarction

· Therapeutic scheme called "accelerated" (90 minutes) (see section Dosage and method of administration ): intended for patients in whom the treatment can be started within 6 hours of the onset of symptoms.

· Therapy pattern called "3 hours" (see section Dosage and method of administration ): intended for patients in whom the treatment can be started between 6 and 12 hours after the onset of symptoms, provided that the indication is obvious .

Alteplase reduces the death rate to 30 days after myocardial infarction.

2 Thrombolytic treatment after massive acute pulmonary embolism with hemodynamic instability

The diagnosis should be confirmed as far as possible by objective methods (angiography, CT).

There is no evidence of a benefit in terms of morbidity and mortality in this indication.

3 Fibrinolytic treatment of ischemic stroke in the acute phase

Treatment should be initiated as early as possible within 4½ hours of the onset of symptoms of stroke and after excluding intracranial hemorrhage by appropriate imaging techniques (eg, cerebral computed tomography or other method of diagnosis). sensitive imaging for the diagnosis of haemorrhage). The effect of treatment is time-dependent; therefore, the earlier the treatment is administered, the higher the probability of a favorable clinical outcome.

Dosage ACTILYSE 10 mg Powder and solvent for solution for injection or for infusion IV Box of 1 vial of powder + vial of solvent of 10 ml

Treatment with alteplase should be initiated as soon as possible after the onset of symptoms. The following dosing recommendations should be applied:

Before administration and under strict aseptic conditions, dissolve the alteplase (10, 20 or 50 mg) in one volume of water for injections according to the following table, in order to obtain a final concentration of 1 mg of alteplase / ml, ie 2 mg of alteplase / ml:

Bottle of ACTILYSE

10 mg

20 mg

50 mg

Final concentration

Volume of water for injections to be added to the dry powder (ml)

(a) 1 mg of alteplase / ml

10

20

50

(b) 2 mg of alteplase / ml

5

10

25

The reconstituted solution should then be administered intravenously. It can be further diluted with sterile sodium chloride 9 mg / ml (0.9%) solution for injection to a minimum concentration of 0.2 mg / ml. It is not recommended to dilute the reconstituted solution with water for injections or a sweet solute (dextrose for example). ACTILYSE should not be mixed with other drugs (including heparin) in the same infusion bottle or catheter. For other practical instructions for preparation and handling, see sections Incompatibilities and Instructions for use, handling and disposal .

The experience is limited in children and adolescents. ACTILYSE is contraindicated in the treatment of acute stroke in children and adolescents (see section 4.3 ).

4.2.1 Myocardial infarction

(a) "Accelerated" (90-minute) schedule suitable for patients who can be treated within 6 hours of symptom onset:

Alteplase concentration

1 mg / ml

2 mg / ml

ml

ml

15 mg intravenous bolus

15

7.5

50 mg infusion over 30 minutes

50

25

Followed by a 35 mg infusion over 60 minutes without exceeding the maximum dose of 100 mg

35

17.5

In patients with a body weight of less than 65 kg, the dose should be adjusted according to weight according to the following schedule of administration:

Alteplase concentration

1 mg / ml

2 mg / ml

ml

ml

15 mg intravenous bolus

15

7.5

ml / kg (pc)

ml / kg (pc)

Infusion of 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

b) "3-hour" dosage schedule adapted to patients in whom treatment is performed between the 6th and 12th hours following onset of symptoms:

Alteplase concentration

1 mg / ml

2 mg / ml

ml

ml

10 mg intravenous bolus

10

5

50 mg infusion over the first 60 minutes

50

25

ml / 30 min.

ml / 30 min.

Followed by successive infusions of 10 mg over 30 minutes up to a maximum dose of 100 mg over 3 hours

10

5

In patients with body weight below 65 kg, the total dose should not exceed 1.5 mg / kg.

The total dose of alteplase should not exceed 100 mg.

Associated treatments:

Antithrombotic adjuvant therapy is recommended in accordance with current international recommendations for the management of patients with ST elevation myocardial infarction. Treatment with acetylsalicylic acid should be started as soon as possible after the onset of symptoms and continued on a long-term basis unless contraindicated.

4.2.2 Pulmonary embolism

A total dose of 100 mg of alteplase should be administered within 2 hours. The experience gained is mainly related to the following dosing regimen:

Alteplase concentration

1 mg / ml

2 mg / ml

ml

ml

10 mg intravenous bolus over 1 to 2 minutes

10

5

Followed by a 90 mg infusion over 2 hours

90

45

For patients weighing less than 65 kg, the total dose should not exceed 1.5 mg / kg.

Associated treatment :

After treatment with ACTILYSE, heparin therapy should be started (or restarted) if the TCA value is less than twice the upper limit of normal. The infusion must be adjusted to obtain a TCA of 50 to 70 seconds (1.5 to 2.5 times the reference value).

4.2.3 Ischemic stroke in the acute phase

The initiation and the follow-up of the treatment must be carried out under the responsibility of a doctor trained and experienced in neurovascular pathology (see headings Contraindications and Warnings and precautions of use ).

The recommended dose is 0.9 mg of alteplase / kg body weight (90 mg maximum dose) as a 60-minute intravenous infusion, with 10% of the total dose to be administered initially by intravenous bolus.

Treatment with ACTILYSE should be initiated as soon as possible within 4h30 of the onset of symptoms. Beyond 4h30 after the onset of symptoms, the administration of ACTILYSE is associated with an adverse benefit / risk ratio, therefore ACTILYSE should not be administered (see section 5.1 Pharmacodynamic properties ).

Associated treatment:

The safety and efficacy of this protocol in combination with heparin and acetylsalicylic acid for the first 24 hours after onset of symptoms have not been adequately studied. Administration of acetylsalicylic acid or intravenous heparin should be avoided within the first 24 hours after administration of ACTILYSE. If administration of heparin is necessary for other indications (eg prevention of deep vein thrombosis), the dosage should not exceed 10, 000 IU per day, subcutaneously.

Against indications

Hypersensitivity to the active substance or to any of the excipients.

Like all thrombolytic agents, ACTILYSE is contraindicated in all cases associated with a high risk of haemorrhage:

· Significant bleeding disorder current or within the last six months.

· Known hemorrhagic diathesis.

· Concomitant treatment with oral anticoagulants (eg warfarin).

· Severe or potentially dangerous haemorrhage, manifest or recent.

· History or suspicion of intracranial hemorrhage.

· Suspicion of subarachnoid hemorrhage or history of subarachnoid haemorrhage related to aneurysm.

· A history of severe central nervous system injury (eg, neoplasia, aneurysm, intracerebral or intraspinal surgery).

· Recent traumatic external cardiac massage (less than 10 days), delivery, recent puncture of a vessel not accessible to compression (eg, subclavian or jugular vein puncture).

· Severe uncontrolled hypertension.

· Bacterial endocarditis, pericarditis.

· Acute pancreatitis.

· Gastrointestinal ulcers documented in the past 3 months, esophageal varices, arterial aneurysm, arterial or venous malformations.

· Neoplasia increasing the risk of bleeding.

Severe hepatopathy, including hepatic failure, cirrhosis, portal hypertension (esophageal varices) and active hepatitis.

· Surgery or major trauma in the last 3 months.

1 Additional counter-indication in the indication of acute myocardial infarction

· Any known history of hemorrhagic stroke or unknown origin.

· History of ischemic stroke or transient ischemic attack (TIA) in previous six months, except if the acute ischemic stroke occurred in the previous three.

2 Additional counter-indication in the indication of acute pulmonary embolism

· Any known history of hemorrhagic stroke or unknown origin.

History of ischemic stroke or transient ischemic attack (TIA) in the previous six months, unless the acute ischemic stroke occurred in the previous three.

3 Additional Contraindications in the Indication of Acute Ischemic Stroke

· Symptoms of ischemic stroke occurred more than 4h30 before the initiation of treatment or whose time of onset is unknown and could potentially be greater than 4h30 (see section 5.1 Pharmacodynamic properties ).

· Minor neurological deficit or symptoms improving rapidly before initiation of treatment.

· A cerebrovascular accident considered clinically severe (for example NIHSS> 25) and / or imaging.

· Convulsive seizure at the beginning of the stroke.

· Signs of intracranial hemorrhage (HIC) on CT.

· Symptoms suggestive of subarachnoid hemorrhage, even in the absence of CT abnormality.

Heparin given within 48 hours with a TCA (partial thromboplastin time + activator) exceeding the upper limit of normal.

· Diabetic patient with a history of stroke.

· History of stroke in the last 3 months.

· Platelets less than 100, 000 / mm 3.

· Systolic blood pressure> 185 mmHg or diastolic blood pressure> 110 mmHg, or the initial treatment (intravenous) necessary to reduce blood pressure to these threshold values.

· BG less than 50 or greater than 400 mg / dL.

Use in children and adolescents

ACTILYSE is not indicated for the treatment of stroke in the acute phase in patients younger than 18 years of age.

Use in the elderly patient

ACTILYSE is not indicated for the treatment of acute stroke in patients over 80 years of age.

Adverse effects Actilyse

The side effects listed below are presented by frequency and system organ class. Frequency groups are defined according to the following convention: Very common (≥1 / 10), Common (≥1 / 100, <1/10), Uncommon (≥1 / 1000, <1/100), Rare (≥ 1/10 000, <1/1000), Very rare (<1 / 10, 000), Not known (can not be estimated from the available data).

With the exception of cases of intracranial hemorrhage as an adverse effect for the treatment of stroke and cases of reperfusion arrhythmias for the treatment of myocardial infarction, there is no medical reason to suggest that the qualitative profile and quantitative side effects of ACTILYSE may be different in the treatment of pulmonary embolism and stroke or in the treatment of myocardial infarction.

hemorrhage

Haemorrhagic disorders associated with a fall in hematocrit and haemoglobinemia are the most common side effects associated with the administration of ACTILYSE:

Very common

Bleeding from damaged vessels (such as hematoma), hemorrhage at the injection site (haemorrhage at the puncture site, hematoma at the catheter site, haemorrhage at the catheter site).

Frequent

Intracranial hemorrhage (such as cerebral hemorrhage, cerebral hematoma, haemorrhagic stroke, haemorrhagic stroke transformation, intracranial hematoma, subarachnoid haemorrhage) in the treatment of an acute stroke. Symptomatic intracerebral hemorrhage is the major adverse effect in the treatment of acute ischemic stroke (up to 10% of patients without increased overall mortality and no significant increase in the combined global mortality + major handicap criterion). that is, presenting a score on the Modified Rankin Scale (mRS) of 5 or 6).

Haemorrhage of the respiratory tract (such as pharyngeal haemorrhage, epistaxis, haemoptysis).

Gastrointestinal haemorrhage (such as gastric bleeding, gastric ulcer bleeding, rectal hemorrhage, haematemesis, melena, oral bleeding, bleeding gums).

Bruising.

Urogenital haemorrhage (such as haematuria, urinary tract bleeding).

Need for a blood transfusion.

Rare

Intracranial hemorrhage (such as cerebral hemorrhage, cerebral hematoma, hemorrhagic stroke, hemorrhagic transformation of stroke, intracranial hematoma, subarachnoid hemorrhage) in the treatment of acute myocardial infarction or embolism acute pulmonary

Otorragies.

Haemopericardium.

Retroperitoneal haemorrhage (such as retroperitoneal hematoma).

Rare

Bleeding of parenchymal organs (such as hepatic hemorrhage, pulmonary hemorrhage).

Very rare

Eye bleeds.

Deaths and irreversible disabilities have been reported in patients who have had a stroke (including intracranial bleeding) or other episodes of serious bleeding.

Fibrinolytic therapy should be discontinued if a potentially dangerous haemorrhage occurs, particularly cerebral hemorrhage. In general, however, it is not necessary to administer coagulation factors because of the short half-life of alteplase and its weak effects on these systemic coagulation factors. In most cases, bleeding can be controlled by interrupting thrombolytic and anticoagulant therapy, by administering a vascular filling solution, or by manual pressure on the injured vessel.

Protamine may be considered if heparin is administered within 4 hours of onset of bleeding. In rare patients who do not respond to these conservative measures, the appropriate use of transfusion products may be considered. Transfusion of cryoprecipitate, fresh frozen plasma or platelets may be considered by monitoring clinical and laboratory parameters after each administration. The fibrinogen level to be reached in case of infusion of cryoprecipitate is 1 g / l. Antifibrinolytics constitute the last therapeutic alternative.

Immune system disorders

Rare

Hypersensitivity Reactions / Anaphylactoid Reactions (eg allergic reactions such as rash, urticaria, bronchospasm, angioedema, hypotension, shock, or any other symptoms associated with an allergic reaction).

Very rare

Severe anaphylaxis.

In rare cases, transient formation of low levels of antibodies against ACTILYSE has been observed, but the clinical relevance of these observations has not been established.

Nervous system disorders

Very rare

Central events (eg epileptic seizures, convulsions, aphasia, speech disorders, delirium, acute neuropsychiatric disorders, agitation, confusion, depression, psychosis), often associated with cerebrovascular events of ischemic or haemorrhagic origin.

Cardiac disorders

As with other thrombolytic agents, the following events have been reported as sequelae of myocardial infarction or thrombolytic therapy:

Very common

Recurrent myocardial ischemia / angina, hypotension and cardiac failure / pulmonary edema, reperfusion arrhythmias (such as arrhythmia, extrasystole, atrioventricular block from 1st degree to complete block, atrial fibrillation, atrial flutter, bradycardia, tachycardia, arrhythmia ventricular, ventricular tachycardia, fibrillation, electromagnetic dissociation).

Frequent

Cardiac arrest, cardiogenic shock and recurrent infarction.

Rare

Mitral regurgitation, pulmonary embolism or other systemic embolism, cerebral embolism, ventricular septal defects.

These heart conditions can be life-threatening and cause death.

Vascular disorders

Rare

Embolism (thrombotic embolization) may have consequences in affected organs.

Gastrointestinal disorders

Frequent

Nausea, vomiting.

investigations

Very common

Decreased blood pressure.

Frequent

Increased body temperature

Injury, poisoning and procedural complications

Rare

Greasy embolism (embolism by cholesterol crystals) may have consequences in the affected organs.

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