Package Insert: Information for the User

Actilyse, powder and solvent for injectable solution and for infusion

alteplasa

Read this package insert carefully before starting to use this medicine, because it contains important information for you.

• Keep this package insert, as you may need to read it again.
• If you have any questions, consult your doctor or nurse.
• If you experience any adverse effects, consult your doctor or nurse, even if they are not listed in this package insert. See section 4.

1. What is Actilyse and how is it used

2. What you need to know before receiving Actilyse

3. How Actilyse is administered

4. Possible adverse effects

5. Storage of Actilyse

6. Contents of the package and additional information

The active ingredient of Actilyse is alteplase. It belongs to a group of medications called thrombolytics. These medications act by dissolving blood clots that have formed in blood vessels.

Actilyse 10mg, 20mg or 50mg is used to treat diseases caused by the formation of blood clots within blood vessels, including:

• heart attacks caused by blood clots in the heart arteries (acute myocardial infarction)
• blood clots in the lungs arteries (acute massive pulmonary embolism)
• stroke caused by a blood clot in a brain artery (acute ischemic stroke)

You should not receive Actilyse:

• if you are allergic (hypersensitive) to alteplase or to any of the other components of this medicine (listed in section 6)
• if you have or have had a condition that increases the risk of bleeding, including:

• bleeding disorder or predisposition to bleeding
• severe or life-threatening bleeding in any part of the body
• bleeding inside the brain or skull
• uncontrolled very high blood pressure

• bacterial infection or inflammation of the heart (endocarditis), or inflammation of the membranes surrounding the heart (pericarditis)

• inflammation of the pancreas (acute pancreatitis)
• stomach ulcers or ulcers in the intestine
• varicose veins in the esophagus (esophageal varices)
• abnormalities of blood vessels, such as localized widening of an artery (aneurysm)
• certain tumors
• severe liver disease

• if you are taking medicines to "thin" the blood (oral anticoagulants), unless appropriate tests do not show clinically relevant activity of the medicine
• if you have ever undergone surgery in the brain or spinal cord
• if you have undergone major surgery or experienced a significant trauma within the last 3 months
• if you have recently had a puncture in a major blood vessel
• if you have had an external cardiac massage within the last 10 days
• if you have given birth within the last 10 days

Your doctor will not administer Actilyse for the treatment of heart attacks or blood clots in the arteries of the lungs

• if you have or have had a stroke caused by bleeding in the brain (hemorrhagic stroke)
• if you have or have had a stroke of unknown cause
• if you have recently (within the last 6 months) had a stroke caused by a blood clot in a brain artery (ischemic stroke), unless it is the stroke for which you are being treated now

Additionally, your doctor will not administer Actilyse for the treatment of acute ischemic stroke

• if the stroke symptoms started more than 4.5 hours ago or if it is possible that the symptoms started more than 4.5 hours ago because you do not know when they started
• if your stroke presents only very mild symptoms
• if there are signs of bleeding in the brain
• if you have had a stroke within the last three months
• if the symptoms improve rapidly before Actilyse is administered
• if you have a very severe stroke
• if you had seizures (convulsions) when the stroke started
• if you have an abnormal thromboplastin time (a test to check how your blood clots). This test may be abnormal if you have been given heparin (a medicine used to "thin" the blood) within the last 48 hours
• if you are diabetic and have had a stroke at any time
• if the number of platelets (thrombocytes) in your blood is very low
• if your blood pressure is very high (above 185/110) and can only be reduced when you are given medicines
• if your blood sugar levels are very low (less than 50 mg/dl)
• if your blood sugar levels are very high (more than 400 mg/dl)
• if you are under 16 years old. (For adolescents 16 years or older, see "Your doctor will have special care with Actilyse").

Your doctor will have special care with Actilyse

• if you have had any allergic reaction other than a sudden and potentially fatal allergic reaction (severe hypersensitivity) to the active ingredient alteplase or to any of the other components of this medicine (listed in section 6)
• if you have or have had any other condition that increases the risk of bleeding, such as:
• minor trauma
• biopsy (a procedure used to obtain tissue samples)
• puncture of major blood vessels
• intramuscular injection
• external cardiac massage
• if you have been given Actilyse at any time
• if you are over 65 years old
• if you are over 80 years old, you may have a worse outcome regardless of treatment with Actilyse. However, in general, the benefit-risk with Actilyse in patients over 80 years old is positive and age alone does not constitute a barrier to treatment with Actilyse
• if you are an adolescent 16 years or older, the benefit-risk of treatment for acute ischemic stroke should be carefully evaluated on an individual basis

Other medicines and Actilyse

Inform your doctor if you are using or have used recently other medicines, even those purchased without a prescription. It is especially important to inform your doctor if you are using or have used recently:

• medicines used to "thin" the blood, including:
• acetylsalicylic acid
• warfarin
• cumarin
• heparin
• some medicines used to treat high blood pressure (angiotensin-converting enzyme inhibitors, ACE)

Pregnancy, lactation, and fertility

If you are pregnant or breastfeeding, or if you think you may be pregnant or plan to become pregnant, consult your doctor. Your doctor will only administer Actilyse if the expected benefits outweigh the risk to your baby.

Actilyse will be prepared and administered by your doctor or a healthcare professional. It is not intended for self-administration.

The treatment with Actilyse should be initiated as soon as possible after the onset of symptoms.

There are three diseases for which Actilyse is indicated:

Heart attack (acute myocardial infarction)

The dose to be administered will depend on your body weight. The maximum dose of Actilyse is 100 mg, but it will be lower if you weigh less than 65 kg.

It can be administered in two different ways:

a) 90-minute dosing regimen, for patients treated within 6 hours after the onset of symptoms. It consists of:

• An initial injection of part of the Actilyse dose in a vein
• Infusion of the remaining dose over the next 90 minutes.

b) 3-hour dosing regimen, for patients treated within 6-12 hours after the onset of symptoms. It consists of:

• An initial injection of part of the Actilyse dose in a vein
• Infusion of the remaining dose over the next 3 hours.

In addition to Actilyse, your doctor will administer another medication to prevent blood clot formation. This medication will be administered as soon as possible after the onset of chest pain.

Massive acute pulmonary embolism

The dose to be administered will depend on your body weight. The maximum dose of Actilyse is 100 mg, but it will be lower if you weigh less than 65 kg.

Normally, the medication is administered as follows:

• An initial injection of part of the dose in a vein
• Infusion of the remaining dose over the next 2 hours.

After treatment with Actilyse, your doctor will start (or continue) treatment with heparin (a medication used to "thin" the blood).

Ischemic stroke caused by a blood clot in a cerebral artery

Actilyse must be administered within 4.5 hours after the onset of the first symptoms. The sooner you receive Actilyse, the more you can benefit from the treatment and the lower the risk of adverse effects. The dose to be administered will depend on your body weight. The maximum dose of this medication is 90 mg, but it will be lower if you weigh less than 100 kg. Actilyse is administered as follows:

• An initial injection of part of the dose in a vein
• Infusion of the remaining dose over the next 60 minutes.

You should not take acetylsalicylic acid during the first 24 hours after being treated for a stroke with Actilyse. Your doctor may administer an injection of heparin if necessary.

If you have any other questions about the use of this product, ask your doctor or a healthcare professional.

Like all medicines, this medicine may cause side effects, although not everyone will experience them.

The side effects described below have been observed in patients to whom Actilyse was administered:

Very common(may affect more than 1 in 10 patients)

• heart failure - treatment may need to be interrupted
• brain hemorrhage (cerebral hemorrhage) after treatment of an ischemic stroke caused by a blood clot in a cerebral artery (acute ischemic stroke) - treatment may need to be interrupted
• fluid in the lungs (pulmonary edema)
• bleeding in the damaged blood vessel (such as hematoma)
• low blood pressure (hypotension)
• chest pain (angina pectoris)

Common(may affect up to 1 in 10 patients)

• more heart attacks
• brain hemorrhage (cerebral hemorrhage) after treatment of a heart attack (myocardial infarction) - treatment may need to be interrupted
• heart stoppage (cardiac arrest) - treatment may need to be interrupted
• shock (very low blood pressure) due to heart failure - treatment may need to be interrupted
• throat hemorrhage
• gastrointestinal hemorrhage, including blood in vomit (hematemesis) or blood in stool (melena or rectal hemorrhage), hemorrhage in the gums
• hemorrhage in body tissues causing purpura (ecchymosis)
• urinary or reproductive tract hemorrhage, which may cause blood in urine (hematuria)
• hemorrhage or formation of hematoma at the injection site

Uncommon(may affect up to 1 in 100 patients)

• pulmonary hemorrhage, such as hemoptysis or respiratory tract hemorrhage - treatment may need to be interrupted
• nasal hemorrhage (epistaxis)
• irregular heartbeats after blood flow to the heart has been restored
• heart valve lesions (mitral regurgitation) or septal defects (ventricular septal defect) in the heart walls - treatment may need to be interrupted
• sudden blockage of a pulmonary artery (pulmonary embolism), cerebral artery (cerebral embolism), or other body area (systemic embolism)
• ear hemorrhage
• low blood pressure

Rare(may affect up to 1 in 1,000 patients)

• pericardial hemorrhage (hemopericardium) - treatment may need to be interrupted
• retroperitoneal hemorrhage (hemorrhage in the posterior abdominal cavity) - treatment may need to be interrupted
• formation of blood clots in blood vessels that may reach other body organs (embolism). Symptoms will depend on the affected organ
• allergic reactions, such as urticaria and rash, difficulty breathing to asthma (bronchospasm), fluid under the skin and mucous membrane (angioedema), low blood pressure or shock - treatment may need to be interrupted
• ocular hemorrhage (hemorrhage in the eye)
• nausea

Very rare(may affect up to 1 in 10,000 patients)

• severe allergic reactions (e.g. anaphylaxis posing a life-threatening risk) - treatment may need to be interrupted
• events affecting the nervous system, such as:

• seizures (convulsions, attacks)
• difficulty speaking
• confusion or delirium (severe confusion)
• anxiety accompanied by restlessness (agitation)
• depression
• altered thoughts (psychosis)

These disorders often occur in association with a stroke caused by a blood clot or hemorrhage in the brain.

Frequency not known(cannot be estimated from available data)

• hemorrhage in internal organs, such as liver hemorrhage (hepatic hemorrhage) - treatment may need to be interrupted
• formation of cholesterol crystals, which may reach other body organs (cholesterol embolization). Symptoms will depend on the affected organ - treatment may need to be interrupted
• hemorrhage that may require blood transfusion
• vomiting
• increased body temperature (fever)

Patients who have experienced a brain hemorrhage or other severe hemorrhagic events may die or suffer permanent disability.

Reporting of side effects

If you experience any type of side effect, consult your doctor or nurse, even if it is a possible side effect that does not appear in this prospectus. You can also report them directly through the Spanish System for Pharmacovigilance of Medicines for Human Use:www.notificaRAM.es. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

You do not usually need to conserve Actilyse as it will be administered by your doctor.

Keep this medication out of the sight and reach of children.

Do not store at a temperature above 25 °C. Store in the original packaging to protect it from light.

Do not use Actilyse after the expiration date that appears on the vial label and the packaging. The expiration date is the last day of the month indicated.

Reconstituted Solution

The reconstituted solution has been shown to be stable for 24 hours at 2 °C – 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, the storage period and usage conditions before use will be the responsibility of the person using it and should not be longer than 24 hours at 2 °C – 8 °C.

Actilyse Composition

• The active ingredient is alteplase. Each vial contains 10 mg (equivalent to 5,800,000 IU), 20 mg (equivalent to 11,600,000 IU), or 50 mg (equivalent to 29,000,000 IU) of alteplase.

The alteplase is produced by recombinant DNA technology, using a Chinese hamster ovary cell line. The other components are arginine, phosphoric acid (for pH adjustment), and polysorbate 80.

• The solvent is water for injection.

Product Appearance and Packaging Contents

Actilyse is a powder and solvent for injection and infusion. Each package contains a vial with powder and a vial with solvent.

Actilyse is available in the following package sizes:

• a vial of powder with 10 mg of alteplase and a vial with 10 ml of solvent.
• a vial of powder with 20 mg of alteplase, a vial with 20 ml of solvent, and a transfer cannula.
• a vial of powder with 50 mg of alteplase, a vial with 50 ml of solvent, and a transfer cannula.

Only some package sizes may be commercially available.

Marketing Authorization Holder

Boehringer Ingelheim International GmbH

55216 Ingelheim am Rhein

Germany

Local Representative:

Boehringer Ingelheim España, S.A.

Prat de la Riba, 50

08174 Sant Cugat del Vallès (Barcelona)

Spain

Responsible for Manufacturing:

Boehringer Ingelheim Pharma GmbH & Co. KG

Birkendorfer Strasse 65

88397 Biberach/Riss

Germany

Boehringer Ingelheim France

100-104 avenue de France

75013 Paris

France

Last Review Date of this Leaflet: 09/2024

The detailed and updated information on this medication is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)

http://www.aemps.gob.es/

-----------------------------------------------------------------------------------------------------------------------------

The following information is intended only for healthcare professionals:

Trajectory

In order to improve the traceability of biological drugs, the name and batch number of the administered medication must be clearly recorded.

The 2 mg vials of alteplase are not indicated for use in the indications of acute myocardial infarction, massive pulmonary embolism, or acute ischemic stroke (due to the risk of massive underdosing). Only the 10 mg, 20 mg, and 50 mg vials are indicated for use in these indications.

Reconstitution

To obtain a final concentration of 1 mg of alteplase per ml after reconstitution, the entire volume of the solvent provided must be transferred to the vial containing the Actilyse powder. For this purpose, the transfer cannula included in the 20 mg and 50 mg package sizes must be used. For the 10 mg presentation, a syringe must be used.

To obtain a final concentration of 2 mg of alteplase per ml after reconstitution, only half of the solvent provided must be used (according to the table below). In these cases, a syringe must always be used to transfer the required amount of solvent to the vial containing the Actilyse powder.

The contents of a vial for injection of Actilyse (10 mg, 20 mg, or 50 mg) must be dissolved under aseptic conditions with water for injection, according to the table below, to obtain a final concentration of alteplase of 1 mg/ml or 2 mg/ml:

The reconstituted solution must be administered intravenously immediately after reconstitution. The reconstituted solution of 1 mg/ml may be further diluted with a sterile injectable solution of sodium chloride 9 mg/ml (0.9%) to a minimum concentration of 0.2 mg/ml, as the appearance of turbidity in the reconstituted solution cannot be ruled out. Dilution of the reconstituted solution of 1 mg/ml with sterile water for injection or, in general, the use of infusion solutions containing carbohydrates, such as dextrose, is not recommended due to the increased formation of turbidity in the reconstituted solution. Actilyse must not be mixed with other medications in the same infusion vial (not even with heparin).

To conserve conditions, please see section 5 of the leaflet.

The reconstituted solution is for single use only. Any unused portion of the solution must be discarded.

Instructions for reconstituting Actilyse

(* If included in the kit, the transfer cannula. Reconstitution can also be performed with a syringe and needle.)

Dosage and Administration

Acute Myocardial Infarction

Dosage

a) 90-minute regimen (accelerated) for patients with acute myocardial infarction, in whom treatment can be initiated within 6 hours after the onset of symptoms.

In patients with a body weight ≥ 65 kg:

In patients with a body weight <65 kg, the total dose must be adjusted according to the following:

b) 3-hour regimen for patients with acute myocardial infarction in whom treatment can be initiated between 6 and 12 hours after the onset of symptoms.

In patients with a body weight ≥ 65 kg:

In patients with a body weight <65 kg:

Adjuvant treatment: Antithrombotic adjuvant treatment should be administered in accordance with current international guidelines for the treatment of patients with myocardial infarction with ST elevation.

Administration: The reconstituted solution must be administered intravenously and is for immediate use.

The 2 mg vials of alteplase are not indicated for use in this indication.

Pulmonary Embolism

Dosage

In patients with a body weight ≥ 65 kg:

A total dose of 100 mg of alteplase must be administered over 2 hours. The following regimen has the most experience:

In patients with a body weight <65 kg:

Adjuvant treatment: After treatment with Actilyse, anticoagulant treatment should be initiated (or resumed) if the aPTT values are below the double upper limit of normal. The infusion should be adjusted to maintain aPTT values in the range of 50-70 seconds (1.5-2.5 times the reference value).

Administration: The reconstituted solution must be administered intravenously and is for immediate use.

The 2 mg vials of alteplase are not indicated for use in this indication.

Ischemic Stroke

The treatment should only be performed under the responsibility and supervision of a trained and experienced neurovascular care physician, see Technical Dossier section 4.3 contraindications and 4.4 special precautions for use.

The treatment with Actilyse must be initiated as soon as possible within 4.5 hours from the onset of symptoms (see Technical Dossier section 4.4). Beyond 4.5 hours after the onset of symptoms, there is a negative benefit-risk ratio associated with treatment with Actilyse and it should not be administered (see Technical Dossier section 5.1).

Dosage

The recommended total dose is 0.9 mg of alteplase per kg of body weight (up to a maximum of 90 mg), starting with 10% of the total dose as an initial intravenous bolus, immediately followed by the remainder of the total dose infused intravenously over 60 minutes.

*Administered at a concentration of 1 mg/ml over 60 minutes at a constant infusion rate.

Adjuvant treatment: The safety and efficacy of this regimen with concomitant administration of heparin or antiplatelet agents such as aspirin during the first 24 hours after the onset of symptoms have not been sufficiently investigated. Therefore, the administration of intravenous heparin or antiplatelet agents such as aspirin should be avoided in the first 24 hours after treatment with Actilyse due to an increased risk of bleeding. 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.

Administration: The reconstituted solution must be administered intravenously and is for immediate use.

The 2 mg vials of alteplase are not indicated for use in this indication.

Pediatric Population

The experience with the use of Actilyse in children and adolescents is limited. Actilyse is contraindicated in the treatment of acute ischemic stroke in children and adolescents under 16 years (see Technical Dossier section 4.3). The dose in adolescents between 16 and 17 years is the same as for adults (see Technical Dossier section 4.4 for the recommended imaging techniques to be used).

Adolescents aged 16 years or older should be treated in accordance with the instructions for use in the leaflet for the adult population after obtaining images using appropriate techniques to rule out false strokes and confirm the corresponding arterial occlusion to the neurological deficit.