Actilyse

Package leaflet: Information for the user

Actilyse 2 mg powder for solution for injection and infusion

alteplase
Please read all of this leaflet carefully before you are given this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor.
• If you get any side effects, talk to your doctor or nurse. This includes any side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

1. What Actilyse is and what it is used for
2. What you need to know before you are given Actilyse
3. How Actilyse is given
4. Possible side effects
5. How to store Actilyse
6. Contents of the pack and other information

1. What Actilyse is and what it is used for

The active substance of Actilyse is alteplase. It belongs to a group of medicines called thrombolytic agents. These medicines work by dissolving blood clots.
Actilyse 2 mg is used to clear catheters that are blocked by blood clots.

2. What you need to know before receiving Actilyse

Do not receive Actilyse

• if you are allergic (hypersensitive) to alteplase or to any of the other ingredients of this medicine (listed in section 6).

Your doctor will exercise special caution with Actilyse

• if you have previously experienced any allergic reaction other than a sudden, life-threatening allergic reaction (severe hypersensitivity) to the active substance alteplase or to any of the other ingredients of this medicine (listed in section 6)
• if you are currently experiencing bleeding anywhere in the body
• if within the past 48 hours you have had any other condition that increases the risk of bleeding, including:
• surgery
• biopsy (a procedure to remove a tissue sample)
• puncture
• childbirth
• if you suffer from coagulation disorders or a tendency to bleed
• if you suffer from severe liver or kidney disease
• if a blood vessel near the catheter is blocked by a blood clot (venous thrombosis)
• if an infection inside the catheter has occurred or may occur

Other medicines and Actilyse
Inform your doctor if you are taking, have recently taken, or might take any other medicine, including those not requiring a prescription. It is particularly important that you tell your doctor if you are taking or have recently taken:

• any medicine used to "thin" the blood, including:
• acetylsalicylic acid
• warfarin
• cumarin
• heparin
• certain medicines used to treat high blood pressure (ACE inhibitors).

Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, planning to become pregnant, or are breastfeeding, consult your doctor. Your doctor will administer Actilyse only if the potential benefit outweighs the potential risk to the unborn child or infant.

3. How Actilyse is administered

Actilyse will be prepared and administered by your doctor or a healthcare professional. It is not intended for self-administration.
The dose you will receive depends on your body weight. The maximum dose of Actilyse is 2 mg, but it will be lower if your body weight is less than 30 kg.
Actilyse is injected into the blocked catheter. After 30 minutes, your doctor will check whether the catheter has become unblocked. If so, treatment with Actilyse will be stopped; otherwise, the product will be left in the catheter for a further 90 minutes.
After treatment, Actilyse is removed from the catheter, which is then flushed with sterile saline solution.
If the catheter is still blocked after the first treatment with Actilyse, the entire procedure may be repeated once.
Actilyse must not be mixed with other medicinal products.
If you have any questions about the use of this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following side effects have been reported in patients treated with Actilyse:
Uncommon (occurs in less than 1 out of 100 patients treated with the medicine)

• release of infection from the catheter into the blood vessels, leading to blood infection (sepsis)
• catheter damage such as:
• blockage
• leakage
• rupture

Rare (occurs in less than 1 out of 1,000 patients treated with the medicine)

• fever

In general, all side effects observed with the use of Actilyse (20, 50 mg alteplase) for heart attacks, pulmonary embolism or stroke may also occur during treatment of catheters occluded by blood clots. However, this is only possible if Actilyse (2 mg alteplase) reaches the bloodstream. The following side effects may occur: for example, bleeding (haemorrhage), sudden blockage of a blood vessel (embolism), allergic reactions (hypersensitivity/anaphylactoid reactions), decreased blood pressure, nausea, vomiting, increased body temperature. However, none of these side effects have so far been observed with the 2 mg dose of Actilyse. It is unlikely that such side effects will occur with the 2 mg dose of Actilyse due to the limited quantity of medicine used – except for allergic reactions, which may occur even with a small amount. Allergic reactions have been observed rarely with the use of Actilyse (20, 50 mg alteplase).
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or nurse. You can also report side effects directly via the national reporting system at: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Actilyse

You will normally not be asked to store Actilyse, as it will be administered to you by a doctor.
Keep this medicine out of the sight and reach of children.
Store in the refrigerator (2 – 8 °C). Keep in the original packaging to protect from light.
Do not use this medicine after the expiry date stated on the vial label and carton. The expiry date refers to the last day of that month.

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 standpoint, the product should be used immediately after reconstitution. If not used immediately, the duration and conditions of storage after reconstitution prior to use are the responsibility of the user and should normally not exceed 24 hours at 2°C – 8°C.

6. Package contents and other information

What Actilyse contains

• The active substance is alteplase. Each vial contains 2 mg (equivalent to 1,160,000 IU) of alteplase. Alteplase is produced by recombinant DNA technology using the Chinese hamster ovary cell line.
• The other ingredients are arginine, phosphoric acid (for pH adjustment), and polysorbate 80.

Description of the appearance of Actilyse and contents of the pack
Actilyse is a powder for solution for injection and infusion.
Each pack contains 5 vials, each containing 2 mg of alteplase.
Marketing Authorization Holder
Boehringer Ingelheim Italia S.p.A.
Via Vezza d'Oglio, 3
20139 Milano
Manufacturer
Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65
88397 Biberach/Riss
Germany
Boehringer Ingelheim France
100-104 avenue de France
75013 Paris
France

The following information is intended for physicians or healthcare professionals only:
Traceability
In order to improve the traceability of biological medicinal products, the name and batch number of the administered medicinal product must be clearly recorded.

Instructions for reconstitution
The 2 mg alteplase vial is not indicated for use in myocardial infarction, acute pulmonary embolism, or acute ischemic stroke (due to the risk of massive underdosing). Only the 20 mg or 50 mg vials are indicated for use in these indications.
The 2 mg vial (supplied with an overage) should be dissolved with 2.2 ml of sterile water for injections to obtain a final concentration of 1 mg of alteplase per ml.

1	Reconstitute immediately before administration.
2	Remove the protective cap from the vial containing Actilyse lyophilized powder by lifting it with the thumb.
3	Wipe the rubber stopper of the vial with an alcohol swab.
4	Draw up 2.2 ml of sterile water for injectable preparations into a syringe with adequate measuring accuracy under aseptic conditions.	Sterile water for injectable preparations
5	Transfer the 2.2 ml of sterile water for injectable preparations into the Actilyse vial by inserting the needle vertically into the center of the rubber stopper, directing the flow of diluent onto the powder.
6	Take the reconstituted Actilyse vial and gently rotate it to dissolve any remaining powder; do not shake, as foam may form. If bubbles are present, allow the solution to stand for a few minutes to let them dissipate.
7	The reconstituted solution contains 1 mg/ml of alteplase. It should be clear and colorless to pale yellow, and free from particles.
8	Withdraw the required amount using a needle and syringe.
9	Use immediately. Any unused medicinal product and waste materials must be disposed of in accordance with local regulations.

The reconstituted solution should therefore be instilled into the occluded central venous catheter. It may be further diluted with sterile sodium chloride solution 9 mg/ml (0.9%) for injection, up to a minimum concentration of 0.2 mg/ml, since the occurrence of turbidity in the reconstituted solution cannot be ruled out. Further dilution of the reconstituted solution from 1 mg/ml with sterile water for injection or, in general, the use of carbohydrate infusion solutions, e.g. dextrose, is not recommended due to increased formation of turbidity in the reconstituted solution. Actilyse must not be mixed with other medicinal products in the same catheter (not even with heparin).
For incompatibilities, see section 6.2 of the SmPC.
For storage conditions, see section 5 of this package leaflet.

Instructions for administration into occluded central venous catheters, including those used for hemodialysis:

1. Reconstitute the contents of one injection vial to a final concentration of 1 mg alteplase per ml. For catheters with a lumen volume greater than 2 ml, the reconstituted solution may be further diluted with sterile sodium chloride solution 9 mg/ml (0.9%) for injection, up to the desired volume. For example, for a catheter with an internal volume of 2.5 ml, the total dose of Actilyse should be 2.0 mg in a volume of 2.5 ml.
2. Instill the appropriate dose of Actilyse into the occluded central venous catheter.
3. After a dwell time of 30 minutes, assess catheter functionality by attempting to aspirate blood. If the catheter is patent, proceed to step 6. If the catheter remains occluded, proceed to step 4.
4. After a dwell time of 120 minutes, assess catheter functionality by attempting to aspirate blood and catheter contents. If the catheter is patent, proceed to step 6. If the catheter remains occluded, proceed to step 5.
5. If catheter functionality is not restored after the first dose, a second dose of equal amount may be instilled. Repeat the procedure starting from step 1. If catheter functionality is not restored after the second dose of alteplase, consider replacing the catheter.
6. If catheter functionality is restored, aspirate 4–5 ml of blood in patients weighing 10 kg or more, or 3 ml in patients with a body weight below 10 kg, to remove Actilyse and residual clot, then gently flush the catheter with sterile sodium chloride solution 9 mg/ml (0.9%) for injection.

Package leaflet: information for the user

Actilyse 10 mg powder and solvent for injectable solution and infusion, 20 mg powder and solvent for injectable solution and infusion, 50 mg powder and solvent for injectable solution and infusion

alteplase
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or nurse.
• If you experience any side effect, including those not listed in this leaflet, contact your doctor or nurse. See section 4.

Contents of this leaflet:

1. What Actilyse is and what it is used for
2. What you need to know before receiving Actilyse
3. How Actilyse is administered
4. Possible side effects
5. How to store Actilyse
6. Contents of the pack and other information

1. What Actilyse is and what it is used for

The active substance of Actilyse is alteplase. It belongs to a group of medicines called thrombolytic agents. These medicines work by dissolving blood clots that have formed in blood vessels.
Actilyse 10, 20 or 50 mg is used to treat several conditions caused by the formation of blood clots in blood vessels, including:

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

2. What you need to know before receiving Actilyse

Do not receive Actilyse

• if you are allergic (hypersensitive) to alteplase or to any of the other ingredients of this medicine (listed in section 6).
• if you currently have or have recently had a condition that increases the risk of bleeding, including:
• blood clotting disorders or a tendency to bleed
• severe or life-threatening bleeding anywhere in the body
• bleeding inside the brain or skull
• very high, uncontrolled 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 or intestinal ulcer
• varicose veins in the esophagus (esophageal varices)
• blood vessel abnormalities, such as a localized swelling of an artery (aneurysm)
• certain tumors
• severe liver disease
• if you are taking medications to "thin" the blood (oral anticoagulants), unless appropriate tests have confirmed the absence of clinically relevant activity of that medication
• if you have ever undergone brain or spinal surgery
• if you have had major surgery or a serious injury within the past 3 months
• if you have recently undergone a puncture of a large blood vessel
• if you have received external cardiac massage within the past 10 days
• if you have given birth within the past 10 days.

Additionally, your doctor will not use Actilyse to treat heart attacks or blood clots
in the arteries of the lungs

• if you currently have or have ever had a stroke caused by bleeding in the brain (hemorrhagic stroke)
• if you currently have or have ever had a stroke of unknown cause
• if you have recently (within the past 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 about to be treated.

Furthermore, your doctor will not use Actilyse to treat a stroke caused by a blood clot
in a brain artery (acute ischemic stroke)

• if stroke symptoms began more than 4.5 hours ago, or if it is possible that symptoms started more than 4.5 hours ago because you do not know when they began
• if the stroke is causing only very mild symptoms
• if there are signs of bleeding in the brain
• if you have had a stroke within the past 3 months
• if symptoms are rapidly improving before receiving Actilyse
• if you have a very severe stroke
• if seizures (convulsions) occurred at the onset of the stroke
• if the prothrombin time (a blood test to assess the degree of blood clotting) is abnormal. This test may be abnormal if you have taken heparin (a medicine used to thin the blood) within the previous 48 hours
• if you are diabetic and have previously had a stroke
• if your platelet count (thrombocytes) in the blood is very low
• if you have very high blood pressure (above 185/110) that can only be reduced with injectable medications
• if your blood sugar (glucose) level is very low (below 50 mg/dL)
• if your blood sugar (glucose) level is very high (above 400 mg/dL)
• if you are under 16 years of age. (For adolescents aged 16 years or older, see the section “Your doctor will exercise particular caution with Actilyse”).

Your doctor will exercise particular caution with Actilyse

• if you have ever had any allergic reaction other than a life-threatening immediate allergic reaction (severe hypersensitivity) to the active substance alteplase or to any of the other ingredients of this medicine (listed in section 6).
• if you currently have or have recently had any other condition that increases the risk of bleeding, such as:
• minor injuries
• biopsy (a procedure to remove a tissue sample)
• puncture of a major blood vessel
• intramuscular injection
• external cardiac massage
• if you have previously been treated with Actilyse.
• if you are over 65 years old.
• if you are over 80 years old, you may have an unfavorable outcome regardless of treatment with Actilyse. However, in general, the benefit-risk ratio of Actilyse in patients over 80 years of age is positive, and age alone does not constitute a barrier to treatment with Actilyse.
• if you are an adolescent aged 16 years or older, the benefit versus risk will be carefully evaluated on an individual basis for the treatment of acute ischemic stroke.

Other medicines and Actilyse
Inform your doctor if you are taking or have recently taken any other medicines, including
those obtained without a prescription. It is especially important that you tell your doctor if you are taking or
have recently taken:

• any medicine used to "thin" the blood, including:
• acetylsalicylic acid
• warfarin
• coumarin
• heparin
• certain medicines used to treat high blood pressure (ACE inhibitors).

Pregnancy, breastfeeding, and fertility
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or are breastfeeding,
consult your doctor. Your doctor will administer Actilyse only if the potential benefit outweighs the potential risk to the unborn child.

3. How Actilyse is administered

Actilyse will be prepared and administered by your doctor or a healthcare professional. It is not intended for self-administration.
Treatment with Actilyse should be started as soon as possible after the onset of symptoms.
There are three different conditions for which this medicine may be administered:

Heart attack (acute myocardial infarction)
The dose administered depends on body weight. The maximum dose of Actilyse is 100 mg, but it will be lower if body weight is less than 65 kg.
It can be administered in two different ways:

a) 90-minute administration regimen, for patients treated within 6 hours of symptom onset.
This consists of:

• an initial injection of part of the Actilyse dose into a vein
• infusion of the remaining portion of the dose over the next 90 minutes.

b) 3-hour administration regimen, for patients treated between 6 and 12 hours after symptom onset.
This consists of:

• an initial injection of part of the Actilyse dose into a vein
• infusion of the remaining portion of the dose over the next 3 hours.

In addition to Actilyse, your doctor will administer another medicine to prevent blood clotting, which will be given as soon as possible after the onset of chest pain.

Blood clots in the lung arteries (acute massive pulmonary embolism)
The dose administered depends on body weight. The maximum dose of Actilyse is 100 mg, but it will be lower if body weight is less than 65 kg.
Administration usually consists of:

• an initial injection of part of the dose into a vein
• infusion of the remaining portion of the dose over the next 2 hours.

After treatment with Actilyse, your doctor will start (or restart) therapy with heparin (a medicine to “thin” the blood).

Stroke caused by a blood clot in a brain artery (acute ischemic stroke)
Actilyse must be administered within 4.5 hours of the first symptoms. The earlier you receive Actilyse, the greater the benefit you may derive from the treatment and the lower the likelihood of harmful side effects. The dose administered depends on body weight. The maximum dose of this medicine is 90 mg, but it will be lower if body weight is less than 100 kg.
Administration consists of:

• an initial injection of part of the dose into a vein
• infusion of the remaining portion of the dose over the next 60 minutes.

Within 24 hours after treatment with Actilyse for stroke, acetylsalicylic acid must not be taken. If necessary, your doctor may administer an injection of heparin.

If you have any doubts about the use of Actilyse, consult your doctor or healthcare professional.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
The following side effects have been reported in patients treated with Actilyse:

Very common (occurs in more than 1 out of 10 patients treated with the medicine)

• Heart failure – treatment may need to be discontinued
• Bleeding in the brain (cerebral haemorrhage) after treatment of a stroke caused by a blood clot in a brain artery (acute ischaemic stroke) – treatment may need to be discontinued
• Fluid in the lungs (pulmonary oedema)
• Bleeding from a damaged blood vessel (such as haematoma)
• Low blood pressure (hypotension)
• Chest pain (angina pectoris)

Common (occurs in less than 1 out of 10 patients treated with the medicine)

• Further heart attack
• Bleeding in the brain (cerebral haemorrhage) after treatment of heart attacks (myocardial infarction) – treatment may need to be discontinued
• Cessation of heartbeat (cardiac arrest) – treatment may need to be discontinued
• Shock (very low blood pressure) due to heart failure – treatment may need to be discontinued
• Bleeding from the throat
• Bleeding from the stomach or intestines, including vomiting blood (haematemesis) or blood in the stool (melena or rectal bleeding), bleeding from the gums
• Bleeding into body tissues causing purplish bruising (ecchymosis)
• Bleeding from the urinary tract or reproductive organs, which may result in blood in the urine (haematuria)
• Bleeding or bruising (haematoma) at the injection site

Uncommon (occurs in less than 1 out of 100 patients treated with the medicine)

• Bleeding in the lungs, such as blood-stained mucus (haemoptysis) or bleeding in the respiratory tract – treatment may need to be discontinued
• Nosebleed (epistaxis)
• Irregular heartbeat after blood flow to the heart has been restored
• Damage to heart valves (mitral regurgitation) or to the wall separating chambers of the heart (ventricular septal defect) – treatment may need to be discontinued
• Sudden blockage of an artery in the lungs (pulmonary embolism), brain (cerebral embolism), or other parts of the body (systemic embolism)
• Bleeding from the ear
• Decrease in blood pressure

Rare (occurs in less than 1 out of 1,000 patients treated with the medicine)

• Bleeding into the sac surrounding the heart (haemopericardium) – treatment may need to be discontinued
• Internal bleeding in the back of the abdomen (retroperitoneal haemorrhage) – treatment may need to be discontinued
• Formation of blood clots in blood vessels that may travel to other organs (embolism). Symptoms depend on the organs affected
• Allergic reactions, e.g. hives and skin rash, difficulty breathing up to asthma (bronchospasm), fluid under the skin and mucous membranes (angioedema), low blood pressure or shock – treatment may need to be discontinued
• Bleeding in the eyes (ocular haemorrhage)
• Stomach discomfort (nausea)

Very rare (occurs in less than 1 out of 10,000 patients treated with the medicine)

• Severe allergic reaction (e.g. life-threatening anaphylaxis) – treatment may need to be discontinued
• Events affecting the central nervous system such as:
  • Seizures (convulsions, epileptic fits)
  • Speech disorders
  • 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 bleeding in the brain.

Not known (frequency cannot be estimated from the available data)

• Bleeding of internal organs, e.g. bleeding in the liver (hepatic haemorrhage) – treatment may need to be discontinued
• Formation of cholesterol crystal clots that may travel to other organs (cholesterol crystal embolisation). Symptoms depend on the organs affected – treatment may need to be discontinued
• Haemorrhage requiring blood transfusion
• Vomiting
• Increase in body temperature (fever)

Death or permanent disability may occur as a result of bleeding in the brain or other severe bleeding episodes.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or nurse. You may also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Actilyse

You will normally not be asked to store Actilyse, as it will be administered to you by a doctor.
Keep this medicine out of the sight and reach of children.
Do not store above 25°C. Store in the original packaging to protect the medicine from light.
Actilyse must not be used after the expiry date stated on the vial label and the outer carton. The expiry date refers to the last day of that month.

Reconstituted solution
The stability of the reconstituted solution has been demonstrated 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 times and conditions of storage after reconstitution prior to use are the responsibility of the user and normally should not exceed 24 hours at 2°C – 8°C.

6. Package contents and other information

What Actilyse contains

• The active substance 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. 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 injections.

Description of the appearance of Actilyse and contents of the pack
Actilyse is a powder and solvent for solution for injection and for infusion.
Each pack contains one vial of powder and one vial of solvent.
Actilyse is available in the following pack sizes:

• One vial containing 10 mg of alteplase powder and one vial containing 10 ml of solvent.
• One vial containing 20 mg of alteplase powder, one vial containing 20 ml of solvent and one transfer cannula.
• One vial containing 50 mg of alteplase powder, one vial containing 50 ml of solvent and one transfer cannula.

Not all pack sizes may be marketed.
Marketing Authorisation Holder
Boehringer Ingelheim Italia S.p.A.
Via Vezza d'Oglio, 3
20139 Milano
Italy
Manufacturer
Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65
88397 Biberach/Riss
Germany
Boehringer Ingelheim France
100-104 avenue de France
75013 Paris
France

The following information is intended exclusively for physicians or healthcare professionals:
Traceability
To improve the traceability of biological medicinal products, the name and batch number of the administered product must be clearly recorded.
The 2 mg alteplase vials are not indicated for use in acute myocardial infarction, massive acute pulmonary embolism or acute ischaemic stroke (due to the risk of massive underdosing). Only the 10 mg, 20 mg or 50 mg vials are authorised for these indications.
Reconstitution
To reconstitute to a final concentration of 1 mg of alteplase/ml, the entire volume of solvent provided must be transferred into the vial containing the lyophilised Actilyse powder. For this purpose, a transfer cannula is provided in the 20 mg and 50 mg packs. For the 10 mg vial, a syringe must be used.
To reconstitute to a final concentration of 2 mg of alteplase/ml, only half of the provided solvent must be used (as indicated in the table below). In these cases, a syringe must always be used to transfer the required amount of solvent into the vial containing the lyophilised Actilyse powder.
The contents of one single-use vial of lyophilised Actilyse (10 mg or 20 mg or 50 mg) should be dissolved under aseptic conditions with water for injections according to one of the following methods to obtain a final concentration of alteplase 1 mg/ml or alteplase 2 mg/ml: