Boehringer Ingelheim

Powder and solvent for solution for injection/infusion 
(Colorless to pale yellow powder)

Read all of this leaflet carefully before you start using this medicine.

  • Save this information, you may need to read it again.
  • If you have any further questions, ask your doctor or nurse.
  • If you get any side effects, talk to your doctor or nurse. This also applies to any side effects not mentioned in this information. See section 4.

This leaflet contains information about: 
1. What Actilyse is and what it is used for 
2. What you need to know before you use Actilyse 
3. How to use Actilyse 
4. Possible side effects 
5. How to store Actilyse 
6. Contents of the packaging and other information 

1. What Actilyse is and what it is used for

The active substance in Actilyse is alteplase. It belongs to a group of medicines called thrombolytic drugs. These drugs work by dissolving blood clots that clog blood vessels.

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

  • heart attack caused by blood clots in the coronary artery s ( acute myocardial infarction)
  • blood clots in the pulmonary artery s ( acute massive pulmonary embolism )
  • stroke caused by the formation of blood clots in the arteries of the brain ( acute ischemic stroke )

2. What you need to know before using Actilyse

Do not use Actilyse

You should not be treated with Actilyse

  • if you are allergic (hypersensitive) to the active substance alteplase, to gentamicin (trace residues from the manufacture), to natural rubber (also called latex included in the packaging material), or to any of the other ingredients of this medicine (listed in section 6).
  • if you have or have recently had a disease that increases the risk of bleeding, for example:
  • bleeding disorder or tendency to increase bleeding
  • severe or dangerous bleeding in any part of the body
  • bleeding in the brain or skull
  • uncontrolled, very high blood pressure
  • bacterial infection or inflammation of the heart or inflammation of the membranes around the heart
  • inflammation of the pancreas
  • ulcers of the gastrointestinal tract
  • varicose veins in the esophagus
  • changes in the blood vessels, which hernia on artery s
  • some tumor you
  • severe liver disease
  • if you are taking blood-thinning medicines (orally) unless appropriate tests show that there is no clinically significant effect of this medicine
  • if you have ever had surgery on your brain or spine
  • if you have undergone major surgery or suffered a serious injury in the last 3 months
  • if you have recently had a puncture of a large blood vessel
  • if you have had a heart massage in the last 10 days
  • if you have given birth in the last 10 days

Your doctor will also not use Actilyse to treat heart attacks or blood clots in the pulmonary arteries:

  • if you have or have ever had a stroke caused by bleeding in the brain
  • if you have or have ever had a stroke for unclear reasons
  • if you have recently (in the last 6 months) had a stroke caused by blood clots in your brain arteries. This does not apply to the stroke you are seeking treatment for.

In addition, your doctor will not use Actilyse to treat strokes caused by a blood clot in the arteries of the brain:

  • if the symptoms of stroke started more than 4.5 hours ago or if it may have been more than 4.5 hours since the start because you do not know when they started
  • if your stroke only produces mild symptoms
  • if there are signs of bleeding in the brain
  • if you have had a stroke in the last 3 months
  • if your symptoms improve rapidly before starting treatment with Actilyse
  • if you have a very severe stroke
  • if you had seizures when the stroke symptoms started
  • if your thromboplastin time (blood test to check blood clotting ability) is different. The test may be different if you have been given heparin (a medicine that thins the blood) for the last 48 hours.
  • if you are diabetic and have had a stroke at some point in the past
  • if you have very few platelets
  • if you have very high blood pressure (above 185/110) which can only be reduced by injecting medicines
  • if the amount of sugar ( glucose ) in the blood is very low (below 2.8 mmol / l)
  • if the amount of sugar ( glucose ) in the blood is very high (above 22.2 mmol / l)
  • if you are younger than 16 years. (For adolescents 16 years of age or older, see section “Your doctor will take special care with Actilyse”.)

Warnings and cautions

Your doctor will be especially careful with Actilyse

  • if you have had an allergic reaction other than a sudden life-threatening allergic reaction (severe hypersensitivity) to the active substance alteplase, to gentamicin (trace residues from the manufacture), to natural rubber (also called latex contained in the packaging material), or to any of the other ingredients in this medicine (listed in section 6).
  • if you have or have recently had any condition that increases the risk of bleeding, such as:
    • minor damage
    • biopsy (tissue sampling)
    • puncture of major blood vessels
    • intramuscular injection
    • external heart massage
  • if you have ever received Actilyse
  • if you are older than 65 years
  • if you are older than 80 years, you may get a worse treatment result even if you are treated with Actilyse. The benefit of treatment outweighs the potential risk even in patients over 80 years of age. Therefore, old age alone is not an obstacle to treatment with Actilyse.
  • if you are a young person who is 16 years or older, the benefit will be carefully weighed against the possible risk in the treatment of stroke ( acute ischemic stroke )

Other medicines and Actilyse

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

It is especially important to tell your doctor if you are taking or have recently taken:

  • any medicine used to thin the blood, such as:
    • acetylsalicylic acid
    • warfarin
    • coumarin
    • heparin
  • certain medicines for high blood pressure ( ACE inhibitors )

Pregnancy, breastfeeding, and fertility

Consult a doctor before taking any medicine. Your doctor will only give you Actilyse if the benefit outweighs the potential risk to your child.

Actilyse may contain traces of gentamicin from the manufacturing process; the package contains natural rubber (latex).

3. How to use Actilyse

Actilyse is prepared and given to you by a doctor or other healthcare professional. You are not supposed to take the medicine yourself.

Actilyse should be given as early as possible after the first symptom.

Actilyse can be used to treat three different diseases:

Heart attack ( acute myocardial infarction)

The dose you receive depends on your body weight. The maximum dose of Actilyse is 100 mg, but if you weigh less than 65 kg, you will receive a lower dose.

Actilyse can be given in two different ways:

a) Delivery for 90 minutes, to patients treated within 6 hours after the first symptoms. This means:

  • the first injection of a portion of dose one into a vein
  • then infusion of the remainder of dose one for the following 90 minutes.

b) Administration for 3 hours, to patients, treated 6 – 12 hours after the first symptoms. This means:

  • the first injection of a portion of dose one into a vein
  • then infusion of the remainder of dose one for the following 3 hours.

In addition, your doctor will give you another medicine to counteract the formation of blood clots. This medicine will be given as soon as possible after you start to feel chest pain.

Blood clots in the artery are the lungs ( acute massive pulmonary embolism )

The dose you receive depends on your body weight. The maximum dose of Actilyse is 100 mg, but if you weigh less than 65 kg, you will receive a lower dose.

Actilyse is usually given as follows:

  • the first injection of a portion of dose one into a vein
  • then infusion of the remainder of dose one for the following 2 hours.

After treatment with Actilyse, your doctor will start (or resume) treatment with heparin (a medicine that thins the blood).

Stroke caused by blood clots in an artery in the brain ( acute ischemic stroke )

Actilyse must be given within 4.5 hours after the first symptoms. The earlier you receive the treatment, the greater the chance that you will benefit from the treatment and the less risk that serious side effects will occur. The dose you receive depends on your body weight. The maximum dose of Actilyse is 90 mg, but it may be lower if you weigh less than 100 kg.

Actilyse is given as follows:

  • the first injection of a portion of dose one into a vein
  • then infusion of the remainder of dose one for the following 60 minutes.

You should not use acetylsalicylic acid for the first 24 hours after treatment with Actilyse for stroke. If necessary, your doctor may give you an injection of heparin.

If you have any further questions on the use of Actilyse, ask 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 by people taking Actilyse:

Very common (affects more than 1 user in 10 who receive the medicine)

  • heart failure – it may be necessary to stop treatment
  • bleeding in the brain after treatment of stroke caused by a blood clot in one of the arteries of the brain ( acute ischemic stroke ) – it may be necessary to discontinue treatment.
  • fluid in the lungs
  • bleeding at the damaged blood vessel (such as bruising / hematoma)
  • low blood pressure
  • angina

Common (affects less than one in 10 people receiving the medicine)

  • another heart attack
  • bleeding in the brain after treatment of heart attack – it may be necessary to discontinue treatment
  • cardiac arrest – it may be necessary to discontinue treatment
  • shock (very low blood pressure ) due to heart failure – it may be necessary to stop treatment
  • bleeding in the throat
  • bleeding in the stomach or intestines, including bloody vomiting or blood in the stool, bleeding in the gums
  • bleeding in body tissues that causes purple bruises
  • bleeding from the urinary tract or genitals that may cause blood in the urine
  • bleeding or bruising at the injection site

Uncommon (affects less than 1 in 100 people who receive the medicine)

  • lung-related bleeding, such as blood-stained mucus, or bleeding in the airways – it may be necessary to discontinue treatment
  • nosebleed
  • an irregular heartbeat after the blood supply to the heart has been restored
  • damage to the heart valves or the wall that separates the two chambers of the heart – it may be necessary to discontinue treatment
  • sudden blockage of an artery in the lungs (pulmonary embolism), the brain, and all other places in the body (systemic embolism)
  • bleeding in the ears
  • lowering blood pressure

Rare (affects less than 1 in 1,000 people receiving the medicine):

  • bleeding in the pericardium surrounding the heart – it may be necessary to discontinue treatment
  • internal bleeding in the back of the torso – it may be necessary to discontinue treatment
  • formation of blood clots that can be transported to various organs in the body. The symptoms depend on which organ is affected
  • allergic reactions, such as hives and rash, difficulty breathing with difficulty up to asthma ( bronchospasm ), fluid under the skin and mucous membranes ( angioedema ), low blood pressure, or shock – it may be necessary to discontinue treatment
  • bleeding in the eyes
  • nausea

Very rare (affects less than 1 in 10,000 people receiving the medicine)

  • severe allergic reactions (eg life-threatening anaphylaxis ) – it may be necessary to discontinue treatment
  • events that affect the nervous system eg:
    • seizures
    • trouble speaking
    • confusion or delirium (very severe confusion)
    • anxiety along with restlessness
    • Depression
    • altered thinking ( psychosis )

These changes often occur in connection with a stroke caused by blood clots or bleeding in the brain.

No known frequency (cannot be calculated from the available data)

  • bleeding in internal organs, such as bleeding in the liver – it may be necessary to discontinue treatment
  • formation of cholesterol crystals that loosen and accompany the blood to other organs. The symptoms depend on which organs are affected – it may be necessary to discontinue treatment
  • bleeding requiring blood transfusion
  • vomiting
  • fever

Death or permanent disability can follow bleeding in the brain or other serious bleeding events.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly to the Medical Products Agency, www.lakemedelsverket.se. By reporting side effects, you can help increase drug safety information. 

5. How to store Actilyse

Normally you will not be asked to keep Actilyse as it will be given to you by your doctor

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

Do not store above 25 ° C. Store in the original package. Sensitive to light.

Do not use this medicine after the expiry date which is stated on the label and carton. The expiration date is the last day of the specified month

Reconstituted solution

The reconstituted solution has been shown to be stable for 24 hours at 2-8 ° o C and for 8 hours at 25 ° C.

From a microbiological perspective, the solution 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 2-8 ° C.

6. Contents of the packaging and other information

Content declaration

  • 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 manufactured using recombinant DNA technology using a Chinese hamster ovarian cell line. The other ingredients are arginine, phosphoric acid (for pH adjustment), and polysorbate 80.
  • The diluent is water for injections.
  • The rubber cork in the package contains natural rubber (latex).

What the medicine looks like and the contents of the pack

Actilyse is a powder and solvent for solution for injection/infusion. One pack contains a vial of powder and a vial of diluent.

Actilyse is available in the following pack sizes:

  • one vial of 10 mg alteplase powder and one vial of 10 ml of diluent
  • one vial of 20 mg alteplase powder and one vial of 20 ml of diluent and one transfer needle
  • one vial of 50 mg alteplase powder and one vial of 50 ml of diluent and one transfer needle

Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH

Binger Strasse 173

D-55216 Ingelheim

Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG

Birkendorfer Straβe 65

D-88397 Biberach / Riβ

Germany

Information provided by:

Boehringer Ingelheim AB

Box 92008

SE-120 06 Stockholm

Tel: +46 (0) 8 721 21 00

This leaflet was last modified on 11/15/2019

The following information is intended for healthcare professionals only:

Traceability

In order to improve the traceability of biological medicinal products, the name and manufacturing batch number of the administered medicinal product must be clearly recorded.

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

Reconstitution

For reconstitution to a final concentration of 1 mg alteplase/ml, the entire volume of diluent provided with the package should be transferred to the vial of Actilyse powder. For this purpose, a transfer cannula is included in the packs of 20 mg and 50 mg. A 10 mg syringe should be used for the 10 mg pack.

For reconstitution to a final concentration of 2 mg alteplase/ml, only half the volume of diluent should be used (as shown in the table below). In these cases, always use a syringe to transfer the intended amount of diluent to the vial of Actilyse powder.

Under aseptic conditions, the contents of one vial of Actilyse powder (10 mg, 20 mg, or 50 mg) should be dissolved in water for injections ( diluent ) according to the table below, to obtain a final concentration of 1 mg alteplase/ml or 2 mg alteplase/ml:

Actilyse powder 10 mg 20 mg 50 mg
(a) Volume of sterile water for injections to be added to the powder 10 ml 20 ml 50 ml
Final concentration: 1 mg alteplas / ml 1 mg alteplas / ml 1 mg alteplas / ml
(b) Volume of sterile water for injections to be added to the powder 5 ml 10 ml 25 ml
Final concentration 2 mg alteplas / ml 2 mg alteplas / ml 2 mg alteplas / ml

The reconstituted solution should then be administered intravenously. The reconstituted 1 mg/ml solution 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 as the reconstituted solution cannot be ruled out as cloudy. Further dilution of the reconstituted 1 mg/ml solution, with sterile water for injections or with carbohydrate solutions for infusion, eg glucose, is not recommended due to increased turbidity of the reconstituted solution. Actilyse should not be mixed with other medicines in the same infusion solution (this also applies to heparin ).

For storage instructions, see section 5 of this leaflet.

The reconstituted solution is for single use only. The unused solution must be destroyed.

Instructions for reconstituting Actilyse:

1 Reconstitute immediately before administration .
2 Use your thumb to remove the protective caps from the vials containing Actilyse powder and diluent.
3 Clean the rubber tops of the vials with an alcohol swab.
4 Remove the transfer needle *. Do not disinfect or sterilize the transfer needle, it is already sterile. Remove one protective cover.
5 Place the vial of diluentupright on a firm surface. Puncture the center of the rubber stopper, straight from the top, with the transfer needle. Press gently but firmly without turning.
6 Hold the vial of diluent and the transfer needle firmly in one hand by holding the middle part of the transfer needle. Remove the second protective cap from the transfer needle.
7 Hold the vial of diluentand the transfer needle firmly in one hand by holding the middle part of the transfer needle.Hold the vial of Actilyse powder above the transfer needle. Place the tip of the transfer needle in the center of the rubber stopper.Push the powder vial onto the transfer needle straight from the top.Puncture the rubber cap carefully but firmly without twisting.
8 Turn the two vials over and allow all diluent to drain to the powder.
9 Remove the now empty diluent vial together with the transfer needle. They can be discarded.
10 Gently swirl the vial of reconstituted Actilyse to dissolve the remaining powder. Do not shake the vial as it will cause foaming. If there are air bubbles: let the solution stand for a few minutes for the bubbles to disappear.
11 The solution consists of 1 mg / ml Actilyse. It should be clear and colorless to light yellow and it should be free of particles.
12 Use a syringe to withdraw the amount needed to avoid leakage, do not insert the syringe needle into the same place as the transfer needle.
13 Use immediately.All unused solution must be discarded.

(* if a transfer needle is included in the package. Reconstitution can also be done with a syringe and needle.)

Dosage and route of administration

Acute myocardial infarction

Dosage

a) 90-minute (accelerated) dosing schedule for patients with acute myocardial infarction, where treatment can be started within 6 hours after the onset of symptoms:

For patients with a bodyweight ≥ 65 kg:


Volume to be given depending on the concentration of alteplas
1 mg / ml 2 mg / ml
15 mg as an intravenousbolus , immediately followed by 15 ml 7.5 ml
50 mg as an intravenous infusion at a constant rate for the first 30 minutes, immediately followed by 50 ml 25 ml
35 mg as a constant rate intravenous infusion over 60 minutes, up to a maximum total dose of 100 mg 35 ml 17.5 ml

For patients with a bodyweight <65 kg, the total dose should be adjusted according to the following table:


Volume to be given depending on the concentration of alteplas
1 mg / ml 2 mg / ml
15 mg as an intravenousbolus dose , immediately followed by 15 ml 7.5 ml
0.75 mg/kg body weight as a constant rate intravenous infusion over the first 30 minutes, immediately followed by 0.75 ml per kg of body weight 0.375 ml per kg of body weight
0.5 mg / kg body weight as a constant rate intravenous infusion over 60 minutes) 0.5 ml per kg body weight 0.25 ml per kg body weight

b) 3-hour dosing schedule for patients with acute myocardial infarction where treatment can be started between 6 and 12 hours after the onset of symptoms.

For patients with a bodyweight ≥ 65 kg:


Volume to be given depending on the concentration of alteplas
1 mg / ml 2 mg / ml
10 mg as an intravenousbolus dose , immediately followed by 10 ml 5 ml
50 mg as a constant rate intravenous infusion for the first hour, immediately followed by 50 ml 25 ml
40 mg as a constant rate intravenous infusion over 2 hours up to a maximum total dose of 100 mg 40 ml 20 ml

In patients with a bodyweight <65 kg:


Volume to be given depending on the concentration of alteplas
1 mg / ml 2 mg / ml
10 mg as an intravenousbolus , immediately followed by 10 ml 5 ml
an intravenous infusion at a constant rate for 3 hours to a maximum total dose of 1.5 mg/kg body weight 1.5 ml / kg body weight 0.75 ml / kg body weight

Supplementary treatment: Supplements with antithrombotic therapy are recommended in accordance with current international guidelines for the treatment of patients with ST-elevation myocardial infarction.

Method of administration

The reconstituted solution should be given intravenously and used immediately.

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

Acute massive pulmonary embolism

Dosage

For patients with a bodyweight ≥ 65 kg:

A total dose of 100 mg should be administered within 2 hours. Most experience is with the following dosing schedule:


Volume to be given depending on the concentration of alteplas
1 mg / ml 2 mg / ml
10 mg as an intravenousbolus dose for 1-2 minutes, immediately followed by 10 ml 5 ml
90 mg as a constant- dose intravenous infusion over 2 hours up to a maximum total dose of 100 mg 90 ml 45 ml

In patients with a bodyweight <65 kg:


Volume to be given depending on the concentration of alteplas
1 mg / ml 2 mg / ml
10 mg as an intravenousbolus for 1-2 minutes, immediately followed by 10 ml 5 ml
an intravenous infusion at a constant rate for 2 hours to a maximum total dose of 1.5 mg/kg body weight 1.5 ml / kg body weight 0.75 ml / kg body weight

Additional therapy: After treatment with Actilyse, treatment with heparin should be started (or resumed) when the APTT values ​​are less than twice the upper limit of normal. Infusion one should be adjusted so that an APTT between 50-70 seconds is maintained (1.5- to 2.5-fold of the reference value).

Method of administration

The reconstituted solution should be given intravenously and used immediately.

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

Acute ischemic stroke

Treatment must be monitored and followed up by physicians with special training and experience in neurovascular care, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use in SmPC.

Treatment with Actilyse must be started as early as possible within 4.5 hours after the onset of symptoms (see SmPC section 4.4). For treatment that is initiated more than 4.5 hours after the onset of symptoms, the risk / benefit balance is negative, which is why treatment after 4.5 hours should not be initiated (see section 5.1 in SmPC ).

Dosage

The recommended total dose is 0.9 mg alteplase/kg body weight (maximum dose 90 mg) starting with 10% of the total dose as an initial intravenous bolus, immediately followed by the rest of the total dose as an intravenous infusion over 60 minutes.

DOSAGE TABLE FOR EMERGENCY ischemic STROKE
Using the standard concentration of 1 mg/ml, the volume (ml) to be administered is equal to the recommended dose one in mg
Weight(kg) Total dos(mg) Bolusdos(mg) Infusion dose *(mg)
40 36.0 3.6 32.4
42 37.8 3.8 34.0
44 39.6 4.0 35.6
46 41.4 4.1 37.3
48 43.2 4.3 38.9
50 45.0 4.5 40.5
52 46.8 4.7 42.1
54 48.6 4.9 43.7
56 50.4 5.0 45.4
58 52.2 5.2 47.0
60 54.0 5.4 48.6
62 55.8 5.6 50.2
64 57.6 5.8 51.8
66 59.4 5.9 53.5
68 61.2 6.1 55.1
70 63.0 6.3 56.7
72 64.8 6.5 58.3
74 66.6 6.7 59.9
76 68.4 6.8 61.6
78 70.2 7.0 63.2
80 72.0 7.2 64.8
82 73.8 7.4 66.4
84 75.6 7.6 68.0
86 77.4 7.7 69.7
88 79.2 7.9 71.3
90 81.0 8.1 72.9
92 82.8 8.3 74.5
94 84.6 8.5 76.1
96 86.4 8.6 77.8
98 88.2 8.8 79.4
100+ 90.0 9.0 81.0

* given at a concentration of 1 mg/ml for 60 minutes at a constant infusion rate.

Additional treatment: The safety and efficacy of this treatment with concomitant administration of heparin or platelet aggregation inhibitors as acetylsalicylic acid within the first 24 hours after the onset of symptoms have not been adequately studied. Therefore, administration of intravenous heparin or platelet aggregation inhibitors such as acetylsalicylic acid should be avoided for the first 24 hours after treatment with Actilyse due to an increased risk of bleeding. If heparin is required for other indications (eg prevention of deep vein thrombosis ) someone does not exceed 10,000 IU per day, administered subcutaneously.

Method of administration

The reconstituted solution should be given intravenously and used immediately.

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

Pediatric population

There is limited experience with the use of Actilyse in children and adolescents. Actilyse is contraindicated for the treatment of acute ischemic stroke in children and adolescents under 16 years of age (see section 4.3 of SmPC ). Dose one for adolescents aged 16-17 years is the same as for adults (see section 4.4 of the SmPCfor recommendations on the use of imaging methods before treatment).

Adolescents 16 years of age or older should be treated according to the instructions for the adult population after imaging has been used to rule out other stroke-like conditions and to confirm arterial occlusion corresponding to the neurological symptoms.

Muhammad Nadeem

Leave a Reply