ACTILYSE Ref.[2482] Active ingredients: Alteplase

Source: Medicines & Healthcare Products Regulatory Agency (GB)  Revision Year: 2012  Publisher: Boehringer Ingelheim Limited Ellesfield Avenue Bracknell Berkshire RG12 8YS

Therapeutic indications

Thrombolytic treatment in acute myocardial infarction

  • 90 minutes (accelerated) dose regimen (see section 4.2): for patients in whom treatment can be started within 6 h after symptom onset
  • 3 h dose regimen (see section 4.2): for patients in whom treatment can be started between 6 – 12 h after symptom onset provided that the diagnosis has been clearly confirmed.

Actilyse has proven to reduce 30-day-mortality in patients with acute myocardial infarction.

Thrombolytic treatment in acute massive pulmonary embolism with haemodynamic instability

The diagnosis should be confirmed whenever possible by objective means such as pulmonary angiography or non-invasive procedures such as lung scanning. There is no evidence for positive effects on mortality and late morbidity related to pulmonary embolism.

Fibrinolytic treatment of acute ischaemic stroke

Treatment must be started as early as possible within 4.5 hours after onset of stroke symptoms and after exclusion of intracranial haemorrhage by appropriate imaging techniques (e.g. cranial computerised tomography or other diagnostic imaging method sensitive for the presence of haemorrhage). The treatment effect is time-dependent; therefore earlier treatment increases the probability of a favourable outcome.

Posology and method of administration

Actilyse should be given as soon as possible after symptom onset. The following dose guidelines apply.

Under aseptic conditions the content of an injection vial of Actilyse (10 mg or 20 mg or 50 mg) is dissolved with water for injections according to the following table to obtain either a final concentration of 1 mg alteplase/ml or 2 mg alteplase/ml:

Actilyse vial10 mg20 mg50 mg
Volume of water for injections to be added to dry powder:
Final concentration
1 mg alteplase/ml (ml)102050
2 mg alteplase/ml (ml)51025

The reconstituted solution should then be administered intravenously. It may be diluted further with sterile sodium chloride 9 mg/ml (0.9 %) solution for injection up to a minimal concentration of 0.2 mg/ml. A dilution of the reconstituted solution with sterilised water for injections or in general, the use of carbohydrate infusion solutions, e.g. dextrose is not recommended. Actilyse should not be mixed with other medicinal products neither in the same infusion-vial nor the same catheter (not even with heparin). For further practical instructions for preparation and handling see sections 6.2 and 6.6.

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

Myocardial infarction

a) 90 minutes (accelerated) dose regimen for patients with myocardial infarction, in whom treatment can be started within 6 hours after symptom onset:

Concentration of alteplase
1 mg/ml2 mg/ml
mlml
15 mg as an intravenous bolus157.5
50 mg as an infusion over 30 minutes5025
followed by an infusion of 35 mg over 60 minutes until the maximal dose of 100 mg3517.5

In patients with a body weight below 65 kg the dose should be weight adjusted according to the following table:

Concentration of alteplase
1 mg/ml2 mg/ml
mlml
15 mg as an intravenous bolus157.5
ml/kg bwml/kg bw
and 0.75 mg/kg body weight (bw) over 30 minutes (maximum 50 mg)0.750.375
followed by an infusion of 0.5 mg/kg body weight (bw) over 60 minutes (maximum 35 mg)0.50.25

b) 3 h dose regimen for patients, in whom treatment can be started between 6 and 12 hours after symptom onset:

Concentration of alteplase
1 mg/ml2 mg/ml
mlml
15 mg as an intravenous bolus105
50 mg as an infusion over the first hour5025
ml/30 minml/ 30 min
followed by infusions of 10 mg over 30 minutes until the maximal dose of 100 mg over 3 hours105

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

The maximum dose of alteplase is 100 mg.

Adjunctive therapy: Antithrombotic adjunctive therapy is recommended according to the current international guidelines for the management of patients with ST-elevation myocardial infarction; acetylsalicylic acid should be initiated as soon as possible after symptom onset and continued with lifelong treatment unless it is contraindicated.

Pulmonary embolism

A total dose of 100 mg of alteplase should be administered in 2 hours. Most experience is available with the following dose regimen:

Concentration of alteplase
1 mg/ml2 mg/ml
mlml
10 mg as an intravenous bolus over 1 – 2 minutes105
followed by an intravenous infusion of 90 mg over 2 hours9045

The total dose should not exceed 1.5 mg/kg in patients with a body weight below 65 kg.

Adjunctive therapy

After treatment with Actilyse heparin therapy should be initiated (or resumed) when aPTT values are less than twice the upper limit of normal. The infusion should be adjusted to maintain aPTT between 50 – 70 seconds (1.5 to 2.5 fold of the reference value).

Acute ischaemic stroke

Treatment must only be performed under the responsibility and follow-up of a physician trained and experienced in neurovascular care, see sections 4.3 and 4.4.

The recommended dose is 0.9 mg alteplase/kg body weight (maximum of 90 mg) infused intravenously over 60 minutes with 10% of the total dose administered as an initial intravenous bolus.

Treatment with Actilyse must be started as early as possible within 4.5 hours of the onset of symptoms. Beyond 4.5 hours after onset of stroke symptoms there is a negative benefit risk ratio associated with actilyse administration and so it should not be administered (see section 5.1).

Adjunctive therapy

The safety and efficacy of this regimen with concomitant administration of heparin and acetylsalicylic acid within the first 24 hours of onset of the symptoms have not been sufficiently investigated. Administration of acetylsalicylic acid or intravenous heparin should be avoided in the first 24 hours after treatment with Actilyse. 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.

Overdose

The relative fibrin specificity notwithstanding, a clinical significant reduction in fibrinogen and other blood coagulation components may occur after overdosage. In most cases, it is sufficient to await the physiological regeneration of these factors after the Actilyse therapy has been terminated. If, however, severe bleeding results, the infusion of fresh frozen plasma or fresh blood is recommended and if necessary, synthetic antifibrinolytics may be administered.

Shelf life

3 years.

After reconstitution, an immediate use is recommended. However, the in-use stability has been demonstrated for 24 hours at 2 °C – 8 °C and for 8 hours at 25 °C.

Special precautions for storage

Store in the original package in order to protect from light.

Do not store above 25 °C.

For storage conditions of the reconstituted medicinal product, see section 6.3.

Nature and contents of container

Powder for solution: 10 ml, 20 ml or 50 ml sterilised glass vials, sealed with sterile siliconised grey butyl-type stoppers with aluminium/plastic flip-off caps.

Solvent: The water for injections is filled into either 10 ml, 20 ml or 50 ml vials, depending on the size of the powder vials. The water for injections vials are sealed with rubber stoppers and aluminium/plastic flip-off caps.

Transfer cannulas (included with pack sizes of 20 mg and 50 mg only)

Pack sizes

10 mg:

  • 1 vial with 467 mg powder for solution for injection and infusion
  • 1 vial with 10 ml of water for injections

20 mg:

  • 1 vial with 933 mg powder for solution for injection and infusion
  • 1 vial with 20 ml of water for injections
  • 1 transfer cannula

50 mg:

  • 1 vial with 2333 mg powder for solution for injection and infusion
  • 1 vial with 50 ml of water for injections
  • 1 transfer cannula

Not all pack sizes may be marketed.

Special precautions for disposal and other handling

For reconstitution to a final concentration of 1 mg altpelase per ml the full volume of solvent provided should be transfered to the vial containing the Actilyse powder. To this purpose a transfer cannula is included with the 20 mg and 50 mg pack sizes, which is to be used. For the 10 mg pack sizes a syringe should be used.

For reconstitution to a final concentration of 2 mg alteplase per ml only half of the solvent provided should be used. In these cases always a syringe should be used to transfer the required amount of solvent to the vial containing the Actilyse powder.

A table giving the volumes of solvent required for reconstitution to the final concentrations for each pack size is provided in section 4.2.

When reconstituting the product from the respective amount of powder and solvent, the mixture should only be agitated gently until complete dissolution. Any vigorous agitation should be avoided to prevent foam formation.

The reconstituted preparation is a clear and colourless to pale yellow solution. Prior to administration it should be inspected visually for particles and colour.

The reconstituted solution is for single use only. Any unused solution should be discarded.

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