ACTILYSE 50 MG

Israel - English - Ministry of Health

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Active ingredient:
ALTEPLASE
Available from:
BOEHRINGER INGELHEIM ISRAEL LTD.
ATC code:
B01AD
Pharmaceutical form:
POWDER AND SOLVENT FOR SOLUTION FOR INJECTION/INFUSION
Composition:
ALTEPLASE 50 MG/VIAL
Administration route:
I.V
Prescription type:
Required
Manufactured by:
BOEHRINGER INGELHEIM PHARMA GMBH & CO.KG, GERMANY
Therapeutic group:
ENZYMES
Therapeutic indications:
Acute myocardial infarction :Actilyse is indicated for use in the management of acute myocardial infraction (AMI) in adults for the lysis of thrombi obstructing coronary arteries, the reduction of infract size, improvement of ventricular function, the reduction of the incidence of congestive heart failure and the reduction of mortality associated with AMI. Treatment should be initiated as soon as possible after the onset of AMI symptoms.Acute massive pulmonary embolism with hemodynamic deprivation:Actylise is indicated in the management of acute massive pulmonary embolism (PE) in adults:- for the lysis of acute pulmonary emboli, defined as obstruction of blood flow to a lobe or multiple segments of the lung, and- for the lysis of pulmonary emboli accompanied by unstable hemodynamics e.g. failure to maintain blood pressure without supportive measures. The diagnosis should be confirmed by objective means, such as pulmonary angiography or noninvasive procedures such as lung scanning. For fibrinolytic treatment o
Authorization number:
059 55 26312 00
Authorization date:
2015-02-28

ילוי

2019

,ה/רקי ה/אפור

ה/רקי ת/חקור

וכדע :ןודנה

ן

ולע

ן

רישכתה לש

mg

50

mg and Actilyse

20

Actilyse

(Alteplase)

תרבח

םייהלגניא רגנירוב םכעידוהל תשקבמ מ"עב לארשי וכדע לע

ןולעב

אפור

לש

.ןודנב רישכתה

יוותה

מושרה

לארשיב רישכתל

Acute Myocardial Infarction

In adults for the lysis of thrombi obstructing coronary arteries, the reduction of infarct size, the

improvement of ventricular function, the reduction of the incidence of congestive heart failure and

the reduction of mortality associated with AMI.

Treatment should be initiated as soon as possible after the onset of AMI symptoms.

Acute Massive Pulmonary embolism with hemodynamic deprivation.

Actilyse is indicated in the management of acute massive pulmonary embolism (PE) in adults:

- for the lysis of acute pulmonary emboli, defined as obstruction of blood flow to a lobe or multiple

segments of the lung,

- for the lysis of pulmonary emboli accompanied by unstable hemodynamics e.g. failure to maintain

blood pressure without supportive measures.

The diagnosis should be confirmed by objective means, such as pulmonary angiography or

noninvasive procedures such as lung scanning.

For 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.

This treatment is restricted to a prescription by a specialist in neurology.

ולעב רתויב םייתועמשמה םייונישה

.הטמ ונמוס

ולעה

כדועמה

לשנ

תואירבה דרשמ רתאבש תופורתה רגאמב םוסרפל

,ןכ ומכ

לבקל ןתינ

לע

:םושירה לעבל היינפ ידי

םידוהיה תנידמ 'חר ,מ"עב לארשי םייהלגניא רגנירוב

חותיפ הילצרה

בו ןופלט

09-9730500

ה כ ר ב ב

ח ירימ ןז

הנוממ תחקור

לארשי םייהלגניא רגנירוב

ןולעב םינוכדע :אפור

Hypersensitivity

[…]

There is also a risk of hypersensitivity reactions mediated through a non-immunological mechanism.

Angio-oedema represents the most common hypersensitivity reaction reported with Actilyse. This risk

may be enhanced in the indication acute ischaemic stroke and/or by concomitant treatment with ACE

inhibitors (see section 4.5). Patients treated for any authorised indication should be monitored for angio-

oedema during and for up to 24h after infusion.

[…]

1. NAME OF THE MEDICINAL PRODUCT

Actilyse 20 mg. Actilyse 50 mg

Powder and solvent for solution for injection or infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 vial with powder contains:

20 mg alteplase (corresponding to 11,600,000 IU) or

50 mg alteplase (corresponding to 29,000,000 IU).

Alteplase is produced by recombinant DNA technique using a Chinese hamster ovary cell-line. The

specific activity of alteplase in-house reference material is 580,000 IU/mg. This has been confirmed

by comparison with the second international WHO standard for t-PA. The specification for the

specific activity of alteplase is 522,000 to 696,000 IU/mg.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for solution for injection and infusion.

The powder is presented as a colourless to pale yellow lyophilizate cake. The reconstituted preparation

is a clear and colourless to pale yellow solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Acute Myocardial Infarction

In adults for the lysis of thrombi obstructing coronary arteries,

the reduction of infarct size, the

improvement of ventricular function, the reduction of the incidence of congestive heart failure and the

reduction of mortality associated with AMI.

Treatment should be initiated as soon as possible after the onset of AMI symptoms.

Acute Massive Pulmonary embolism with hemodynamic deprivation.

Actilyse is indicated in the management of acute massive pulmonary embolism (PE) in adults:

- for the lysis of acute pulmonary emboli, defined as obstruction of blood flow to a lobe or multiple

segments of the lung,

- for the lysis of pulmonary emboli accompanied by unstable hemodynamics e.g. failure to maintain

blood pressure without supportive measures.

The diagnosis should be confirmed by objective means, such as pulmonary angiography or

noninvasive procedures such as lung scanning.

For 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

intracranial

haemorrhage

appropriate

imaging

techniques

(e.g.

cranial

computerised

tomography

other

diagnostic

imaging

method

sensitive

presence

haemorrhage). The

treatment

effect

is time-dependent; therefore

earlier

treatment

increases

probability of a favourable outcome.

This treatment is restricted to a prescription by a specialist in neurology.

4.2 Posology and method of administration

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

apply.

Acute myocardial infarction

Posology

90 minutes (accelerated) dose regimen for patients with acute myocardial infarction, in whom

treatment can be started within 6 hours after symptom onset.

In patients with a body weight ≥65 kg:

Volume to be administered

according to alteplase

concentration

1 mg/ml 2 mg/ml

15 mg as an intravenous bolus, immediately

followed by

15 ml

7.5 ml

50 mg as an intravenous constant rate infusion over

the first 30 minutes, immediately followed by

50 ml

25 ml

35 mg as an intravenous constant rate infusion over

60 minutes, until the maximum total dose of 100 mg

35 ml

17.5 ml

In patients with a body weight < 65 kg the total dose should be weight adjusted according to the

following table:

Volume to be administered

according to alteplase

concentration

1 mg/ml 2 mg/ml

15 mg as an intravenous bolus, immediately

followed by

15 ml

7.5 ml

0.75 mg/kg body weight (bw) as an intravenous

constant rate infusion over the first 30 minutes,

immediately followed by

0.75 ml/kg

0.375 ml/kg

0.5 mg/kg body weight (bw) as an intravenous

constant rate infusion over 60 minutes

0.5 ml/kg

0.25

ml/kg bw

3 h dose regimen for patients with acute myocardial infarction, in whom treatment can be

started between 6 and 12 hours after symptom onset.

In patients with body weight ≥65 kg:

Volume to be administered

according to alteplase

concentration

1 mg/ml 2 mg/ml

10 mg as an intravenous bolus, immediately

followed by

10 ml

5 ml

50 mg as an infusion over the first hour

50 ml

25 ml

40 mg as an intravenous infusion for the next two

hours, until the maximum total dose of 100 mg

10 ml/30

5 ml/30 min

In patients with a body weight <65 kg:

Volume

administered

according

alteplase

concentration

1 mg/ml

2 mg/ml

intravenous

bolus,

immediately

followed by

10 ml

5 ml

an intravenous constant rate infusion

over 3 hours

to a maximum total dose of 1.5 mg/kg bw.

ml/kg

0.75 ml/kg bw

Adjunctive therapy

Antithrombotic adjunctive therapy is recommended according to the current international guidelines

for the management of patients with ST-elevation myocardial infarction;

Method of administration

The reconstituted solution should be administered intravenously and is for immediate use.

For instructions prior to reconstitution / administration, see section 6.6.

Acute Massive pulmonary embolism

Posology

In patients with a body weight ≥65 kg:

A total dose of 100 mg of alteplase should be administered in 2 hours. Most experience is available

with the following dose regimen:

Volume to be administered

according to alteplase

concentration

1 mg/ml 2 mg/ml

10 mg as an intravenous bolus over 1 - 2 minutes,

immediately followed by

10 ml

5 ml

90 mg as an intravenous constant rate infusion over

2 hours until the maximum total dose of 100 mg

90 ml

45 ml

In patients with a body weight < 65 kg:

Volume

administered

according

alteplase

concentration

1 mg/ml

2 mg/ml

10 mg as an intravenous bolus over 1 - 2 minutes,

immediately followed by

10 ml

5 ml

an intravenous infusion up to a maximum total dose

of 1.5 mg/kg

ml/kg

0.75 ml/kg bw

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).

Method of administration

The reconstituted solution should be administered intravenously and is for immediate use.

For instructions prior to reconstitution / administration, see section 6.6.

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.

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).

Posology

The recommended total dose is 0.9 mg alteplase/kg body weight (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 minute.

DOSING TABLE FOR ACUTE ISCHAEMIC STROKE

Weight

(kg)

Total Dose

(mg)

Bolus Dose

(mg)

Infusion Dose*

(mg)

36.0

32.4

37.8

34.0

39.6

35.6

41.4

37.3

43.2

38.9

45.0

40.5

46.8

42.1

48.6

43.7

50.4

45.4

52.2

47.0

54.0

48.6

55.8

50.2

57.6

51.8

59.4

53.5

61.2

55.1

63.0

56.7

64.8

58.3

66.6

59.9

68.4

61.6

70.2

63.2

72.0

64.8

73.8

66.4

75.6

68.0

77.4

69.7

79.2

71.3

81.0

72.9

82.8

74.5

84.6

76.1

86.4

77.8

88.2

79.4

100+

90.0

81.0

*given in a concentration of 1mg/mL over 60 min

as a constant rate infusion

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 due to an increased haemorrhagic risk. 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.

Method of administration

The reconstituted solution should be administered intravenously and is for immediate use.

For instructions prior to reconstitution / administration, see section 6.6.

Paediatric population

There is limited experience with the use of Actilyse in children and adolescents. Actilyse is

contraindicated for the treatment of acute ischaemic stroke in children and adolescents under 16 years

of age (see section 4.3). The dose for adolescents 16-17 years old is the same as for adults (see section

4.4 for recommendations on prior imaging techniques to be used).

4.3 Contraindications

Generally

indications

Actilyse

should

administered

patients

with

known

hypersensitivity to the active substance alteplase, gentamicin (a trace residue from the manufacturing

process) or to any of the excipients listed in section 6.1.

Contraindications in acute myocardial infarction, acute massive pulmonary embolism and acute

ischaemic stroke:

Actilyse is contraindicated in cases where there is a high risk of haemorrhage such as:

significant bleeding disorder at present or within the past 6 months

known haemorrhagic diathesis

patients receiving effective oral anticoagulant treatment, e.g. warfarin sodium

((INR>1.3) (see

section 4.4)

manifest or recent severe or dangerous bleeding

known history of or suspected intracranial haemorrhage

suspected

subarachnoid

haemorrhage

condition after

subarachnoid haemorrhage from

aneurysm

any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal

surgery)

recent (less than 10 days) traumatic external heart massage, obstetrical delivery, recent

puncture of a non-compressible blood-vessel (e.g. subclavian or jugular vein puncture)

severe uncontrolled arterial hypertension

bacterial endocarditis, pericarditis

acute pancreatitis

documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices,

arterial-aneurysm, arterial/venous malformations

neoplasm with increased bleeding risk

severe liver disease, including hepatic failure, cirrhosis, portal hypertension (oesophageal

varices) and active hepatitis

major surgery or significant trauma in past 3 months.

Additional contraindications in acute myocardial infarction:

any known history of haemorrhagic stroke or stroke of unknown origin .

known history of ischaemic stroke or transient ischaemic attack (TIA) in the preceding

6 months, except current acute ischaemic stroke within 4.5 hours.

Additional contraindications in acute massive pulmonary embolism:

any known history of haemorrhagic stroke or stroke of unknown origin.

known history of ischaemic stroke or transient ischaemic attack (TIA) in the preceding

6 months, except current acute ischaemic stroke within 4.5 hours.

Additional contraindications in acute ischaemic stroke:

symptoms of ischaemic attack beginning more than 4.5 hours prior to infusion start or

symptoms for which the onset time is unknown and could potentially be more than 4.5 hours

ago (see section 5.1)

minor neurological deficit or symptoms rapidly improving before start of infusion

severe stroke as assessed clinically (e.g. NIHSS>25) and/or by appropriate imaging techniques

seizure at onset of stroke

evidence of intracranial haemorrhage (ICH) on the CT-scan

symptoms suggestive of subarachnoid haemorrhage, even if CT-scan is normal

administration of heparin within the previous 48 hours and a thromboplastin time exceeding

the upper limit of normal for laboratory

patients with any history of prior stroke and concomitant diabetes

prior stroke within the last 3 months

platelet count of below 100,000/mm

systolic

blood

pressure

>

diastolic

>

aggressive

management (intravenous pharmacotherapy) necessary to reduce BP to these limits

blood glucose < 50 mg/dl or > 400 mg/dl (<2.8mM or >22.2mM).

Use in children and adolescents

Actilyse is not indicated for the treatment of acute ischaemic stroke in children under 16 years of age

(for adolescents ≥ 16 years of age see section 4.4).

4.4 Special warnings and precautions for use

Traceability

In order to improve traceability of biological medicinal products, the trade name and the batch number

of the administered product should be clearly recorded in the patient file.

.

Thrombolytic/ fibrinolytic treatment requires adequate monitoring. Actilyse should only be used under

the responsibility and follow-up of physicians trained and experienced in the use of thrombolytic

treatments and with the facilities to monitor that use. It is recommended that when Actilyse is

administered, standard resuscitation equipment and pharmacotherapy is available in all circumstances.

Hypersensitivity

Immune-mediated hypersensitivity reactions associated with the administration of Actilyse can be

caused by the active substance alteplase, gentamicin (a trace residue from the manufacturing process),

any of the excipients, or the stopper of the glass vial with Actilyse powder which contains natural

rubber (a derivative of latex). No sustained antibody formation to the recombinant human tissue-type

plasminogen activator molecule has been observed after treatment. There is no systematic experience

with re-administration of Actilyse.

There is also a risk of hypersensitivity reactions mediated through a non-immunological mechanism.

Angio-oedema represents the most common hypersensitivity reaction reported with Actilyse. This risk

may be enhanced in the indication acute ischaemic stroke and/or by concomitant treatment with ACE

inhibitors (see section 4.5). Patients treated for any authorised indication should be monitored for

angio-oedema during and for up to 24h after infusion.

If a severe hypersensitivity reaction (e.g. angio-oedema) occurs, the infusion should be discontinued

and appropriate treatment promptly initiated. This may include intubation.

Haemorrhages

The most common complication encountered during Actilyse therapy is bleeding. The concomitant

use of heparin anticoagulation may contribute to bleeding. As fibrin is lysed during Actilyse therapy,

bleeding from recent puncture sites may occur. Therefore, thrombolytic therapy requires careful

attention to all possible bleeding sites (including those following catheter insertion, arterial and venous

puncture cutdown and needle puncture). The use of rigid catheters, intramuscular injections and non-

essential handling of the patient should be avoided during treatment with Actilyse.

If a potentially dangerous haemorrhage occurs, in particular cerebral haemorrhage, the fibrinolytic

therapy

must

discontinued

concomitant

heparin

administration

should

terminated

immediately.. In general, however, it is not necessary to replace the coagulation factors because of the

short half-life and the minimal effect on the systemic coagulation factors. Most patients who have

bleeding

managed

interruption

thrombolytic

anticoagulant

therapy,

volume

replacement, and manual pressure applied to an incompetent vessel. Protamine should be considered if

heparin has been administered within 4 hours of the onset of bleeding. In the few patients who fail to

respond to these conservative measures, judicious use of transfusion products may be indicated.

Transfusion of cryoprecipitate, fresh frozen plasma, and platelets should be considered with clinical

and laboratory reassessment after each administration. A target fibrinogen level of 1 g/l is desirable

with cryoprecipitate infusion. Antifibrinolytic agents are available as a last alternative.

The risk of intracranial haemorrhage is increased in elderly patients, therefore in these patients the

risk/benefit evaluation should be carried out carefully.

As with all thrombolytic agents, the expected therapeutic benefit should be weighed up particularly

carefully against the possible risk, especially in patients with

small recent traumas, such as biopsies, puncture of major vessels, intramuscular injections,

cardiac massage for resuscitation

conditions with an increased risk of haemorrhage which are not mentioned in section 4.3.

Patients receiving oral anticoagulant treatment:

The use of Actilyse may be considered when dosing or time since the last intake of anticoagulant

treatment makes residual efficacy unlikely confirmed by appropriate test(s) of anticoagulant activity

for the product(s) concerned showing no clinically relevant activity on the coagulation system (e.g.

INR≤ 1.3 for vitamin K antagonists or other relevant test(s) for other oral anticoagulants are within the

respective upper limit of normal).

Paediatric population As yet, there is only limited experience with the use of Actilyse in children and

adolescents. When Actilyse is considered for the treatment of acute ischaemic stroke in carefully

selected adolescents ≥ 16 years of age the benefit should be weighed carefully against the risks on an

individual basis and discussed with the patient and parent/guardian as appropriate. Adolescents ≥ 16

years of age should be treated according to the instruction in the label for the adult population after

imaging by appropriate techniques to rule out stroke mimics and confirming arterial occlusion

corresponding to the neurological deficit (see section 5.1).

Additional

special

warnings

precautions

acute

myocardial

infarction

acute

massive

pulmonary embolism:

A dose exceeding 100 mg of alteplase must not be given because it has been associated with an

additional increase in intracranial bleeding.

Therefore special care must be taken to ensure that the dose of alteplase infused is as described in

section 4.2.

The expected therapeutic benefit should be weighed up particularly carefully against the possible risk,

especially in patients with systolic blood pressure > 160 mm Hg (see section 4.3)

and with advanced

age which may increase the risk of intracerebral haemorrhage. As the therapeutic benefit is also

positive in elderly patients, the risk-benefit-evaluation should be carried out carefully.

GPIIb/IIIa antagonists:

Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.

Additional special warnings and precautions in acute myocardial infarction

Arrhythmias:

Coronary thrombolysis may result in arrhythmia associated with reperfusion.

Reperfusion arrhythmias may lead to cardiac arrest, can be life threatening and may require the use of

conventional antiarrhythmic therapies.

Thromboembolism:

The use of thrombolytics can increase the risk of thrombo-embolic events in patients with left heart

thrombus, e.g., mitral stenosis or atrial fibrillation.

Additional special warnings and precautions in acute ischaemic stroke:

Special precautions for use:

Treatment must only be performed under the responsibility and follow-up of a physician trained and

experienced in neurovascular care. For the verification of treatment indication remote diagnostic

measures may be considered as appropriate (see section 4.1).

Special warnings / conditions with a decreased benefit/risk ratio:

Intracerebral haemorrhage represents the major adverse reaction in the treatment of acute ischaemic

stroke (up to 15 % of patients without any increase of overall mortality and without any relevant

increase in overall mortality and severe disability combined, i.e.

modified Rankin scale (

mRS) score of 5

and 6).

Compared to other indications, patients with acute ischaemic stroke treated with Actilyse have a

markedly increased risk of intracranial haemorrhage as the bleeding occurs predominantly into the

infarcted area. This applies in particular in the following cases:

all situations listed in section 4.3. and in general all situations involving a high risk of

haemorrhage

time

treatment

from

onset

stroke

symptoms

increases,

clinical

benefit

decreases.Therefore, the administration of Actilyse should not be delayed.

patients pre-treated with acetyl salicylic acid (ASA) may have a greater risk of intracerebral

haemorrhage, particularly if Actilyse treatment is delayed.

Compared to younger patients, patients of advanced age (over 80 years) may have a somewhat

poorer outcome independent of treatment. They are also more likely to have more severe

strokes which are associated with a higher absolute risk of intracerebral haemorrhage when

thrombolysed compared with milder strokes when thrombolysed or with non-thrombolysed

patients. Although available data indicate that the net benefit of Actilyse in patients over 80

years is smaller compared with younger patients, Actilyse can be used in patients over 80

years on an individual benefit-risk basis (see section 5.1). Patients of advanced age should be

selected very carefully taking into account both the general health and the neurological status.

The therapeutic benefit is reduced in patients that had a prior stroke (see also section 4.3) or in

those

with

known

uncontrolled

diabetes,

thus

benefit/risk

ratio

considered

less

favourable, but still positive in these patients.

In patients with very mild stroke, the risks outweigh the expected benefit (see section 4.3).

Patients with very severe stroke are at higher risk for intracerebral haemorrhage and death and

should not be treated (see section 4.3).

Patients with extensive infarctions are at greater risk of poor outcome including severe

haemorrhage

death.

such

patients,

benefit/risk

ratio

should

thoroughly

considered.

In stroke patients the likelihood of good outcomes decreases with longer time to treatment

from onset of symptoms, increasing age, increasing stroke severity and increased levels of

blood glucose on admission while the likelihood of severe disability and death or symptomatic

intracranial bleedings increases, independently from treatment.

Treatment must not be initiated later than 4.5 hours after the onset of symptoms because of

unfavourable benefit/risk ratio mainly based on the following:

positive treatment effects decrease over time

particularly in patients with prior ASA treatment the mortality rate increases

increased risk of symptomatic haemorrhage

Blood pressure monitoring

Blood pressure (BP) monitoring during treatment administration and up to 24 hours seems justified; an

intravenous antihypertensive therapy is also recommended if systolic BP > 180 mm Hg or diastolic

>

105 mm Hg.

Other special warnings

Reperfusion of the ischaemic area may induce cerebral oedema in the infarcted zone.

Due to an increased haemorrhagic risk, treatment with platelet aggregation inhibitors should not be

initiated within the first 24 hours following thrombolysis with alteplase.

4.5 Interaction with other medicinal products and other forms of interaction

No formal interaction studies with Actilyse and medicinal products commonly administered in patients

with acute myocardial infarction have been performed.

Drugs affecting coagulation/platelet function

risk

haemorrhage

increased

coumarine

derivatives,

oral

anticoagulants,

platelet

aggregation inhibitors, unfractionated heparin or LMWH or active substances which interfere with

coagulation are administered (before, during or within the first 24 hours after treatment with Actilyse)

(see section 4.3).

ACE inhibitors

Concomitant treatment with ACE inhibitors may enhance the risk of suffering a hypersensitivity

reaction (see section 4.4)

Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.

4.6 Fertility, pregnancy and lactation

Pregnancy:

There is a limited amount of data from the use of Actilyse in pregnant women. Nonclinical studies

performed with alteplase in doses higher than human doses exhibited fetal immaturity and/or

embryotoxicity, secondary to the known pharmacological activity of the drug. Alteplase is not

considered to be teratogenic (see section 5.3).

In cases of an acute life-threatening disease the benefit has to be evaluated against the potential risk.

Breast-feeding:

It is not known if alteplase is excreted into human milk.

Fertility:

Clinical data on fertility are not available for Actilyse. Nonclinical studies performed with alteplase

showed no adverse effect on fertility (see section 5.3)

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

The most frequent adverse reaction associated with Actilyse is bleeding in different forms resulting in

a fall in haematocrit and/or haemoglobin values.

Adverse

reactions

listed

below

classified

according

frequency

system

organ

class.

Frequency groupings are defined according to the following convention: Very common (≥1/10),

Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very

rare (<1/10,000), Not known (cannot be estimated from the available data).

Except for intracerebral

intracranial haemorrhage as adverse reaction in the indication stroke

as well as

reperfusion arrhythmias in the indication acute myocardial infarction, there is no medical reason to

assume that the qualitative and quantitative adverse reaction profile of Actilyse in the indications acute

massive pulmonary embolism and acute ischaemic stroke is different from the profile in the indication

acute myocardial infarction.

Table 1 Adverse reactions in acute myocardial infarction, acute massive pulmonary embolism and

acute ischaemic stroke

System Organ Class

Adverse Reaction

Haemorrhage

very common

intracerebral haemorrhage represents the major adverse reaction in the treatment

of acute ischaemic stroke

all haemorrhages including those in this table, e.g. ICH and non-ICH

common

intracerebral haemorrhage (such as cerebral haemorrhage, cerebral haematoma,

haemorrhagic stroke, haemorrhagic transformation of stroke, intracranial

haematoma, subarachnoid haemorrhage) in the treatment of acute myocardial

infarction and acute massive pulmonary embolism

pharyngeal haemorrhage

gastrointestinal haemorrhage (such as gastric haemorrhage, gastric ulcer

haemorrhage, rectal haemorrhage, haematemesis, melaena, mouth haemorrhage,

gingival bleeding)

ecchymosis

urogenital haemorrhage (such as haematuria, haemorrhage urinary tract)

injection site haemorrhage (puncture site haemorrhage, catheter site haematoma,

catheter site haemorrhage)

uncommon

pulmonary haemorrhage (such as haemoptysis, hemothorax, respiratory tract

haemorrhage)

epistaxis

ear haemorrhage

rare

eye haemorrhage

pericardial haemorrhage

retroperitoneal bleeding (such as retroperitoneal haematoma)

not known***

bleeding in parenchymatous organs (such as hepatic haemorrhage)

Immune system disorders

rare

hypersensitivity reactions (e.g. rash, urticaria, bronchospasm, angio-oedema,

hypotension, shock*)

very rare

serious anaphylaxis

Nervous system disorders

very rare

events related to the nervous system (e.g. epileptic seizure, convulsion, aphasia,

speech disorder, delirium, acute brain syndrome, agitation, confusion, depression,

psychosis) often in association with concurrent ischaemic or haemorrhagic

cerebrovascular events

Cardiac disorders**

very common

recurrent ischaemia / angina pectoris, hypotension and heart failure / pulmonary

oedema,

common

cardiogenic shock, cardiac arrest and reinfarction

uncommon

reperfusion arrhythmias (such as arrhythmia, extrasystoles, AV block first degree

to atrioventricular block complete, atrial fibrillation / flutter, bradycardia,

tachycardia, ventricular arrhythmia, ventricular tachycardia / fibrillation,

electromechanical dissociation [EMD])

mitral regurgitation, pulmonary embolism, other systemic embolism / cerebral

embolism, ventricular septal defect

Vascular disorders

rare

Embolism which may lead to corresponding consequences in the organs

concerned

Gastrointestinal disorders

rare

nausea

not known***

vomiting

Investigations

uncommon

blood pressure decreased

not known***

body temperature increased

Injury and poisoning and procedural complications

not known***

fat embolism (cholesterol crystal embolisation), which may lead to corresponding

consequences in the organs concerned

Surgical and medicinal procedures

not known***

Blood transfusions (necessary)

* See sections 4.4 and 4.5

**Cardiac disorders

As with other thrombolytic agents, the events described above under the respective section have been reported as

sequelae of myocardial infarction and / or thrombolytic administration. These cardiac events can be life-

threatening and may lead to death.

***Frequency calculation

This adverse reaction has been observed in post-marketing experience. With 95 % certainty, the frequency

category is not greater than “rare”, but might be lower. Precise frequency estimation is not possible as the

adverse drug reaction did not occur in a clinical trial database of 8299 patients.

Death and permanent disability are reported in patients who have experienced stroke (including intracranial

bleeding) and other serious bleeding episodes.

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.h

ealth.gov.il

4.9 Overdose

Symptoms

If the maximum recommended dose is exceeded the risk of intracranial bleeding increases.

The relative fibrin specificity notwithstanding, a clinical significant reduction in fibrinogen and other

blood coagulation components may occur after overdosage.

Therapy

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

is recommended and if necessary, synthetic antifibrinolytics may be administered.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, ATC-code: B01AD02.

Mechanism of action

The active ingredient of Actilyse is alteplase, a recombinant human tissue-type plasminogen activator,

a glycoprotein, which activates plasminogen directly to plasmin. When administered intravenously,

alteplase remains relatively inactive in the circulatory system. Once bound to fibrin, it is activated,

inducing the conversion of plasminogen to plasmin leading to the dissolution of the fibrin clot.

Pharmacodynamic effects

Due to its relative fibrin-specificity, alteplase at a dose of 100 mg leads to a modest decrease of the

circulating fibrinogen levels to about 60 % at 4 hours, which is generally reverted to more than 80 %

after 24 hours. Plasminogen and alpha-2-antiplasmin decrease to about 20 % and 35 % respectively

after 4 hours and increase again to more than 80 % at 24 hours. A marked and prolonged decrease of

the circulating fibrinogen level is only seen in few patients.

Clinical efficacy and safety

In a study including more than 40,000 patients with an acute myocardial infarction (GUSTO) the

administration of 100 mg alteplase over 90 minutes, with concomitant intravenous heparin infusion,

led to a lower mortality after 30 days (6.3 %) as compared to the administration of streptokinase, 1.5

million U over 60 minutes, with subcutaneous or intravenous heparin (7.3 %). Actilyse-treated patients

showed higher infarct related vessel patency rates at 60 and 90 minutes after thrombolysis than the

streptokinase-treated patients. No differences in patency rates were noted at 180 minutes or longer.

30-day-mortality is reduced as compared to patients not undergoing thrombolytic therapy.

The release of alpha-hydroxybutyrate-dehydrogenase (HBDH) is reduced. Global ventricular function

as well as regional wall motion is less impaired as compared to patients receiving no thrombolytic

therapy.

Acute myocardial infarction

A placebo controlled trial with 100 mg alteplase over 3 hours (LATE) showed a reduction of 30 day-

mortality compared to placebo for patients treated within 6-12 hours after symptom onset. In cases, in

which clear signs of myocardial infarction are present, treatment initiated up to 24 hours after

symptom onset may still be beneficial.

Acute massive pulmonary embolism

In patients with acute massive pulmonary embolism with haemodynamic instability thrombolytic

treatment with Actilyse leads to a fast reduction of the thrombus size and a reduction of pulmonary

artery pressure. Mortality data are not available.

Acute ischaemic stroke Patients

In two USA studies (NINDS A/B) a significant higher proportion of patients, had a favourable

outcome with alteplase, compared to placebo (no or minimal disability).

These findings were confirmed in the ECASS III trial (see paragraph below), after in the meantime

two European studies and an additional USA study had failed to provide the respective evidence in

settings essentially not compliant with the current EU product information.

The ECASS III trial was a placebo-controlled, double-blind trial conducted in patients with acute

stroke in a time-window of 3 to 4.5 hours in Europe. Treatment administration in the ECASS III study

was in line with the European SmPC for Actilyse in its stroke indication, except

the upper end of the

time

treatment

window

i.e.

hours.

primary

point

disability

days,

dichotomized for favourable (modified Rankin scale [mRS] 0 to 1) or unfavourable (mRS 2 to 6)

outcome. A total of 821 patients (418 alteplase/403 placebo) were randomized. More patients achieved

favourable outcome with alteplase (52.4%) vs. placebo (45.2%; odds ratio [OR] 1.34; 95% CI 1.02 -

1.76; P=0.038). The incidence of any ICH/SICH was higher with alteplase vs. placebo (any ICH

27.0% vs 17.6%, p=0.0012; SICH by ECASS III definition 2.4% versus 0.2 %, p = 0.008). Mortality

was low and not significantly different between alteplase (7.7%) and placebo (8.4%; P=0.681).

Subgroup results of ECASS III confirm that a longer OTT is associated with an increasing risk for

mortality and symptomatic intracranial haemorrhage. The results of ECASS III show a positive net-

clinical benefit for Actilyse in the 3 to 4.5 hour time window, while pooled data demonstrate that the

net-clinical benefit is no longer favourable for alteplase in the time window beyond 4.5 hours.

The safety and efficacy of Actilyse

for acute ischaemic stroke treatment up to 4.5 hours time

stroke

onset time to start of treatment

(OTT) has been assessed by an ongoing registry (SITS-ISTR: The

Safe Implementation of Thrombolysis in Stroke registry). In this observational study safety outcome

data of 21.566 treated patients in the 0 to 3 hour time window were compared with data from 2.376

patients treated between 3 to 4.5 hours after onset of AIS. The incidence of symptomatic intracranial

haemorrhage (according to the SITS-MOST definition) was found to be higher in the 3 to 4.5 hour

time window (2.2%) as compared with the up to 3 hour time window (1.7%). Mortality rates at 3

months were similar comparing the 3 to 4.5 hour time window (12.0%) with the 0 to 3.0 hours time

window (12.3%) with an unadjusted OR 0.97 (95% CI: 0.84-1.13, p=0.70) and an adjusted OR 1.26

(95% CI: 1.07-1.49, p=0.005. The SITS observational data support clinical trial evidence of

stroke

onset time to start of treatment

(OTT) as an important predictor of outcome following acute stroke

treatment with alteplase.

Elderly (> 80 years)

Individual patient data adjusted meta-analyses from 6,756 patients including those aged > 80 years in

nine randomised trials comparing alteplase with placebo or open control were used to assess the

benefit-risk of alteplase in patients > 80 years. The probability of a good stroke outcome (mRS 0 - 1 at

day 90/180) was increased and was associated with a larger benefit when treated earlier for all age

groups (p-value for interaction of 0.0203) and was independent of age.

The effect of alteplase treatment was similar for patients aged 80 years or younger [mean treatment

delay 4.1 hours: 990/2512 (39%) alteplase treated vs 853/2515 (34%) controls achieved good stroke

outcome at day 90/180; OR 1.25, 95% CI 1.10-1.42] and for those older than 80 years [mean treatment

delay 3.7 hours: 155/879 (18%) alteplase treated vs 112/850 (13%) controls achieved good stroke

outcome; OR 1.56, 95% CI 1.17-2.08].

In patients older than 80 years treated with alteplase less or equal to 3 hours, a good stroke outcome

was achieved in 55/302 (18.2%) vs 30/264 (11.4%) in controls (OR 1.86, 95% CI 1.11-3.13) and in

those treated with alteplase 3 hours-4.5 hours 58/342 (17.0%) achieved a good stroke outcome vs

50/364 (13.7%) in controls (OR 1.36, 95% CI 0.87-2.14).

Type 2 parenchymal haemorrhage within 7 days occurred in 231 (6.8%) of 3,391 patients assigned to

alteplase versus 44 (1.3%) of 3,365 assigned to control (OR 5.55, 95% CI 4.01-7.70).

Fatal type 2 parenchymal haemorrhage within 7 days occurred in 91 (2.7%) patients assigned to

alteplase versus 13 (0.4%) assigned to control (OR 7.14, 95% CI 3.98-12.79).

In patients older than 80 years treated by alteplase a fatal intracranial haemorrhage within 7 days

occurred in 32/879 (3.6%) vs 4/850 (0.5%) in controls (OR 7.95, 95% CI 2.79-22.60).

From a total of 8,658 patients > 80 years treated < 4.5 hours of stroke onset in the SITS-ISTR, the data

of the 2,157 patients treated > 3 to 4.5 hours from stroke onset were compared to those of the 6,501

patients treated < 3 hours.

Three-month functional independence (mRS score 0 - 2) was 36 vs 37% (adjusted OR 0.79, 95% CI

0.68- 0.92), mortality was 29.0% vs 29.6% (adjusted OR 1.10, 95% CI 0.95-1.28), and sICH (per

SITS-MOST definition) was 2.7% vs 1.6% (adjusted OR 1.62, 95% CI 1.12-2.34).

Paediatric population

Observational non-randomised and non-comparative data on stroke patients of 16 -17 years of age

with confirmed alteplase treatment was obtained from SITS-ISTR (Safe Implementation of Treatments

in Stroke - International Stroke Thrombolysis Register, an independent, international registry).

Between 2003 and the end of 2017, a total of 25 paediatric patients with confirmed alteplase use

within the age group of 16 – 17 years were collected in the SITS registry. The median dose of

alteplase used in this age group was 0.9mg/kg (range: 0.83 - 0.99mg/kg). 23 of 25 patients initiated

treatment within the 4.5h after stroke symptoms onset (19 by 3h; 4 by 3 - 4.5h; 1 by 5 – 5.5h; 1 case

not reported). The weight ranged from 56 – 90 kg. Most patients presented with moderate or moderate

to severe stroke with a median NIHSS of 9.0 (range 1 – 30) at baseline.

Day 90 mRS scores were available in 21/25 patients. At day 90, 14/21 patients had a mRS score of 0-1

(no symptoms or no significant disability) and 5 further patients had mRS = 2 (slight disability). This

means that 19/21 (over 90%) of the patients had a favourable outcome at day 90 according to mRS.

The remaining 2 patients had either a reported outcome of moderate severe disability (mRS=4; n=1),

or death (mRS=6) within 7 days (n=1).

Four patients did not have a day 90 mRS score reported. The last available information showed that

2/4 patients had a mRS of 2 at day 7 and 2/4 patients reported a clear global improvement at day 7.

Safety data on adverse events for haemorrhages and oedema were also available in the registry. Of the

25 patients from age category 16 -17 years, none had symptomatic intracerebral haemorrhage (sICH,

ICH bleeding type PH2). 5 cases developed cerebral oedema after alteplase treatment. 4/5 patients

with cerebral oedema had either a reported day 90 mRS between 0 and 2 or showed a global

improvement at day 7 post treatment. One patient had a mRS=4 (moderate severe disability) reported

at day 90. None of the cases experienced a fatal outcome.

In summary, there were 25 reports from the SITS Register of patients between 16 and 17 years of age

with acute ischaemic stroke who have been treated according to adult recommendations with alteplase.

Although the small sample size precludes a statistical analysis, the overall results show a positive trend

with the respective adult dose used in these patients. The data do not appear to show an increased risk

of symptomatic intracerebral haemorrhage or oedema compared to adults.

5.2 Pharmacokinetic properties

Alteplase is cleared rapidly from the circulating blood and metabolised mainly by the liver (plasma

clearance 550 - 680 ml/min.). The relevant plasma half-life t

alpha is 4-5 minutes. This means that

after 20 minutes less than 10% of the initial value is present in the plasma. For the residual amount

remaining in a deep compartment, a beta-half-life of about 40 minutes was measured.

5.3 Preclinical safety data

In subchronic toxicity studies in rats and marmosets no unexpected undesirable effects were found. No

indications of a mutagenic potential were found in mutagenic tests.

pregnant

animals

teratogenic

effects

were

observed

after

intravenous

infusion

pharmacologically effective doses. In rabbits embryotoxicity (embryolethality, growth retardation)

was induced by more than 3 mg/kg/day. No effects on peri-postnatal development or on fertility

parameters were observed in rats with doses up to 10 mg/kg/day.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder:

L-arginine

Phosphoric acid, dilute

Polysorbate 80

Solvent:

Water for injections

6.2 Incompatibilities

The reconstituted solution may be diluted with sterile sodium chloride 9 mg/ml (0.9%) solution for

injection up to a minimal concentration of 0.2 mg alteplase per ml.

Further dilution, the use of water for injections for dilution or in general the use of carbohydrate

infusion solutions, e.g. dextrose, is not recommended due to increasing formation of turbidity of the

reconstituted solution.

Actilyse should not be mixed with other medicinal products neither in the same infusion vial nor the

same catheter (not even with heparin).

6.3 Shelf life

Unopened vials

The expiry date of the product is indicated on the packaging materials

Reconstituted solution

The reconstituted solution has been demonstrated 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, 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 to 8°C.

6.4 Special precautions for storage

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

Do not store above 25°C.

For storage conditions

after reconsititution

of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Powder:

20 ml or 50 ml sterilised glass vials, sealed with sterile siliconised grey butyl-type stoppers with

aluminium/plastic flip-off caps.

Solvent:

For the 20 mg and 50 mg presentations, the water for injections is filled into either 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

Presentations:

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 presentations may be marketed.

6.6 Special precautions for disposal and other handling

For reconstitution to a final concentration of 1 mg alteplase per ml the full volume of solvent provided

should be transferred to the vial containing the Actilyse powder. To this purpose a transfer cannula is

included with the pack, which is to be used.

For reconstitution to a final concentration of 2 mg alteplase per ml only half of the solvent provided

should be used (as per table below). In these cases always a syringe should be used to transfer the

required amount of solvent to the vial containing the Actilyse powder.

Under aseptic conditions the content of an injection vial of Actilyse (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 dry substance

20 mg

50 mg

(a) Volume of sterilised water for

injections to be added to dry

substance

20 mL

50 mL

Final concentration:

1 mg alteplase/mL

1 mg alteplase/mL

(b) Volume of sterilised water for

injections to be added to dry

substance

10 mL

25 mL

Final concentration:

2 mg alteplase/mL

2 mg alteplase/mL

The reconstituted solution should then be administered intravenously. The 1 mg/ml reconstituted

solution 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 since the occurrence of turbidity of the reconstituted solution

cannot be excluded. A further dilution of the 1 mg/ml reconstituted solution with sterilised water for

injections or in general, the use of carbohydrate infusion solutions, e.g. dextrose is not recommended

due to increasing formation of turbidity of the reconstituted solution. Actilyse should not be mixed

with other medicinal products in the same infusion-vial (not even with heparin).

For incompatibilities see section 6.2.

The reconstituted solution is for single use only. Any unused solution or waste material should be

disposed in accordance with the local requirements.

Instructions for reconstituting Actilyse

Reconstitute immediately before administration.

Remove the protective cap on the two vials

containing the sterile water and Actilyse dry

substance by flipping them up with a thumb.

Swab the rubber top of each vial with an alcohol

wipe.

Remove the transfer cannula from its cover. Do

not disinfect or sterilize the transfer cannula; it is

sterile.

Take one cap off.

Stand the sterile water vial upright on a stable

surface. From directly above, puncture the

rubber stopper vertically in the stopper center

with the transfer cannula, by pressing gently but

firmly, without twisting.

Hold the sterile water vial and the transfer

cannula steady with one hand using the two side

flaps.

Remove the remaining cap on top of the transfer

cannula.

Hold the sterile water vial and the transfer

cannula steady with one hand using the two side

flaps.

Hold the vial with Actilyse dry substance above

the transfer cannula and position the tip of the

transfer cannula right in the center of the

stopper.

Push down the vial with the dry substance onto

the transfer cannula from directly above,

puncturing the rubber stopper vertically and

gently but firmly without twisting.

Invert the two vials and allow the water to drain

completely into the dry substance.

Remove the empty water vial together with the

transfer cannula.

They can be disposed of.

Take the vial with reconstituted Actilyse and

swirl gently to dissolve any remaining powder,

but do not shake, as this will produce foam.

If there are bubbles, let the solution stand

undisturbed for a few minutes to allow them to

disappear.

The solution consists of 1mg/mL Actilyse. It should be clear and colourless to pale yellow and it

should not contain any particles.

Remove the amount required using a needle and

a syringe.

Do not use the puncture location from the

transfer cannula to avoid leakage.

Use immediately.

Dispose of any unused solution.

MANUFACTURER

Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany

For Boehringer Ingelheim Pharma International, Ingelheim/Rhein, Germany

MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim Israel Ltd.

Medinat Ha-Yehudim 89 St.

P.O. Box 4124

Herzliya Pituach 4676672

MARKETING AUTHORISATION NUMBER(S)

Actilyse 20 mg

136 78 31438

Actilyse 50 mg

059 55 26312

This leaflet format has been determined by the Ministry of Health and the content thereof

has been checked and approved. Date of approval: July 2019.

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