1. Name of the medicinal product
Actilyse 10 mg powder and solvent for solution for injection and
infusion
Actilyse 20 mg powder and solvent for solution for injection and
infusion
Actilyse 50 mg powder and solvent for solution for injection and
infusion
2. Qualitative and quantitative composition
1 vial with powder contains:
10 mg alteplase (corresponding to 5,800,000 IU) or
20 mg alteplase (corresponding to 11,600,000 IU) or
50 mg alteplase (corresponding to 29,000,000 IU), respectively
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
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.
4.2 Posology and method of administration
Actilyse should be given as soon as possible after symptom onset. The
following dose guidelines apply.
Acute Myocardial infarction
Posology
a) 90 minutes (accelerated) dose regimen for patients with acute
myocardial infarction, in whom treatment can be started within 6 hours after
symptom onset:
|
|
Concentration of
alteplase
|
|
1 mg/ml
|
2 mg/ml
|
|
ml
|
ml
|
|
15 mg as an intravenous
bolus
|
15
|
7.5
|
|
50 mg as an infusion
over 30 minutes
|
50
|
25
|
|
followed by an infusion
of 35 mg over 60 minutes until the maximal dose of 100 mg
|
35
|
17.5
|
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/ml
|
2 mg/ml
|
|
ml
|
ml
|
|
15 mg as an intravenous
bolus
|
15
|
7.5
|
|
|
ml/kg bw
|
ml/kg bw
|
|
and 0.75 mg/kg body
weight (bw) over 30 minutes (maximum 50 mg)
|
0.75
|
0.375
|
|
followed by an infusion
of 0.5 mg/kg body weight (bw) over 60 minutes (maximum 35 mg)
|
0.5
|
0.25
|
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/ml
|
2 mg/ml
|
|
ml
|
ml
|
|
10 mg as an intravenous
bolus
|
10
|
5
|
|
50 mg as an infusion
over the first hour
|
50
|
25
|
|
|
ml/30 min
|
ml/30 min
|
|
followed by infusions of
10 mg over 30 minutes until the maximal dose of 100 mg over 3 hours
|
10
|
5
|
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.
Method of administration
The reconstituted solution should be administered intravenously.
2 mg vials of alteplase are not indicated for use in this indication.
For instructions prior to reconstitution / administration, see section 6.6.
Pulmonary embolism
Posology
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/ml
|
2 mg/ml
|
|
ml
|
ml
|
|
10 mg as an intravenous
bolus over 1 - 2 minutes
|
10
|
5
|
|
followed by an
intravenous infusion of 90 mg over 2 hours
|
90
|
45
|
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).
Method of administration
The reconstituted solution should be administered intravenously.
2 mg vials of alteplase are not indicated for use in this indication.
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.
Posology
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.
Method of administration
The reconstituted solution should be administered intravenously.
2 mg vials of alteplase are not indicated for use in this indication.
For instructions prior to reconstitution / administration, see section 6.6.
Paediatric population
The safety and efficacy of Actilyse in children and adolescents has not
yet been established. Actilyse is contraindicated for the treatment of acute
stroke in children and adolescents (see section 4.3).
4.3 Contraindications
Generally, in all indications Actilyse should not be administered to
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.
Additional contraindications in acute myocardial infarction, acute
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 (see section 4.4)
• manifest or recent severe or dangerous bleeding
• known history of or suspected intracranial haemorrhage
• suspected subarachnoid haemorrhage or 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 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/mm3
• systolic blood pressure > 185 or diastolic BP > 110 mm Hg, or
aggressive management (intravenous pharmacotherapy) necessary to reduce BP to
these limits
• blood glucose < 50 or > 400 mg/dl.
Use in children and adolescents
Actilyse is not indicated for the treatment of acute stroke in
paediatric patients under 18 years.
Use in elderly patients
Actilyse is not indicated for the treatment of acute stroke in adults
over 80 years of age.
4.4 Special warnings and precautions for use
The appropriate presentation of alteplase product should be chosen
carefully and in accordance with the intended use. The 2 mg presentation of
alteplase is not indicated for use in acute myocardial infarction, acute
pulmonary embolism or acute ischaemic stroke (due to risk of massive under
dosing). Only 10, 20 or 50 mg presentations are indicated for use in these
indications.
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
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. Anaphylactoid
reactions associated with the administration of Actilyse are rare and can be
caused by hypersensitivity to the active substance alteplase, gentamicin (a
trace residue from the manufacturing process) or to any of the excipients. The
stopper of the glass vial with Actilyse powder contains natural rubber (a
derivative of latex) which may cause allergic reactions.
If an anaphylactoid reaction occurs, the infusion should be discontinued
and appropriate treatment initiated.
Haemorrhages
If a potentially dangerous haemorrhage occurs, in particular cerebral
haemorrhage, the fibrinolytic therapy must be discontinued. 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 can be managed by interruption of thrombolytic and
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.
The use of rigid catheters should be avoided.
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.
Additional special warnings and precautions in acute myocardial
infarction and acute 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.
GPIIb/IIIa antagonists:
Concomitant use of GPIIb/IIIa antagonists increases the risk of
bleeding.
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:
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
• small asymptomatic aneurysms of the cerebral vessels
• with later time-to-treatment from onset of stroke symptoms the net
clinical benefit is reduced and may be associated with a higher risk of ICH and
death compared to patients treated earlier. 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.
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 BP > 105
mm Hg.
The therapeutic benefit is reduced in patients that had a prior stroke
or in those with known uncontrolled diabetes, thus the benefit/risk ratio is
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 and death. In such patients, the benefit/risk ratio
should be thoroughly considered.
In stroke patients the likelihood of good outcomes decreases with
increasing age, increasing stroke severity and increased levels of blood
glucose on admission while the likelihood of severe disability and death or
relevant intracranial bleedings increases, independently from treatment.
Patients over 80, patients with severe stroke (as assessed clinically and/or by
appropriate imaging techniques) and patients with blood glucose levels < 50
mg/dl or > 400 mg/dl at baseline should not be treated with Actilyse (see
section 4.3).
Data available from ECASS III and the pooled analysis indicate that the
net clinical benefit becomes smaller in elderly with increasing age compared to
younger patients as benefit from treatment with Actilyse appears to decrease
and the risk of mortality appears to increase with increasing age.
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.
The risk of haemorrhage is increased if 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).
Concomitant treatment with ACE inhibitors may enhance the risk of suffering
an anaphylactoid reaction, as in the cases describing such reactions a
relatively larger proportion of patients were receiving ACE inhibitors
concomitantly.
Concomitant use of GPIIb/IIIa antagonists increases the risk of
bleeding.
4.6 Fertility, pregnancy and lactation
Pregnancy
There is 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 are classified according to frequency and
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 for reperfusion arrhythmias in the indication
myocardial infarction, there is no medical reason to assume that the qualitative
and quantitative adverse reaction profile of Actilyse in the indications
pulmonary embolism and acute ischaemic stroke is different from the profile in
the indication myocardial infarction.
Table 1 Adverse reactions in myocardial infarction, pulmonary embolism
and ischaemic stroke
|
System
Organ Class
|
Adverse
Reaction
|
|
Haemorrhage
|
|
very common
|
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. mRS of 5 and 6).
bleeding from damaged
blood vessels (such as haematoma)
|
|
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 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 /
anaphylactoid reactions (e.g. allergic reactions including rash, urticaria,
bronchospasm, angio-oedema, hypotension, shock or any other symptom
associated with allergic reactions)
|
|
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)
|
*Immune system disorders
Transient antibody formation to Actilyse has been observed in rare cases
and with low titres, but a clinical relevance of this finding could not be
established.
**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. Healthcare professionals are
asked to report any suspected adverse reactions via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard.
4.9 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 is recommended
and if necessary, synthetic antifibrinolytics may be administered.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antithrombotic agents, ATC code: B01AD02
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.
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.
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.
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.
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 twoUSAstudies (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 inEurope. 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 of treatment window i.e. 4.5 hours. The
primary end point was disability at 90 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.
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 t1/2 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.
In pregnant animals no teratogenic effects were observed after
intravenous infusion of 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:
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
3 years
The 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 reconstitution of the medicinal product,
see section 6.3.
6.5 Nature and contents of container
Powder:
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:
For the 10 mg, 20 mg and 50 mg presentations, 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
presentations of 20 mg and 50 mg only)
Presentations:
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 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 20
mg and 50 mg presentations, which is to be used. For the 10 mg presentation 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 (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
(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 dry substance
|
10 mg
|
20 mg
|
50 mg
|
|
(a) Volume of sterilised
water for injections to be added to dry substance
|
10 mL
|
20 mL
|
50 mL
|
|
Final concentration:
|
1 mg alteplase/mL
|
1 mg alteplase/mL
|
1 mg alteplase/mL
|
|
(b) Volume of sterilised
water for injections to be added to dry substance
|
5 mL
|
10 mL
|
25 mL
|
|
Final concentration:
|
2 mg alteplase/mL
|
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. 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. 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
|
1
|
Reconstitute immediately
before administration.
|
|
|
2
|
Remove the protective
cap on the two vials containing the sterile water and Actilyse dry substance
by flipping them up with a thumb.
|
|
|
3
|
Swab the rubber top of
each vial with an alcohol wipe.
|
|
|
4
|
Remove the transfer
cannula* from its cover. Do not disinfect or sterilize the transfer cannula;
it is sterile. Take one cap off.
|
|
|
5
|
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.
|
|
|
6
|
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.
|
|
|
7
|
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.
|
|
|
8
|
Invert the two vials and
allow the water to drain completely into the dry substance.
|
|
|
9
|
Remove the empty water
vial together with the transfer cannula.
They can be disposed of.
|
|
|
10
|
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.
|
|
|
11
|
The solution consists of
1mg/mL Actilyse. It should be clear and colourless to pale yellow and it
should not contain any particles.
|
|
12
|
Remove the amount
required using a needle and a syringe.
Do not use the puncture
location from the transfer cannula to avoid leakage.
|
|
|
13
|
Use immediately.
Dispose of any unused
solution.
|
(*if a transfer cannula is included in the kit. The reconstitution can
also be performed with a syringe and a needle.)
7. Marketing authorisation holder
Boehringer Ingelheim Limited
Ellesfield Avenue
Bracknell
BerkshireRG12 8YS
8. Marketing authorisation number(s)
PL 00015/0120
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 12 October 1988
Date of last renewal: 26 April 2009
10. Date of revision of the text
April 2017
