ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Metalyse 6,000 units. Powder and solvent for solution for injection
2.
Metalyse 6,000 units
1 vial contains 6,000 units (30 mg) tenecteplase.
1 prefilled syringe contains 6 ml water for injections.
The reconstituted solution contains 1,000 units (5 mg) tenecteplase per ml.
Potency of tenecteplase is expressed in units (U) by using a reference standard which is specific for
tenecteplase and is not comparable with units used for other thrombolytic agents.
Tenecteplase is a fibrin-specific plasminogen activator produced in a Chinese hamster ovary cell line
by recombinant DNA technology.
For a full list of excipients, see section 6.1.
3.
Powder and solvent for solution for injection.
The powder is white to off-white.
The reconstituted preparation is a clear and colourless to
slightly yellow solution
.
4.
Metalyse is indicated in adults
for the thrombolytic treatment of suspected myocardial infarction with
persistent ST elevation or recent left Bundle Branch Block within 6 hours after the onset of acute
myocardial infarction (AMI) symptoms.
Metalyse should be prescribed by physicians experienced in the use of thrombolytic treatment and
with the facilities to monitor that use.
Treatment with Metalyse should be initiated as soon as possible after onset of symptoms.
Metalyse should be administered on the basis of body weight, with a maximum dose of 10,000 units
(50 mg tenecteplase). The volume required to administer the correct dose can be calculated from the
following scheme:
2
Patients’ body weight
category
(kg)
Tenecteplase
(U)
Tenecteplase
(mg)
Corresponding volume of
reconstituted solution
(ml)
< 60
6,000
30
6
≥
60 to < 70
7,000
35
7
≥
70 to < 80
8,000
40
8
≥
80 to < 90
9,000
45
9
≥
90
10,000
50
10
For details see section 6.6: Special precautions for disposal and other handling
The required dose should be administered as a single intravenous bolus over approximately 10
seconds.
A pre-existing intravenous line may be used for administration of Metalyse in 0.9% sodium chloride
solution only. Metalyse is incompatible with dextrose solution.
No other medicinal product should be added to the injection solution.
Paediatric population
Metalyse is not recommended for use in children (below 18 years) due to a lack of data on safety and
efficacy.
Adjunctive therapy
Antithrombotic adjunctive therapy with platelet inhibitors and anticoagulants should be administered
according to the current relevant treatment guidelines for the management of patients with ST-
elevation myocardial infarction.
Unfractionated heparin and enoxaparin have been used as antithrombotic adjunctive therapy in clinical
studies with Metalyse.
Acetylsalicylic acid should be initiated as soon as possible after symptom onset and continued with
lifelong treatment unless it is contraindicated.
Metalyse must not be administered to patients with a history of an anaphylactic (i.e. life-threatening)
reaction to any of the constituents (i.e. tenecteplase or any excipient) or gentamicin (a trace residue
from the manufacturing process). If treatment with Metalyse is nevertheless considered to be
necessary, facilities for resuscitation should be immediately available in case of need.
Furthermore, Metalyse is contraindicated in the following situations because thrombolytic therapy is
associated with a higher risk of bleeding:
-
Significant bleeding disorder either at present or within the past 6 months
Patients with current concomitant oral anticoagulant therapy (INR > 1.3)
-
Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal
surgery)
-
Known haemorrhagic diathesis
-
Severe uncontrolled hypertension
-
-
Major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months
(this includes any trauma associated with the current AMI)
-
Recent trauma to the head or cranium
-
-
Prolonged cardiopulmonary resuscitation (> 2 minutes) within the past 2 weeks
3
-
Acute pericarditis and/or subacute bacterial endocarditis
Acute pancreatitis
-
Severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension
(oesophageal varices) and active hepatitis
-
Active peptic ulceration
-
Arterial aneurysm and known arterial/venous malformation
-
-
Neoplasm with increased bleeding risk
Any known history of haemorrhagic stroke or stroke of unknown origin
-
Known history of ischaemic stroke or transient ischaemic attack in the preceding 6 months
-
-
Dementia
Bleeding
The most common complication encountered during Metalyse therapy is bleeding. The concomitant
use of heparin anticoagulation may contribute to bleeding. As fibrin is lysed during Metalyse therapy,
bleeding from recent puncture site may occur. Therefore, thrombolytic therapy requires careful
attention to all possible bleeding sites (including catheter insertion sites, arterial and venous puncture
sites, cutdown sites and needle puncture sites). The use of rigid catheters as well as intramuscular
injections and non-essential handling of the patient should be avoided during treatment with Metalyse.
Most frequently haemorrhage at the injection site, and occasionally genitourinary and gingival
bleeding were observed.
Should serious bleeding occur, in particular cerebral haemorrhage, concomitant heparin administration
should be terminated immediately. Administration of protamine should be considered if heparin has
been administered within 4 hours before 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. In the following
conditions, the risk of Metalyse therapy may be increased and should be weighed against the
anticipated benefits:
-
Systolic blood pressure > 160 mm Hg
-
Cerebrovascular disease
Recent gastrointestinal or genitourinary bleeding (within the past 10 days)
-
-
High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation
Any known recent (within the past 2 days) intramuscular injection
-
Advanced age, i.e. over 75 years
-
-
Low body weight < 60 kg
Arrhythmias
Coronary thrombolysis may result in arrhythmias associated with reperfusion. It is recommended that
antiarrhythmic therapy for bradycardia and/or ventricular tachyarrhythmias (pacemaker, defibrillator)
be available when Metalyse is administered.
GPIIb/IIIa antagonists
Concomitant use of GPIIb/IIIa antagonists increases bleeding risk.
Hypersensitivity/Re-administration
No sustained antibody formation to the tenecteplase molecule has been observed after treatment.
However
,
there is no systematic
experience with re-administration of Metalyse. Caution is needed
when administering Metalyse to persons with a known hypersensitivity (other than anaphylactic
reaction) to the active substance, to any of the excipients, or to gentamicin (a residue from the
manufacturing process). If an anaphylactoid reaction occurs, the injection should be discontinued
immediately and appropriate therapy should be initiated. In any case, tenecteplase should not be re-
4
administered before assessment of haemostatic factors like fibrinogen, plasminogen and alpha2-
antiplasmin.
Primary Percutaneous Coronary Intervention (PCI)
If primary PCI is scheduled according to the current relevant treatment guidelines, Metalyse as
administered in the ASSENT-4 PCI study (see section 5.1) should not be given.
Paediatric population
Metalyse is not recommended for use in children (below 18 years) due to a lack of data on safety and
efficacy.
No formal interaction studies with Metalyse and medicinal products commonly administered in
patients with AMI have been performed. However, the analysis of data from more than 12,000 patients
treated during phase I, II and III did not reveal any clinically relevant interactions with medicinal
products commonly used in patients with AMI and concomitantly used with Metalyse.
Medicinal products that affect coagulation or those that alter platelet function (e.g. ticlopidine,
clopidogrel, LMWH) may increase the risk of bleeding prior to, during or after Metalyse therapy.
Concomitant use of GPIIb/IIIa antagonists increases bleeding risk.
Pregnancy
No experience in pregnant women is available for tenecteplase. Because animal studies (see also
section 5.3) have shown a high risk of vaginal bleeding presumably from the placenta and of
pregnancy loss, the benefit of treatment has to be evaluated against the potential risks which may
aggravate an acute life-threatening situation.
Lactation
It is not known if tenecteplase is excreted into breast milk. Breast milk should be discarded within the
first 24 hours after thrombolytic therapy.
Fertility
No preclinical fertility studies were performed for tenecteplase. In the preclinical repeat-dose toxicity
studies conducted with tenecteplase, histopathology did not reveal any findings regarding the male
reproductive organs.
Not relevant.
Haemorrhage is a very common undesirable effect associated with the use of tenecteplase. The type of
haemorrhage is predominantly superficial at the injection site. Ecchymoses are observed commonly
but usually do not require any specific action. Death and permanent disability are reported in patients
who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.
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).
Table 1 displays the frequency of adverse reactions.
5
System Organ Class
Adverse Reaction
Immune system disorders
Rare
Anaphylactoid reaction (including rash, urticaria,
bronchospasm, laryngeal oedema)
Nervous system disorders
Uncommon
Intracranial haemorrhage (such as cerebral haemorrhage,
cerebral haematoma, haemorrhagic stroke, haemorrhagic
transformation stroke, intracranial haematoma, subarachnoid
haemorrhage) including associated symptoms as somnolence,
aphasia, hemiparesis, convulsion
Eye disorders
Uncommon
Eye haemorrhage
Cardiac disorders
Uncommon
Reperfusion arrhythmias (such as asystole, accelerated
idioventricular arrhythmia, arrhythmia, extrasystoles, atrial
fibrillation, atrioventricular first degree to atrioventricular
block complete, bradycardia, tachycardia, ventricular
arrhythmia, ventricular fibrillation, ventricular tachycardia)
occur in close temporal relationship to treatment with
tenecteplase. Reperfusion arrhythmias may lead to cardiac
arrest, can be life threatening and may require the use of
conventional antiarrhythmic therapies.
Rare
Pericardial haemorrhage
Vascular disorders
Very common Haemorrhage
Rare Embolism (thrombotic embolisation)
Respiratory, thoracic and mediastinal disorders
Common
Epistaxis
Rare
Pulmonary haemorrhage
Gastrointestinal disorders
Common
Gastrointestinal haemorrhage (such as gastric haemorrhage,
gastric ulcer haemorrhage, rectal haemorrhage,
haematemesis, melaena, mouth haemorrhage)
Uncommon
Retroperitoneal haemorrhage (such as retroperitoneal
haematoma)
Not known
Nausea, vomiting
Skin and subcutaneous tissue disorders
Common
Ecchymosis
Renal and urinary disorders
Common Urogenital haemorrhage (such as haematuria, haemorrhage
urinary tract)
General disorders and administration site conditions
Common
Injection site haemorrhage, puncture site haemorrhage
Investigations
Rare Blood pressure decreased
Not known Body temperature increased
Injury, poisoning and procedural complications
Not known
Fat embolism, which may lead to corresponding
consequences in the organs concerned
As with other thrombolytic agents, the following events have been reported as sequelae of myocardial
infarction and/or thrombolytic administration:
-
very common (>1/10): hypotension, heart rate and rhythm disorders, angina pectoris
-
common (>1/100, <1/10): recurrent ischaemia, cardiac failure, myocardial infarction,
cardiogenic shock, pericarditis, pulmonary oedema
6
-
uncommon (>1/1,000, <1/100): cardiac arrest, mitral valve incompetence, pericardial effusion,
venous thrombosis, cardiac tamponade, myocardial rupture
-
rare (>1/10,000, <1/1,000): pulmonary embolism
These cardiovascular events can be life-threatening and may lead to death.
In the event of overdose there may be an increased risk of bleeding. In case of severe prolonged
bleeding substitution therapy may be considered (plasma, platelets), see also section 4.4.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group
Antithrombotic agents, ATC code: B01A D11
Mechanism of action
Tenecteplase is a recombinant fibrin-specific plasminogen activator that is derived from native t-PA
by modifications at three sites of the protein structure. It binds to the fibrin component of the thrombus
(blood clot) and selectively converts thrombus-bound plasminogen to plasmin, which degrades the
fibrin matrix of the thrombus. Tenecteplase has a higher fibrin specificity and greater resistance to
inactivation by its endogenous inhibitor (PAI-1) compared to native t-PA.
2-antiplasmin (the fluid-phase
inhibitor of plasmin) with consequent increase in the level of systemic plasmin generation have been
observed. This observation is consistent with the intended effect of plasminogen activation. In
comparative studies a less than 15% reduction in fibrinogen and a less than 25% reduction in
plasminogen were observed in subjects treated with the maximum dose of tenecteplase (10,000 U,
corresponding to 50 mg), whereas alteplase caused an approximately 50% decrease in fibrinogen and
plasminogen levels. No clinically relevant antibody formation was detected at 30 days.
α
Clinical effects
Patency data from the phase I and II angiographic studies suggest that tenecteplase, administered as a
single intravenous bolus, is effective in dissolving blood clots in the infarct-related artery of subjects
experiencing an AMI on a dose related basis.
A large scale mortality trial (ASSENT II) in approx. 17,000 patients showed that tenecteplase is
therapeutically equivalent to alteplase in reducing mortality (6.2% for both treatments, at 30 days,
upper limit of the 95% CI for the relative risk ratio 1.124) and that the use of tenecteplase is associated
with a significantly lower incidence of non-intracranial bleedings (26.4% vs. 28.9%, p=0.0003). This
translates into a significantly lower need of transfusions (4.3% vs. 5.5%, p=0.0002). Intracranial
haemorrhage occurred at a rate of 0.93% vs. 0.94% for tenecteplase and alteplase, respectively.
Coronary patency and limited clinical outcome data showed that AMI patients have been successfully
treated later than 6 hours after symptom onset.
The ASSENT-4 PCI study was designed to show if in 4000 patients with large myocardial infarctions
pre-treatment with full dose tenecteplase and concomitant single bolus of up to 4,000 IU
unfractionated heparin administered prior to primary Percutaneous Coronary Intervention (PCI) to be
performed within 60 to 180 minutes leads to better outcomes than primary PCI alone. The trial was
prematurely terminated with 1667 randomised patients due to a numerically higher mortality in the
facilitated PCI group receiving tenecteplase. The occurrence of the primary endpoint, a composite of
7
Pharmacodynamic effects
After administration of tenecteplase dose dependent consumption of
death or cardiogenic shock or congestive heart failure within 90 days, was significantly higher in the
group receiving the exploratory regimen of tenecteplase followed by routine immediate PCI: 18.6%
(151/810) compared to 13.4% (110/819) in the PCI only group, p=0.0045. This significant difference
between the groups for the primary endpoint at 90 days was already present in-hospital and at 30 days.
Numerically all of the components of the clinical composite endpoint were in favour of the PCI only
regimen: death: 6.7% vs. 4.9% p=0.14; cardiogenic shock: 6.3% vs. 4.8% p=0.19; congestive heart
failure: 12.0% vs. 9.2% p=0.06 respectively. The secondary endpoints re-infarction and repeat target
vessel revascularisation were significantly increased in the group pre-treated with tenecteplase: re-
infarction: 6.1% vs. 3.7% p=0.0279; repeat target vessel revascularisation: 6.6% vs. 3.4% p=0.0041.
The following adverse events occurred more frequently with tenecteplase prior to PCI: intracranial
haemorrhage: 1% vs. 0% p=0.0037; stroke: 1.8% vs. 0% p<0.0001; major bleeds: 5.6% vs. 4.4%
p=0.3118; minor bleeds: 25.3% vs. 19.0% p= 0.0021; blood transfusions: 6.2% vs. 4.2% p=0.0873;
abrupt vessel closure: 1.9% vs. 0.1% p=0.0001.
5.2 Pharmacokinetic properties
Tenecteplase is an intravenously administered, recombinant protein that activates plasminogen.
Tenecteplase is cleared from circulation by binding to specific receptors in the liver followed by
catabolism to small peptides. Binding to hepatic receptors is, however, reduced compared to native t-
PA, resulting in a prolonged half-life. Data on tissue distribution and elimination were obtained in
studies with radioactively labelled tenecteplase in rats. The main organ to which tenecteplase
distributed was the liver. It is not known whether and to what extent tenecteplase binds to plasma
proteins in humans.
After single intravenous bolus injection of tenecteplase in patients with acute myocardial infarction,
tenecteplase antigen exhibits biphasic elimination from plasma. There is no dose dependence of
tenecteplase clearance in the therapeutic dose range. The initial, dominant half life is 24 ± 5.5 (mean
+/-SD) min, which is 5 times longer than native t-PA. The terminal half-life is 129 ± 87 min, and
plasma clearance is 119 ± 49 ml/min.
Increasing body weight resulted in a moderate increase of tenecteplase clearance, and increasing age
resulted in a slight decrease of clearance. Women exhibit in general lower clearance than men, but this
can be explained by the generally lower body weight of women.
The effect of renal and hepatic dysfunction on pharmacokinetics of tenecteplase in humans is not
known. There is no specific experience to guide the adjustment to tenecteplase dose in patients with
hepatic and severe renal insufficiency. However, based on animal data it is not expected that renal
dysfunction will affect the pharmacokinetics.
5.3 Preclinical safety data
Intravenous single dose administration in rats, rabbits and dogs resulted only in dose-dependent and
reversible alterations of the coagulation parameters with local haemorrhage at the injection site, which
was regarded as a consequence of the pharmacodynamic effect of tenecteplase. Multiple-dose toxicity
studies in rats and dogs confirmed these above-mentioned observations, but the study duration was
limited to two weeks by antibody formation to the human protein tenecteplase, which resulted in
anaphylaxis.
Safety pharmacology data in cynomolgus monkeys revealed reduction of blood pressure followed by
changes of ECG, but these occurred at exposures that were considerably higher than the clinical
exposure.
With regard to the indication and the single dose administration in humans, reproductive toxicity
testing was limited to an embryotoxicity study in rabbits, as a sensitive species. Tenecteplase induced
total litter deaths during the mid-embryonal period. When tenecteplase was given during the mid- or
8
late-embryonal period maternal animals showed vaginal bleeding on the day after the first dose.
Secondary mortality was observed 1-2 days later. Data on the foetal period are not available.
Mutagenicity and carcinogenicity are not expected for this class of recombinant proteins and
genotoxicity and carcinogenicity testing were not necessary.
No local irritation of the blood vessel was observed after intravenous, intra-arterial or paravenous
administration of the final formulation of tenecteplase.
6.
6.1 List of excipients
Powder:
L-arginine
Phosphoric acid
Polysorbate 20.
Solvent:
Water for injections.
6.2 Incompatibilities
Metalyse is incompatible with dextrose infusion solutions.
6.3 Shelf life
Shelf life as packaged for sale
2 years
Reconstituted solution
Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8°C and 8 hours at
30°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 2-8°C.
6.4 Special precautions for storage
Do not store above 30°C. Keep the container in the outer carton.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
20 ml glass vial type I, with a coated (B2-42) grey rubber stopper and a flip-off cap filled with powder
for solution for injection.
10 ml plastic syringe pre-filled with 6 ml of water for injections for reconstitution.
Sterile vial adapter.
Sterile needle for single use.
6.6
Special precautions for disposal and other handling
Metalyse should be reconstituted by adding the complete volume of water for injections from the pre-
filled syringe to the vial containing the powder for injection.
9
1.
Ensure that the appropriate vial size is chosen according to the body weight of the patient.
Patients’ body weight
category
(kg)
Volume of
reconstituted solution
(ml)
Tenecteplase
(U)
Tenecteplase
(mg)
< 60
6
6,000
30
≥
60 to < 70
7
7,000
35
≥
70 to < 80
8
8,000
40
≥
80 to < 90
9
9,000
45
≥
90
10
10,000
50
2. Check that the cap of the vial is still intact.
3. Remove the flip-off cap from the vial.
4. Remove the tip-cap from the syringe. Then immediately screw the pre-filled syringe on the vial
adapter and penetrate the vial stopper in the middle with the spike of the vial adapter.
5. Add the water for injections into the vial by pushing the syringe plunger down slowly to avoid
foaming.
6. Reconstitute by swirling gently.
7. The reconstituted preparation results in a colourless to pale yellow, clear solution. Only clear
solution without particles should be used.
8. Directly before the solution will be administered, invert the vial with the syringe still attached,
so that the syringe is below the vial.
9. Transfer the appropriate volume of reconstituted solution of Metalyse into the syringe, based on
the patient’s weight.
10. Disconnect the syringe from the vial adapter.
11. Metalyse is to be administered to the patient, intravenously in about 10 seconds. It should not be
administered in a line containing dextrose.
12. Any unused solution should be discarded.
Alternatively the reconstitution can be performed with the included needle.
7.
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
8.
EU/1/00/169/004
9.
Date of first authorisation: 23 February 2001
Date of last renewal: 23 February 2006
10
1.
Metalyse 8,000 units. Powder and solvent for solution for injection
2.
Metalyse 8,000 units
1 vial contains 8,000 units (40 mg) tenecteplase.
1 prefilled syringe contains 8 ml water for injections.
The reconstituted solution contains 1,000 units (5 mg) tenecteplase per ml.
Potency of tenecteplase is expressed in units (U) by using a reference standard which is specific for
tenecteplase and is not comparable with units used for other thrombolytic agents.
Tenecteplase is a fibrin-specific plasminogen activator produced in a Chinese hamster ovary cell line
by recombinant DNA technology.
For a full list of excipients, see section 6.1.
3.
Powder and solvent for solution for injection.
The powder is white to off-white.
The reconstituted preparation is a clear and colourless to
slightly yellow solution
4.
Metalyse is indicated in adults for the thrombolytic treatment of suspected myocardial infarction with
persistent ST elevation or recent left Bundle Branch Block within 6 hours after the onset of acute
myocardial infarction (AMI) symptoms.
Metalyse should be prescribed by physicians experienced in the use of thrombolytic treatment and
with the facilities to monitor that use.
Treatment with Metalyse should be initiated as soon as possible after onset of symptoms.
Metalyse should be administered on the basis of body weight, with a maximum dose of 10,000 units
(50 mg tenecteplase). The volume required to administer the correct dose can be calculated from the
following scheme:
11
Patients’ body weight
category
(kg)
Tenecteplase
(U)
Tenecteplase
(mg)
Corresponding volume of
reconstituted solution
(ml)
< 60
6,000
30
6
≥
60 to < 70
7,000
35
7
≥
70 to < 80
8,000
40
8
≥
80 to < 90
9,000
45
9
≥
90
10,000
50
10
For details see section 6.6: Special precautions for disposal and other handling
The required dose should be administered as a single intravenous bolus over approximately 10
seconds.
A pre-existing intravenous line may be used for administration of Metalyse in 0.9% sodium chloride
solution only. Metalyse is incompatible with dextrose solution.
No other medicinal product should be added to the injection solution.
Paediatric population
Metalyse is not recommended for use in children (below 18 years) due to a lack of data on safety and
efficacy.
Adjunctive therapy
Antithrombotic adjunctive therapy with platelet inhibitors and anticoagulants should be administered
according to the current relevant treatment guidelines for the management of patients with ST-
elevation myocardial infarction.
Unfractionated heparin and enoxaparin have been used as antithrombotic adjunctive therapy in clinical
studies with Metalyse.
Acetylsalicylic acid should be initiated as soon as possible after symptom onset and continued with
lifelong treatment unless it is contraindicated.
Metalyse must not be administered to patients with a history of an anaphylactic (i.e. life-threatening)
reaction to any of the constituents (i.e. tenecteplase or any excipient) or gentamicin (a trace residue
from the manufacturing process). If treatment with Metalyse is nevertheless considered to be
necessary, facilities for resuscitation should be immediately available in case of need.
Furthermore, Metalyse is contraindicated in the following situations because thrombolytic therapy is
associated with a higher risk of bleeding:
-
Significant bleeding disorder either at present or within the past 6 months
Patients with current concomitant oral anticoagulant therapy (INR > 1.3)
-
-
Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal
surgery)
Known haemorrhagic diathesis
-
-
Severe uncontrolled hypertension
Major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months
-
(this includes any trauma associated with the current AMI)
-
-
Recent trauma to the head or cranium
12
-
Prolonged cardiopulmonary resuscitation (> 2 minutes) within the past 2 weeks
Acute pericarditis and/or subacute bacterial endocarditis
-
Acute pancreatitis
-
-
Severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension
(oesophageal varices) and active hepatitis
Active peptic ulceration
-
-
Arterial aneurysm and known arterial/venous malformation
Neoplasm with increased bleeding risk
-
Any known history of haemorrhagic stroke or stroke of unknown origin
-
-
Known history of ischaemic stroke or transient ischaemic attack in the preceding 6 months
Dementia
-
Bleeding
The most common complication encountered during Metalyse therapy is bleeding. The concomitant
use of heparin anticoagulation may contribute to bleeding. As fibrin is lysed during Metalyse therapy,
bleeding from recent puncture site may occur. Therefore, thrombolytic therapy requires careful
attention to all possible bleeding sites (including catheter insertion sites, arterial and venous puncture
sites, cutdown sites and needle puncture sites). The use of rigid catheters as well as intramuscular
injections and non-essential handling of the patient should be avoided during treatment with Metalyse.
Most frequently haemorrhage at the injection site, and occasionally genitourinary and gingival
bleeding were observed.
Should serious bleeding occur, in particular cerebral haemorrhage, concomitant heparin administration
should be terminated immediately. Administration of protamine should be considered if heparin has
been administered within 4 hours before 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. In the following
conditions, the risk of Metalyse therapy may be increased and should be weighed against the
anticipated benefits:
-
Systolic blood pressure > 160 mm Hg
Cerebrovascular disease
-
-
Recent gastrointestinal or genitourinary bleeding (within the past 10 days)
High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation
-
Any known recent (within the past 2 days) intramuscular injection
-
-
Advanced age, i.e. over 75 years
Low body weight < 60 kg
-
Arrhythmias
Coronary thrombolysis may result in arrhythmias associated with reperfusion. It is recommended that
antiarrhythmic therapy for bradycardia and/or ventricular tachyarrhythmias (pacemaker, defibrillator)
be available when Metalyse is administered.
GPIIb/IIIa antagonists
Concomitant use of GPIIb/IIIa antagonists increases bleeding risk.
Hypersensitivity/Re-administration
No sustained antibody formation to the tenecteplase molecule has been observed after treatment.
However, there is no systematic experience with re-administration of Metalyse. Caution is needed
when administering Metalyse to persons with a known hypersensitivity (other than anaphylactic
reaction) to the active substance, to any of the excipients, or to gentamicin (a residue from the
manufacturing process). If an anaphylactoid reaction occurs, the injection should be discontinued
13
immediately and appropriate therapy should be initiated. In any case, tenecteplase should not be re-
administered before assessment of haemostatic factors like fibrinogen, plasminogen and alpha2-
antiplasmin.
Primary Percutaneous Coronary Intervention (PCI)
If primary PCI is scheduled according to the current relevant treatment guidelines, Metalyse as
administered in the ASSENT-4 PCI study (see section 5.1) should not be given.
Paediatric population
Metalyse is not recommended for use in children (below 18 years) due to a lack of data on safety and
efficacy.
No formal interaction studies with Metalyse and medicinal products commonly administered in
patients with AMI have been performed. However, the analysis of data from more than 12,000 patients
treated during phase I, II and III did not reveal any clinically relevant interactions with medicinal
products commonly used in patients with AMI and concomitantly used with Metalyse.
Medicinal products that affect coagulation or those that alter platelet function (e.g. ticlopidine,
clopidogrel, LMWH) may increase the risk of bleeding prior to, during or after Metalyse therapy.
Concomitant use of GPIIb/IIIa antagonists increases bleeding risk.
Pregnancy
No experience in pregnant women is available for tenecteplase. Because animal studies (see also
section 5.3) have shown a high risk of vaginal bleeding presumably from the placenta and of
pregnancy loss, the benefit of treatment has to be evaluated against the potential risks which may
aggravate an acute life-threatening situation.
Lactation
It is not known if tenecteplase is excreted into breast milk. Breast milk should be discarded within the
first 24 hours after thrombolytic therapy.
Fertility
No preclinical fertility studies were performed for tenecteplase. In the preclinical repeat-dose toxicity
studies conducted with tenecteplase, histopathology did not reveal any findings regarding the male
reproductive organs.
Not relevant.
Haemorrhage is a very common undesirable effect associated with the use of tenecteplase. The type of
haemorrhage is predominantly superficial at the injection site. Ecchymoses are observed commonly
but usually do not require any specific action. Death and permanent disability are reported in patients
who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.
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).
14
Table 1 displays the frequency of adverse reactions.
System Organ Class
Adverse Reaction
Immune system disorders
Rare
Anaphylactoid reaction (including rash, urticaria,
bronchospasm, laryngeal oedema)
Nervous system disorders
Uncommon
Intracranial haemorrhage (such as cerebral haemorrhage,
cerebral haematoma, haemorrhagic stroke, haemorrhagic
transformation stroke, intracranial haematoma, subarachnoid
haemorrhage) including associated symptoms as somnolence,
aphasia, hemiparesis, convulsion
Eye disorders
Uncommon
Eye haemorrhage
Cardiac disorders
Uncommon
Reperfusion arrhythmias (such as asystole, accelerated
idioventricular arrhythmia, arrhythmia, extrasystoles, atrial
fibrillation, atrioventricular first degree to atrioventricular
block complete, bradycardia, tachycardia, ventricular
arrhythmia, ventricular fibrillation, ventricular tachycardia)
occur in close temporal relationship to treatment with
tenecteplase. Reperfusion arrhythmias may lead to cardiac
arrest, can be life threatening and may require the use of
conventional antiarrhythmic therapies.
Rare
Pericardial haemorrhage
Vascular disorders
Very common Haemorrhage
Rare Embolism (thrombotic embolisation)
Respiratory, thoracic and mediastinal disorders
Common
Epistaxis
Rare
Pulmonary haemorrhage
Gastrointestinal disorders
Common
Gastrointestinal haemorrhage (such as gastric haemorrhage,
gastric ulcer haemorrhage, rectal haemorrhage,
haematemesis, melaena, mouth haemorrhage)
Uncommon
Retroperitoneal haemorrhage (such as retroperitoneal
haematoma)
Not known
Nausea, vomiting
Skin and subcutaneous tissue disorders
Common
Ecchymosis
Renal and urinary disorders
Common Urogenital haemorrhage (such as haematuria, haemorrhage
urinary tract)
General disorders and administration site conditions
Common
Injection site haemorrhage, puncture site haemorrhage
Investigations
Rare Blood pressure decreased
Not known Body temperature increased
Injury, poisoning and procedural complications
Not known
Fat embolism, which may lead to corresponding
consequences in the organs concerned
As with other thrombolytic agents, the following events have been reported as sequelae of myocardial
infarction and/or thrombolytic administration:
-
very common (>1/10): hypotension, heart rate and rhythm disorders, angina pectoris
-
common (>1/100, <1/10): recurrent ischaemia, cardiac failure, myocardial infarction,
cardiogenic shock, pericarditis, pulmonary oedema
15
-
uncommon (>1/1,000, <1/100): cardiac arrest, mitral valve incompetence, pericardial effusion,
venous thrombosis, cardiac tamponade, myocardial rupture
-
rare (>1/10,000, <1/1,000): pulmonary embolism
These cardiovascular events can be life-threatening and may lead to death.
In the event of overdose there may be an increased risk of bleeding. In case of severe prolonged
bleeding substitution therapy may be considered (plasma, platelets), see also section 4.4.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group
Antithrombotic agents, ATC code: B01A D11
Mechanism of action
Tenecteplase is a recombinant fibrin-specific plasminogen activator that is derived from native t-PA
by modifications at three sites of the protein structure. It binds to the fibrin component of the thrombus
(blood clot) and selectively converts thrombus-bound plasminogen to plasmin, which degrades the
fibrin matrix of the thrombus. Tenecteplase has a higher fibrin specificity and greater resistance to
inactivation by its endogenous inhibitor (PAI-1) compared to native t-PA.
2-antiplasmin (the fluid-phase
inhibitor of plasmin) with consequent increase in the level of systemic plasmin generation have been
observed. This observation is consistent with the intended effect of plasminogen activation. In
comparative studies a less than 15% reduction in fibrinogen and a less than 25% reduction in
plasminogen were observed in subjects treated with the maximum dose of tenecteplase (10,000 U,
corresponding to 50 mg), whereas alteplase caused an approximately 50% decrease in fibrinogen and
plasminogen levels. No clinically relevant antibody formation was detected at 30 days.
α
Clinical effects
Patency data from the phase I and II angiographic studies suggest that tenecteplase, administered as a
single intravenous bolus, is effective in dissolving blood clots in the infarct-related artery of subjects
experiencing an AMI on a dose related basis.
A large scale mortality trial (ASSENT II) in approx. 17,000 patients showed that tenecteplase is
therapeutically equivalent to alteplase in reducing mortality (6.2% for both treatments, at 30 days,
upper limit of the 95% CI for the relative risk ratio 1.124) and that the use of tenecteplase is associated
with a significantly lower incidence of non-intracranial bleedings (26.4% vs. 28.9%, p=0.0003). This
translates into a significantly lower need of transfusions (4.3% vs. 5.5%, p=0.0002). Intracranial
haemorrhage occurred at a rate of 0.93% vs. 0.94% for tenecteplase and alteplase, respectively.
Coronary patency and limited clinical outcome data showed that AMI patients have been successfully
treated later than 6 hours after symptom onset.
The ASSENT-4 PCI study was designed to show if in 4000 patients with large myocardial infarctions
pre-treatment with full dose tenecteplase and concomitant single bolus of up to 4,000 IU
unfractionated heparin administered prior to primary Percutaneous Coronary Intervention (PCI) to be
performed within 60 to 180 minutes leads to better outcomes than primary PCI alone. The trial was
prematurely terminated with 1667 randomised patients due to a numerically higher mortality in the
facilitated PCI group receiving tenecteplase. The occurrence of the primary endpoint, a composite of
16
Pharmacodynamic effects
After administration of tenecteplase dose dependent consumption of
death or cardiogenic shock or congestive heart failure within 90 days, was significantly higher in the
group receiving the exploratory regimen of tenecteplase followed by routine immediate PCI: 18.6%
(151/810) compared to 13.4% (110/819) in the PCI only group, p=0.0045. This significant difference
between the groups for the primary endpoint at 90 days was already present in-hospital and at 30 days.
Numerically all of the components of the clinical composite endpoint were in favour of the PCI only
regimen: death: 6.7% vs. 4.9% p=0.14; cardiogenic shock: 6.3% vs. 4.8% p=0.19; congestive heart
failure: 12.0% vs. 9.2% p=0.06 respectively. The secondary endpoints re-infarction and repeat target
vessel revascularisation were significantly increased in the group pre-treated with tenecteplase: re-
infarction: 6.1% vs. 3.7% p=0.0279; repeat target vessel revascularisation: 6.6% vs. 3.4% p=0.0041.
The following adverse events occurred more frequently with tenecteplase prior to PCI: intracranial
haemorrhage: 1% vs. 0% p=0.0037; stroke: 1.8% vs. 0% p<0.0001; major bleeds: 5.6% vs. 4.4%
p=0.3118; minor bleeds: 25.3% vs. 19.0% p= 0.0021; blood transfusions: 6.2% vs. 4.2% p=0.0873;
abrupt vessel closure: 1.9% vs. 0.1% p=0.0001.
5.2 Pharmacokinetic properties
Tenecteplase is an intravenously administered, recombinant protein that activates plasminogen.
Tenecteplase is cleared from circulation by binding to specific receptors in the liver followed by
catabolism to small peptides. Binding to hepatic receptors is, however, reduced compared to native t-
PA, resulting in a prolonged half-life. Data on tissue distribution and elimination were obtained in
studies with radioactively labelled tenecteplase in rats. The main organ to which tenecteplase
distributed was the liver. It is not known whether and to what extent tenecteplase binds to plasma
proteins in humans.
After single intravenous bolus injection of tenecteplase in patients with acute myocardial infarction,
tenecteplase antigen exhibits biphasic elimination from plasma. There is no dose dependence of
tenecteplase clearance in the therapeutic dose range. The initial, dominant half life is 24 ± 5.5 (mean
+/-SD) min, which is 5 times longer than native t-PA. The terminal half-life is 129 ± 87 min, and
plasma clearance is 119 ± 49 ml/min.
Increasing body weight resulted in a moderate increase of tenecteplase clearance, and increasing age
resulted in a slight decrease of clearance. Women exhibit in general lower clearance than men, but this
can be explained by the generally lower body weight of women.
The effect of renal and hepatic dysfunction on pharmacokinetics of tenecteplase in humans is not
known. There is no specific experience to guide the adjustment to tenecteplase dose in patients with
hepatic and severe renal insufficiency. However, based on animal data it is not expected that renal
dysfunction will affect the pharmacokinetics.
5.3 Preclinical safety data
Intravenous single dose administration in rats, rabbits and dogs resulted only in dose-dependent and
reversible alterations of the coagulation parameters with local haemorrhage at the injection site, which
was regarded as a consequence of the pharmacodynamic effect of tenecteplase. Multiple-dose toxicity
studies in rats and dogs confirmed these above-mentioned observations, but the study duration was
limited to two weeks by antibody formation to the human protein tenecteplase, which resulted in
anaphylaxis.
Safety pharmacology data in cynomolgus monkeys revealed reduction of blood pressure followed by
changes of ECG, but these occurred at exposures that were considerably higher than the clinical
exposure.
With regard to the indication and the single dose administration in humans, reproductive toxicity
testing was limited to an embryotoxicity study in rabbits, as a sensitive species. Tenecteplase induced
total litter deaths during the mid-embryonal period. When tenecteplase was given during the mid- or
17
late-embryonal period maternal animals showed vaginal bleeding on the day after the first dose.
Secondary mortality was observed 1-2 days later. Data on the foetal period are not available.
Mutagenicity and carcinogenicity are not expected for this class of recombinant proteins and
genotoxicity and carcinogenicity testing were not necessary.
No local irritation of the blood vessel was observed after intravenous, intra-arterial or paravenous
administration of the final formulation of tenecteplase.
6.
6.1 List of excipients
Powder:
L-arginine
Phosphoric acid
Polysorbate 20.
Solvent:
Water for injections.
6.2 Incompatibilities
Metalyse is incompatible with dextrose infusion solutions.
6.3 Shelf life
Shelf life as packaged for sale
2 years
Reconstituted solution
Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8°C and 8 hours at
30°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 2-8°C.
6.4 Special precautions for storage
Do not store above 30°C. Keep the container in the outer carton.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
20 ml glass vial type I, with a coated (B2-42) grey rubber stopper and a flip-off cap filled with powder
for solution for injection.
10 ml plastic syringe pre-filled with 8 ml of water for injections for reconstitution.
Sterile vial adapter.
Sterile needle for single use.
6.6 Special precautions for disposal
and other handling
Metalyse should be reconstituted by adding the complete volume of water for injections from the pre-
filled syringe to the vial containing the powder for injection.
18
1.
Ensure that the appropriate vial size is chosen according to the body weight of the patient.
Patients’ body weight
category
(kg)
Volume of
reconstituted solution
(ml)
Tenecteplase
(U)
Tenecteplase
(mg)
< 60
6
6,000
30
≥
60 to < 70
7
7,000
35
≥
70 to < 80
8
8,000
40
≥
80 to < 90
9
9,000
45
≥
90
10
10,000
50
2. Check that the cap of the vial is still intact.
3. Remove the flip-off cap from the vial.
4. Remove the tip-cap from the syringe. Then immediately screw the pre-filled syringe on the vial
adapter and penetrate the vial stopper in the middle with the spike of the vial adapter.
5. Add the water for injections into the vial by pushing the syringe plunger down slowly to avoid
foaming.
6. Reconstitute by swirling gently.
7. The reconstituted preparation results in a colourless to pale yellow, clear solution. Only clear
solution without particles should be used.
8. Directly before the solution will be administered, invert the vial with the syringe still attached,
so that the syringe is below the vial.
9. Transfer the appropriate volume of reconstituted solution of Metalyse into the syringe, based on
the patient’s weight.
10. Disconnect the syringe from the vial adapter.
11. Metalyse is to be administered to the patient, intravenously in about 10 seconds. It should not be
administered in a line containing dextrose.
12. Any unused solution should be discarded.
Alternatively the reconstitution can be performed with the included needle.
7.
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
8.
EU/1/00/169/005
9.
Date of first authorisation: 23 February 2001
Date of last renewal: 23 February 2006
19
1.
Metalyse 10,000 units. Powder and solvent for solution for injection
2.
Metalyse 10,000 units
1 vial contains 10,000 units (50 mg) tenecteplase.
1 prefilled syringe contains 10 ml water for injections.
The reconstituted solution contains 1,000 units (5 mg) tenecteplase per ml.
Potency of tenecteplase is expressed in units (U) by using a reference standard which is specific for
tenecteplase and is not comparable with units used for other thrombolytic agents.
Tenecteplase is a fibrin-specific plasminogen activator produced in a Chinese hamster ovary cell line
by recombinant DNA technology.
For a full list of excipients, see section 6.1.
3.
Powder and solvent for solution for injection.
The powder is white to off-white.
The reconstituted preparation is a clear and colourless to
slightly yellow solution.
4.
Metalyse is indicated in adults for the thrombolytic treatment of suspected myocardial infarction with
persistent ST elevation or recent left Bundle Branch Block within 6 hours after the onset of acute
myocardial infarction (AMI) symptoms.
Metalyse should be prescribed by physicians experienced in the use of thrombolytic treatment and
with the facilities to monitor that use.
Treatment with Metalyse should be initiated as soon as possible after onset of symptoms.
Metalyse should be administered on the basis of body weight, with a maximum dose of 10,000 units
(50 mg tenecteplase). The volume required to administer the correct dose can be calculated from the
following scheme:
20
Patients’ body weight
category
(kg)
Tenecteplase
(U)
Tenecteplase
(mg)
Corresponding volume of
reconstituted solution
(ml)
< 60
6,000
30
6
≥
60 to < 70
7,000
35
7
≥
70 to < 80
8,000
40
8
≥
80 to < 90
9,000
45
9
≥
90
10,000
50
10
For details see section 6.6: Special precautions for disposal and other handling
The required dose should be administered as a single intravenous bolus over approximately 10
seconds.
A pre-existing intravenous line may be used for administration of Metalyse in 0.9% sodium chloride
solution only. Metalyse is incompatible with dextrose solution.
No other medicinal product should be added to the injection solution.
Paediatric population
Metalyse is not recommended for use in children (below 18 years) due to a lack of data on safety and
efficacy.
Adjunctive therapy
Antithrombotic adjunctive therapy with platelet inhibitors and anticoagulants should be administered
according to the current relevant treatment guidelines for the management of patients with ST-
elevation myocardial infarction.
Unfractionated heparin and enoxaparin have been used as antithrombotic adjunctive therapy in clinical
studies with Metalyse.
Acetylsalicylic acid should be initiated as soon as possible after symptom onset and continued with
lifelong treatment unless it is contraindicated.
Metalyse must not be administered to patients with a history of an anaphylactic (i.e. life-threatening)
reaction to any of the constituents (i.e. tenecteplase or any excipient) or gentamicin (a trace residue
from the manufacturing process). If treatment with Metalyse is nevertheless considered to be
necessary, facilities for resuscitation should be immediately available in case of need.
Furthermore, Metalyse is contraindicated in the following situations because thrombolytic therapy is
associated with a higher risk of bleeding:
-
Significant bleeding disorder either at present or within the past 6 months
Patients with current concomitant oral anticoagulant therapy (INR > 1.3)
-
Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal
surgery)
-
Known haemorrhagic diathesis
-
Severe uncontrolled hypertension
-
-
Major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months
(this includes any trauma associated with the current AMI)
-
Recent trauma to the head or cranium
-
-
Prolonged cardiopulmonary resuscitation (> 2 minutes) within the past 2 weeks
21
-
Acute pericarditis and/or subacute bacterial endocarditis
Acute pancreatitis
-
Severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension
(oesophageal varices) and active hepatitis
-
Active peptic ulceration
-
Arterial aneurysm and known arterial/venous malformation
-
-
Neoplasm with increased bleeding risk
Any known history of haemorrhagic stroke or stroke of unknown origin
-
Known history of ischaemic stroke or transient ischaemic attack in the preceding 6 months
-
-
Dementia
Bleeding
The most common complication encountered during Metalyse therapy is bleeding. The concomitant
use of heparin anticoagulation may contribute to bleeding. As fibrin is lysed during Metalyse therapy,
bleeding from recent puncture site may occur. Therefore, thrombolytic therapy requires careful
attention to all possible bleeding sites (including catheter insertion sites, arterial and venous puncture
sites, cutdown sites and needle puncture sites). The use of rigid catheters as well as intramuscular
injections and non-essential handling of the patient should be avoided during treatment with Metalyse.
Most frequently haemorrhage at the injection site, and occasionally genitourinary and gingival
bleeding were observed.
Should serious bleeding occur, in particular cerebral haemorrhage, concomitant heparin administration
should be terminated immediately. Administration of protamine should be considered if heparin has
been administered within 4 hours before 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. In the following
conditions, the risk of Metalyse therapy may be increased and should be weighed against the
anticipated benefits:
-
Systolic blood pressure > 160 mm Hg
-
Cerebrovascular disease
Recent gastrointestinal or genitourinary bleeding (within the past 10 days)
-
-
High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation
Any known recent (within the past 2 days) intramuscular injection
-
Advanced age, i.e. over 75 years
-
-
Low body weight < 60 kg
Arrhythmias
Coronary thrombolysis may result in arrhythmias associated with reperfusion. It is recommended that
antiarrhythmic therapy for bradycardia and/or ventricular tachyarrhythmias (pacemaker, defibrillator)
be available when Metalyse is administered.
GPIIb/IIIa antagonists
Concomitant use of GPIIb/IIIa antagonists increases bleeding risk.
Hypersensitivity/Re-administration
No sustained antibody formation to the tenecteplase molecule has been observed after treatment.
However
,
there is no systematic
experience with re-administration of Metalyse. Caution is needed
when administering Metalyse to persons with a known hypersensitivity (other than anaphylactic
reaction) to the active substance, to any of the excipients, or to gentamicin (a residue from the
manufacturing process). If an anaphylactoid reaction occurs, the injection should be discontinued
immediately and appropriate therapy should be initiated. In any case, tenecteplase should not be re-
22
administered before assessment of haemostatic factors like fibrinogen, plasminogen and alpha2-
antiplasmin.
Primary Percutaneous Coronary Intervention (PCI)
If primary PCI is scheduled according to the current relevant treatment guidelines, Metalyse as
administered in the ASSENT-4 PCI study (see section 5.1) should not be given.
Paediatric population
Metalyse is not recommended for use in children (below 18 years) due to a lack of data on safety and
efficacy.
No formal interaction studies with Metalyse and medicinal products commonly administered in
patients with AMI have been performed. However, the analysis of data from more than 12,000 patients
treated during phase I, II and III did not reveal any clinically relevant interactions with medicinal
products commonly used in patients with AMI and concomitantly used with Metalyse.
Medicinal products that affect coagulation or those that alter platelet function (e.g. ticlopidine,
clopidogrel, LMWH) may increase the risk of bleeding prior to, during or after Metalyse therapy.
Concomitant use of GPIIb/IIIa antagonists increases bleeding risk.
Pregnancy
No experience in pregnant women is available for tenecteplase. Because animal studies (see also
section 5.3) have shown a high risk of vaginal bleeding presumably from the placenta and of
pregnancy loss, the benefit of treatment has to be evaluated against the potential risks which may
aggravate an acute life-threatening situation.
Lactation
It is not known if tenecteplase is excreted into breast milk. Breast milk should be discarded within the
first 24 hours after thrombolytic therapy.
Fertility
No preclinical fertility studies were performed for tenecteplase. In the preclinical repeat-dose toxicity
studies conducted with tenecteplase, histopathology did not reveal any findings regarding the male
reproductive organs.
Not relevant.
Haemorrhage is a very common undesirable effect associated with the use of tenecteplase. The type of
haemorrhage is predominantly superficial at the injection site. Ecchymoses are observed commonly
but usually do not require any specific action. Death and permanent disability are reported in patients
who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.
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).
Table 1 displays the frequency of adverse reactions.
23
System Organ Class
Adverse Reaction
Immune system disorders
Rare
Anaphylactoid reaction (including rash, urticaria,
bronchospasm, laryngeal oedema)
Nervous system disorders
Uncommon
Intracranial haemorrhage (such as cerebral haemorrhage,
cerebral haematoma, haemorrhagic stroke, haemorrhagic
transformation stroke, intracranial haematoma, subarachnoid
haemorrhage) including associated symptoms as somnolence,
aphasia, hemiparesis, convulsion
Eye disorders
Uncommon
Eye haemorrhage
Cardiac disorders
Uncommon
Reperfusion arrhythmias (such as asystole, accelerated
idioventricular arrhythmia, arrhythmia, extrasystoles, atrial
fibrillation, atrioventricular first degree to atrioventricular
block complete, bradycardia, tachycardia, ventricular
arrhythmia, ventricular fibrillation, ventricular tachycardia)
occur in close temporal relationship to treatment with
tenecteplase. Reperfusion arrhythmias may lead to cardiac
arrest, can be life threatening and may require the use of
conventional antiarrhythmic therapies.
Rare
Pericardial haemorrhage
Vascular disorders
Very common Haemorrhage
Rare Embolism (thrombotic embolisation)
Respiratory, thoracic and mediastinal disorders
Common
Epistaxis
Rare
Pulmonary haemorrhage
Gastrointestinal disorders
Common
Gastrointestinal haemorrhage (such as gastric haemorrhage,
gastric ulcer haemorrhage, rectal haemorrhage,
haematemesis, melaena, mouth haemorrhage)
Uncommon
Retroperitoneal haemorrhage (such as retroperitoneal
haematoma)
Not known
Nausea, vomiting
Skin and subcutaneous tissue disorders
Common
Ecchymosis
Renal and urinary disorders
Common Urogenital haemorrhage (such as haematuria, haemorrhage
urinary tract)
General disorders and administration site conditions
Common
Injection site haemorrhage, puncture site haemorrhage
Investigations
Rare Blood pressure decreased
Not known Body temperature increased
Injury, poisoning and procedural complications
Not known
Fat embolism, which may lead to corresponding
consequences in the organs concerned
As with other thrombolytic agents, the following events have been reported as sequelae of myocardial
infarction and/or thrombolytic administration:
-
very common (>1/10): hypotension, heart rate and rhythm disorders, angina pectoris
-
common (>1/100, <1/10): recurrent ischaemia, cardiac failure, myocardial infarction,
cardiogenic shock, pericarditis, pulmonary oedema
24
-
uncommon (>1/1,000, <1/100): cardiac arrest, mitral valve incompetence, pericardial effusion,
venous thrombosis, cardiac tamponade, myocardial rupture
-
rare (>1/10,000, <1/1,000): pulmonary embolism
These cardiovascular events can be life-threatening and may lead to death.
In the event of overdose there may be an increased risk of bleeding. In case of severe prolonged
bleeding substitution therapy may be considered (plasma, platelets), see also section 4.4.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group
Antithrombotic agents, ATC code: B01A D11
Mechanism of action
Tenecteplase is a recombinant fibrin-specific plasminogen activator that is derived from native t-PA
by modifications at three sites of the protein structure. It binds to the fibrin component of the thrombus
(blood clot) and selectively converts thrombus-bound plasminogen to plasmin, which degrades the
fibrin matrix of the thrombus. Tenecteplase has a higher fibrin specificity and greater resistance to
inactivation by its endogenous inhibitor (PAI-1) compared to native t-PA.
2-antiplasmin (the fluid-phase
inhibitor of plasmin) with consequent increase in the level of systemic plasmin generation have been
observed. This observation is consistent with the intended effect of plasminogen activation. In
comparative studies a less than 15% reduction in fibrinogen and a less than 25% reduction in
plasminogen were observed in subjects treated with the maximum dose of tenecteplase (10,000 U,
corresponding to 50 mg), whereas alteplase caused an approximately 50% decrease in fibrinogen and
plasminogen levels. No clinically relevant antibody formation was detected at 30 days.
α
Clinical effects
Patency data from the phase I and II angiographic studies suggest that tenecteplase, administered as a
single intravenous bolus, is effective in dissolving blood clots in the infarct-related artery of subjects
experiencing an AMI on a dose related basis.
A large scale mortality trial (ASSENT II) in approx. 17,000 patients showed that tenecteplase is
therapeutically equivalent to alteplase in reducing mortality (6.2% for both treatments, at 30 days,
upper limit of the 95% CI for the relative risk ratio 1.124) and that the use of tenecteplase is associated
with a significantly lower incidence of non-intracranial bleedings (26.4% vs. 28.9%, p=0.0003). This
translates into a significantly lower need of transfusions (4.3% vs. 5.5%, p=0.0002). Intracranial
haemorrhage occurred at a rate of 0.93% vs. 0.94% for tenecteplase and alteplase, respectively.
Coronary patency and limited clinical outcome data showed that AMI patients have been successfully
treated later than 6 hours after symptom onset.
The ASSENT-4 PCI study was designed to show if in 4000 patients with large myocardial infarctions
pre-treatment with full dose tenecteplase and concomitant single bolus of up to 4,000 IU
unfractionated heparin administered prior to primary Percutaneous Coronary Intervention (PCI) to be
performed within 60 to 180 minutes leads to better outcomes than primary PCI alone. The trial was
prematurely terminated with 1667 randomised patients due to a numerically higher mortality in the
facilitated PCI group receiving tenecteplase. The occurrence of the primary endpoint, a composite of
25
Pharmacodynamic effects
After administration of tenecteplase dose dependent consumption of
death or cardiogenic shock or congestive heart failure within 90 days, was significantly higher in the
group receiving the exploratory regimen of tenecteplase followed by routine immediate PCI: 18.6%
(151/810) compared to 13.4% (110/819) in the PCI only group, p=0.0045. This significant difference
between the groups for the primary endpoint at 90 days was already present in-hospital and at 30 days.
Numerically all of the components of the clinical composite endpoint were in favour of the PCI only
regimen: death: 6.7% vs. 4.9% p=0.14; cardiogenic shock: 6.3% vs. 4.8% p=0.19; congestive heart
failure: 12.0% vs. 9.2% p=0.06 respectively. The secondary endpoints re-infarction and repeat target
vessel revascularisation were significantly increased in the group pre-treated with tenecteplase: re-
infarction: 6.1% vs. 3.7% p=0.0279; repeat target vessel revascularisation: 6.6% vs. 3.4% p=0.0041.
The following adverse events occurred more frequently with tenecteplase prior to PCI: intracranial
haemorrhage: 1% vs. 0% p=0.0037; stroke: 1.8% vs. 0% p<0.0001; major bleeds: 5.6% vs. 4.4%
p=0.3118; minor bleeds: 25.3% vs. 19.0% p= 0.0021; blood transfusions: 6.2% vs. 4.2% p=0.0873;
abrupt vessel closure: 1.9% vs. 0.1% p=0.0001.
5.2 Pharmacokinetic properties
Tenecteplase is an intravenously administered, recombinant protein that activates plasminogen.
Tenecteplase is cleared from circulation by binding to specific receptors in the liver followed by
catabolism to small peptides. Binding to hepatic receptors is, however, reduced compared to native t-
PA, resulting in a prolonged half-life. Data on tissue distribution and elimination were obtained in
studies with radioactively labelled tenecteplase in rats. The main organ to which tenecteplase
distributed was the liver. It is not known whether and to what extent tenecteplase binds to plasma
proteins in humans.
After single intravenous bolus injection of tenecteplase in patients with acute myocardial infarction,
tenecteplase antigen exhibits biphasic elimination from plasma. There is no dose dependence of
tenecteplase clearance in the therapeutic dose range. The initial, dominant half life is 24 ± 5.5 (mean
+/-SD) min, which is 5 times longer than native t PA. The terminal half-life is 129 ± 87 min, and
plasma clearance is 119 ± 49 ml/min.
Increasing body weight resulted in a moderate increase of tenecteplase clearance, and increasing age
resulted in a slight decrease of clearance. Women exhibit in general lower clearance than men, but this
can be explained by the generally lower body weight of women.
The effect of renal and hepatic dysfunction on pharmacokinetics of tenecteplase in humans is not
known. There is no specific experience to guide the adjustment to tenecteplase dose in patients with
hepatic and severe renal insufficiency. However, based on animal data it is not expected that renal
dysfunction will affect the pharmacokinetics.
5.3 Preclinical safety data
Intravenous single dose administration in rats, rabbits and dogs resulted only in dose-dependent and
reversible alterations of the coagulation parameters with local haemorrhage at the injection site, which
was regarded as a consequence of the pharmacodynamic effect of tenecteplase. Multiple-dose toxicity
studies in rats and dogs confirmed these above-mentioned observations, but the study duration was
limited to two weeks by antibody formation to the human protein tenecteplase, which resulted in
anaphylaxis.
Safety pharmacology data in cynomolgus monkeys revealed reduction of blood pressure followed by
changes of ECG, but these occurred at exposures that were considerably higher than the clinical
exposure.
With regard to the indication and the single dose administration in humans, reproductive toxicity
testing was limited to an embryotoxicity study in rabbits, as a sensitive species. Tenecteplase induced
total litter deaths during the mid-embryonal period. When tenecteplase was given during the mid- or
26
late-embryonal period maternal animals showed vaginal bleeding on the day after the first dose.
Secondary mortality was observed 1-2 days later. Data on the foetal period are not available.
Mutagenicity and carcinogenicity are not expected for this class of recombinant proteins and
genotoxicity and carcinogenicity testing were not necessary.
No local irritation of the blood vessel was observed after intravenous, intra-arterial or paravenous
administration of the final formulation of tenecteplase.
6.
6.1 List of excipients
Powder:
L-arginine
Phosphoric acid
Polysorbate 20.
Solvent:
Water for injections.
6.2 Incompatibilities
Metalyse is incompatible with dextrose infusion solutions.
6.3 Shelf life
Shelf life as packaged for sale
2 years
Reconstituted solution
Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8°C and 8 hours at
30°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 2-8°C.
6.4 Special precautions for storage
Do not store above 30°C. Keep the container in the outer carton.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
20 ml glass vial type I, with a coated (B2-42) grey rubber stopper and a flip-off cap filled with powder
for solution for injection.
10 ml plastic syringe pre-filled with 10 ml of water for injections for reconstitution.
Sterile vial adapter.
Sterile needle for single use.
6.6 Special precautions for disposal and other handling
Metalyse should be reconstituted by adding the complete volume of water for injections from the pre-
filled syringe to the vial containing the powder for injection.
27
1.
Ensure that the appropriate vial size is chosen according to the body weight of the patient.
Patients’ body weight
category
(kg)
Volume of
reconstituted solution
(ml)
Tenecteplase
(U)
Tenecteplase
(mg)
< 60
6
6,000
30
≥
60 to < 70
7
7,000
35
≥
70 to < 80
8
8,000
40
≥
80 to < 90
9
9,000
45
≥
90
10
10,000
50
2. Check that the cap of the vial is still intact.
3. Remove the flip-off cap from the vial.
4. Remove the tip-cap from the syringe. Then immediately screw the pre-filled syringe on the vial
adapter and penetrate the vial stopper in the middle with the spike of the vial adapter.
5. Add the water for injections into the vial by pushing the syringe plunger down slowly to avoid
foaming.
6. Reconstitute by swirling gently.
7. The reconstituted preparation results in a colourless to pale yellow, clear solution. Only clear
solution without particles should be used.
8. Directly before the solution will be administered, invert the vial with the syringe still attached,
so that the syringe is below the vial.
9. Transfer the appropriate volume of reconstituted solution of Metalyse into the syringe, based on
the patient’s weight.
10. Disconnect the syringe from the vial adapter.
11. Metalyse is to be administered to the patient, intravenously in about 10 seconds. It should not be
administered in a line containing dextrose.
12. Any unused solution should be discarded.
Alternatively the reconstitution can be performed with the included needle.
7.
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
8.
EU/1/00/169/006
9.
Date of first authorisation: 23 February 2001
Date of last renewal: 23 February 2006
28
ANNEX II
A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE
SUBSTANCE(S) AND MANUFACTURING
AUTHORISATION HOLDER(S) RESPONSIBLE FOR
BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
29
A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND
MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) of the biological active substance(s)
Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65, 88397 Biberach/Riss
Germany
Name and address of the manufacturer(s) responsible for batch release
Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65, 88397 Biberach/Riss
Germany
B.
CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
30
ANNEX III
LABELLING AND PACKAGE LEAFLET
31
A. LABELLING
32
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
CARTON LABEL (CYCLOOLEFINE-COPOLYMER) SYRINGE/OUTER PACKAGING
1.
Metalyse 6,000 U
Powder and solvent for solution for injection
Tenecteplase
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
6,000 U tenecteplase per vial
When reconstituted with 6 ml water for injections each ml contains 1,000 U tenecteplase
3.
LIST OF EXCIPIENTS
Excipients: L-Arginine, Phosphoric Acid, Polysorbate 20
Trace residue from manufacturing process: Gentamicin
4.
1 vial of powder for solution for injection
1 pre-filled syringe of solvent for parenteral use
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use after reconstitution with 6 ml solvent
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Please follow accurately the instructions for use. Failure to do so may lead to greater than the required
dose of Metalyse being administered.
8.
EXPIRY DATE
EXP {MM/YYYY}
33
9.
SPECIAL STORAGE CONDITIONS
C.
Keep the container in the outer carton in order to protect from light.
°
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
EU/1/00/169/004
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
PARTICULARS TO APPEAR ON THE INNER SIDE OF THE LID OF THE CARTON
IN FORM OF A PICTOGRAMM
34
Do not store above 30
16. INFORMATION IN BRAILLE
35
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
VIAL LABEL FOR POWDER FOR SOLUTION FOR INJECTION/IMMEDIATE
PACKAGING
1.
Metalyse 6,000 U
Powder for solution for injection.
Tenecteplase
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
6,000 U tenecteplase per vial
3.
LIST OF EXCIPIENTS
4.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use after reconstitution with 6 ml solvent
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
C.
Keep the container in the outer carton.
°
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
36
Do not store above 30
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
37
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
SYRINGE LABEL FOR SOLVENT
1.
Solvent for Metalyse 6,000 U
Solvent for parenteral use
2.
METHOD OF ADMINISTRATION
Reconstituted solution, for patients of body weight (kg):
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
6 ml water for injections
6.
OTHER
38
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
CARTON LABEL (CYCLOOLEFINE-COPOLYMER) SYRINGE/OUTER PACKAGING
1.
Metalyse 8,000 U
Powder and solvent for solution for injection
Tenecteplase
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
8,000 U tenecteplase per vial
When reconstituted with 8 ml water for injections each ml contains 1,000 U tenecteplase
3.
LIST OF EXCIPIENTS
Excipients: L-Arginine, Phosphoric Acid, Polysorbate 20
Trace residue from manufacturing process: Gentamicin
4.
1 vial of powder for solution for injection
1 pre-filled syringe of solvent for parenteral use
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use after reconstitution with 8 ml solvent
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Please follow accurately the instructions for use. Failure to do so may lead to greater than the required
dose of Metalyse being administered.
8.
EXPIRY DATE
EXP {MM/YYYY}
39
9.
SPECIAL STORAGE CONDITIONS
C.
Keep the container in the outer carton in order to protect from light.
°
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
EU/1/00/169/005
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
PARTICULARS TO APPEAR ON THE INNER SIDE OF THE LID OF THE CARTON
IN FORM OF A PICTOGRAMM
40
Do not store above 30
16. INFORMATION IN BRAILLE
41
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
VIAL LABEL FOR POWDER FOR SOLUTION FOR INJECTION/IMMEDIATE
PACKAGING
1.
Metalyse 8,000 U
Powder for solution for injection.
Tenecteplase
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
8,000 U tenecteplase per vial
3.
LIST OF EXCIPIENTS
4.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use after reconstitution with 8 ml solvent
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
C.
Keep the container in the outer carton.
°
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
42
Do not store above 30
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
43
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
SYRINGE LABEL FOR SOLVENT
1.
Solvent for Metalyse 8,000 U
Solvent for parenteral use
2.
METHOD OF ADMINISTRATION
Reconstituted solution, for patients of body weight (kg):
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
8 ml water for injections
6.
OTHER
44
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
CARTON LABEL (CYCLOOLEFINE-COPOLYMER) SYRINGE/OUTER PACKAGING
1.
Metalyse 10,000 U
Powder and solvent for solution for injection
Tenecteplase
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
10,000 U tenecteplase per vial
When reconstituted with 10 ml water for injections each ml contains 1,000 U tenecteplase
3.
LIST OF EXCIPIENTS
Excipients: L-Arginine, Phosphoric Acid, Polysorbate 20
Trace residue from manufacturing process: Gentamicin
4.
1 vial of powder for solution for injection
1 pre-filled syringe of solvent for parenteral use
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use after reconstitution with 10 ml solvent
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Please follow accurately the instructions for use. Failure to do so may lead to greater than the required
dose of Metalyse being administered.
8.
EXPIRY DATE
EXP {MM/YYYY}
45
9.
SPECIAL STORAGE CONDITIONS
C.
Keep the container in the outer carton in order to protect from light.
°
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
EU/1/00/169/006
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
PARTICULARS TO APPEAR ON THE INNER SIDE OF THE LID OF THE CARTON
IN FORM OF A PICTOGRAMM
46
Do not store above 30
16. INFORMATION IN BRAILLE
47
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
VIAL LABEL FOR POWDER FOR SOLUTION FOR INJECTION/IMMEDIATE
PACKAGING
1.
Metalyse 10,000 U
Powder for solution for injection.
Tenecteplase
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
10,000 U tenecteplase per vial
3.
LIST OF EXCIPIENTS
4.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use after reconstitution with 10 ml solvent
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
C.
Keep the container in the outer carton.
°
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
48
Do not store above 30
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
49
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
SYRINGE LABEL FOR SOLVENT
1.
Solvent for Metalyse 10,000 U
Solvent for parenteral use
2.
METHOD OF ADMINISTRATION
Reconstituted solution, for patients of body weight (kg):
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
10 ml water for injections
6.
OTHER
50
B. PACKAGE LEAFLET
51
PACKAGE LEAFLET: INFORMATION FOR THE USER
METALYSE 6,000 units powder and solvent for solution for injection
Tenecteplase
Read all of this leaflet carefully before you start receiving this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What METALYSE is and what it is used for
3.
How is METALYSE administered
4.
Possible side effects
5
How to store METALYSE
6.
Further information
1.
WHAT METALYSE IS AND WHAT IT IS USED FOR
METALYSE is a powder and solvent for solution for injection. This means that each pack contains:
−
one vial of 6,000 units METALYSE powder and one pre-filled syringe containing 6 ml water
for injections
Before use, the solvent (water for injections) is added to the powder to form a solution that is given by
injection.
METALYSE belongs to a group of medicines called thrombolytic agents. These medicines help to
dissolve blood clots. Tenecteplase is a recombinant fibrin-specific plasminogen activator.
METALYSE is used to treat myocardial infarctions (heart attacks) within 6 hours after the onset of
symptoms and helps to dissolve the blood clots that have formed in the blood vessels of the heart. This
helps to prevent the damage caused by heart attacks and has been shown to save lives.
2.
BEFORE YOU RECEIVE METALYSE
METALYSE will not be prescribed and given by your doctor
−
if you have previously had a sudden life-threatening allergic reaction (severe hypersensitivity)
to the active ingredient tenecteplase, to gentamicin (a trace residue from the manufacturing
process) or any of the other ingredients of METALYSE. If treatment with Metalyse is
nevertheless considered to be necessary, facilities for reanimation should be immediately
available in case of need;
−
if you have, or have recently had, an illness that increases your risk of bleeding (haemorrhage),
including:
a bleeding disorder or tendency to bleed (haemorrhage)
stroke (cerebrovascular event)
very high, uncontrolled blood pressure
a head injury
severe liver disease
a stomach ulcer (peptic ulcer)
52
-
Keep this leaflet. You may need to read it again.
2.
Before you receive METALYSE
varicose veins in the gullet (oesophageal varices)
abnormality of the blood vessels (e.g. an aneurysm)
certain tumours
inflammation of the lining around the heart (pericarditis); inflammation or infection of the
heart valves (endocarditis);
−
if you are taking tablets/capsules used to ”thin” the blood, such as warfarin or coumarin (anti-
coagulants);
−
if you have an inflamed pancreas (pancreatitis);
−
if you have recently had major surgery including surgery to your brain or spine;
−
if you have been given cardiopulmonary resuscitation (chest compressions) for more than 2
minutes duration, in the last two weeks.
Your doctor will take special care with METALYSE
−
if you have had any allergic reaction other than a sudden life-threatening allergic
reaction (severe hypersensitive) to the active substance tenecteplase, to gentamicin (a
trace residue from the manufacturing process), or to any of the other ingredients of
Metalyse (see section 6: “Further information”);
−
if you have high blood pressure;
−
if you have problems with circulation of blood in the brain (cerebrovascular disease);
−
if you have had gastrointestinal (gut) or genitourinary bleeding within the last ten days (this may
cause blood in stools or urine);
−
if you have a heart valve abnormality (e.g. mitral stenosis) with an abnormal heart rhythm (e.g.
atrial fibrillation);
−
if you have had an intramuscular injection in the last two days;
−
if you are aged over 75 years;
−
if you weigh less than 60 kg.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Pregnancy and breast-feeding
Ask your doctor for advice before you are given METALYSE.
3.
HOW IS METALYSE ADMINISTERED
The doctor calculates your dose of METALYSE according to your bodyweight, based on the
following scheme:
Bodyweight (kg)
less than 60 60 to 70
70 to 80
80 to 90
above 90
Metalyse (U)
6,000
7,000
8,000
9,000
10,000
Your doctor will give you medication to prevent blood clotting in addition to METALYSE, as soon as
possible after your chest pain starts.
METALYSE is given by a single injection into a vein by a doctor who is experienced in the use of this
type of drug.
Your doctor will give METALYSE as soon as possible after your chest pain starts as a single dose.
Repetition is not recommended.
53
4.
POSSIBLE SIDE EFFECTS
Like all medicines, METALYSE can cause side effects, although not everybody gets them.
Evaluation of side effects is based on the following frequencies:
very common:
affects more than 1 user in 10
common:
affects 1 to 10 users in 100
uncommon:
affects 1 to 10 users in 1,000
rare:
affects 1 to 10 users in 10,000
very rare:
affects less than 1 user in 10,000
not known:
frequency cannot be estimated from the available
data
The side effects described below have been experienced by people given METALYSE:
Very Common:
−
bleeding
Common:
−
bleeding at the injection or puncture site
−
nosebleeds
−
genitourinary bleeding (you may notice blood in your urine)
−
bruising
−
gastro-intestinal bleeding (e.g. bleeding from the stomach or bowel)
Uncommon:
−
irregular heart beat (reperfusion arrhythmias), sometimes leading to cardiac arrest
−
internal bleeding in the abdomen (retroperitoneal bleeding)
−
bleeding in the brain (cerebral haemorrhage). Death or permanent disability may occur
following bleeding in the brain or other serious bleeding events
−
bleeding in the eyes (eye haemorrhage)
Rare:
−
low blood pressure (hypotension)
−
bleeding in the lungs (pulmonary haemorrhage)
−
hypersensitivity (anaphylactoid reactions) e.g. rash, hives (urticaria), swelling of the throat
−
bleeding into the area surrounding the heart (haemopericardium)
−
blood clot in the lung (pulmonary embolism) and in the vessels of other organ systems
(thrombotic embolisation)
Not known:
−
fat embolism (clots consisting of fat)
−
nausea
−
vomiting
−
body temperature increased (fever)
−
blood transfusions as consequence of bleedings
54
As with other thrombolytic agents, the following events have been reported as sequelae of myocardial
infarction and/or thrombolytic administration:
Very common:
−
Low blood pressure (hypotension)
−
Irregular heart beat
−
Chest pain (angina pectoris)
Common:
−
Further heart attack (recurrent ischaemia)
−
Heart failure
−
Shock due to heart failure
−
Inflammation of the lining around the heart
−
Fluid in the lungs (pulmonary oedema)
Uncommon:
−
Heart arrest
−
Problem with the heart valve or heart lining (mitral valve incompetence, pericardial effusion)
−
Blood clot in the veins (venous thrombosis)
−
Fluid between the heart lining and the heart (cardiac tamponade)
−
Rupture of the heart muscle (myocardial rupture)
Rare:
−
Blood clot in the lung (pulmonary embolism)
These cardiovascular events can be life-threatening and may lead to death.
In case of bleeding in the brain events related to the nervous system have been reported e.g.
drowsiness (somnolence), speech disorders, palsy of parts of the body (hemiparesis) and fits
(convulsions).
Tell your doctor immediately if you think you are experiencing any of these side effects.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE METALYSE
Keep out of the reach and sight of children.
Do not store above 30°C.
Keep the container in the outer carton in order to protect from light.
Once METALYSE has been reconstituted it may be stored for 24 hours at 2-8°C and 8 hours at 30°C.
However, for microbiological reasons your doctor will normally use the reconstituted solution for
injection immediately.
Do not use METALYSE after the expiry date which is stated on the label/carton.
55
6.
FURTHER INFORMATION
What METALYSE contains
−
The active substance is tenecteplase. One vial contains 6,000 units of tenecteplase. One pre-
filled syringe contains 6 ml of water for injections.
−
The other ingredients are L-arginine, phosphoric acid and polysorbate 20.
−
The METALYSE solvent is water for injections.
−
Gentamicin is contained as trace residue from the manufacturing process
What METALYSE looks like and contents of the pack
The folding box contains one vial with a lyophilised powder, one ready for use syringe with a solvent,
one vial adapter and one needle.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
Manufacturer
Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65
D-88397 Biberach/Riss
Germany
56
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11
Tél/Tel: +32 2 773 33 11
България Magyarország
Бьорингер Ингелхайм
РЦВ
ГмбХ
и Ко КГ
Boehringer Ingelheim RCV
GmbH & Co KG
- клон България
Magyarországi Fióktelepe
Česká republika
Malta
Boehringer Ingelheim spol. s r.o.
Boehringer Ingelheim Ltd.
Tel: +420 234 655 111
Tel: +44 1344 424 600
Danmark
Nederland
Boehringer Ingelheim Danmark A/S
Boehringer Ingelheim b.v.
Tlf : +45 39158888
Tel: +31 (0) 800 22 55 889
Deutschland Norge
Boehringer Ingelheim Pharma GmbH & Co. KG Boehringer Ingelheim Norway KS
Tel: +49 (0) 800 77 90 900
Tlf: +47 66 76 13 00
Boehringer Ingelheim RCV GmbH & Co KG
Boehringer Ingelheim RCV GmbH & Co
Eesti filiaal
KG
Tel: +372 60 80 940
Tel: +43 1 80 105-0
Eλλάδα
Polska
Boehringer Ingelheim Ellas A.E.
Boehringer Ingelheim Sp.zo.o.
Tηλ: +30 2 10 89 06 300
Tel.: +48 22 699 0 699
España
Portugal
Boehringer Ingelheim España S.A.
Boehringer Ingelheim, Lda.
Tel: +34 93 404 58 00
Tel: +351 21 313 53 00
France
România
Boehringer Ingelheim France S.A.S.
Boehringer Ingelheim RCV
GmbH & Co KG
Tél: +33 3 26 50 45 33
Viena - Sucursala Bucuresti
Tel: +40 21 330 99 63
Ireland
Slovenija
Boehringer Ingelheim Ireland Ltd.
Boehringer Ingelheim RCV
GmbH & Co KG
Tel: +353 1 295 9620
Podružnica Ljubljana
Tel: +386 1 586 40 00
Ísland
Slovenská republika
Vistor hf.
Boehringer Ingelheim RCV
GmbH & Co KG
Sími
: +354 535 7000
organizačná zložka
Tel: +421 2 5810 1211
Italia
Suomi/Finland
Boehringer Ingelheim Italia S.p.A.
Boehringer Ingelheim Finland Ky
Tel: +39 02 5355 1
Puh/Tel: +358 10 3102 800
Κύπρος
Sverige
Boehringer Ingelheim Ellas A.E.
Boehringer Ingelheim AB
Tηλ: +30 2 10 89 06 300
Tel: +46 8 721 21 00
57
Тел: +359 2 958 79 98
Tel.: +36 1 299 8900
Eesti
Österreich
Latvija
United Kingdom
Boehringer Ingelheim Pharma GmbH
Boehringer Ingelheim Ltd.
Pārstāvniecība Latvijā
Tel: +44 1344 424 600
Tel: +371 67 240 068
Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel.: +370 37 473922
This leaflet was last approved in {MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu
58
PACKAGE LEAFLET: INFORMATION FOR THE USER
METALYSE 8,000 units powder and solvent for solution for injection
Tenecteplase
Read all of this leaflet carefully before you start receiving this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What METALYSE is and what it is used for
3.
How is METALYSE administered
4.
Possible side effects
5
How to store METALYSE
6.
Further information
1.
WHAT METALYSE IS AND WHAT IT IS USED FOR
METALYSE is a powder and solvent for solution for injection. This means that each pack contains:
−
one vial of 8,000 units METALYSE powder and one pre-filled syringe containing 8 ml water
for injections
Before use, the solvent (water for injections) is added to the powder to form a solution that is given by
injection.
METALYSE belongs to a group of medicines called thrombolytic agents. These medicines help to
dissolve blood clots. Tenecteplase is a recombinant fibrin-specific plasminogen activator.
METALYSE is used to treat myocardial infarctions (heart attacks) within 6 hours after the onset of
symptoms and helps to dissolve the blood clots that have formed in the blood vessels of the heart. This
helps to prevent the damage caused by heart attacks and has been shown to save lives.
2.
BEFORE YOU RECEIVE METALYSE
METALYSE
will not be prescribed and given by your doctor
−
if you have previously had a sudden life-threatening allergic reaction (severe hypersensitivity)
to the active ingredient tenecteplase, to gentamicin (a trace residue from the manufacturing
process) or any of the other ingredients of METALYSE. If treatment with Metalyse is
nevertheless considered to be necessary, facilities for reanimation should be immediately
available in case of need;
−
if you have, or have recently had, an illness that increases your risk of bleeding (haemorrhage),
including:
a bleeding disorder or tendency to bleed (haemorrhage)
stroke (cerebrovascular event)
very high, uncontrolled blood pressure
a head injury
severe liver disease
a stomach ulcer (peptic ulcer)
59
-
Keep this leaflet. You may need to read it again.
2.
Before you receive METALYSE
varicose veins in the gullet (oesophageal varices)
abnormality of the blood vessels (e.g. an aneurysm)
certain tumours
inflammation of the lining around the heart (pericarditis); inflammation or infection of the
heart valves (endocarditis);
−
if you are taking tablets/capsules used to ”thin” the blood, such as warfarin or coumarin (anti-
coagulants);
−
if you have an inflamed pancreas (pancreatitis);
−
if you have recently had major surgery including surgery to your brain or spine;
−
if you have been given cardiopulmonary resuscitation (chest compressions) for more than 2
minutes duration, in the last two weeks.
Your doctor will take special care with METALYSE
−
if you have had any allergic reaction other than a sudden life-threatening allergic
reaction (severe hypersensitive) to the active substance tenecteplase, to gentamicin (a
trace residue from the manufacturing process), or to any of the other ingredients of
Metalyse (see section 6: “Further information”);
−
if you have high blood pressure;
−
if you have problems with circulation of blood in the brain (cerebrovascular disease);
−
if you have had gastrointestinal (gut) or genitourinary bleeding within the last ten days (this may
cause blood in stools or urine);
−
if you have a heart valve abnormality (e.g. mitral stenosis) with an abnormal heart rhythm (e.g.
atrial fibrillation);
−
if you have had an intramuscular injection in the last two days;
−
if you are aged over 75 years;
−
if you weigh less than 60 kg.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Pregnancy and breast-feeding
Ask your doctor for advice before you are given METALYSE.
3.
HOW IS METALYSE ADMINISTERED
The doctor calculates your dose of METALYSE according to your bodyweight, based on the
following scheme:
Bodyweight (kg)
less than 60 60 to 70
70 to 80
80 to 90
above 90
Metalyse (U)
6,000
7,000
8,000
9,000
10,000
Your doctor will give you medication to prevent blood clotting in addition to METALYSE, as soon as
possible after your chest pain starts.
METALYSE is given by a single injection into a vein by a doctor who is experienced in the use of this
type of drug.
Your doctor will give METALYSE as soon as possible after your chest pain starts as a single dose.
Repetition is not recommended.
60
4.
POSSIBLE SIDE EFFECTS
Like all medicines, METALYSE can cause side effects, although not everybody gets them.
Evaluation of side effects is based on the following frequencies:
very common:
affects more than 1 user in 10
common:
affects 1 to 10 users in 100
uncommon:
affects 1 to 10 users in 1,000
rare:
affects 1 to 10 users in 10,000
very rare:
affects less than 1 user in 10,000
not known:
frequency cannot be estimated from the available
data
The side effects described below have been experienced by people given METALYSE:
Very Common:
−
bleeding
Common:
−
bleeding at the injection or puncture site
−
nosebleeds
−
genitourinary bleeding (you may notice blood in your urine)
−
bruising
−
gastro-intestinal bleeding (e.g. bleeding from the stomach or bowel)
Uncommon:
−
irregular heart beat (reperfusion arrhythmias), sometimes leading to cardiac arrest
−
internal bleeding in the abdomen (retroperitoneal bleeding)
−
bleeding in the brain (cerebral haemorrhage). Death or permanent disability may occur
following bleeding in the brain or other serious bleeding events
−
bleeding in the eyes (eye haemorrhage)
Rare:
−
low blood pressure (hypotension)
−
bleeding in the lungs (pulmonary haemorrhage)
−
hypersensitivity (anaphylactoid reactions) e.g. rash, hives (urticaria), swelling of the throat
−
bleeding into the area surrounding the heart (haemopericardium)
−
blood clot in the lung (pulmonary embolism) and in the vessels of other organ systems
(thrombotic embolisation)
Not known:
−
fat embolism (clots consisting of fat)
−
nausea
−
vomiting
−
body temperature increased (fever)
−
blood transfusions as consequence of bleedings
61
As with other thrombolytic agents, the following events have been reported as sequelae of myocardial
infarction and/or thrombolytic administration:
Very common:
−
Low blood pressure (hypotension)
−
Irregular heart beat
−
Chest pain (angina pectoris)
Common:
−
Further heart attack (recurrent ischaemia)
−
Heart failure
−
Shock due to heart failure
−
Inflammation of the lining around the heart
−
Fluid in the lungs (pulmonary oedema)
Uncommon:
−
Heart arrest
−
Problem with the heart valve or heart lining (mitral valve incompetence, pericardial effusion)
−
Blood clot in the veins (venous thrombosis)
−
Fluid between the heart lining and the heart (cardiac tamponade)
−
Rupture of the heart muscle (myocardial rupture)
Rare:
−
Blood clot in the lung (pulmonary embolism)
These cardiovascular events can be life-threatening and may lead to death.
In case of bleeding in the brain events related to the nervous system have been reported e.g.
drowsiness (somnolence), speech disorders, palsy of parts of the body (hemiparesis) and fits
(convulsions).
Tell your doctor immediately if you think you are experiencing any of these side effects.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE METALYSE
Keep out of the reach and sight of children.
Do not store above 30°C.
Keep the container in the outer carton in order to protect from light.
Once METALYSE has been reconstituted it may be stored for 24 hours at 2-8°C and 8 hours at 30°C.
However, for microbiological reasons your doctor will normally use the reconstituted solution for
injection immediately.
Do not use METALYSE after the expiry date which is stated on the label/carton.
62
6.
FURTHER INFORMATION
What METALYSE contains
−
The active substance is tenecteplase. One vial contains 8,000 units of tenecteplase. One pre-
filled syringe contains 8 ml of water for injections.
−
The other ingredients are L-arginine, phosphoric acid and polysorbate 20.
−
The METALYSE solvent is water for injections.
−
Gentamicin is contained as trace residue from the manufacturing process
What METALYSE looks like and contents of the pack
The folding box contains one vial with a lyophilised powder, one ready for use syringe with a solvent,
one vial adapter and one needle.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
Manufacturer
Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65
D-88397 Biberach/Riss
Germany
63
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11
Tél/Tel: +32 2 773 33 11
България Magyarország
Бьорингер Ингелхайм
РЦВ
ГмбХ
и Ко КГ
Boehringer Ingelheim RCV
GmbH & Co KG
- клон България
Magyarországi Fióktelepe
Česká republika
Malta
Boehringer Ingelheim spol. s r.o.
Boehringer Ingelheim Ltd.
Tel: +420 234 655 111
Tel: +44 1344 424 600
Danmark
Nederland
Boehringer Ingelheim Danmark A/S
Boehringer Ingelheim b.v.
Tlf : +45 39158888
Tel: +31 (0) 800 22 55 889
Deutschland Norge
Boehringer Ingelheim Pharma GmbH & Co. KG Boehringer Ingelheim Norway KS
Tel: +49 (0) 800 77 90 900
Tlf: +47 66 76 13 00
Boehringer Ingelheim RCV GmbH & Co KG
Boehringer Ingelheim RCV GmbH & Co
Eesti filiaal
KG
Tel: +372 60 80 940
Tel: +43 1 80 105-0
Eλλάδα
Polska
Boehringer Ingelheim Ellas A.E.
Boehringer Ingelheim Sp.zo.o.
Tηλ: +30 2 10 89 06 300
Tel.: +48 22 699 0 699
España
Portugal
Boehringer Ingelheim España S.A.
Boehringer Ingelheim, Lda.
Tel: +34 93 404 58 00
Tel: +351 21 313 53 00
France
România
Boehringer Ingelheim France S.A.S.
Boehringer Ingelheim RCV
GmbH & Co KG
Tél: +33 3 26 50 45 33
Viena - Sucursala Bucuresti
Tel: +40 21 330 99 63
Ireland
Slovenija
Boehringer Ingelheim Ireland Ltd.
Boehringer Ingelheim RCV
GmbH & Co KG
Tel: +353 1 295 9620
Podružnica Ljubljana
Tel: +386 1 586 40 00
Ísland
Slovenská republika
Vistor hf.
Boehringer Ingelheim RCV
GmbH & Co KG
Sími
: +354 535 7000
organizačná zložka
Tel: +421 2 5810 1211
Italia
Suomi/Finland
Boehringer Ingelheim Italia S.p.A.
Boehringer Ingelheim Finland Ky
Tel: +39 02 5355 1
Puh/Tel: +358 10 3102 800
Κύπρος
Sverige
Boehringer Ingelheim Ellas A.E.
Boehringer Ingelheim AB
Tηλ: +30 2 10 89 06 300
Tel: +46 8 721 21 00
64
Тел: +359 2 958 79 98
Tel.: +36 1 299 8900
Eesti
Österreich
Latvija
United Kingdom
Boehringer Ingelheim Pharma GmbH
Boehringer Ingelheim Ltd.
Pārstāvniecība Latvijā
Tel: +44 1344 424 600
Tel: +371 67 240 068
Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel.: +370 37 473922
This leaflet was last approved in {MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu
65
PACKAGE LEAFLET: INFORMATION FOR THE USER
METALYSE 10,000 units powder and solvent for solution for injection
Tenecteplase
Read all of this leaflet carefully before you start receiving this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What METALYSE is and what it is used for
3.
How is METALYSE administered
4.
Possible side effects
5
How to store METALYSE
6.
Further information
1.
WHAT METALYSE IS AND WHAT IT IS USED FOR
METALYSE is a powder and solvent for solution for injection. This means that each pack contains:
−
one vial of 10,000 units METALYSE powder and one pre-filled syringe containing 10 ml water
for injections.
Before use, the solvent (water for injections) is added to the powder to form a solution that is given by
injection.
METALYSE belongs to a group of medicines called thrombolytic agents. These medicines help to
dissolve blood clots. Tenecteplase is a recombinant fibrin-specific plasminogen activator.
METALYSE is used to treat myocardial infarctions (heart attacks) within 6 hours after the onset of
symptoms and helps to dissolve the blood clots that have formed in the blood vessels of the heart. This
helps to prevent the damage caused by heart attacks and has been shown to save lives.
2.
BEFORE YOU RECEIVE METALYSE
METALYSE will not be prescribed and given by your doctor
−
if you have previously had a sudden life-threatening allergic reaction (severe hypersensitivity)
to the active ingredient tenecteplase, to gentamicin (a trace residue from the manufacturing
process) or any of the other ingredients of METALYSE. If treatment with Metalyse is
nevertheless considered to be necessary, facilities for reanimation should be immediately
available in case of need;
−
if you have, or have recently had, an illness that increases your risk of bleeding (haemorrhage),
including:
a bleeding disorder or tendency to bleed (haemorrhage)
stroke (cerebrovascular event)
very high, uncontrolled blood pressure
a head injury
severe liver disease
a stomach ulcer (peptic ulcer)
66
-
Keep this leaflet. You may need to read it again.
2.
Before you receive METALYSE
varicose veins in the gullet (oesophageal varices)
abnormality of the blood vessels (e.g. an aneurysm)
certain tumours
inflammation of the lining around the heart (pericarditis); inflammation or infection of the
heart valves (endocarditis);
−
if you are taking tablets/capsules used to ”thin” the blood, such as warfarin or coumarin (anti-
coagulants);
−
if you have an inflamed pancreas (pancreatitis);
−
if you have recently had major surgery including surgery to your brain or spine;
−
if you have been given cardiopulmonary resuscitation (chest compressions) for more than 2
minutes duration, in the last two weeks.
Your doctor will take special care with METALYSE
−
if you have had any allergic reaction other than a sudden life-threatening allergic
reaction (severe hypersensitive) to the active substance tenecteplase, to gentamicin (a
trace residue from the manufacturing process), or to any of the other ingredients of
Metalyse (see section 6: “Further information”);
−
if you have high blood pressure;
−
if you have problems with circulation of blood in the brain (cerebrovascular disease);
−
if you have had gastrointestinal (gut) or genitourinary bleeding within the last ten days (this may
cause blood in stools or urine);
−
if you have a heart valve abnormality (e.g. mitral stenosis) with an abnormal heart rhythm (e.g.
atrial fibrillation);
−
if you have had an intramuscular injection in the last two days;
−
if you are aged over 75 years;
−
if you weigh less than 60 kg.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Pregnancy and breast-feeding
Ask your doctor for advice before you are given METALYSE.
3.
HOW IS METALYSE ADMINISTERED
The doctor calculates your dose of METALYSE according to your bodyweight, based on the
following scheme:
Bodyweight (kg)
less than 60 60 to 70
70 to 80
80 to 90
above 90
Metalyse (U)
6,000
7,000
8,000
9,000
10,000
Your doctor will give you medication to prevent blood clotting in addition to METALYSE, as soon as
possible after your chest pain starts.
METALYSE is given by a single injection into a vein by a doctor who is experienced in the use of this
type of drug.
Your doctor will give METALYSE as soon as possible after your chest pain starts as a single dose.
Repetition is not recommended.
67
4.
POSSIBLE SIDE EFFECTS
Like all medicines, METALYSE can cause side effects, although not everybody gets them.
Evaluation of side effects is based on the following frequencies:
very common:
affects more than 1 user in 10
common:
affects 1 to 10 users in 100
uncommon:
affects 1 to 10 users in 1,000
rare:
affects 1 to 10 users in 10,000
very rare:
affects less than 1 user in 10,000
not known:
frequency cannot be estimated from the available
data
The side effects described below have been experienced by people given METALYSE:
Very Common:
−
bleeding
Common:
−
bleeding at the injection or puncture site
−
nosebleeds
−
genitourinary bleeding (you may notice blood in your urine)
−
bruising
−
gastro-intestinal bleeding (e.g. bleeding from the stomach or bowel)
Uncommon:
−
irregular heart beat (reperfusion arrhythmias), sometimes leading to cardiac arrest
−
internal bleeding in the abdomen (retroperitoneal bleeding)
−
bleeding in the brain (cerebral haemorrhage). Death or permanent disability may occur
following bleeding in the brain or other serious bleeding events
−
bleeding in the eyes (eye haemorrhage)
Rare:
−
low blood pressure (hypotension)
−
bleeding in the lungs (pulmonary haemorrhage)
−
hypersensitivity (anaphylactoid reactions) e.g. rash, hives (urticaria), swelling of the throat
−
bleeding into the area surrounding the heart (haemopericardium)
−
blood clot in the lung (pulmonary embolism) and in the vessels of other organ systems
(thrombotic embolisation)
Not known:
−
fat embolism (clots consisting of fat)
−
nausea
−
vomiting
−
body temperature increased (fever)
−
blood transfusions as consequence of bleedings
68
As with other thrombolytic agents, the following events have been reported as sequelae of myocardial
infarction and/or thrombolytic administration:
Very common:
−
Low blood pressure (hypotension)
−
Irregular heart beat
−
Chest pain (angina pectoris)
Common:
−
Further heart attack (recurrent ischaemia)
−
Heart failure
−
Shock due to heart failure
−
Inflammation of the lining around the heart
−
Fluid in the lungs (pulmonary oedema)
Uncommon:
−
Heart arrest
−
Problem with the heart valve or heart lining (mitral valve incompetence, pericardial effusion)
−
Blood clot in the veins (venous thrombosis)
−
Fluid between the heart lining and the heart (cardiac tamponade)
−
Rupture of the heart muscle (myocardial rupture)
Rare:
−
Blood clot in the lung (pulmonary embolism)
These cardiovascular events can be life-threatening and may lead to death.
In case of bleeding in the brain events related to the nervous system have been reported e.g.
drowsiness (somnolence), speech disorders, palsy of parts of the body (hemiparesis) and fits
(convulsions).
Tell your doctor immediately if you think you are experiencing any of these side effects.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE METALYSE
Keep out of the reach and sight of children.
Do not store above 30°C.
Keep the container in the outer carton in order to protect from light.
Once METALYSE has been reconstituted it may be stored for 24 hours at 2-8°C and 8 hours at 30°C.
However, for microbiological reasons your doctor will normally use the reconstituted solution for
injection immediately.
Do not use METALYSE after the expiry date which is stated on the label/carton.
69
6.
FURTHER INFORMATION
What METALYSE contains
−
The active substance is tenecteplase. One vial contains 10,000 units of tenecteplase. One pre-
filled syringe contains 10 ml of water for injections.
−
The other ingredients are L-arginine, phosphoric acid and polysorbate 20.
−
The METALYSE solvent is water for injections.
−
Gentamicin is contained as trace residue from the manufacturing process
What METALYSE looks like and contents of the pack
The folding box contains one vial with a lyophilised powder, one ready for use syringe with a solvent,
one vial adapter and one needle.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
Manufacturer
Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65
D-88397 Biberach/Riss
Germany
70
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11
Tél/Tel: +32 2 773 33 11
България Magyarország
Бьорингер Ингелхайм
РЦВ
ГмбХ
и Ко КГ
Boehringer Ingelheim RCV
GmbH & Co KG
- клон България
Magyarországi Fióktelepe
Česká republika
Malta
Boehringer Ingelheim spol. s r.o.
Boehringer Ingelheim Ltd.
Tel: +420 234 655 111
Tel: +44 1344 424 600
Danmark
Nederland
Boehringer Ingelheim Danmark A/S
Boehringer Ingelheim b.v.
Tlf : +45 39158888
Tel: +31 (0) 800 22 55 889
Deutschland Norge
Boehringer Ingelheim Pharma GmbH & Co. KG Boehringer Ingelheim Norway KS
Tel: +49 (0) 800 77 90 900
Tlf: +47 66 76 13 00
Boehringer Ingelheim RCV GmbH & Co KG
Boehringer Ingelheim RCV GmbH & Co
Eesti filiaal
KG
Tel: +372 60 80 940
Tel: +43 1 80 105-0
Eλλάδα
Polska
Boehringer Ingelheim Ellas A.E.
Boehringer Ingelheim Sp.zo.o.
Tηλ: +30 2 10 89 06 300
Tel.: +48 22 699 0 699
España
Portugal
Boehringer Ingelheim España S.A.
Boehringer Ingelheim, Lda.
Tel: +34 93 404 58 00
Tel: +351 21 313 53 00
France
România
Boehringer Ingelheim France S.A.S.
Boehringer Ingelheim RCV
GmbH & Co KG
Tél: +33 3 26 50 45 33
Viena - Sucursala Bucuresti
Tel: +40 21 330 99 63
Ireland
Slovenija
Boehringer Ingelheim Ireland Ltd.
Boehringer Ingelheim RCV
GmbH & Co KG
Tel: +353 1 295 9620
Podružnica Ljubljana
Tel: +386 1 586 40 00
Ísland
Slovenská republika
Vistor hf.
Boehringer Ingelheim RCV
GmbH & Co KG
Sími
: +354 535 7000
organizačná zložka
Tel: +421 2 5810 1211
Italia
Suomi/Finland
Boehringer Ingelheim Italia S.p.A.
Boehringer Ingelheim Finland Ky
Tel: +39 02 5355 1
Puh/Tel: +358 10 3102 800
Κύπρος
Sverige
Boehringer Ingelheim Ellas A.E.
Boehringer Ingelheim AB
Tηλ: +30 2 10 89 06 300
Tel: +46 8 721 21 00
71
Тел: +359 2 958 79 98
Tel.: +36 1 299 8900
Eesti
Österreich
Latvija
United Kingdom
Boehringer Ingelheim Pharma GmbH
Boehringer Ingelheim Ltd.
Pārstāvniecība Latvijā
Tel: +44 1344 424 600
Tel: +371 67 240 068
Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel.: +370 37 473922
This leaflet was last approved in {MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu
72
Source: European Medicines Agency
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