ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Rapilysin 10 U powder and solvent for solution for injection.
2.
1 vial contains 10 U* reteplase ** in 0.56 g powder
1 prefilled syringe contains 10 ml water for injections.
The reconstituted solution contains 1 U reteplase per ml.
For a full list of excipients see section 6.1.
* Potency of reteplase is expressed in units (U) by using a reference standard which is specific
for reteplase and is not comparable with units used for other thrombolytic agents.
** Recombinant plasminogen activator produced in Escherichia coli by recombinant DNA
technology.
3.
Powder and solvent for solution for injection.
White powder and clear colourless liquid (water for injections).
4.
Rapilysin is indicated for the thrombolytic treatment of suspected myocardial infarction with persistent
ST elevation or recent left Bundle Branch Block within 12 hours after the onset of acute myocardial
infarction AMI symptoms.
Treatment with reteplase should be initiated as soon as possible after the onset of AMI symptoms.
Rapilysin should be prescribed by physicians experienced in the use of thrombolytic treatment and
with the facilities to monitor its use.
Reteplase is supplied as a freeze-dried substance in vials. The lyophilisate is reconstituted with the
contents of the accompanying syringe (see section 6.6).
Rapilysin should be injected preferably through an intravenous line whose sole purpose is the injection
of Rapilysin. No other medicines should be injected through the line reserved for Rapilysin, neither at
the same time, nor prior to, nor following Rapilysin injection. This applies to all products including
heparin, and acetylsalicylic acid, which should be administered before and following the
administration of reteplase to reduce the risk of re-thrombosis.
In those patients where the same line has to be used, this line (including Y-line) must be flushed
thoroughly with 0.9 % sodium chloride or 5 % dextrose solution prior to and following the Rapilysin
injection.
2
Dosage of Rapilysin
Rapilysin is administered as a 10 U bolus dose followed by a second 10 U bolus dose 30 minutes later
(double bolus).
Each bolus is administered as a slow intravenous injection within 2 minutes. Ensure that the injection
is not mistakenly given paravenously.
Heparin and acetylsalicylic acid
should be administered before and following the administration of
Rapilysin to reduce the risk of rethrombosis.
Dosage of Heparin
The recommended dose of heparin is 5000 I.U. given as a bolus injection prior to reteplase therapy
followed by an infusion of 1000 I.U. per hour starting after the second reteplase bolus. Heparin should
be administered for at least 24 hours, preferably for 48 – 72 hours, aiming to keep aPTT values 1.5 to
2 times normal.
Dosage of Acetylsalicylic Acid
The initial dose of acetylsalicylic acid prior to thrombolysis should be at least 250 mg (250 – 350 mg)
followed by 75 – 150 mg/day at least until discharge.
Use in children
There is no experience in children
Hypersensitivity to reteplase, polysorbate 80 or any of the other ingredients.
Because thrombolytic therapy increases the risk of bleeding, reteplase is contra-indicated in the
following situations:
-
known haemorrhagic diathesis
-
patients with current concomitant therapy with oral anticoagulants (e.g. warfarin sodium)
-
intracranial neoplasm, arteriovenous malformation or aneurysm
-
neoplasm with increased bleeding risk
-
history of cerebrovascular accident
-
recent (< 10 days) prolonged and vigorous external heart massage
-
severe uncontrolled hypertension
-
active peptic ulceration
-
portal hypertension (oesophageal varices)
-
severe liver or renal dysfunction
-
acute pancreatitis, pericarditis, bacterial endocarditis
-
within 3 months of severe bleeding, major trauma or major surgery (e.g. coronary artery bypass
graft, intracranial or intraspinal surgery or trauma), obstetrical delivery, organ biopsy, previous
puncture of non-compressible vessels.
3
Each patient being considered for therapy with reteplase should be carefully evaluated.
For information on product incompatibilities see section 6.2
Bleeding
The most common complication encountered during reteplase therapy is bleeding. In the following
conditions the risks of reteplase therapy may be increased and should be weighed against the
anticipated benefits:
-
cerebrovascular disease
-
systolic blood pressure at entry > 160 mmHg
-
recent gastrointestinal or genitourinary bleeding (within 10 days)
-
high likelihood of left heart thrombus, e.g. mitral stenosis with atrial fibrillation
-
septic thrombophlebitis or occluded arteriovenous cannula at seriously infected site
-
age over 75 years
-
any other condition in which bleeding constitutes a significant hazard or would be particularly
difficult because of its location
The concomitant use of heparin anticoagulation may contribute to bleeding. As fibrin is lysed during
reteplase therapy, bleeding from recent puncture sites may occur. Therefore, thrombolytic therapy
requires careful attention to all possible bleeding sites (including catheter insertion sites, arterial and
venous puncture sites, cut down sites and needle puncture sites). The use of rigid catheter as well as
intramuscular injections and nonessential handling of the patient should be avoided during treatment
with reteplase.
Caution should be employed when used with other medicinal products affecting haemostasis such as
heparin, low-molecular-weight heparins, heparinoids, oral anticoagulants and antiplatelet agents other
than acetylsalicylic acid, such as dipyridamole, ticlopidine, clopidogrel or glycoprotein IIb/IIIa
receptor antagonists.
Should serious bleeding, in particular cerebral haemorrhage, occur any concomitant heparin should be
terminated immediately. In addition, the second bolus of reteplase should not be given if the serious
bleeding occurs before it is administered. In general, however, it is not necessary to replace the
coagulation factors because of the relatively short half-life of reteplase. Most patients who have
bleeding can be managed by interruption of thrombolytic and anticoagulant therapy, volume
replacement and manual pressure applied to an incompetent vessel. Protamine should be considered if
heparin has been administered within 4 hours of the onset of bleeding. In the patients who fail to
respond to these conservative measures, judicious use of transfusion products may be indicated.
Transfusions of cryoprecipitate, fibrinogen, 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 or fibrinogen infusion.
At present, insufficient data in patients with a diastolic blood pressure > 100 mmHg prior to
thrombolytic therapy are available for reteplase.
4
Arrhythmias
Coronary thrombolysis may result in arrhythmias associated with reperfusion. It is strongly
recommended that antiarrhythmic therapy for bradycardia and/or ventricular tachyarrhythmias (e.g.
ventricular tachycardia or fibrillation) be available when reteplase is administered.
Readministration
Since at present there is no experience with readministration of reteplase, the readministration is not
recommended. However, no antibody formation to the reteplase molecule has been observed.
If an anaphylactoid reaction occurs, the injection should be discontinued immediately and appropriate
therapy should be initiated.
No interaction studies with reteplase and medicinal product commonly administered in patients with
AMI have been performed. Retrospective analyses of clinical studies did not reveal any clinically
relevant interactions with medicinal product used concomitantly with reteplase in patients with acute
myocardial infarction. Heparin, vitamin K antagonists and medicinal product that alter platelet
function (such as acetylsalicylic acid, dipyridamole and abciximab) may increase the risk of bleeding
if administered prior to, during or after reteplase therapy.
Attention should be paid to this effect especially during periods of low plasma fibrinogen (up to about
2 days after fibrinolytic therapy of AMI).
For information on product incompatibilities see section 4.2.
There are no adequate data on the use of reteplase in pregnant women. The only relevant available
animal data refer to studies performed in rabbits, which showed vaginal bleedings associated with
abortions (see section 5.3) The potential risk for humans is unknown.
Except in life-threatening situations, Rapilysin should not be used in pregnant women.
It is not known whether reteplase is excreted into breast milk. Breast milk should be discarded within
the first 24 hours after thrombolytic therapy.
Not relevant
The most commonly reported adverse drug reaction associated with reteplase treatment is
haemorrhage, predominantly at the injection site. Local reactions at injection site can also occur.
As with other thrombolytic agents, recurrent ischaemia / angina, hypotension and heart failure /
pulmonary oedema have been reported frequently as sequelae of myocardial infarction and / or
thrombolytic administration.
The frequency of the adverse drug reactions is described using the following convention:
Very common ≥ 1/10
Common
≥ 1/100, < 1/10
Uncommon
≥ 1/1,000, < 1/100
Rare
≥ 1/10,000>, < 1/1,000
Very rare
< 1/10,000, (including isolated reports)
5
Haemorrhage
The most frequent adverse drug reaction associated with reteplase treatment is haemorrhage.
-
very common: bleeding at the injection site (e.g. haematoma)
-
common: as gastrointestinal (haematemesis, melena), gingival or genitourinary bleeding
-
uncommon: haemopericardium, retroperitoneal bleeding, cerebral haemorrhage, epistaxis,
haemoptysis, eye haemorrhage and ecchymosis were observed.
Reports of intracranial bleeding, many of which are fatal, are of particular concern.
Systolic blood pressure over 160 mmHg before thrombolysis with reteplase was associated with
greater risk for cerebral bleeding. The risk of intracranial bleeding and fatal intracranial bleeding
increases with increasing age. Blood transfusions were rarely
required. Death and permanent disability
are not uncommonly reported in patients who have experienced stroke (including intracranial
bleeding) and other serious bleeding episodes.
Cardiovascular disorders
As with other thrombolytic agents, the following events have been reported as sequelae of myocardial
infarction and / or thrombolytic administration.
-
very common
: recurrent ischaemia / angina, hypotension and heart failure / pulmonary oedema
-
common
: arrhythmias (e.g. AV block, atrial fibrillation / flutter, ventricular tachycardia /
fibrillation, electromechanical dissociation (EMD)), cardiac arrest, cardiogenic shock and
reinfarction
-
uncommon
: mitral regurgitation, pulmonary embolism, other systemic embolism / cerebral
embolism and ventricular septal defect
These cardiovascular events can be life-threatening and may lead to death.
Nervous system disorders
-
uncommon :
cerebral haemorrhage was observed.
-
very rare
:
events related to the nervous system (e.g. epileptic seizure, convulsion, aphasia,
speech disorder, delirium, acute brain syndrome, agitation, confusion, depression, psychosis)
Ischaemic or haemorrhagic cerebrovascular events may be contributing or underlying conditions.
General disorders and administration site conditions
-
very common
: haemorrhage at the injection site (e.g. haematoma); a local reaction at injection
site for example a burning sensation can occur.
Immune system disorders
-
uncommon
: hypersensitivity reactions (e.g. allergic reactions)
-
very rare
: serious anaphylaxis/ anaphylactoid reactions
Available evidence on reteplase does not indicate an antibody-mediated origin of these
hypersensitivity reactions.
6
In the event of overdosage one might expect depletion of fibrinogen and other blood coagulation
components (e.g. coagulation factor V) with a consequent risk of bleeding.
For further information see section 4.4 , section bleeding.
5.
5.1 Pharmacodynamic properties
Pharmaco-therapeutic group: antithrombotic agent, ATC Code:
B01AD
Reteplase is a recombinant plasminogen activator that catalyzes the cleavage of endogenous
plasminogen to generate plasmin. This plasminogenolysis occurs preferentially in the presence of
fibrin. Plasmin in turn degrades fibrin, which is the main component of the matrix of thrombi, thereby
exerting its thrombolytic action.
Reteplase (10+10 U) dose-dependently reduces plasma fibrinogen levels by about 60 to 80 %. The
fibrinogen level normalises within 2 days. As with other plasminogen activators a rebound
phenomenon then occurs during which fibrinogen levels reach a maximum within 9 days and remain
elevated for up to 18 days.
Reductions of plasma levels of plasminogen and α2-antiplasmin normalise within 1 to 3 days.
Coagulation factor V, clotting factor VIII, α2-macroglobulin, and C1-esterase inhibitor are only
slightly reduced and normalise within 1 to 2 days. Plasminogen activator inhibitor 1 (PAI-1) activity
can be reduced to around zero, but rapidly normalises within two hours showing a rebound
phenomenon. Prothrombin activation fragment 1 levels and thrombin-antithrombin III-complexes
increase during thrombolysis indicating thrombin production of which the clinical relevance is
unknown.
A large comparative mortality trial (INJECT) in approx. 6000 patients showed that reteplase reduced
the incidence of heart failure (secondary efficacy criterion) in a significant manner and was at least
equally effective in terms of reducing mortality (primary efficacy criterion) when compared to
streptokinase. In two clinical trials aiming primarily at coronary artery patency (RAPID I and II)
reteplase was associated with higher early patency rates (primary efficacy criterion), as well as with a
lower incidence of heart failure (secondary efficacy criterion) than alteplase (3 hour and "accelerated"
dosage regimens). A clinical trial in approximately 15 000 patients comparing reteplase with the
accelerated dose regimen of alteplase (GUSTO III) (2:1 randomisation reteplase: alteplase) did not
show statistically different results for the primary endpoint of 30-day mortality (reteplase: 7.47 %,
alteplase 7.23 %, p = 0.61) or for the combined endpoint of 30-day mortality and non-fatal disabling
stroke (reteplase: 7.89 %, alteplase 7.88 %, p = 0.99). Overall stroke rates were 1.64 % in the reteplase
and 1.79 % in the alteplase group. In the reteplase group, 49.4 % of these strokes were fatal and
27.1 % were disabling. In the alteplase group 33.0 % were fatal and 39.8 % were disabling.
5.2 Pharmacokinetic properties
Following intravenous bolus injection of 10 + 10 U in patients with acute myocardial infarction
reteplase antigen is distributed in plasma with a dominant half-life (t1/2α) of 18±5 min and eliminated
with a terminal half-life (t1/2ß) of 5.5 hours±12.5 min at a clearance rate of 121±25 ml/min. Reteplase
activity is cleared from the plasma at a rate of 283±101 ml/min, resulting in a dominant half-life
(t1/2α) of 14.6±6.7 min and a terminal half-life (t1/2ß) of 1.6 hours±39 min. Only minor amounts of
reteplase were immunologically detected in the urine. Exact data on the main elimination routes for
reteplase in humans are not available and the consequences of hepatic or renal insufficiency are not
known. Experiments in rats indicate that the liver and the kidneys are the main organs of active uptake
and lysosomal degradation.
7
Additional studies in human plasma samples
in vitro
suggest that complexation with C1-inactivator,
α2-antiplasmin and α2-antitrypsin contributes to the inactivation of reteplase in plasma. The relative
contribution of the inhibitors to inactivation of reteplase decreases as follows: C1-inactivator > α2-
antiplasmin > α2-antitrypsin.
The half-life of reteplase was increased in patients with AMI as compared to healthy volunteers. An
additional increase of half-life of activity in patients with myocardial infarction and severely impaired
liver and renal function cannot be excluded, but no clinical data of pharmacokinetics of reteplase in
these patients are available. Animal data show that in case of severely impaired renal function with a
pronounced increase in serum creatinine and serum urea an increase in half-life of reteplase has to be
expected. Mild impairment of renal function did not significantly affect the pharmacokinetic
properties of reteplase.
5.3 Preclinical safety data
Acute toxicity studies were performed in rats, rabbits and monkeys Subacute toxicity studies were
performed in rats, dogs and monkeys. The predominant acute symptom after single high doses of
reteplase in rats and rabbits was transient apathy shortly after injection. In cynomolgus monkeys, the
sedative effect ranged from slight apathy to unconsciousness, caused by a reversible dose-related drop
in blood pressure. There was increased local haemorrhage at the injection site.
Subacute toxicity studies did not reveal any unexpected adverse events. In dogs repeated dosing of the
human peptide reteplase led to immunologic-allergic reactions. Genotoxicity of reteplase was
excluded by a complete battery of tests at different genetic end points in vitro and in vivo.
Reproductive toxicity studies were performed in rats (fertility and embryo-foetotoxicity study
including a littering phase) and in rabbits (embryo-foetotoxicity study, dose-range finding only). In
rats, a species insensitive to the pharmacological effects of reteplase, there were no adverse effects on
fertility, embryo-foetal development and offspring. In rabbits, vaginal bleedings and abortions
possibly associated to prolonged haemostasis, but no foetal abnormalities were noted. A pre- and
postnatal toxicity study was not performed with reteplase.
6.
6.1 List of excipients
Powder
:
Tranexamic acid
di potassium-hydrogen phosphate
phosphoric acid
sucrose
Polysorbate 80
Solvent:
Water for injections
6.2 Incompatibilities
This medicinal product should not be mixed with Heparin and/or acetylsalicylic acid.
In the absence of compatibility studies with other medicinal products, this medicinal product must not
be mixed with other medicinal products.
Heparin and Rapilysin are incompatible when combined in solution
.
Other incompatibilities may also
exist. No other medicines should be added to the injection solution.
8
6.3 Shelf life
Shelf-life as package for sale:
3 years.
Reconstituted product:
Chemical and physical in-use stability has been demonstrated for 8 hours between 2° and 30 °C after
dissolving with water for injection.
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user.
6.4 Special precautions for storage
Do not store above 25 °C.
Keep the vial in the outer carton in order to protect from light.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
Each pack contains:
2 colorless vials of 10 U of powder with a rubber closure
2 prefilled syringes with 10 ml solvent for single use 2 reconstitution
Spikes
2 needles 19 G1
6.6 Instrucions for use
Incompatibility of some prefilled glass syringes (including Rapilysin) with certain needle free
connectors has been reported. Therefore, the compatibility of the glass syringe and intravenous access
should be ensured before use. In case of incompatibility an adaptor can be used and removed together
with the glass syringe immediately after administration
Use aseptic technique throughout.
1.
Remove the protective flip-cap from the vial of Rapilysin 10 U and clean the rubber closure
with an alcohol wipe.
2.
Open the package containing the reconstitution spike, remove both protective caps from the
reconstitution spike.
3.
Insert the spike through the rubber closure into the vial of Rapilysin 10 U.
4.
Take the 10 ml syringe out of the package. Remove the tip cap from the syringe. Connect the
syringe to the reconstitution spike and transfer the 10 ml of solvent into the vial of Rapilysin
10 U.
5.
With the reconstitution spike and syringe still attached to the vial, swirl the vial gently to
dissolve the Rapilysin 10 U powder. DO NOT SHAKE.
6.
The reconstituted preparation results in a clear, colourless solution. If the solution is not clear
and colourless it should be discarded.
7.
Withdraw 10 ml of Rapilysin 10 U solution back into the syringe. A small amount of solution
may remain in the vial due to overfill.
8.
Disconnect the syringe from the reconstitution spike. The dose is now ready for intravenous
administration
9
9.
The reconstituted solution must be used immediately. Visual inspection of the solution is
necessary after reconstitution. Only clear, colourless solutions should be injected. If the solution
is not clear and colourless it should be discarded.
10. No other medicines should be injected through the line reserved for Rapilysin either at the same
time, or prior to, or following Rapilysin injection. This applies to all products including heparin
and acetylsalicylic acid, which should be administered before and following the administration
of reteplase to reduce the risk of re-thrombosis
11. In those patients where the same line has to be used, this line (including Y-line) must be flushed
thoroughly with a 0.9 % sodium chloride or 5 % dextrose solution prior to and following the
Precaution for disposal:
Any unused product or waste material should be disposed of in accordance with local
requirements.
7.
Actavis Group PTC ehf
Reykjavíkurvegi 76-78
220 Hafnarfjordur
Iceland.
8.
EU/1/96/018/001
9.
Date of first authorisation: 29 August 1996
Date of last renewal: 29 August 2006
10
ANNEX II
A.
MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER(S) RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
11
A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE
AND MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR
BATCH RELEASE
Name and address of the manufacturer of the biological active substance
Roche Diagnostics GmbH
Nonnenwald 2
82377 Penzberg
Germany
Name and address of the manufacturer responsible for batch release
Cenexi
52, Rue Marcel et Jacques Gaucher
94120 Fontenay-Sous-Bois
France
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
12
ANNEX III
LABELLING AND PACKAGE LEAFLET
13
A. LABELLING
14
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND , THE IMMEDIATE
PACKAGING
OUTER CARTON
1.
Rapilysin 10 U powder and solvent for solution for injection
Water for injections for Rapilysin 10 U solution for intravenous use
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Reteplase 10 U (recombinant plasminogen activator, thrombolytic agent)
3.
LIST OF EXCIPIENTS
Powder
:
Tranexamic acid
di potassium-hydrogen phosphate
phosphoric acid
sucrose
Polysorbate 80
Solvent:
Water for injections
4.
Powder and solvent for injection (contains 2x [0.56 g of powder in a vial and 10 ml solvent in a pre-
filled syringe with reconstitution spike and needle])
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use
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
Use the solution immediately after reconstitution
15
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25 °C
Keep the vial 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
Actavis Group PTC ehf
Reykjavíkurvegi 76-78
220 Hafnarfjordur
Iceland.
EU/1/96/018/001
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
16
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
LABEL OF THE VIAL
1.
Rapilysin 10 U powder and solvent for solution for injection
Reteplase Intravenous use
2.
METHOD OF ADMINISTRATION
Use the solution immediately after reconstitution
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
10 U reteplase
6.
OTHER
17
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
LABEL OF THE SYRINGE
1.
Water for injections
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
10 ml
6.
OTHER
18
B. PACKAGE LEAFLET
19
PACKAGE LEAFLET: INFORMATION FOR THE USER
Rapilysin 10 U powder and solvent for solution for injection
reteplase
Read all of this leaflet carefully before you start using this medicine
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, please ask your doctor or your 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 Rapilysin is and what it is used for
2.
Before the doctor gives you Rapilysin
3.
How to use Rapilysin
4.
Possible side effects
5.
How to store Rapilysin
6.
Further information
1.
WHAT RAPILYSIN IS AND WHAT IT IS USED FOR
Rapilysin (a recombinant plasminogen activator) is a thrombolytic medicine used to dissolve blood
clots that have formed in certain blood vessels and to restore the blood flow in these blocked vessels
(=thrombolysis).
Rapilysin is used after an acute myocardial infarction (heart attack) in order to dissolve the blood clot
causing the heart attack. It is given within 12 hours after the onset of symptoms.
2.
BEFORE YOU USE RAPILYSIN
The doctor will ask you questions before giving you Rapilysin, to find out if you have an increased
risk of bleeding.
Do not use Rapilysin:
Before treatment with Rapilysin, make sure your doctor knows if you
•
are allergic (hypersensitive) to reteplase or any of the other ingredients of Rapilysin
•
have a bleeding disorder
•
are taking medicine to thin your blood (oral anticoagulants, e.g. warfarin)
•
have a brain tumour or a malformed blood vessel or a vessel wall dilatation (aneurysm) in the
brain
•
have other tumours associated with an increased risk of bleeding
•
have had a stroke
•
have had external heart massage within the past 10 days
•
have severe uncontrolled high blood pressure (hypertension)
•
have an ulcer in the stomach or small intestine
•
have enlarged blood vessels in the gullet (oesophagus) (frequently caused by liver disease)
20
•
have severe liver or kidney disease
•
have acute inflammation of the pancreas or pericardium (the sac surrounding the heart), or an
infection of the heart muscle (bacterial endocarditis)
•
have in the past 3 months had severe bleeding, a major injury or major surgery (e.g. coronary
artery bypass graft, or surgery or injury to the head or spine), given birth, or had an organ
biopsy or other medical / surgical procedure.
Take special care with Rapilysin :
Bleeding
The most common side effect of Rapilysin is bleeding. Therefore Rapilysin must be given only in the
presence and under the instructions of an emergency doctor.
Pay careful attention to all possible bleeding sites (e.g. injection sites). Heparin, which is given
together with Rapilysin, may also increase bleeding.
The risks of Rapilysin treatment may be increased if you have any of the following conditions:
•
diseases of the blood vessels in the brain
•
systolic blood pressure higher than 160 mmHg
•
bleeding in the gastrointestinal, urinary or genital tract within the past 10 days
•
high likelihood of a blood clot in the heart (e.g. as a result of narrowing of a heart valve or atrial
fibrillation)
•
septic inflammation of a vein with blood clotting (septic thrombophlebitis) or blocked blood
vessels at an infected site
•
age over 75 years
•
any other condition in which bleeding might be especially dangerous or might occur at a site
where it would be difficult to control
At present, little data are available on the use of Rapilysin in patients with diastolic blood pressure
higher than 100 mmHg
Abnormal heart beats (arrhythmias)
Thrombolytic treatment may cause the heart to beat irregularly. Therefore tell the medical staff
immediately if you
•
feel palpitations or an irregular heart beat
Repeated use
At present there is no experience with repeated use of Rapilysin. Therefore, repeated use is not
recommended. Antibody formation to the reteplase molecule has not been seen.
Use in children
Safety and effectiveness of Rapilysin in children have not been established. Treatment of children with
Rapilysin is not recommended.
21
Using other medicines:
Heparin and other medicines that thin the blood (anticoagulants) and acetylsalicylic acid (a substance
used in many medicines used to relieve pain and lower fever) may increase the risk of bleeding.
Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines,
even those not prescribed.
For information on medicines that should not be physically mixed with Rapilysin solution for injection
see section 3.
Pregnancy
There is no experience with Rapilysin in pregnant women. Therefore it should not be used except in
life-threatening situations. You must tell your doctor if you are pregnant or think you are pregnant.
Your doctor can tell you the risks and benefits of using Rapilysin during pregnancy.
Breast-feeding
You should not breast-feed your baby during treatment with Rapilysin as it is not known whether
Rapilysin is excreted into mother’s milk. Mother’s milk should be thrown away during the first 24
hours after thrombolytic treatment. Discuss with your doctor when you can take up breast-feeding
again.
3.
HOW TO USE RAPILYSIN
Rapilysin is usually given in a hospital. The medicine is supplied in vials as a powder for injection.
Before use, the powder for injection must be dissolved in the water for injection supplied in the
prefilled syringe that is in the package. Do not add any other medicines . The resulting solution must
be used immediately. The solution must be examined to ensure that only clear, colourless solution is
injected. If the solution is not clear and colourless it should be thrown away.
Treatment with Rapilysin 10 U should be started as soon as possible after the symptoms of heart attack
begin.
Heparin and Rapilysin cannot be mixed in the same solution
. Other medicines may also not mix well
with Rapilysin. No other medicines should be added to the injection solution (see below). Rapilysin
should be injected preferably through an intravenous line that is used only for the injection of
Rapilysin. No other medicines should be injected through the line reserved for Rapilysin, either at the
same time, or before or after Rapilysin injection. This applies to all medicines including heparin and
acetylsalicylic acid, which are given before and after Rapilysin to reduce the risk of new blood clots
forming.
If the same line has to be used, this line (including Y-line) must be flushed thoroughly with a 0.9 %
sodium chloride or 5 % dextrose solution before and after the Rapilysin injection.
Dosage of Rapilysin
Rapilysin is given as a 10 U injection followed by a second 10 U injection 30 minutes later (double
bolus).
Each injection should be given slowly within 2 minutes. The injection must not be given mistakenly
outside the vein. Therefore, be sure to tell the medical staff if you experience pain during the injection.
Heparin
and acetylsalicylic
acid
are given before and after Rapilysin to reduce the risk of new blood
clots forming.
22
Dosage of Heparin
The recommended dose of heparin is 5000 I.U. given as a single injection before Rapilysin, followed
by an infusion of 1000 I.U. per hour starting after the second Rapilysin injection. Heparin should be
given for at least 24 hours, preferably for 48 - 72 hours, in order to keep aPTT values 1.5 to 2 times
normal.
Dosage of Acetylsalicylic Acid
The dose of acetylsalicylic acid given before Rapilysin should be at least 250 mg – 350 mg and should
be followed by 75 – 150 mg/day, at least until discharge from hospital.
Instructions for use/handling
Incompatibility of some prefilled glass syringes (including Rapilysin) with certain needle free
connectors has been reported. Therefore, the compatibility of the glass syringe and intravenous access
should be ensured before use. In case of incompatibility an adaptor can be used and removed together
with the glass syringe immediately after administration
Use aseptic technique throughout.
1.
Remove the protective flip-cap from the vial of Rapilysin 10 U and clean the rubber closure
with an alcohol wipe.
2.
Open the package containing the reconstitution spike, remove both protective caps from the
reconstitution spike.
3.
Insert the spike through the rubber closure into the vial of Rapilysin 10 U.
4.
Take the 10 ml syringe out of the package. Remove the tip cap from the syringe. Connect the
syringe to the reconstitution spike and transfer the 10 ml of solvent into the vial of Rapilysin
10 U.
5.
With the reconstitution spike and syringe still attached to the vial, swirl the vial gently to
dissolve the Rapilysin 10 U powder. DO NOT SHAKE.
6.
The reconstituted preparation results in a clear, colourless solution. If the solution is not clear
and colourless it should be discarded.
7.
Withdraw 10 ml of Rapilysin 10 U solution back into the syringe. A small amount of solution
may remain in the vial due to overfill.
8.
Disconnect the syringe from the reconstitution spike. The dose is now ready for intravenous
administration.
9.
No other medicines should be injected through the line reserved for Rapilysin either at the same
time, or prior to, or following Rapilysin injection. This applies to all products including heparin
and acetylsalicylic acid, which should be administered before and following the administration
of reteplase to reduce the risk of re-thrombosis.
10. In those patients where the same line has to be used, this line (including Y-line) must be flushed
thoroughly with a 0.9 % sodium chloride or 5 % dextrose solution prior to and following the
Rapilysin injection.
If more Rapilysin is used than recommended:
In the event of overdosage there may be an increased risk of bleeding.
23
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Rapilysin can cause side effects, although not everybody gets them.
The most common side effects of Rapilysin which may affect more than 10 % of the treated patients:
•
Bleeding at the injection site, e.g. blood blister (haematoma)
•
Chest Pain / angina, low blood pressure and heart failure /shortness of breath may reappear
•
Burning sensation when Rapilysin is injected
Common side effects occurring in 1 to 10 % of the treated patients are:
•
Bleeding in the digestive tract (e.g. bloody or black vomit, or stools) in the gums or in the
urinary or genital tract
•
Abnormal heart beats (arrhythmias), cardiac arrest, circulatory collapse or another heart attack
may occur
Uncommon side effects occurring in 0,1 to 1 % of the treated patients are:
•
Bleeding around the heart, in the abdomen, the brain or the eyes, under the skin, from the nose
or as coughed up blood
•
Damage to the heart or heart valves, or a blood clot in the lung, brain or other part of body may
occur
•
hypersensitivity (e.g.
allergic reactions)
Other less common side effects occurring in less than 0.01 % of the treated patients are:
•
Events related to the nervous system (e.g. epileptic seizure, convulsion, speech disorder,
delirium, agitation, confusion, depression, psychosis)
•
severe allergic reaction, causing shock or collapse
Cardiovascular events can be life-threatening or cause death.
Patients with systolic blood pressure over 160 mmHg have a greater risk of bleeding in the brain. The
risk of intracranial bleeding and fatal intracranial bleeding increases with increasing age. Blood
transfusions were rarely required. Death or permanent disability are not uncommon in patients who
have a stroke (including bleeding in the brain) or other serious bleeding problem.
Be sure to tell hospital staff immediately if any of these symptoms appear. If you notice any side
effects not mentioned in this leaflet, please inform 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.
5.
HOW TO STORE RAPILYSIN
•
Keep out of the reach and sight of children.
•
Do not use Rapilysin after the expiry date stated on the carton and on the label of the vial.
•
Do not store above 25 °C.
•
Keep the vial in the outer carton in order to protect from light.
•
After reconstitution (“when dissolved”), the solution must be used immediately.
24
6.
FURTHER INFORMATION
What Rapilysin contains:
-
The active substance of Rapilysin is reteplase 10U/10ml after reconstitution.
-
The other ingredients in the vials are:
Powder:
Tranexamic acid
di-potassium-hydrogen phosphate
phosphoric acid
sucrose
polysorbate 80
Solvent:
10 ml Water for injection (prefilled syringe)
What Rapilysin looks like and content of the pack
Rapilysin is presented as a powder and a solvent for injection (0.56 g powder in a vial and 10 ml
solvent in a pre-filled syringe with a reconstitution spike and a needle-pack of 2)
Marketing authorisation holder
Actavis Group PTC ehf
Reykjavíkurvegi 76-78
220 Hafnarfjordur
Iceland.
Manufacturer
Cenexi
52, Rue Marcel et Jacques Gaucher
94120 Fontenay-Sous-Bois
France
25
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
ALL-in-1 bvba
Tél/Tel: +32 (0) 32 86 88 88
Luxembourg/Luxemburg
(Voir/siehe Belgique/Belgien)
България
Актавис ЕАД
+359 2 9321 680
Magyarország
Actavis Hungary Kft.,
Tel.: +36 52 431-313
Ceská republika
Pharma Avalanche s.r.o.
Tel.: +420251001680
Malta
Actavis Ltd,
Tel : +356023679641
Danmark
Actavis A/S
Tlf: +45 - 72 22 30 00
Nederland
Actavis B.V.
Tel: +31 35 54 299 33
Deutschland
Actavis Deutschland GmbH & Co. KG
Telefon: +49 (0) 2173/1674 – 0
Norge
Actavis Norway AS
Tlf: +47 815 22 099
Eesti
UAB „Actavis Baltics”Eesti Filiaal
Tel: +372 6100 565
Österreich
Actavis GmbH
Tel: +43 (662) 435 235 00
Ελλάδα
ALAPIS ABEE
Τηλ: +30 2130 175064
Polska
Actavis Polska sp. z o.o.
Tel: +48 22 814 12 39
España
Laboratorio Ramón Sala S.L.
Tel.: + 34 93 480 67 15
Portugal
Actavis A/S Sucursal
Tel: +351 - 21 722 06 50
France
Actavis
Tél: +33 (0) 1 40 83 77 77
România
Actavis SRL
Tel: (+40)21 318 17 67
Ireland
Actavis UK Limited
+44 (0) 1271 311257
Slovenija
Sanolabor, d.d.
Tel: +386 1 585 43 10
Ísland
Actavis Group PTC ehf.
Sími: +354 550 3300
Slovenská republika
Actavis s.r.o, Bratislava
Tel: +421 2 3255 3801
26
Italia
Actavis Italy S.p.A.
Tel: +39-0331-583111
Suomi/Finland
Actavis Oy
Puh/Tel: +358 (0) 9 348 233
Kύπρος
A. Potamitis Medicare Ltd
Τηλ: +357 - 22 31 36 11
Sverige
Actavis AB
Tel: +46 (0) 8 13 63 70
Latvija
Actavis Baltics pārstāvniecība Latvijā
Tel: +371 67067876
United Kingdom
Actavis UK Limited
+44 (0) 1271 311257
Lietuva
UAB “Actavis Baltics”
Tel: +370 5 2609615
This leaflet was last approved in
27
Source: European Medicines Agency
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