ACTILYSE CATHFLO 2 MG

Active substance: ALTEPLASE

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A1;2 mg/J/PI(PIL)/3

07/12/09

PACKAGE LEAFLET: INFORMATION FOR THE USER
Actilyse Cathflo 2 mg
Powder and solvent for solution for injection and infusion
Alteplase
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, ask your doctor.
- This medicine has been prescribed for you. Do not pass it on to others. It may
harm them, even if their symptoms are the same as yours.
- If any of the side effects gets serious, or if you notice any side effects not listed in
this leaflet, please tell your doctor.

In this leaflet:
1.
What Actilyse Cathflo is and what it is used for
2.
Before you receive Actilyse Cathflo
3.
How is Actilyse Cathflo administered
4.
Possible side effects
5.
How to store Actilyse Cathflo
6.
Further information

1.

WHAT ACTILYSE CATHFLO IS AND WHAT IT IS USED FOR

The active substance in Actilyse Cathflo is alteplase (see section 6: “Further
information”). It belongs to a group of medicines called thrombolytic agents. These
medicines act by dissolving blood clots.
Actilyse Cathflo is used to clear catheters which are blocked by blood clots.

2.

BEFORE YOU RECEIVE ACTILYSE CATHFLO

Actilyse Cathflo will not be given by your doctor,
- if you are allergic (hypersensitive) to the active substance alteplase or any of the
other ingredients of Actilyse Cathflo (see section 6: “Further information”).
Your doctor will take special care with Actilyse Cathflo
- if you have a bleeding in any part of the body
- if in the past 48 hours you have had a condition that increases your risk of
bleeding, including:
• surgery
• biopsy (a procedure for obtaining a tissue specimen)
• puncture
• delivery of a baby
- if you have a bleeding disorder or tendency to bleed
- if you have severe liver or kidney disease

- if a blood vessel located close to the catheter is blocked by blood clots (venous
thrombosis)
- if there is or may be an infection located in the catheter
Taking other medicines
Please tell your doctor if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription. It is particularly important that
you tell your doctor if you are taking or have recently taken:
- any medicines which are used to “thin “ the blood, including:
• aspirin
• warfarin
• coumarin
• heparin
- certain medicines used to treat high blood pressure (ACE inhibitors).
Pregnancy and breast-feeding
Ask your doctor for advice before taking any medicine. Your doctor will only give
you Actilyse Cathflo if the possible benefit outweighs the possible risk to your baby.

3.

HOW IS ACTILYSE CATHFLO ADMINISTERED

Actilyse Cathflo will be administered to you by your doctor or by a health care
professional. It is not for self-administration.
Actilyse Cathflo is supplied as a powder and solvent. This means that each pack
contains one or more vials with powder and an equal amount of ampoules with the
solvent (water for injections). Before use, the solvent is added to the powder to form a
solution ready for administration.
The dose you are given depends on your body weight. The maximum dose of Actilyse
Cathflo is 2 mg but will be lower if you weigh less than 30 kg.
Actilyse Cathflo is filled in the blocked catheter. After 30 min your doctor will check
if the catheter has already been cleared. If this is the case, treatment with Actilyse
Cathflo will be stopped. If this is not yet the case, the product will remain in the
catheter for another 90 min.
After treatment, Actilyse Cathflo is removed from the catheter. The catheter is rinsed
with sterile saline solution.
If the catheter is still blocked after your first treatment with Actilyse Cathflo, the
whole procedure may be repeated once.
Actilyse Cathflo should not be mixed with other medicines.
If you have any further questions on the use of Actilyse Cathflo, ask your doctor.

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4.

POSSIBLE SIDE EFFECTS

Like all medicines, Actilyse Cathflo can cause side effects, although not everybody
gets them.
The side effects described below have been experienced by people given Actilyse
Cathflo:
Uncommon (occurs in less than 1 in 100 patients receiving the medicine)
- release of an infection from the catheter to the blood vessels leading to blood
poisoning (sepsis)
- damage to the catheter such as:
• blockage
• leakage
• burst
Rare (occurs in less than 1 in 1,000 patients receiving the medicine)
- fever
In general, all undesirable effects as found for the systemic application of Actilyse
(10, 20, 50 mg of alteplase) may also occur during treatment of catheters blocked by
blood clots in cases where Actilyse Cathflo (2 mg of alteplase) reaches the blood
circulation (e.g. bleeding (haemorrhage), sudden blocking of a blood vessel
(embolism), allergic (hypersensitivity/anaphylactoid) reactions, blood pressure
decreased, nausea, vomiting, body temperature increased).
Tell your doctor immediately if you think you are experiencing one 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.

5.

HOW TO STORE ACTILYSE CATHFLO

Keep out of the reach and sight of children.
Actilyse Cathflo should not be used after the expiry date which is stated on the vial
label and the carton. The expiry date refers to the last day of that month.
Normally you will not be asked to store Actilyse Cathflo as it will be given to you by
your doctor. Actilyse Cathflo should be stored in a refrigerator (2 – 8 °C). Store in the
original package in order to protect from light.
Once the solution is ready for administration, it should be used immediately. When
necessary however, the solution may be stored for 24 hours at 2 °C – 8 °C or for 8
hours at up to 25 °C. However your doctor will normally use the solution
immediately.

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6.

FURTHER INFORMATION

What Actilyse Cathflo contains
- The active substance is alteplase. Each vial contains 2 mg (corresponding to
1,160,000 IU) alteplase. Alteplase is produced by means of recombinant DNA
technique using a Chinese hamster ovary cell-line.
- The other ingredients are arginine, phosphoric acid (dilute) and polysorbate 80.
- The solvent is water for injections.
What Actilyse Cathflo looks like and contents of the pack
Actilyse Cathflo is a powder and solvent for solution for instillation into a blocked
catheter. This means that each complete pack contains several vials with powder and
an equal amount of ampoules with the solvent.
For clearance of blocked catheters Actilyse Cathflo is available in the following
complete pack:
- Five vials, each with 2 mg alteplase, and five ampoules, each with 2.2 ml water
for injections.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Boehringer Ingelheim Limited
Ellesfield Avenue
Bracknell
Berkshire
RG12 8YS
United Kingdom
Manufacturer
Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65
D-88397 Biberach/Riss
Germany
This leaflet was last approved in 12/2009
©Boehringer Ingelheim Limited 2009

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7/12/10

A1;2 mg/J/PI(ProL)/4

PROFESSIONAL LEAFLET
Actilyse Cathflo 2 mg Powder and solvent for solution for injection and infusion
Alteplase

1.

NAME OF THE MEDICINAL PRODUCT
Actilyse Cathflo 2 mg Powder and solvent for solution for injection and
infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
1 vial with powder contains:
2 mg alteplase (corresponding to 1,160,000 IU)
Alteplase is produced by recombinant DNA technique using a Chinese
hamster ovary cell-line. The specific activity of alteplase in-house reference
material is 580,000 IU/mg. This has been confirmed by comparison with the
second international WHO standard for t-PA. The specification for the specific
activity of alteplase is 522,000 to 696,000 IU/mg.
For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM
Powder and solvent for solution for injection and infusion.
The powder is presented as a colourless to pale yellow lyophilizate cake.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications
Thrombolytic treatment of occluded central venous access devices including
those used for haemodialysis
The 2 mg vial is the only recommended presentation for use in this indication.

4.2

Posology and method of administration
Actilyse Cathflo should be given as soon as possible after symptom onset. The
following dose guidelines apply.
Posology
A dose of up to 2 mg alteplase administered up to two times for any one
occlusion can be used to restore function of ports, single and multiple lumen
catheters including those used for haemodialysis, which became dysfunctional
due to thrombotic occlusion.
For use in this indication reconstitution to a final concentration of 1 mg
alteplase per ml is recommended.

In patients with a body weight of 30 kg or more, a total dose of 2 mg alteplase
in 2 ml of reconstituted solution should be instilled into the dysfunctional
central venous access device.
In patients with a body weight below 30 kg, the volume of reconstituted
solution to be instilled into the dysfunctional central venous access devices
should correspond to 110% of the internal lumen volume of the device. The
total dose of alteplase should not exceed 2 mg. I.e. for a catheter with internal
volume of 1.0 ml the total dose of Actilyse Cathflo would be 1.1 mg in a
volume of 1.1 ml.
If central venous access device function is not restored at 120 minutes after the
first dose, a second dose of equal amount may be instilled.
Method of catheter clearance
The reconstituted solution should be instilled into the occluded central venous
access device.
Only 2 mg vials of alteplase are indicated for use in this indication. For
instructions prior to reconstitution prior to administration, see section 6.6.
1. Reconstitute the content of an injection vial to a final concentration of 1 mg
alteplase per ml. For catheters with a lumen volume greater than 2 ml, the
reconstituted solution can be further diluted with sterile sodium chloride 9
mg/ml (0.9 %) solution for injection to the desired volume. I.e. for a catheter
with internal volume of 2.5 ml the total dose of Actilyse Cathflo would be 2.0
mg in a volume of 2.5 ml.
2. Instil the appropriate dose of Actilyse Cathflo into the dysfunctional central
venous access device.
3. After 30 minutes of dwell time, assess catheter function by attempting to
aspirate blood. If the catheter is functional, go to Step 6. If the catheter is not
functional, go to Step 4.
4. After 120 minutes of dwell time, assess catheter function by attempting to
aspirate blood and catheter contents. If the catheter is functional, go to Step 6.
If the catheter is not functional, go to Step 5.
5. If catheter function is not restored after the first dose, a second dose of equal
amount may be instilled. Repeat the procedure beginning with Step 1. If after a
second dose of alteplase the device remains dysfunctional consider device
replacement.
6. If catheter function has been restored, aspirate 4–5 ml of blood in patients
weighing 10 kg or more, or 3 ml in patients with a body weight below 10 kg to
remove Actilyse Cathflo and residual clot, and gently irrigate the catheter with
sterile sodium chloride 9 mg/ml (0.9 %) solution for injection.

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4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients.

4.4

Special warnings and precautions for use
2 mg vials are not indicated for use in the indications myocardial infarction,
pulmonary embolism or acute ischaemic stroke (due to risk of massive
underdosing). Only 10, 20 or 50 mg vials are indicated for use in those
indications.
Special warnings and precautions in the treatment of occluded central venous
access devices including those used for haemodialysis:
General:
The coadministation of heparin with Actilyse Cathflo has not been shown to
improve the rates of catheter function restoration and is not recommended. If
heparin is considered necessary to prevent reocclusion this should be
administered separately after catheter function has been restored.
Catheter dysfunction may be caused by a variety of conditions other than
thrombus formation, such as catheter malposition, mechanical failure,
constriction by a suture, and lipid deposits or drug precipitates within the
catheter lumen. Because of the risk of damage to the vascular wall or collapse
of soft-walled catheters, vigorous suction should not be applied during
attempts to determine catheter occlusion. Excessive pressure should be
avoided when Actilyse Cathflo is instilled into the catheter. Such force could
cause rupture of the catheter or expulsion of the clot into the circulation.
Particular caution is necessary if small volume syringes (≤ 1 ml) are used for
application, especially if small volume catheters are used as typical in the
paediatric population.
Bleeding:
The most frequent adverse reaction associated with all thrombolytics in all
approved indications is bleeding. Actilyse Cathflo has not been studied in
patients with occluded catheters known to be at risk for bleeding events that
may be associated with the use of thrombolytics. Caution should be exercised
with patients who have active internal bleeding or who have had any of the
following within 48 hours: surgery, obstetrical delivery, percutaneous biopsy
of viscera or deep tissues, or puncture of non-compressible vessels. In
addition, caution should be exercised with patients who have
thrombocytopenia, other haemostatic defects (including those secondary to
severe hepatic or renal disease), or any condition for which bleeding
constitutes a significant hazard or would be particularly difficult to manage
because of its location, or who are at high risk for embolic complications (e.g.,
venous thrombosis in the region of the catheter). Death and permanent
disability have been reported in patients who have experienced stroke and
other serious bleeding episodes when receiving pharmacologic doses of a
thrombolytic. Should serious bleeding in a critical location (e.g., intracranial,
gastrointestinal, retroperitoneal, pericardial) occur, treatment with Actilyse

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Cathflo should be stopped and the drug should be withdrawn from the
catheter.
Infection:
Using Actilyse Cathflo in patients whose catheters are occluded by infected
thrombi may release microorganisms into the systemic circulation leading to
sepsis. As with all catheterisation procedures, care should be taken to maintain
aseptic technique and appropriate antibiotic treatment used as necessary.
Re-administration:
Patients may receive up to 2 mg alteplase administered up to two times for any
one occlusion. In the event of continuing catheter dysfunction other causes for
dysfunction should be sought. Subsequent occlusions may be treated similarly
although it should be noted that frequent re-occlusions may indicate the need
for catheter replacement. Antibody formation in patients receiving one or more
doses of alteplase for restoration of dysfunctional central venous access
devices has not been studied.
4.5

Interaction with other medicinal products and other forms of interaction
The risk of haemorrhage is increased if coumarine derivatives, oral
anticoagulants, platelet aggregation inhibitors, unfractionated heparin or
LMWH or other agents inhibiting coagulation are administered (before, during
or within the first 24 hours after treatment with Actilyse Cathflo).
Concomitant treatment with ACE inhibitors may enhance the risk of suffering
an anaphylactoid reaction, as in the cases describing such reactions a relatively
larger proportion of patients were receiving ACE inhibitors concomitantly.

4.6

Pregnancy and lactation
There is very limited experience with the use of alteplase during pregnancy
and lactation. Studies in animals have shown reproductive toxicity (see section
5.3). In cases of an acute life-threatening disease the benefit has to be
evaluated against the potential risk. It is not known if alteplase is excreted into
breast milk.

4.7

Effects on ability to drive and use machines
Not relevant.

4.8

Undesirable effects
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).
In clinical trials investigating treatment of occluded catheters with Actilyse
Cathflo the following undesirable effects were observed:
Infections and infestations
uncommon: sepsis

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General disorders and administration site conditions
uncommon: catheter related complications
rare:
fever
In general, all undesirable effects as found for the systemic application of
Actilyse (10, 20, 50 mg of alteplase) may also occur during treatment of
occluded catheters in cases where Actilyse Cathflo (2mg of alteplase) reaches
the systemic circulation (e.g. haemorrhage, embolism, hypersensitivity
reactions/anaphylactoid reactions, blood pressure decreased, nausea, vomiting,
body temperature increased).
4.9

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

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: antithrombotic agent, ATC code: B 01 A D 02
Alteplase is a recombinant human tissue-type plasminogen activator, a
glycoprotein, which activates plasminogen directly to plasmin. When
administered intravenously, alteplase remains relatively inactive in the
circulatory system. Once bound to fibrin, it is activated, inducing the
conversion of plasminogen to plasmin leading to the dissolution of the fibrin
clot.
Due to its relative fibrin-specificity alteplase at a dose of 100 mg leads to a
modest decrease of the circulating fibrinogen levels to about 60 % at 4 hours,
which is generally reverted to more than 80 % after 24 hours. Plasminogen
and alpha-2-antiplasmin decrease to about 20 % and 35 % respectively after
4 hours and increase again to more than 80 % at 24 hours. A marked and
prolonged decrease of the circulating fibrinogen level is only seen in few
patients.
Occluded central venous access devices including those used for
haemodialysis
In two clinical studies more than 1,100 mainly adult patients with improperly
functioning central venous access devices were treated with alteplase.
Restoration rates of catheter function were between 74 % and 77 % following
one dose and between 87 % and 90 % following two doses of alteplase. In

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studies with haemodialysis catheters using dwell times ranging from ≥ 2 hours
to the next dialysis session comparable restoration rates were reported.
In a study of 310 children the overall rate of catheter function restoration of
83 % after up to two doses of alteplase was similar to that observed in adults.
A total of 432 patients under age of 17 have received a dose of up to 2 mg
alteplase for up to two administrations in pivotal trials of catheter clearance.
Overall safety and efficacy results were similar in the paediatric and adult
patients.
5.2

Pharmacokinetic properties
Alteplase is cleared rapidly from the circulating blood and metabolised mainly
by the liver (plasma clearance 550 - 680 ml/min.). The relevant plasma halflife t1/2 alpha is 4-5 minutes. This means that after 20 minutes less than 10 %
of the initial value is present in the plasma. For the residual amount remaining
in a deep compartment, a beta-half-life of about 40 minutes was measured.
When Actilyse Cathflo is administered for restoration of dysfunctional central
venous access devices according to the instructions circulating plasma levels
of alteplase are not expected to reach pharmacologic concentrations. If a 2 mg
dose of alteplase was administered by bolus injection directly into the systemic
circulation (rather than instilled into the catheter), the concentration of
circulating alteplase would be expected to return to undetectable limits within
30-60 minutes.

5.3

Preclinical safety data
In subchronic toxicity studies in rats and marmosets no unexpected
undesirable effects were found. No indications of a mutagenic potential were
found in mutagenic tests.
In pregnant animals no teratogenic effects were observed after intravenous
infusion of pharmacologically effective doses. In rabbits embryotoxicity
(embryolethality, growth retardation) was induced by more than
3 mg/kg/day. No effects on peri-postnatal development or on fertility
parameters were observed in rats with doses up to 10 mg/kg/day.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Powder:
Arginine
Phosphoric acid, dilute
Polysorbate 80
Solvent:
Water for injections
The pH of the reconstituted solution is 7.3 ± 0.5.

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6.2

Incompatibilities
The reconstituted solution may be diluted with sterile sodium chloride 9
mg/ml (0.9 %) solution for injection up to a minimal concentration of 0.2 mg
alteplase per ml.
Further dilution, the use of water for injections for dilution or in general the
use of carbohydrate infusion solutions, e.g. dextrose, is not recommended due
to increasing formation of turbidity of the reconstituted solution.
Actilyse Cathflo should not be mixed with other medicinal products (not even
with heparin).

6.3

Shelf life
2 mg pack size: 3 years
After reconstitution, an immediate use is recommended. However, the in-use
stability has been demonstrated for 24 hours at 2 °C – 8 °C and for 8 hours at
25 °C.

6.4

Special precautions for storage
Store in the original package in order to protect from light.
For 2 mg pack size: Store in a refrigerator (2 – 8 °C).
For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5

Nature and contents of container
Powder:
2 ml sterilised glass vials, sealed with sterile siliconised grey butyl-type
stoppers with aluminium/plastic flip-off caps.
Solvent:
For the 2 mg pack size the water for injections is filled into 5 ml sterilised
glass ampoules. The water for injections vials are sealed with rubber stoppers
and aluminium/plastic flip-off caps.
Pack sizes:
5 vials with 93 mg powder for solution for injection and infusion
5 ampoules with 2.2 ml of water for injections

6.6

Special precautions for disposal and other handling
2 mg vials of alteplase are not indicated for use in the indications myocardial
infarction, pulmonary embolism or ischaemic stroke (due to risk of massive
underdosing).
The 2 mg vial should always be reconstituted to a final concentration of 1 mg
alteplase per ml.

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To this end, the full volume of solvent provided should be transferred to the
vial containing the Actilyse Cathflo powder by use of a syringe.
Under aseptic conditions the content of an injection vial of Actilyse Cathflo (2
mg,) is dissolved with water for injections according to the following table to
obtain a final concentration of 1 mg alteplase/ml:
Actilyse Cathflo vial

Final concentration
(a) 1 mg alteplase/ml
(ml)
(b) 2 mg alteplase/ml
(ml)

2 mg
Volume of water for
injections to be added
to dry powder:
2.2
not recommended

The reconstituted solution should then be instilled into the dysfunctional
central venous access device. It may be diluted further with sterile sodium
chloride 9 mg/ml (0.9 %) solution for injection up to a minimal concentration
of 0.2 mg/ml. A dilution of the reconstituted solution with sterilised water for
injections or in general, the use of carbohydrate infusion solutions, e.g.
dextrose is not recommended. Actilyse Cathflo should not be mixed with other
medicinal products in the same catheter (not even with heparin).
For incompatibilities see section 6.2.
When reconstituting the product from the respective amount of powder and
solvent, the mixture should only be agitated gently until complete dissolution.
Any vigorous agitation should be avoided to prevent foam formation.
The reconstituted preparation is a clear and colourless to pale yellow solution.
Prior to administration it should be inspected visually for particles and colour.
The reconstituted solution is for single use only. Any unused solution should
be discarded.

7.

MARKETING AUTHORISATION HOLDER
Boehringer Ingelheim Limited,
Ellesfield Avenue,
Bracknell,
Berkshire, RG12 8YS
United Kingdom.

8.

MARKETING AUTHORISATION NUMBER
Ireland: PA 7/43/5
UK: PL 00015/0325

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9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation: Ireland: 09/04/09
United Kingdom: 29/11/10

10.

DATE OF REVISION OF THE TEXT
December 2010

LEGAL CATEGORY
POM
©Boehringer Ingelheim Limited 2010

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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