1.    NAME OF THE MEDICINAL PRODUCT

Actilyse Cathflo 2 mg powder 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.

Each constituted vial will deliver 2 mg of alteplase.

For the full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Powder for solution for injection and infusion.

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

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Thrombolytic treatment 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.

4.3 Contraindications

Actilyse Cathflo should not be administered to patients with known hypersensitivity to the active substance alteplase, gentamicin (a trace residue from the manufacturing process) or to any of the excipients listed in section 6.1.

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 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.

Hypersensitivity

Antibody formation in patients receiving one or more doses of alteplase for restoration of dysfunctional central venous access devices has not been studied. Although physiologically relevant plasma concentrations are not reached, hypersensitivity might occur. Anaphylactoid reactions associated with the administration of Actilyse Cathflo can be caused by hypersensitivity to the active substance alteplase, gentamicin (a trace residue from the manufacturing process) or to any of the excipients. The stopper of the glass vial with Actilyse Cathflo powder contains natural rubber (a derivative of latex) which may cause allergic reactions.

If anaphylactoid reaction occurs, the instillation should be discontinued and appropriate treatment should be initiated.

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:

Class	Adverse reaction
Infections and infestations
uncommon	sepsis
General disorders and administration site conditions
uncommon	catheter related complication
rare	pyrexia

Under systemic application of alteplase (i.e. high dose in thrombo-embolic indications), the following dose-independent side effects have been reported:

Immune system disorders*
rare	hypersensitivity / anaphylactoid reactions (e.g. allergic reactions including rash, urticaria, bronchospasm, angio-oedema, hypotension, shock or any other symptom associated with allergic reactions)
very rare	serious anaphylaxis

*Transient antibody formation to Actilyse has been observed in rare cases and with low titres, but a clinical relevance of this finding could not be established.

In principle, all undesirable effects as found for the systemic application of Actilyse (using the 10, 20, 50 mg presentations of alteplase, please refer to respective SmPC) may also occur during treatment of occluded catheters in cases where Actilyse Cathflo (2 mg of alteplase) reaches the systemic circulation (e.g. haemorrhage, embolism, hypersensitivity/anaphylactoid reactions, blood pressure decreased, nausea, vomiting, body temperature increased). However, pharmacokinetic data indicate that physiologically relevant plasma concentrations are not reached using this dosage.

Immune system disorders, on the other hand, can be regarded dose-independent and have therefore been copied from the systemic application; immune system disorders have however not been observed in clinical trials with Actilyse Cathflo.

Paediatric Population

Based on clinical study data, the safety profile for use in children is comparable with the one observed in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

The relative fibrin specificity notwithstanding, a clinical significant reduction in fibrinogen and other blood coagulation components may occur after overdosage. In most cases, it is sufficient to await the physiological regeneration of these factors after the Actilyse 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 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 half-life t_J/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.

6.1 List of excipients

Powder:

Arginine

Phosphoric acid (for pH-adjustment) Polysorbate 80

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.

Pack sizes:

5 vials with 93 mg powder for solution for injection and infusion

6.6 Special precautions for disposal and other handling

The 2 mg presentation of alteplase is not indicated for use in myocardial infarction, acute pulmonary embolism or acute ischaemic stroke (due to risk of massive underdosing). Only 10, 20 or 50 mg presentations are indicated for use in those indications.

The 2 mg vial (with a total amount of 2.2 mg alteplase including 0.2 mg overage which will remain in the transfer syringe so that the amount practically administered is 2 mg alteplase) should always be reconstituted to a final concentration of 1 mg alteplase per ml.