4.1. Therapeutic indications

Thrombolytic treatment in acute myocardial infarction (AMI)

• 90 minutes (accelerated) dose regimen (see section 4.2): for patients in whom treatment can be started within 6 hours after symptom onset

• 3 hour dose regimen (see section 4.2): for patients in whom treatment can be started between 6 - 12 hours after symptom onset provided that the diagnosis has been clearly confirmed.

Actilyse has proven to reduce 30-day-mortality in patients with acute myocardial infarction.

Thrombolytic treatment in acute massive pulmonary embolism with haemodynamic instability (PE)

The diagnosis should be confirmed whenever possible by objective means such as pulmonary angiography or non-invasive procedures such as lung scanning. There is no evidence for positive effects on mortality and late morbidity related to pulmonary embolism.

Thrombolytic treatment of acute ischaemic stroke (AIS) within 4.5 hours from last known well and after exclusion of intracranial haemorrhage.

4.2. Posology and method of administration

Actilyse should be prescribed by physicians experienced in the use of thrombolytic treatment and with the facilities to monitor that use.

Actilyse should be given as early as possible after symptom onset. The following dose guidelines apply.

Acute myocardial infarction

Posology

a) 90 minutes (accelerated) dose regimen for patients with acute myocardial infarction, in whom treatment can be started within 6 hours after symptom onset.

In patients with a body weight ≥ 65 kg:

Volume to be administered according to alteplase concentration

1 mg/ml

2 mg/ml

15 mg as an intravenous bolus, immediately followed by

15 ml

7.5 ml

50 mg as an intravenous constant rate infusion over the first 30 minutes, immediately followed by

50 ml

25 ml

35 mg as an intravenous constant rate infusion over 60 minutes, until the maximum total dose of 100 mg

35 ml

17.5 ml

In patients with a body weight < 65 kg the total dose should be weight adjusted according to the following table:

Volume to be administered according to alteplase concentration

1 mg/ml

2 mg/ml

15 mg as an intravenous bolus, immediately followed by

15 ml

7.5 ml

0.75 mg/kg body weight (bw) as an intravenous constant rate infusion over the first 30 minutes, immediately followed by

0.75 ml/kg bw

0.375 ml/kg bw

0.5 mg/kg body weight (bw) as an intravenous constant rate infusion over 60 minutes

0.5 ml/kg bw

0.25 ml/kg bw

b) 3 h dose regimen for patients with acute myocardial infarction, in whom treatment can be started between 6 and 12 hours after symptom onset.

In patients with a body weight ≥ 65 kg:

Volume to be administered according to alteplase concentration

1 mg/ml

2 mg/ml

10 mg as an intravenous bolus, immediately followed by

10 ml

5 ml

50 mg as an intravenous constant rate infusion over the first hour, immediately followed by

50 ml

25 ml

40 mg as an intravenous constant rate infusion over 2 hours, until the maximum total dose of 100 mg

40 ml

20 ml

In patients with a body weight < 65 kg:

Volume to be administered according to alteplase concentration

1 mg/ml

2 mg/ml

10 mg as an intravenous bolus, immediately followed by

10 ml

5 ml

an intravenous constant rate infusion over 3 hours up to a maximum total dose of 1.5 mg/kg bw

1.5 ml/kg bw

0.75 ml/kg bw

Adjunctive therapy: Antithrombotic adjunctive therapy is recommended according to the current international guidelines for the management of patients with ST-elevation myocardial infarction.

Method of administration

The reconstituted solution should be administered intravenously and is for immediate use.

2 mg vials of alteplase are not indicated for use in this indication. For instructions prior to reconstitution / administration, see section 6.6.

Acute massive pulmonary embolism

Posology

In patients with a body weight ≥ 65 kg:

A total dose of 100 mg of alteplase should be administered in 2 hours. Most experience is available with the following dose regimen:

Volume to be administered according to alteplase concentration

1 mg/ml

2 mg/ml

10 mg as an intravenous bolus over 1 - 2 minutes, immediately followed by

10 ml

5 ml

90 mg as an intravenous constant rate infusion over 2 hours until the maximum total dose of 100 mg

90 ml

45 ml

In patients with a body weight < 65 kg:

Volume to be administered according to alteplase concentration

1 mg/ml

2 mg/ml

10 mg as an intravenous bolus over 1 - 2 minutes, immediately followed by

10 ml

5 ml

an intravenous constant rate infusion over 2 hours up to a maximum total dose of 1.5 mg/kg bw

1.5 ml/kg bw

0.75 ml/kg bw

Adjunctive therapy

After treatment with Actilyse heparin therapy should be initiated (or resumed) when aPTT values are less than twice the upper limit of normal. The infusion should be adjusted to maintain aPTT between 50 ‑ 70 seconds (1.5 to 2.5 fold of the reference value).

Method of administration

The reconstituted solution should be administered intravenously and is for immediate use.

2 mg vials of alteplase are not indicated for use in this indication. For instructions prior to reconstitution / administration, see section 6.6.

Acute ischaemic stroke

Treatment must only be performed under the responsibility and follow-up of a physician trained and experienced in neurovascular care, see sections 4.3 and 4.4.

Treatment with Actilyse must be started for adults and adolescents ≥ 16 years of age (see sections 4.3 and 4.4) as early as possible and no later than 4.5 hours after last known well and after exclusion of intracranial haemorrhage by appropriate imaging techniques. The treatment effect is time-dependent; therefore, earlier treatment increases the probability of a favourable outcome. Beyond 4.5 hours after onset of stroke symptoms there is a negative benefit risk ratio associated with Actilyse administration and so it should not be administered (see section 5.1).

Posology

The recommended total dose is 0.9 mg alteplase/kg body weight (maximum of 90 mg) starting with 10% of the total dose as an initial intravenous bolus, immediately followed by the remainder of the total dose infused intravenously over 60 minutes.

DOSING TABLE FOR ACUTE ISCHAEMIC STROKE

By using the recommended standard concentration of 1 mg/ml the volume (ml) to be administered is equal to the recommended dosing value (mg)

Weight

(kg)

Total Dose

(mg)

Bolus Dose

(mg)

Infusion Dose*

(mg)

40

36.0

3.6

32.4

42

37.8

3.8

34.0

44

39.6

4.0

35.6

46

41.4

4.1

37.3

48

43.2

4.3

38.9

50

45.0

4.5

40.5

52

46.8

4.7

42.1

54

48.6

4.9

43.7

56

50.4

5.0

45.4

58

52.2

5.2

47.0

60

54.0

5.4

48.6

62

55.8

5.6

50.2

64

57.6

5.8

51.8

66

59.4

5.9

53.5

68

61.2

6.1

55.1

70

63.0

6.3

56.7

72

64.8

6.5

58.3

74

66.6

6.7

59.9

76

68.4

6.8

61.6

78

70.2

7.0

63.2

80

72.0

7.2

64.8

82

73.8

7.4

66.4

84

75.6

7.6

68.0

86

77.4

7.7

69.7

88

79.2

7.9

71.3

90

81.0

8.1

72.9

92

82.8

8.3

74.5

94

84.6

8.5

76.1

96

86.4

8.6

77.8

98

88.2

8.8

79.4

100+

90.0

9.0

81.0

*given in a concentration of 1mg/mL over 60 min as a constant rate infusion.

Adjunctive therapy

Drugs affecting coagulation/platelet function

The safety and efficacy of this regimen with concomitant administration of heparin or platelet aggregation inhibitors such as acetylsalicylic acid within the first 24 hours after treatment with Actilyse have not been sufficiently investigated. Therefore, administration of intravenous heparin or platelet aggregation inhibitors such as acetylsalicylic acid should be avoided in the first 24 hours after treatment with Actilyse due to an increased haemorrhagic risk. If heparin is required for other indications (e.g. prevention of deep vein thrombosis) the dose should not exceed 10,000 IU per day, administered subcutaneously.

Method of administration

The reconstituted solution should be administered intravenously and is for immediate use.

2 mg vials of alteplase are not indicated for use in this indication. For instructions prior to reconstitution / administration, see section 6.6.

Paediatric population

There is limited experience with the use of Actilyse in children and adolescents. Actilyse is contraindicated for the treatment of acute ischaemic stroke in children and adolescents under 16 years of age (see section 4.3). The dose for adolescents ≥ 16 years of age is the same as for adults (see section 4.4 for recommendations on prior imaging techniques to be used).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Contraindications in acute myocardial infarction, acute massive pulmonary embolism and acute ischaemic stroke:

Actilyse is contraindicated in situations associated with a high risk of bleeding such as:

• significant bleeding disorder at present or within the past 6 months

• known haemorrhagic diathesis

• manifest or recent severe or dangerous bleeding

• any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery)

• recent (less than 10 days) obstetrical delivery, recent puncture of a non-compressible blood-vessel (e.g. subclavian or jugular vein puncture)

• severe uncontrolled arterial hypertension (see section 4.4)

• bacterial endocarditis, pericarditis

• acute pancreatitis

• active ulcerative gastrointestinal disease, oesophageal varices, known arterial-aneurysm and/or arterial/venous malformation

• neoplasm with increased bleeding risk

• severe liver disease, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis

• major surgery or significant trauma in past 3 months.

Additional contraindications in acute myocardial infarction and acute massive pulmonary embolism:

• any known history of haemorrhagic stroke or stroke of unknown origin

• known history of ischaemic stroke or transient ischaemic attack (TIA) in the preceding 6 months except current acute ischaemic stroke within 4.5 hours

• patients receiving effective oral anticoagulant treatment (e.g. vitamin K antagonists with INR > 1.3) (see section 4.4).

Additional contraindications in acute ischaemic stroke:

• minor neurological deficit or symptoms rapidly improving before start of infusion

• severe stroke as assessed clinically (e.g. NIHSS>25) and/or by appropriate imaging techniques

• known history of or suspected intracranial haemorrhage

• evidence of intracranial haemorrhage (ICH) on the CT-scan

• symptoms suggestive of subarachnoid haemorrhage, even if CT-scan is normal

• patients receiving effective anticoagulation (e.g. vitamin K antagonists with INR > 1.7) (see section 4.4)

• administration of heparin within the previous 48 hours and a thromboplastin time exceeding the upper limit of normal for laboratory

• patients with any history of prior stroke and concomitant diabetes

• prior stroke within the last 3 months

• platelet count of below 100 000/mm3

• systolic blood pressure > 185 mm Hg or diastolic BP > 110 mm Hg, or when BP cannot be reduced below these limits by careful management

• blood glucose < 50 mg/dL (see section 4.4) or > 400 mg/dL (< 2.8 mM or > 22.2 mM).

Use in children and adolescents

Actilyse is not indicated for the treatment of acute ischaemic stroke in children under 16 years of age (for adolescents ≥ 16 years of age see section 4.4).

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

The appropriate pack size of alteplase product should be chosen carefully and in accordance with the intended use. The 2 mg vial of alteplase is not indicated for use in acute myocardial infarction, acute massive pulmonary embolism or acute ischaemic stroke (due to risk of massive under dosing). Only 10 mg, 20 mg or 50 mg vials are indicated for use in these indications.

It is recommended that when Actilyse is administered, standard resuscitation equipment and pharmacotherapy is available in all circumstances.

Hypersensitivity

Immune-mediated hypersensitivity reactions associated with the administration of Actilyse can be caused by the active substance alteplase or any of the excipients. No sustained antibody formation to the recombinant human tissue-type plasminogen activator molecule has been observed after treatment. There is no systematic experience with re-administration of Actilyse.

There is also a risk of hypersensitivity reactions mediated through a non-immunological mechanism.

Angio-oedema represents the most common hypersensitivity reaction reported with Actilyse. This risk may be enhanced in the indication acute ischaemic stroke and/or by concomitant treatment with ACE inhibitors (see section 4.5). Patients treated with Actilyse should be monitored for angio‑oedema during and for up to 24h after infusion.

If a severe hypersensitivity reaction (e.g. angio-oedema) occurs, the infusion should be discontinued and appropriate treatment promptly initiated. This may include intubation.

Bleeding

The most common complication encountered during Actilyse therapy is bleeding. The concomitant use of other active substances affecting coagulation or platelet function may contribute to bleeding (see section 4.3) (see section 4.2 for AIS). As fibrin is lysed during Actilyse therapy, bleeding from recent puncture sites may occur. Therefore, thrombolytic therapy requires careful attention to all possible bleeding sites (including those following catheter insertion, arterial and venous puncture cutdown and needle puncture). The use of rigid catheters, intramuscular injections and non-essential handling of the patient should be avoided during treatment with Actilyse.

If a potentially dangerous bleeding occurs, in particular cerebral haemorrhage, the fibrinolytic therapy must be discontinued and concomitant heparin administration should be terminated immediately. In general, however, it is not necessary to replace the coagulation factors because of the short half-life and the minimal effect on the systemic coagulation factors. Most patients who have bleeding can be managed by interruption of thrombolytic and anticoagulant therapy, volume replacement, and manual pressure applied to an incompetent vessel. Protamine should be considered if heparin has been administered within 4 hours of the onset of bleeding. In the few patients who fail to respond to these conservative measures, judicious use of transfusion products may be indicated. Transfusion of cryoprecipitate, fresh frozen plasma, and platelets should be considered with clinical and laboratory reassessment after each administration. A target fibrinogen level of 1 g/l is desirable with cryoprecipitate infusion. Antifibrinolytic agents are available as a last alternative.

The risk of intracranial haemorrhage is increased in elderly patients, therefore in these patients the risk/benefit evaluation should be carried out carefully.

The expected therapeutic benefit should be weighed up particularly carefully against the possible risk, especially in patients with

• small recent traumas, such as biopsies, puncture of major vessels, intramuscular injections

• prolonged (> 2 minutes) or traumatic cardiopulmonary resuscitation or cardiac massage

• patients receiving oral anticoagulant treatment: The use of Actilyse may be considered when dosing or time since the last intake of anticoagulant treatment makes residual efficacy unlikely confirmed by appropriate test(s) of anticoagulant activity for the product(s) concerned showing no clinically relevant activity on the coagulation system (e.g. INR ≤ 1.3 (AMI and PE) or INR ≤ 1.7 (AIS) for vitamin K antagonists or other relevant test(s) for other oral anticoagulants are within the respective upper limit of normal).

Thrombo-embolism

The use of Actilyse can increase the risk of thrombo-embolic events in patients with existing thrombi, e.g., left heart thrombus (mitral stenosis or atrial fibrillation, etc.).

Paediatric population

As yet, there is only limited experience with the use of Actilyse in children and adolescents.

When Actilyse is considered for the treatment of acute ischaemic stroke in carefully selected adolescents ≥ 16 years of age the benefit should be weighed carefully against the risks on an individual basis and discussed with the patient and parent/guardian as appropriate. Adolescents ≥ 16 years of age should be treated according to the instruction in the label for the adult population after imaging by appropriate techniques to rule out stroke mimics and confirming arterial occlusion corresponding to the neurological deficit (see section 5.1).

Additional special warnings and precautions in acute myocardial infarction and acute massive pulmonary embolism:

A dose exceeding 100 mg of alteplase must not be given because it has been associated with an additional increase in intracranial bleeding. Therefore, special care must be taken to ensure that the dose of alteplase infused is as described in section 4.2.

The expected therapeutic benefit should be weighed up particularly carefully against the possible risk, especially in patients with:

• systolic blood pressure > 160 mm Hg (see section 4.3)

• body weight < 50 kg

• advanced age, i.e. patients 75 years or older, which may increase the risk of intracerebral haemorrhage.

GPIIb/IIIa antagonists:

Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.

Additional special warnings and precautions in acute myocardial infarction

Arrhythmias:

Coronary thrombolysis may result in arrhythmia associated with reperfusion.

Reperfusion arrhythmias may lead to cardiac arrest, can be life threatening and may require the use of conventional antiarrhythmic therapies.

Additional special warnings and precautions in acute ischaemic stroke:

Thrombolytic treatment requires adequate monitoring. Treatment must be performed under the responsibility and follow-up of a physician trained and experienced in neurovascular care and the use of thrombolytic treatments, with the facilities to monitor that use. For the verification of treatment indication remote diagnostic measures may be considered as appropriate see section 4.1 and 4.2.

Special warnings / conditions with a decreased benefit/risk ratio:

Bleeding

Intracerebral haemorrhage represents the major adverse reaction in the treatment of acute ischaemic stroke (up to 15 % of patients without any increase of overall mortality and without any relevant increase in overall mortality and severe disability combined, i.e. modified Rankin scale [mRS] score of 5 and 6).

Compared to other indications patients with acute ischaemic stroke treated with Actilyse have a markedly increased risk of intracranial haemorrhage as the bleeding occurs predominantly into the infarcted area. This applies in particular in the following cases:

• as time to treatment from onset of stroke symptoms increases, net clinical benefit decreases. Therefore, the administration of Actilyse should not be delayed.

• patients pre-treated with acetylsalicylic acid (ASA) may have a greater risk of intracerebral haemorrhage and/or mortality, particularly if Actilyse treatment is delayed.

• compared to younger patients, patients of advanced age (over 80 years) may have a somewhat poorer outcome independent of treatment. They are also more likely to have more severe strokes which are associated with a higher absolute risk of intracerebral haemorrhage when thrombolysed compared with milder strokes when thrombolysed or with non-thrombolysed patients. Although available data indicate that the net benefit of Actilyse in patients over 80 years is smaller compared with younger patients, Actilyse can be used in patients over 80 years on an individual benefit-risk basis (see section 5.1). Patients of advanced age should be selected very carefully taking into account both the general health and the neurological status.

Special groups at reduced benefit/risk ratio

The benefit/risk ratio of Actilyse administration should be thoroughly considered in AIS patients with the following conditions:

• the therapeutic benefit is reduced in patients that had a prior stroke (see also section 4.3) or in those with known uncontrolled diabetes, thus the benefit/risk ratio is considered less favourable, but still positive in these patients

• in patients with very mild stroke, the risks outweigh the expected benefit (see section 4.3)

• patients with very severe stroke are at higher risk for intracerebral haemorrhage and death and should not be treated (see section 4.3)

• patients with extensive infarctions are at greater risk of poor outcome including severe haemorrhage and death. In such patients, the benefit/risk ratio should be thoroughly considered

• in stroke patients the likelihood of good outcomes decreases with longer time to treatment from onset of symptoms, increasing age, increasing stroke severity and increased levels of blood glucose on admission while the likelihood of severe disability and death or symptomatic intracranial bleedings increases, independently from treatment

• seizure at the onset of stroke (Thrombolytic therapy in these patients should only be considered when there is no suspicion of a stroke mimic or significant head trauma)

• in patients initially presenting with blood glucose < 50 mg/dL, thrombolysis may be considered after correction to normal blood glucose values, if the diagnosis of AIS persists (see section 4.3).

Blood pressure monitoring

Blood pressure (BP) monitoring during treatment administration and the first 24 hours after alteplase treatment is necessary; an intravenous antihypertensive therapy is recommended if systolic BP > 180 mm Hg or diastolic BP > 105 mm Hg.

Other special warnings

Reperfusion of the ischaemic area may induce cerebral oedema in the infarcted zone.

Due to an increased haemorrhagic risk, treatment with platelet aggregation inhibitors should not be initiated within the first 24 hours following thrombolysis with alteplase.

Actilyse contains polysorbate 80

This medicine contains 1.0 mg, 2.0 mg or 5.0 mg of polysorbate 80 in each 10 mg, 20 mg or 50 mg vial, respectively. Polysorbates may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

No formal interaction studies with Actilyse and medicinal products commonly administered in patients with acute myocardial infarction, acute massive pulmonary embolism or acute ischaemic stroke have been performed.

Drugs affecting coagulation/platelet function

Medicinal products that affect coagulation or those that alter platelet function may increase the risk of bleeding (when administered prior to, during or after alteplase therapy). These products should be avoided in the first 24 hours after Actilyse treatment for acute ischaemic stroke. With regard to pre-treatment with these substances, see sections 4.2, 4.3, and 4.4.

ACE inhibitors

Concomitant treatment with ACE inhibitors may enhance the risk of experiencing a hypersensitivity reaction (see section 4.4).

Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.

4.6. Fertility, pregnancy and lactation

Pregnancy

There is a limited amount of data from the use of alteplase in pregnant women. Nonclinical studies performed with alteplase in doses higher than human doses exhibited fetal immaturity and/or embryotoxicity, secondary to the known pharmacological activity of the drug. Alteplase is not considered to be teratogenic (see section 5.3).

In cases of an acute life-threatening disease the benefit has to be evaluated against the potential risk.

Breast-feeding

It is unknown whether alteplase is excreted into human milk and there is insufficient information on the excretion of alteplase in animal milk.

Caution should be exercised when Actilyse is used for a nursing woman and a decision must be made whether breast-feeding should be discontinued for the first 24 hours after use of Actilyse.

Fertility

Clinical data on fertility are not available for Actilyse. Nonclinical studies performed with alteplase showed no adverse effect on fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Not relevant.

4.8. Undesirable effects

The most frequent adverse reaction associated with Actilyse is bleeding in different forms resulting in a fall in haematocrit and/or haemoglobin values.

Adverse reactions listed below are classified according to frequency and system organ class. Frequency groupings are defined according to the following convention: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1 000 to <1/100), Rare (≥1/10 000 to <1/1 000), Very rare (<1/10 000), Not known (cannot be estimated from the available data).

Except for intracerebral/intracranial haemorrhage as adverse reaction in the indication stroke as well as for reperfusion arrhythmias in the indication acute myocardial infarction, there is no medical reason to assume that the qualitative and quantitative adverse reaction profile of Actilyse in the indications acute massive pulmonary embolism and acute ischaemic stroke is different from the profile in the indication acute myocardial infarction.

Table 1 Adverse reactions in acute myocardial infarction, acute massive pulmonary embolism and acute ischaemic stroke

System Organ Class

Adverse Reaction

Haemorrhage

very common

intracerebral haemorrhage represents the major adverse reaction in the treatment of acute ischaemic stroke

all haemorrhages including those in this table, e.g. ICH and non-ICH

common

intracerebral haemorrhage (such as cerebral haemorrhage, cerebral haematoma, haemorrhagic stroke, haemorrhagic transformation of stroke, intracranial haematoma, subarachnoid haemorrhage) in the treatment of acute myocardial infarction and acute massive pulmonary embolism

pharyngeal haemorrhage

gastrointestinal haemorrhage (such as gastric haemorrhage, gastric ulcer haemorrhage, rectal haemorrhage, haematemesis, melaena, mouth haemorrhage, gingival bleeding)

ecchymosis

urogenital haemorrhage (such as haematuria, haemorrhage urinary tract)

injection site haemorrhage (puncture site haemorrhage, catheter site haematoma, catheter site haemorrhage)

uncommon

pulmonary haemorrhage (such as haemoptysis, hemothorax, respiratory tract haemorrhage)

epistaxis

ear haemorrhage

rare

eye haemorrhage

pericardial haemorrhage

retroperitoneal bleeding (such as retroperitoneal haematoma)

not known***

bleeding in parenchymatous organs (such as hepatic haemorrhage)

Immune system disorders

rare

hypersensitivity reactions (e.g. rash, urticaria, bronchospasm, angio-oedema, hypotension, shock)*

very rare

serious anaphylaxis

Nervous system disorders

very rare

events related to the nervous system (e.g. epileptic seizure, convulsion, aphasia, speech disorder, delirium, acute brain syndrome, agitation, confusion, depression, psychosis) often in association with concurrent ischaemic or haemorrhagic cerebrovascular events

Cardiac disorders**

very common

recurrent ischaemia / angina pectoris, hypotension and heart failure / pulmonary oedema,

common

cardiogenic shock, cardiac arrest and reinfarction

uncommon

reperfusion arrhythmias (such as arrhythmia, extrasystoles, AV block first degree to atrioventricular block complete, atrial fibrillation / flutter, bradycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia / fibrillation, electromechanical dissociation [EMD])

mitral regurgitation, pulmonary embolism, other systemic embolism / cerebral embolism, ventricular septal defect

Vascular disorders

rare

Embolism which may lead to corresponding consequences in the organs concerned

Gastrointestinal disorders

rare

nausea

not known***

vomiting

Investigations

uncommon

blood pressure decreased

not known***

body temperature increased

Injury and poisoning and procedural complications

not known***

fat embolism (cholesterol crystal embolisation), which may lead to corresponding consequences in the organs concerned

Surgical and medicinal procedures

not known***

Blood transfusions (necessary)

* See sections 4.4 and 4.5

**Cardiac disorders

As with other thrombolytic agents, the events described above under the respective section have been reported as sequelae of myocardial infarction and / or thrombolytic administration. These cardiac events can be life-threatening and may lead to death.

***Frequency calculation

This adverse reaction has been observed in post-marketing experience. With 95 % certainty, the frequency category is not greater than “rare” but might be lower. Precise frequency estimation is not possible as the adverse drug reaction did not occur in a clinical trial database of 8299 patients.

Death and permanent disability are reported in patients who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

If the maximum recommended dose is exceeded the risk of intracranial bleeding increases.

The relative fibrin specificity notwithstanding, a clinically significant reduction in fibrinogen and other blood coagulation components may occur after overdosage.

Therapy

In most cases, it is sufficient to await the physiological regeneration of these factors after the Actilyse therapy has been terminated. If, however, severe bleeding results, the infusion of fresh frozen plasma is recommended and if necessary, synthetic antifibrinolytics may be administered.