Actilyse 10 mg

Availability of gentamicin free stock.

The following sections of the SmPC have been updated:

Section 4.3 & 4.4: Updated to remove the information referring to gentamicin. 

The following sections of the SmPC have been updated:

• Section 6.3: Updated to reduce the shelf life from 3 years to 2 years
• Section 10: Date of revision has been updated to May 2023.

• Section 4.3: Minor editorial change
• Section 4.4: Updated to include information of the concomitant use of other active substances affecting coagulation or platelet function
• Section 4.5: Updated to in order to improve readability
• Section 4.6: Inclusion of a statement to advice on the use of Actilyse during breastfeeding.
• Section 5.2: Updated to complement the information on pharmacokinetics for the active substance
• Section 6.6: Minor editorial changes to provide clearer instructions
• Section 10: Date of revision has been updated to 03/2023

The following sections have been updated:

• Section 2 and 6: Updated to remove the information mentioning the stopper contains natural rubber (a derivatives of latex)

• Section 4.4 (Hypersensitivity): Updated to remove the information mentioning the stopper contains natural rubber (a derivatives of latex)
• Section 10: Date of revision has been updated to March 2022

Minor administrative/typographical changes to active ingredient name, manufacturer address and Section ‘What Actilyse looks like and contents of the pack’. Reporting of side effects section updated in line with QRD template (Irish contact details).

Changes include the implementation of QRD template change (revised AE reporting statement), ‘D-‘ removal from zip code and minor/editorial changes associated with RMS renewal comments.  Sections 4.4, 4.8, 6.5 and 6.6 of the SmPC have been revised as a result of this variation.  The date of revision (section 10) has been updated to June 2021 

Section 6 'What Actilyse contains' section updated - information added on how Alteplase is produced.

Minor clarifications; correction of spelling errors

Sections 4.1, 4.2, 4.3, 4.5, 4.6, 4.9, 5.1, 6.6:  Administrative / clarifications and the product information has been updated in line with excipient guidelines

Sections 4.2, 4.3, 4.4, 4.8, 4.9, 6.6:  Traceability statement added regarding recording batch number and sections updated with extensive changes.

Specifically, section 4.2 updated to introduce a structure to specify more clearly which recommended or maximum dosage applies to which registered indication and patient body weight and to add a dosing table for alteplase use in the indication acute ischaemic stroke. Section 4.4 updated to cluster already existing safety information broken down by indication. Section 4.4 updated to include a statement that the name and batch number of the administered product should be clearly recorded in the patient file to improve traceability. Section 4.8 update to reword the side effect "Bleeding" (MedDRA Lowest Level Term) to its corresponding MedDRA preferred term "Haemorrhage" (MedDRA Version 21.0). Section 4.9 updated to include the information regarding the symptoms occurring in case of an overdose.

Section 10 Date of Revision has been updated

Section 7:  Marketing Authorisation Holder updated

Section 8:  Marketing Authorisation Number updated

Section 10, date of revision updated

• Sections 4.2: Minor update to the sub-heading from ‘Pulmonary embolism’ to ‘Acute massive pulmonary embolism’.
• Sections 4.3: Deletion of ‘Use in elderly patients’ section to remove reference regarding Actilyse not indicated for the treatment of acute stroke in adults over 80 years and minor update to the sub-headings from ‘acute pulmonary embolism’ to ‘acute massive pulmonary embolism’ .
• Section 4.4: Update to the information in the ‘Additional special warnings and precautions in acute ischaemic stroke’ section, addition of cross-references to section 4.3, and update to the sub-headings as section 4.3.
• Section 4.8: Minor wording update to the description of Table 1.
• Section 5.1: Addition of information in the ‘Elderly (>80 years)’ section regarding nine randomised trials to assess benefit-risk of alteplase in patients > 80 years and addition of multiple sub-headings.
• Section 6.1: Editorial update to the excipient  ‘Phosphoric acid, dilute to ‘Phosphoric acid (for pH-adjustment)’
• Section 10: Date of revision has been updated to September 2018

• Sections 4.2: Wording update in the ‘Paediatric population’ section to specify inclusion of 16 - 17 years in the adolescents group.
• Sections 4.3: Wording update in the ‘Use in children and adolescents’ section to specify inclusion of 16 - 17 years in the adolescents group.
• Section 4.4: Addition of information in the ‘Paediatric population’ section with cross-reference to section 5.1.
• Section 5.1: Addition of information in the ‘Paediatric population’ section regarding Observational non-randomised and non-comparative data in stroke patients of 16 – 17 years.
• Section 6.3: Editorial update to align with RMS annex text.
• Section 10: Date of revision has been updated to August 2018 to align with the HPRA approval date of 13-Aug-2018. For reference, the RMS approval date was 23-Apr-2018.
• Other editorial changes within the SmPCs to align with the HPRA approved versions of the SmPC, where relevant.

Previous version of SmPC reinstated

• Sections 4.2: Wording update in the ‘Paediatric population’ section to specify inclusion of 16 - 17 years in the adolescents group.
• Sections 4.3: Wording update in the ‘Use in children and adolescents’ section to specify inclusion of 16 - 17 years in the adolescents group.
• Section 4.4: Addition of information in the ‘Paediatric population’ section with cross-reference to section 5.1.
• Section 5.1: Addition of information in the ‘Paediatric population’ section regarding Observational non-randomised and non-comparative data in stroke patients of 16 – 17 years.
• Section 6.3: Editorial update to align with RMS annex text.

-        Section 6.3 Shelf Life (clarification / editorial / wording changes –  actual shelf life not changed).

-        Section 6.6 Special precautions for disposal and other handling (includes substantial changes to Instructions for reconstituting Actilyse).

-        Section 10 (Revision date updated).  The date of revision of the text has updated to align with the RMS approval dated 25Apr17.

Further to receipt of renewal approval, the following are updated:

Sections 1, 2 and 7 (with minor typographical changes)

Sections 3 (re appearance), 4.2, 4.3, 4.4, 4.6, 4.8, 4.9, 5.1, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6 and 9 (with significant changes)

Section 10 (revision date updated from August 2013 to March 2015) 

Section 4.3 Contraindications

This section has been updated to include warnings for latex and gentamicin.

This section has been updated to include additional anticoagulation statements.

Section 4.4 Special Warnings and Precautions for Use

This section has been updated to include warnings for latex and gentamicin.

This section has been updated to include additional anticoagulation statements.

Section 6.6 Special Precautions for Disposal and Other Handling

The section header has been updated to now read Special precautions for disposal and other handling i.e. … of a used medicinal product or waste materials derived from such medicinal product and … of the product have been deleted.

Section 10 Date of Revision of the Text

The date has been updated from October 2011 to August 2013.

Section 4.1 Therapeutic Indications

The final paragraph (regarding fibrinolytic treatment of acute ischaemic stroke) has had text both added to and deleted from.  The text … as early as possible …,

… 4.5 …, … after … and all that after … imaging techniques … is new.

Section 4.2 Posology and Method of Administration

The Acute ischaemic stroke sub-heading of this section has had both text added to and deleted from. 

The text … only …, … under the responsibility and follow-up of …, … trained and experienced …, and … neurovascular … is new in the first paragraph.

The text … as early as possible …, … 4.5 … and the complete final sentence of the third paragraph is new.

Section 4.3 Contraindications

The second paragraph of this section has been added as new text.

The first bullet point of the Additional contraindications in acute ischaemic stroke sub-heading has been amended.  The text … 4.5 …, … symptoms for which the …, … time … and … and could potentially be more than 4.5 hours ago (see section 5.1) has been added.

A new sub-heading entitled Use in elderly patients, together with corresponding text, has been added.

Section 4.4 Special Warnings and Precautions for Use

A new first paragraph has been added to this section.

The sub-heading Additional special warnings and precautions in acute ischaemic stroke has had both text added to and deleted from.  The text … only …, … under the responsibility and follow-up of a … and … neurovascular … has been added.

A new third bullet point has been added to the Special warnings/conditions with a decreased benefit/risk ratio sub-heading.

A new penultimate paragraph (regarding data available from ECASS III) has been added to this section.

Section 4.5 Interaction with Other Medicinal Products and Other Forms of Interaction

The text … active substances which interfere with … has replaced the text … other agents inhibiting … in the second paragraph of this section.

Section 4.8 Undesirable Effects

The first paragraph of this section (regarding adverse reactions frequency and system organ class) has had text both added to and deleted from.

The text … and without any relevant increase in overall mortality and severe disability combined, i.e. mRS of 5 and 6 … has been added to the common category of the Haemorrhage sub-heading.

The text … ear haemorrhage … has been added to the uncommon category of the Haemorrhage sub-heading.

Section 4.9 Overdose

The text … severe bleeding results, the infusion of fresh frozen plasma or fresh blood is recommended and if necessary, synthetic antifibryinolytics may be administered … has been added to the first paragraph of this section.

Section 5.1 Pharmacodynamic Properties

The text … iv… and … s.c… has been replaced with the text … intravenous … and … subcutaneous … in the fourth paragraph of this section.

The Acute stroke sub-heading of this section has had both text added to and deleted from, including the addition of a new second paragraph regarding the ECASS III trial and the addition of a new third paragraph regarding the safety and efficacy of Actilyse for acute ischaemic stroke treatment.

Section 6.6 Special Precautions for Disposal and Other Handling

Minor editorial changes have been made to this section.

Section 10 Date of Revision of the Text

The date has been amended from November 2009 to October 2011.

Changes to section 4.2 - Posology and method of administration, Change to section 4.3 – Contraindications, Change to section 4.4 – Special warnings and special precautions for use, Change to section 4.5 – Interaction with other medicinal products and other forms of interaction, Change to section 4.8 – Undesirable effects.

Change details:

Section 4.2 Posology and method of administration.

The section on adjunctive therapy has been updated to incorporate current recommendations.  It now states “Antithrombotic adjunctive therapy is recommended according to the current international guidelines for the management of patients with ST-elevation myocardial infarction”

Section 4.3 Contraindications

Acitylase is contraindicated in cases where there is a high risk of haemorrhage in a number of situations; this now includes patients with a “significant bleeding disorder at present or within the past 6 months”.

An additional contraindication for use in acute myocardial infarction and acute pulmonary embolism was any history of stroke.  This has now been changed to include

“any known history of haemorrhagic stroke or stroke of unknown origin”

and “any known history of ischaemic stroke if transient ischaemic attack in the preceding 6 months, except current acute ischaemic stroke in the last 3 hours”.

Section 4.4 Special warnings and special precautions for use

This section now notes that the concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.

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

This section now notes that the concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.

Section 4.8 – Undesirable effects

Corrections in the frequency classification of some undesirable effects.  The following effects have been reclassified from uncommon to common:

Respiratory tract haemorrhage (such as pharyngeal haemorrhage, epistaxis, haemoptysis)

Gastrointestinal haemorrhage (such as gastric haemorrhage, gastric ulcer haemorrhage, haemorrhage rectum, haematemesis, melaena, mouth haemorrhage)

As with other thrombolytic agents some cardiac disorders have been reported as sequelae of myocardial infarction and / or thrombolytic treatment. Reperfusion arrythmias are now classified as a very common undesirable effect.

Gastrointestinal disorders: Nausea and vomiting have been reclassified from a rare to a common undesirable effect.

The following effect has been added

Injury and poisoning and procedural complications:

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