Eliquis 2.5 mg film-coated tablets

Eliquis EU grouped paediatric Extension Applications procedure (EMEA/H/C/002148/X/0089/G)

Eliquis EU grouped paediatric Extension Applications procedure (EMEA/H/C/002148/X/0089/G)

Type IAin-092 - To update Pfizer Freiburg site address.

Eliquis Type II-088 variation to reflect the paediatric prevention data of PIP01 in the Eliquis Product Information (PI).

SmPC:

• Section 4.2 (Posology and method of administration) was amended to indicate that currently available data on thromboembolism prevention are described in section 5.1 but no recommendation on a posology can be made
• Section 5.1 (Pharmacodynamic properties) was updated with addition of available paediatric data on thromboembolism prevention (results of the paediatric studies CV185155 and CV185362 performed in compliance with the PIP01 (for prevention))

The Package leaflet is updated with ‘cutaneous vasculitis’ with a frequency ‘not known’. 

Name change of the manufacturing site, Swords Laboratories, by adding “Unlimited Company” at the end of the current legal entity name. 

The Product Information (PI) has been updated in section 4.8 with ‘cutaneous vasculitis’ with a frequency ‘not known’. The Package leaflet is updated accordingly. In addition, minor editorial changes were implemented in Section 4.4, 5.1 and 5.2 of the SmPC.

EDITORIAL CHANGES TO THE PRODUCT INFORMATION:

· In the Package Leaflet, the list of local representative has been removed

KEY CHANGES TO THE PRODUCT INFORMATION:

• Modification of the section 4.4 Special warnings and precautions for use, Patients with active cancer. “Efficacy and safety of apixaban in the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) in patients with active cancer have not been established.” Has been replaced by “Patients with active cancer can be at high risk of both venous thromboembolism and bleeding events. When apixaban is considered for DVT or PE treatment in cancer patients, a careful assessment of the benefits against the risks should be made (see also section4.3).”

EDITORIAL CHANGES TO THE PRODUCT INFORMATION:

· In table3, “anti-Xa activity” has been changed to “anti-Factor Xa activity”

· In section5.1, Pharmacodynamic properties, NVAF patients with ACS and/or undergoing PCI. A correction to the AUGUSTUS trial information - “10% received lower dose” corrected to “4.2% received lower dose”.

· In the Package Leaflet, the list of local representative has been removed

* corrected SmPC re-uploaded

SmPC 4.8: Inclusion of 'Erythema multiforme' as an adverse drug reaction
SmPC 10: Updated to 31 March 2021

SmPC 4.8: Inclusion of 'Erythema multiforme' as an adverse drug reaction
SmPC 8: Inclusion of Product License - Great Britain (PLGB) number
SmPC 10: Updated to 31 March 2021

Formatting and editorial changes throughout the SmPC to bring it in line with the current product information (QRD) template

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of apixaban in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of apixaban during pregnancy.. Apixaban is not recommended during pregnancy.

Breast-feeding

It is unknown whether apixaban or its metabolites are excreted in human milk. Available data in animals have shown excretion of apixaban in milk (see section 5.3). In rat milk, a high milk to maternal plasma ratio (C_max about 8, AUC about 30) was found, possibly due to active transport into the milk. A risk to the suckling child newborns and infants cannot be excluded.

A decision must be made whether to either discontinue breast-feeding or to discontinue/abstain from apixaban apixaban therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

5.3 Preclinical safety data:

In rat milk, a high milk to maternal plasma ratio (C_max about 8, AUC about 30) was found, possibly due to active transport into the milk.

Formatting and editorial changes throughout the SmPC to bring it in line with the current product information (QRD) template

Date of revision updated to align with SmPC date of revision

SmPC Update: Addition of angioedema as an adverse drug reaction in the SmPC

• To add Swords Laboratories T/A Bristol-Myers Squibb Pharmaceutical Operations, External Manufacturing as an alternative site responsible for batch release
• To change the name and amend the address of the site responsible for batch release to CATALENT ANAGNI S.R.L.

• To add Swords Laboratories T/A Bristol-Myers Squibb Pharmaceutical Operations, External Manufacturing as an alternative site responsible for batch release
• To change the name and amend the address of the site responsible for batch release to CATALENT ANAGNI S.R.L.

The SmPC date of revision has been updated to align with the patient leaflet date of revision (30 March 2020)

Update to the product information to reflect the results of study CV185-316 (AUGUSTUS)

Date of Revision: 17 February 2020

Periodic Safety Update Report (PSUR) - SmPC section 4.5 Inhibitors of CYP3A4 and P-gp updated with ‘fluconazole’

Date of Revision updated (20 December 2019) to align with date of EU Product Information revision - To include updated details from the Maltese list of representatives in the patient leaflet
 

Date of Revision updated (20 December 2019) to align with date of EU Product Information revision - To include updated details from the Maltese list of representatives in the patient leaflet
 

Updated Eliquis Prescriber Guide, Nov 2019

Changes include:

• Harmonisation of the UK/Ireland Eliquis Prescriber Guides into one document

• Update to the contraindication statement on unfractionated heparin co-administration to clarify an exception applies during catheter ablation for atrial fibrillation

• Clarification added on use in patients undergoing cardioversion (with reference to a transesophageal echocardiogram [TEE]-guided approach to exclude left atrial thrombus)

• Availability of a reversal agent, intended for use when reversal of anticoagulation with apixaban is needed due to life-threatening or uncontrolled bleeding

• Editorial modifications

To update the product information on the availability of reversal agent, andexanet alfa (Ondexxya).

To update the product information on the availability of reversal agent, andexanet alfa (Ondexxya):

To update the product information on the availability of reversal agent, andexanet alfa (Ondexxya):

 4.4 Special warnings and precautions for use

An agent to reverse the anti-factor Xa activity of apixaban is available.

 4.9 Overdose

There is no antidote to Eliquis. Overdose of apixaban may result in a higher risk of bleeding. In the event of haemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. The initiation of appropriate treatment, e.g., surgical haemostasis, or the transfusion of fresh frozen plasma or the administration of a reversal agent for factor Xa inhibitors should be considered.

For situations when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding, a reversal agent for factor Xa inhibitors is available (see section 4.4).

If life-threatening bleeding cannot be controlled by the above measures, an agent to reverse the anti-factor Xa activity of apixaban is available. Aa Administration of prothrombin complex concentrates (PCCs) or recombinant factor VIIa may also be considered

 6.1 List of excipients (removal of E number)

Film coat:

Lactose monohydrate

Hypromellose (E464)

Titanium dioxide (E171)

Triacetin (E1518)

 Yellow iron oxide (E172)

4.2 Posology:

Patients undergoing catheter ablation (NVAF)

Patients can continue apixaban use while undergoing catheter ablation (see sections 4.3, 4.4 and 4.5)

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Patients undergoing cardioversion

Apixaban can be initiated or continued in NVAF patients who may require cardioversion.

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For patients not previously treated with anticoagulants, exclusion of left atrial thrombus using an image guided approach (e.g. transesophogeal echocardiography (TEE) or computed tomographic scan (CT)) prior to cardioversion should be considered, in accordance with established medical guidelines.

at least 5 doses of apixaban 5 mg twice daily (2.5 mg twice daily in patients who qualify for a dose reduction (see above sections Dose reduction and Renal impairment)) should be given before cardioversion to ensure adequate anticoagulation (see section 5.1). For patients initiating treatment with apixaban, 5 mg should be given twice daily for at least 2.5 days (5 single doses) before cardioversion to ensure adequate anticoagulation (see section 5.1). The dosing regimen should be reduced to 2.5 mg apixaban given twice daily for at least 2.5 days (5 single doses) if the patient meets the criteria for dose reduction (see above sections Dose reduction and Renal impairment).

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4.3 Contraindications:

·         Concomitant treatment with any other anticoagulant agent e.g., unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.) except under specific circumstances of switching anticoagulant therapy (see section 4.2), or when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see sections 4.4 and 4.5).

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4.4 Special Warnings and precuations for use

​​For patients undergoing catheter ablation for atrial fibrillation, Eliquis treatment does not need to be interrupted (see sections 4.3, 4.4 and 4.5).

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4.5 Interaction with other medicinal products and other forms of interactions

Anticoagulants, platelet aggregation inhibitors, SSRIs/SNRIs and NSAIDs

Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated except under specific circumstances of switching anticoagulant therapy, when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see section 4.3).

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4.8 - Alopecia added as an AE

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To include warning regarding thromboembolic risk in patients with antiphospholipid syndrome.

Section 7: MAH address change

Prescriber guide updated in line with SPC updates to include information on the following:

• posology recommendations in Non-valvular Atrial Fibrillation (NVAF) patients undergoing cardioversion
• drug interaction with selective serotonin reuptake inhibitors (SSRIs) / serotonin norepinephrine reuptake inhibitors (SNRIs) leading to an increased risk of bleeding

Section 4.2 - ‘Patients undergoing cardioversion’ subsection - Text amended to state that ‘Apixaban can be initiated or continued in NVAF patients who may require cardioversion’. Section also updated to include detail on dosage in relation to cardioversion.

Section 5.1 – EMANATE study information added.

Section 7 – amendment of MAH address

Section 10 – updated date of revision

Type II variation - to assign a frequency to all adverse drug reactions for each indication.

• • • • SmPC Section 4.8 Undesirable effects (Table 2)

Section 4.5: This section has been updated with information on the effects of clarithromycin on apixaban treatment

Section 4.2 Posology and method of administration
- Update of section 4.2 of the SmPC to clarify the wording about the dose in patients with renal impairment.

Section 9 Date of first authorisation/renewal of the authorisation
- Updated to include the date of the latest renewal

Section 10 Date of Revision of the Text
- Updated to include the current date of revision to the text

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

4.2         Posology and method of administration

Prevention of VTE (VTEp): elective hip or knee replacement surgery

The recommended dose of Eliquis apixaban is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery.

Switching

Switching treatment from parenteral anticoagulants to Eliquis (and vice versa) can be done at the next scheduled dose (see section 4.5). These medicinal products agents should not be administered simultaneously.

Switching from vitamin K antagonist (VKA) therapy to Eliquis

When converting patients from vitamin K antagonist (VKA) therapy to Eliquis, warfarin or other VKA therapy should be discontinued and start Eliquis started when the international normalised ratio (INR) is < 2.0.

4.4     Special warnings and precautions for use

There is no clinical experience with the use of apixaban with indwelling intrathecal or epidural catheters. In case there is such need and based on the general PK characteristics of apixaban, a time interval of 20‑30 hours (i.e., 2 x half-life) between the last dose of apixaban and catheter withdrawal should elapse, and at least one dose should be omitted before catheter withdrawal. The next dose of apixaban may be given at least 5 hours after catheter removal. As with all new anticoagulant medicinal products agents, experience with neuraxial blockade is limited and extreme caution is therefore recommended when using apixaban in the presence of neuraxial blockade.

Common adverse reactions event were haemorrhage, contusion, epistaxis, and haematoma (see Table 2 for adverse reaction profile and frequencies by indication).

In the VTEp studies, in total, 11% of the patients treated with apixaban 2.5 mg twice daily experienced adverse reactions. The overall incidence of adverse reactions related to bleeding with apixaban was 10% in the apixaban vs enoxaparin studies.

In the NVAF studies, the overall incidence of adverse reactions related to bleeding with apixaban was 24.3% in the apixaban vs warfarin study and 9.6% in the apixaban vs acetylsalicylic acid aspirin study. In the apixaban vs warfarin study the incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal bleeding) with apixaban was 0.76%/year. The incidence of ISTH major intraocular bleeding with apixaban was 0.18%/year.

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:- 18 May 2011

Date of latest renewal: 14 January 2016

EMEA/H/C/002148/II/0030 - crushed

Type II variation C.I.4, to update sections 4.2 and 5.2 of the SmPC to include recommendations in the labelling regarding the use of alternative methods of administration of apixaban tablets (crushed tablets)

Approval date (CHMP Opinion):                24 Sept 2013

EMEA/H/C/002148/II/0029 - PCC

Type II variation, C.I.4, to provide the final study results from study CV185156 evaluating the ability of prothrombin complex concentrates (PCCs) to reverse the anticoagulant effect of apixaban in healthy subjects and to propose use recommendations in sections 4.9 and 5.1 of the SmPC based on the study results (PfLEET 2015-0010043).

Approval date (CHMP Opinion):                17 Sept 2015

Addition of black triangle and text:

“This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.”

- Section 4.4     Special warnings and precautions for use

Addition of the text:

Patients with prosthetic heart valves

Safety and efficacy of Eliquis have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of Eliquis is not recommended in this setting.

- Section 4.8   Undesirable effects

Adverse Event omission of Haemoptysis -  uncommon (NVAF)  has been corrected

In section 4.8   Undesirable effects

Adverse Event omission of Haemoptysis -  uncommon (NVAF) has been corrected

Addition of the below text:

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.

- In section 4.9 Overdose

Addition of the below text:

Haemodialysis decreased apixaban AUC by 14% in subjects with end stage renal disease, when a single dose of apixaban 5 mg was administered orally.  Therefore, haemodialysis is unlikely to be an effective means of managing apixaban overdose.

- In section 5.2 Pharmacokinetic properties

Addition of text:

In section 5.2 Addition of text:

In subjects with end-stage renal disease (ESRD), the AUC of apixaban was increased by 36% when a single dose of apixaban 5 mg was administered immediately after hemodialysis, compared to that seen in subjects with normal renal function. Hemodialysis, started two hours after administration of a single dose of apixaban 5 mg, decreased apixaban AUC by 14% in these ESRD subjects, corresponding to an apixaban dialysis clearance of 18 mL/min. Therefore, haemodialysis is unlikely to be an effective means of managing apixaban overdose.

In section 4.3 (Contraindications)

The second bullet has been updated to:

• Clinically significant a Active clinically significant bleeding.

The fourth bullet point has been updated to:

• Lesion or condition if considered a at significant risk factor for of major bleeding. This may include such as current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.

The fifth bullet point to:

• Concomitant treatment with any other anticoagulant agent e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.) except under the circumstances of switching therapy to or from apixaban (see section 4.2) or when UFH is given at doses necessary to maintain an open patent central venous or arterial catheter (see section 4.5).

Inclusion of  Pharmacotherapeutic Group “direct factor Xa inhibitors” in section 5.1.Minor editorial and typographical corrections have also been introduced.