Zusammenfassung der Merkmale des Arzneimittels - Apixaban HEC 5 mg Filmtabletten
V.1 Proposed list of recommendations not falling under Article 21a/22 of Directive
| Proposed name of the medicinal product in the RMS | Apixaban HEC 2,5 mg; 5 mg Filmtabletten |
| Name of the drug substance (INN name): | Apixaban |
| Pharmaco-therapeutic group (ATC Code): | B01AF02 |
| Pharmaceutical form(s) and strength(s): | Film-coated tablet |
| Reference Number(s) for the Decentralised Procedure | DE/H/6542/001–002/DC |
| Reference Member State: | DE |
| Concerned Member States: | LU |
| Legal basis of application: | Generic Art 10.1 Dir 2001/83/EC |
| Applicant (name and address) | HEC Pharm GmbH Gabriele-Tergit-Promenade 17 D-10963 Berlin Germany |
| Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA | Formula Pharmazeutische und chemische Entwicklungs GmbH Goerzallee 305b, D-14167 Berlin, Germany |
Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Apixaban HEC 2,5 mg / 5 mg Filmtabletten in the treatment of
2,5 mg strength only
Prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.
2,5 mg and 5 mg strengths
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age ≥ 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II).
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (see section 4.4 for haemodynamically unstable PE patients)
is approved.
II.1 Problem statement
For generic application, this section is not applicable.
II.2 About the product
Apixaban is an orally active, direct, selective inhibitor of the coagulation factor Xa (FXa) that reversibly binds directly to the active site of FXa. It inhibits free and clot-bound factor Xa, and prothrombinase activity. By inhibiting factor Xa, apixaban prevents thrombin generation and thrombus development.
Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code: B01AF02
The proposed indications for Apixaban HEC are in line with the reference medicinal product:
2,5 mg strength only
Prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.
2,5 mg and 5 mg strengths
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age ≥ 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II).
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (see section 4.4 for haemodynamically unstable PE patients).
II.3 General comments on the submitted dossier
This decentralised application concerns a generic version of Apixaban, under the name Apixaban HEC 2,5 mg / 5 mg Filmtabletten (Article 10(1) of Directive 2001/83/EC, so-called "generic application”). In this Assessment Report, the name Apixaban HEC is used.
The originator product is Eliquis 5 mg film-coated tablets by Bristol-Myers Squibb / Pfizer EEIG, UK, registered since 2011–05–18, EU/1/11/691/006–012+014.
With DE as the Reference Member State in this Decentralized Procedure HEC Pharm GmbH applied for the Marketing Authorisations in LU.
Sections 1.6.1–3 of the paediatric regulation EC No 1901/2006 are not applicable for a generic medicinal product. No PIP has been submitted.
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.
The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product.
For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.
For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, issued by the inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those non-Community sites.
In line with EMA guidance, it has been accepted that GMP certificates and time-limited manufacturing and import authorisations are automatically extended until the end of 2023for sites in and outside the European Economic Area (EEA).
GMP active substance
Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer(s) responsible for manufacture of the batch release situated in the EU, covering the API manufacturing sites.
GCP/GLP
A statement on the application of appropriate GCP and GLP standards in the submitted study has been provided.
The study centres of the study have been inspected by EU-authorities. The outcomes of the most recent inspections are provided.
III.1 Quality aspects
The Applicant provided a full dossier including full drug substance as well as drug product information for immediate release film-coated tablets 2,5 mg and 5 mg containing Apixaban as active substance.
The active substance is apixaban. It is not described in the European Pharmacopoeia. The active substance is practically insoluble in water.
A full application is used for this DCP procedure. Therefore, no ASMF or CEP is used in the dossier. The drug substance section is approved.
The proposed generic product Apixaban 2,5 mg & 5 mg film-coated tablets is identical in the active substance as well as in the dosage form (film-coated tablets) to the originator product Eliquis 2,5 mg & 5 mg film-coated tablets (Bristol-Myers Squibb).
An extensive pharmaceutical development program has been presented. The development report summarizes the development of the two proposed strengths of the generic product Apixaban 2,5 mg and 5 mg tablets. A BE study was performed with 5 mg strength and a biowaiver is requested for the 2,5 mg strengths. In-vitro dissolution data is presented. However, for conclusion on BE and acceptability of the biowaiver, reference is made to the clinical AR. The dossier should be updated accordingly. Dissolution profile has been studied but discriminatory power has not been shown. However, this is acceptable due to hight solubility of Apixaban and dissolution is adequatly specified. For the crushed tablets to be administered through gastric tubes, suitable in-vitro data has been provided.
The two strengths are directly proportional and one bulk batch of blended granules is used to manufacture both strengths. The manufacturing process has been described and suitable IPCs are included. No process validation is currently available and will be finalized prior to marketing. A suitable process validation scheme is presented. The applicant confirmed that the shelf-life will be calculated in accordance with the Note for Guidance on start of shelf-life of the finished product form (CPMP/QWP/072/96).
The excipients are suitable.
The product specifications for release and shelf life are presented and included in the dossier. Appropriate parameters for this dosage form are included.
Batch analysis data is presented for three submission batches for each strength among them the 5mg biobatch and confirm compliance with the proposed release specification.
Potential impurities have been adequately addressed.
Major objection on nitrosamine risk assessment has adequately been solved and is acceptable now.
Elemental risk assessment is presented and included in the dossier as requested.
Reference standards are identical to the standards used for API and data is presented to confirm suitability of standards.
The presented stability studies (photo, bulk and product) are in accordance with the respective stability guideline. A shelf-life of 24 months withoug any special storage conditions can be granted.
The dossier is, drug substance as well as drug product part, is aceptable.
III.2 Non clinical aspects
Pharmacodynamic, pharmacokinetic and toxicological properties of apixaban are well known. As apixaban is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required.
The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.
Since Apixaban HEC is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.
There are no objections to approval of Apixaban HEC from a non-clinical point of view.
III.3 Clinical aspects
The applicant has applied for 2 strengths, 2,5 mg and 5 mg, based on a bioequivalence study (5 mg strength) and an extrapolation approach.
No BCS-based biowaver was proposed. Linearity of PK was assumed by the PKWP. Extrapolation to the 2,5 mg strength respectively was justified based on the following considerations:
The following requirements of the Guideline CPMP/QWP/EWP/1401/98 Rev.1. section 4.1.6, are fulfilled: a) the pharmaceutical products are manufactured by the same manufacturing process
b) the qualitative composition of the different strengths is the same
c) the quantitative composition of the higher strengths are dose-proportional. i.e. the ratio between the
amount of each excipient to the amount of active substance(s) is the same for all strengths (for immediate release products coating components, capsule shell, colour agents and flavours are not required to follow this rule).
d) Comparative in vitro dissolution studies between the batches used in the bioequivalence studies (Test and Reference product) were performed. Taking the complete set of submitted data into account, this is accepted and an additional BE-study with the 2,5 mg tablet can be waived.
One BE study was provided as report.
An open label, balanced, randomized, two-treatment, two-period, two-sequence, single oral dose, crossover bioequivalence study of Apixaban HEC 5 mg Film-coated Tablets in comparison with Eliquis 5 mg Filmtabletten in normal, healthy, adult, human subjects under fasting conditions.
The concentrations of Apixaban in human plasma were determined using a selective, reproducible, precise and accurate LC-MS/MS method using Apixaban 13CD3 as an internal standard.
The mean and SD of pharmacokinetic parameters estimated for test product (T) and reference product ® are as follows
| Pharmacokinetic Parameter | Arithmetic Means ± SD | |
| Test Product | Reference Product | |
| AUC 0-t (ng*h/ml) | 2212 ± 434 | 2192 ± 481 |
| AUC 0- ∞ (ng*h/ml) | 2250 ± 447 | 2227 ± 490 |
| C max (ng/ml) | 224.5 ± 38.4 | 225.9 ± 32.0 |
| T max (h) 1 | 2.500 (1.500 – 5.017) | 3.267 (1.000 – 5.033) |
1Median (Min – Max)
| Pharmacokinetic Parameter | Geometric Mean Ratio Test/Ref | 90% Confidence Intervals | Intrasubject CV%1 |
| AUC0-t | 101.5 | 95.93 – 107.46 | 11.5 |
| Cmax | 98.9 | 92.79 – 105.47 | 13.0 |
Pharmacokinetic conclusion
The results are consistent with the assumption of bioequivalence between test and reference medicinal product.
No data were submitted.
No data were submitted.
There were no deaths, serious or significant AEs during the conduct of the study.
The safety data do not indicate a difference in the safety profile between Test and Reference.
The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided, that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.
The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Apixaban HEC 2,5 mg and 5 mg Filmtabletten.
Safety specification
| Summary of safety concerns | |
| Important identified risks | Bleeding |
| Important potential risks | Liver injury Potential risk of bleeding or thrombosis due to overdose or underdose |
| Missing information | Use in patients with severe renal impairment |
Pharmacovigilance Plan
Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.
Risk minimisation measures
| Safety concern | Risk minimisation measures | Pharmacovigilance activities |
| Bleeding | Routine risk minimisation measures: SmPC sections 4.2, 4.3, 4.4, 4.5, 4.8 and 4.9 Additional risk minimisation measures: Prescriber Guide | Routine pharmacovigilance activities beyond adverse reactions reporting and signal detection: Specific adverse reactions follow-up form Additional pharmacovigilance activities: None |
| Patient Alert Card | ||
| Liver Injury | Routine risk minimisation measures: SmPC Sections 4.2, 4.3, 4.4 and 4.8 Additional risk minimisation measures: None | Routine pharmacovigilance activities beyond adverse reactions reporting and signal detection: Specific adverse reactions follow-up form Additional pharmacovigilance activities: None |
| Potential risk of bleeding or thrombosis due to overdose or underdose | Routine risk minimisation measures: SmPC Sections 4.2 and 4.9 Additional risk minimisation measures: Prescriber Guide | Routine pharmacovigilance activities beyond adverse reactions reporting and signal detection: None Additional pharmacovigilance activities: None |
| Use in patients with severe renal impairment | Routine risk minimisation measures: SmPC Sections 4.2, 4.4 and 5.2 Additional risk minimisation measures: None | Routine pharmacovigilance activities beyond adverse reactions reporting and signal detection: None Additional pharmacovigilance activities: None |
Summary of the RMP
The summary of safety concerns is in line with the summary of safety concerns in the RMP for the reference medicinal product.
Routine pharmacovigilance is suggested, and no additional pharmacovigilance activities are proposed by the applicant, which is considered acceptable. In line with the RMP for the reference medicinal product, the applicant has established specific adverse drug reactions follow-up forms for bleeding and liver events as a tool of routine pharmacovigilance, which is endorsed.
Proposed additional risk minimisation measures include the Patient Alert Card and Prescriber Guide. The key elements of the proposed additional risk minimisation measures are in line with those of the reference medicinal product. The future MAH shall agree the content and format of the Prescriber Guide, together with a communication plan, with the national competent authority in each Member State prior to distribution of the educational pack in their territory. The Patient Alert Card has to be included in each medicinal product pack.
The submitted Risk Management Plan is considered acceptable.
The future MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in the dossier of the Marketing Authorisation and any agreed subsequent updates of the RMP.
An updated RMP should be submitted:
At the request of the RMS Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.With regard to PSUR submission, the MAH should take the following into account:
PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification.The common renewal date is 18.01.2028.
Medicinal product subject to medical prescription.
The results of this test indicate that the PIL is well structured and organised, easy to understand and written in a comprehensible manner. The test shows that the leaflet is readable and patients/users are able to act upon the information that it contains.
Acceptable readability of the package leaflet is shown.
Regarding clinical aspects, the application contains an adequate review of published clinical data.
– Bioequivalence to the reference product has been demonstrated for the 5 mg strength.
– Extrapolation of the results of the BE study with 5 mg to the 2,5 mg strength is sufficiently justified.
Regarding the quality aspects, the application contains full dossier with drug substance as well as drug product dossier. The dossier is acceptable and marketing authorization can be granted in view of pharmaceutical quality.
The application is approved. For intermediate amendments, see the current product information.