Zusammenfassung der Merkmale des Arzneimittels - Rivaroxaban HEC Pharm 20 mg Filmtabletten
ADMINISTRATIVE INFORMATION
| Proposed name of the medicinal product(s) in the RMS | Rivaroxaban HEC Pharm 10 mg, 15mg, 20mg Filmtabletten |
| Name of the drug substance (INN name): | Rivaroxaban |
| Pharmaco-therapeutic group (ATC Code): | B01AF01 |
| Pharmaceutical form(s) and strength(s): | Film-coated tablet |
| Reference Number(s) for the Decentralised Procedure | DE/H/6415/001–003/DC |
| Reference Member State: | DE |
| Member States concerned: | ES, FR and IT |
| Legal basis of application: | Generic Art 10.1 Dir 2001/83/EC |
| Marketing Authorisation Holder (name and address) | HEC Pharm GmbH Gabriele-Tergit-Promenade 17 D-10963 Berlin Germany |
| Names and addresses of all manufacturer(s) responsible for batch release in the EEA | Formula Pharmazeutische und chemische Entwicklungs GmbH Goerzallee 305 b D-14167 Berlin |
Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Rivaroxaban HEC 10 mg, 15mg and 20 mg Filmtabletten, in the treatment of the following indications:
10 mg:
Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery.
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.)
15 mg and 20 mg:
15 mg and 20 mg:Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack.
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
This is a generic application.
II.2 About the product
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated factor II) and no effects on platelets have been demonstrated.
The therapeutic indications are:
10 mg:
Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.
15 mg and 20 mg:
15 mg and 20 mg:Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.
For details on posology, clinical efficacy and safety and on PK in special populations, it is referred to the SmPCs.
II.3 General comments on the submitted dossier
This decentralised application is submitted in accordance with Article 10(1) of directive 2001/83/EC.
With Germany as the Reference Member State in this decentralized procedure, the applicant applied for the marketing authorisations for Rivaroxaban HEC 10 mg, 15 mg and 20 mg Filmtabletten in ES, FR and IT.
The active substance is not considered a new active substance.
To support this application, the results of two bioequivalence studies have been submitted:
Study 1: An open label, balanced, randomized, two-treatment, two-sequence, two-period, cross-over, single-dose, oral bioequivalence study of Rivaroxaban Tablets, 10 mg (Test) of HEC Pharm GmbH., and Xarelto® Filmtabletten Rivaroxaban 10 mg (Reference) of Bayer Pharma AG, in healthy, adult human subjects under fasting conditions.
Study 2: An open label, balanced, randomized, two-treatment, two-sequence, two-period, cross-over, single-dose, oral bioequivalence study of Rivaroxaban Tablets, 20 mg (Test) of HEC Pharm GmbH, and Xarelto® Filmtabletten Rivaroxaban 20 mg (Reference) of Bayer Pharma AG, in healthy, adult human subjects under fed conditions.
Submission of two single-dose studies with two strengths (10 mg and 20 mg) is adequate, because these studies are also recommended by the rivaroxaban product-specific bioequivalence guidance (EMA/CHMP/160650/2016). The study with the 10 mg dose (Study 1) was conducted under fasting conditions, while the study with the 20 mg dose (Study 2) was performed under fed conditions. This corresponds to the recommendations of the product-specific bioequivalence guidance for rivaroxaban (different food effect for lower and higher strengths; fasted study required for for 2.5 mg and 10 mg, but fed conditions necessary for 15 mg and 20 mg).
A biowaiver is requested for the 15 mg strength.
European Reference Product
The European reference product is Xarelto (10 mg, 15 mg and 20 mg film-coated tablets) marketed by Bayer Pharma AG., registered since 30/09/2008 (marketing authorization numbers: 10 mg: EU/1/08/472/001–010, 022, 042–045; 15 mg: EU/1/08/472/011–016, 023, 036, 038, 048 and 20 mg: EU/1/08/472/017–021, 024, 037, 039, 049).
No scientific advice was given to the applicant. The applicant followed the CHMP guidance documents (CPMP/QWP/EWP/1401/98 Rev. 1, January 2010 (bioequivalence guideline).
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, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites.
GMP active substance
Regarding the statement on GMP for the active substance, a statement/declaration is provided from the manufacturer responsible batch release of the finished product situated in the EU.
Clinical:
A statement on the application of appropriate GCP standards in the submitted studies has been provided. Inspection reports did not reveal critical findings. During assessment, no issue of GCP noncompliance arose.
The Applicant provided a full dossier including full drug substance as well as drug product information for immediate release film-coated tablets 10 mg, 15 mg or 20 mg containing Rivaroxaban as active substance.
Meanwhile, a Ph.Eur. monograph exists for rivaroxaban drug substance. The API manufacturer updated the dossier accordingly. Ph.Eur. monograph has sufficiently implemented and changes are fully justified.
Nomenclature and structure have been satisfactorily described and relevant physical-chemical properties have been sufficiently presented.
GMP compliance for the current manufacturing site has been demonstrated.
A suitable TSE declaration is included in the dossier confirming that the drug substance is of synthetic orgin.
The reaction scheme, a flow diagram and a description of the manufacturing process is provided. Reagents and solvents are included.
The synthesis of the drug product Rivaroxaban has been described in 5 steps, four reaction steps and one purification steps. Three starting materials have been defined and are acceptable. Potential formation of N-nitrosamines in the manufacturing process has been sufficiently discussed and test results of NDMA in representative batches confirm that NDMA could not be detected. This is sufficient.
Rivaroxaban has been sufficiently characterized. Rivaroxaban contains one stereogenic center. The enantiomer produced by Ruyuan HEC is the (S)-configuration. Rivaroxaban exhibits polymorphism. The manufacturing process consistently leads to Modification 1. Polymorphic form is controlled in the drug substance specification by XRD pattern.
Structure of Rivaroxaban has been confirmed.
Potential impurities have been comprehensively discussed; potential genotoxic impurities are suitably addressed now. All impurities from Ph.Eur transparency list have been investigated.
Acetic acid used in the manufacturing process is specified in the drug substance as residual solvent with suitable limit according to Ph. Eur. 5.4 requirements.
Particle size distribution is included in the API specification of the finished product manufacturer. Micronization process is described and validated.
Analytical methods for the test parameters have been described in detail. The validation data provided are in accordance with the requirements of the relevant ICH guidelines and acceptable.
Additional batch analysis data are presented and confirm batch to batch consistency and the suitability of the updated specification.
Sufficient reference standards are used and Ph.Eur. standards are proposed wherever possible. However, the applicant is reminded that changes of reference standards need to be indicated by variation procedure.
The Container closure system is sufficiently described and of sufficient quality.
Stability studies have been performed in line with CPMP/QWP/122/02, rev 1 corr and re-test period of 36 months is acceptable. Photostability has been shown in forced degradation studies.
A suitable stability commitment and stability protocol is presented.
The proposed generic product Rivaroxaban HEC Pharm 10 mg, 15 mg and 20 mg Filmtablettents is identical in the active substance as well as in the dosage form (film-coated tablets) to the originator product Xarelto 10 mg, 15 mg & 20 mg film-coated tablets (Bayer Pharma AG).
An extensive pharmaceutical development program has been presented. The development report summarizes the development of the three proposed strengths of the generic product Rivaroxaban HEC Pharm 10 mg, 15 mg and 20 mg Filmtabletten. Two BE studies were performed with 10 mg and 20 mg strengths and a biowaiver is requested for 15 mg strengths. In-vitro dissolution profiles are presented. BE has been shown and biowaiver is acceptable. Here, reference is made to the clinical assessment for details.
A suitable dissolution method in line with FDA recommendation is developed and justified.
For the crushed tablets to be administered through gastric tubes, suitable data are presented.
The manufacturing process for 10mg tablets is not completely identical to that one for 15 mg and 20 mg tablets. The differences in process parameters are sufficiently detailed and IPCs are suitable.
The manufacturing process has sufficiently been validated. The investigated submission batches are of same size as the proposed commercial production scale batches. This is acceptable and no commitment on further process validation is needed.
Confirmation is given that the shelf-life will be calculated in accordance with the Note for Guidance on start of shelf-life of the finished product (CPMP/QWP/072/96).
The excipients are suitable, functionality-related characteristics are included in the respective specifications.
The product specifications cover appropriate parameters for this dosage form and has been brought in line with Ph. Eur. monograph “rivaroxaban tablets”. Limits for dissolution, related substances and assay are adequate. Hardness and average mass are controlled within the manufacturing process as IPC. Loss on drying and dimension have been included in specification additionally.
Analytical methods are suitably described and validated.
Batch analysis data are presented for three submission (=commercial) scale batches including biobatches for 10 mg and 20 mg strength and confirm compliance with drug product specification. This is acceptable.
Potential impurities have been adequately addressed. Nitrosamine risk assessment has been presented considering drug substance, excipients, manufacturing equipment and process and environment, container closure system. Overall, low risk for nitrosamine formation was concluded and is considered plausible.
Reference standards are identical to the standards used for API.
The presented stability studies (photo, bulk and product) are in accordance with the respective stability guideline and support the proposed shelf-life of 24 months.
The application is approvable from quality perspective.
I II.2 Non-clinical aspects
Pharmacodynamic, pharmacokinetic and toxicological properties of rivaroxaban are well known. As rivaroxaban 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 is dated 10 August 2019. The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.
Since Rivaroxaban HEC is a generic product, it 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 Rivaroxaban HEC from a non-clinical point of view.
I II.3 Clinical aspects
To support the application, the applicant has submitted as report two bioequivalence studies conducted with the 10 mg and 20 mg dose strengths. For Rivaroxaban HEC 15 mg a biowaiver was requested.
Study 1 An open label, balanced, randomized, two-treatment, two-sequence, two-period, cross-over, single-dose, oral bioequivalence study of Rivaroxaban Tablets, 10 mg (Test) of HEC Pharm GmbH., and Xarelto® Filmtabletten Rivaroxaban 10 mg (Reference) of Bayer Pharma AG, in healthy, adult human subjects under fasting conditions.
The mean pharmacokinetic parameters of Rivaroxaban for reference product ® and test product (T) are summarised in the following tables:
Descriptive Statistics of Formulation Means for Rivaroxaban (N=36)
| Parameter (Unit) | Mean ± SD (Based on un-transformed data) (CV%) | |
| Reference Product ® | Test Product (T) | |
| C™s(ng/niL) | 201.592 ±58.4472 (29.0) | 190.384 ± 57.3488 (30.1) |
| AUCo., (hr. ng/mL) | 1700.873 ±427.2428 (25.1) | 1716.877 ±487.9291 (28.4) |
| AUC0^ (la. ng/iiiL) | 1763.957 ±414.2530 (23.5) | 1772.424 = 475.9893 (26.9) |
| AUC ^Extrapolation | 3.909 ±3.5177 (90.0) | 3.535 ±3.2665 (92.4) |
| Mln')* | 2.50 (0.25–5.00) | 2.50 (O.5O-5.OO) |
| ^(la1) | 0.10824 ±0.023764 (22.0) | 0.10465 ±0.023812 (22.8) |
| (la) | 6.731 ± 1.5865 (23.6) | 7.020± 1.9144 (27.3) |
*For Tmal Median has been represented instead of Mean and Range instead ofSD.
Geometric Least Square Mean, Ratios and 90% Confidence Interval for Rivaroxaban
| Parameter | (Ln-transformed) Geometric Least Square Mean (N=36) | 90% Confidence Interval T vs R (%) | Intra Subject CV(%) | Power (%) | ||
| Test Product (T) | Reference Product ® | Ratio (T/R)% | ||||
| max | 181.9811 | 193.4721 | 94.06 | 87.02–101.67 | 19.7 | 100 |
| AUG, | 1646.6058 | 1647.5116 | 99.95 | 95.52–104.58 | 11.4 | 100 |
The 90% confidence intervals for geometric least square mean ratios of ln-transformed data of Cmax and AUC0-t of Rivaroxaban were within the bioequivalence acceptance range (80.00–125.00%).
Based on these results, Rivaroxaban Tablets, 10 mg (Test) of HEC Pharm was bioequivalent with that of Xarelto® Filmtabletten Rivaroxaban 10 mg (Reference) of Bayer Pharma AG in healthy, adult human subjects under fasting conditions.
Study 2 : An open label, balanced, randomized, two-treatment, two-sequence, two-period, cross-over, single-dose, oral bioequivalence study of Rivaroxaban Tablets, 20 mg (Test) of HEC Pharm GmbH, and Xarelto® Filmtabletten Rivaroxaban 20 mg (Reference) of Bayer Pharma AG, in healthy, adult human subjects under fed conditions.
The mean pharmacokinetic parameters of Rivaroxaban for reference product ® and test product (T) are summarised in the following tables:
Descriptive Statistics of Formulation Means for Rivaroxaban (N=22)
| Parameter (Unit) | Mean ± SD (Based on un-transformed data) | |
| Reference Product ® | Test Product (T) | |
| C,^ (ng/mL) | 348.305i82.5468 | 3 3 8.467i76.9927 |
| AUCo_t (hr. ng/mL) | 3089.512±734.3746 | 3015.327i678.7187 |
| AUC^ (hr. ng/mL) | 3135.36Ü726.7585 | 3062.059i680.4814 |
| AITC ’/(»Extrapolation | 1.565Ü.4917 | 1.595i0.8544 |
| (hr)* | 4.00(1.00–5.00) | 4.00(1.50–5.00) |
| Kei (hl1) | 0.12597i0.019097 | 0.12210i0.020714 |
| L (hr) | 5.626i0.8601 | 5.825i0.9269 |
*For Tmm Median has been represented instead of Mean and Range instead of SD.
Geometric Least Square Mean. Ratios and 90% Confidence Interval for Rivaroxaban
| Parameters | Lntransforined Data | |||||
| Geometric Mean | (T/R) Ratio % | 90% Confidence Interval | Intra Subject CV (%) | Power (%) | ||
| Test-T | Reference -R | |||||
| C max | 330.1870 | 3 3 8.7409 | 97.47 | 93.90–101.18 | 7.2 | 100 |
| AUCot | 2948.3 799 | 3006.8400 | 98.06 | 93.79–102.51 | 8.6 | 100 |
The 90% confidence intervals for geometric least square mean ratios of ln-transformed data of Cmax and AUC0-t of Rivaroxaban were within the bioequivalence acceptance range (80.00–125.00%).
Based on these results, Rivaroxaban Tablets, 20 mg (Test) of HEC Pharm were bioequivalent with that of Xarelto® Filmtabletten Rivaroxaban 20 mg (Reference) of Bayer Pharma AG in healthy, adult human subjects under fed conditions.
A waiver of an in-vivo BE study is requested for Rivaroxaban HEC 15 mg. The waiver request is substantiated by the following:
a) Rivaroxaban HEC 15 mg and 20 mg Filmtabletten are manufactured by the same manufacturing process and the same manufacturer.
b) Proportional similarity of the formulations across strengths of Rivaroxaban HEC 15 mg and 20 mg Filmtabletten is met. The ratio of the amount of each ingredient to the amount of total core tablet or coating weight is the same for two strengths,
c) Acceptable in vitro dissolution testing of two strengths.
In section 4.2 of the SmPC it is stated (in line with the wording of the Reference product):
“For patients who are unable to swallow whole tablets, Rivaroxaban HEC tablet may be crushed and mixed with water or apple puree immediately prior to use and administered orally.
The crushed Rivaroxaban HEC tablet may also be given through gastric tubes after confirmation of the correct gastric placement of the tube. The crushed tablet should be administered in a small amount of water via a gastric tube after which it should be flushed with water (see section 5.2).”
In this context, the applicant was requested to provide appropriate data to demonstrate comparable properties of the test and reference product with regard to the passage of crushed and suspended tablets through differently sized nasogastric tubes. These in-vitro data have been submitted at day 120 of the DCP; these data resolved the issue.
Pharmacodynamics N/A
Clinical efficacy N/A
Clinical safety N/A
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 applicant has submitted a revised 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 Rivaroxaban HEC Pharm 10 mg/15 mg/20 mg Filmtabletten.
Safety specification
| Important identified risks | Haemorrhage |
| Important potential risks | Embryo-foetal toxicity |
| Missing information | Patients with severe renal impairment (CrCl < 30 mL/min) Patients receiving concomitant systemic inhibitors of CYP 3A4 or P-gp other than azole antimycotics (e.g. ketoconazole) and HIV-protease inhibitors (e.g. ritonavir) Remedial pro-coagulant therapy for excessive haemorrhage Pregnant or breast-feeding women Patients with atrial fibrillation (AF) and a prosthetic heart valve Long-term therapy with rivaroxaban in treatment of DVT, PE, SPAF and ACS in real-life setting Patients with significant liver diseases (severe hepatic impairment/Child Pugh C) |
Pharmacovigilance
Plan
Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant.
Risk minimisation measures
Additional risk minimisation measures are proposed for the important identified risk of haemorrhage (Prescriber Guide, Patient Alert Card). For other safety concerns, routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant.
Summary of the RMP
The summary of safety concerns is line with the RMP for the reference medicinal product.
No additional pharmacovigilance activities are proposed by the applicant, which is considered acceptable. The future MAH should monitor the outcomes of the additional pharmacovigilance activities that are in place for the reference medicinal product. In line with the RMP for the reference medicinal product, the applicant has established specific adverse reaction follow-up forms for liver-related adverse events, renal impairment/renal failure, severe hypersensitivity, and severe skin reactions as a tool of routine pharmacovigilance, which is endorsed.
Additional risk minimisation measures are proposed by the applicant for the important identified risk of haemorrhage (Prescriber Guide, Patient Alert Card), which is endorsed. The key elements are in line with the key elements of the additional risk minimisation measures that are in place for the reference medicinal product.
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 23.02.2027.
Medicinal product subject to medical prescription.
With the Response (day 106 of the procedure) the Applicant submitted the Outcome Report for a readability testing (dated 9.9.2020). Assessment of the User Testing is attached in the ‘QRD Guidance and Checklist for the Review of User Testing Results’. The requirements specified in Article 59(3) of Directive 2001/83/EC as amended by Directive 2004/27/EU are considered fulfilled by the Package Leaflet for Rivaroxaban HEC. Potential users could locate, understand and act upon the information contained in the leaflet.