Zusammenfassung der Merkmale des Arzneimittels - Everolimus Ascend 0,5 mg Tabletten
| Proposed name of the medicinal product in the RMS | Everolimus Ascend 0.25 mg Tabletten; Everolimus Ascend 0.5 mg Tabletten; Everolimus Ascend 0.75 mg Tabletten; Everolimus Ascend 1 mg Tabletten |
| Name of the drug substance (INN name): | Everolimus |
| Pharmaco-therapeutic group (ATC Code): | L04AA18 |
| Pharmaceutical form(s) and strength(s): | tablet |
| Reference Number(s) for the Decentralised Procedure | DE/H/7213/001–004/DC |
| Reference Member State: | DE |
| Concerned Member States: | MT |
| Legal basis of application: | Generic Art 10.1 Dir 2001/83/EC |
| Applicant (name and address) | Ascend GmbH Sebastian-Kneipp-Strasse 41 60439 Frankfurt Am Main Germany |
| Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA | Interpharma Services Ltd. 43A Cherni Vrach Blvd, Sofia, 1407 Bulgaria |
Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Everolimus Ascend 0.25, 0.5, 0.75 and 1 mg Tabletten, in the treatment of
Kidney and heart transplantation
Everolimus Ascend 0.25, 0.5, 0.75 and 1 mg Tabletten is indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving an allogeneic renal or cardiac transplant. In kidney and heart transplantation, <Invented name> should be used in combination with ciclosporin for microemulsion and corticosteroids.
Liver transplantation
Everolimus Ascend 0.25, 0.5, 0.75 and 1 mg Tabletten is indicated for the prophylaxis of organ rejection in adult patients receiving a hepatic transplant. In liver transplantation, Everolimus Ascend 0.25, 0.5, 0.75 and 1 mg Tabletten should be used in combination with tacrolimus and corticosteroids.
is approved.
II.1 Problem statement
N/A
II.2 About the product
Everolimus (ATC codes L01EG02 and L04AA18, mTOR inhibitor and selective immunosuppressants, respectively), prevents as aselective immunosuppressant allograft rejection in rodent and non-human primate models of allotransplantation. It exerts its immunosuppressive effect by inhibiting the proliferation, and thus clonal expansion, of antigen-activated T cells, which is driven by T cell-specific interleukins, e.g. interleukin-2 and interleukin-15. Everolimus inhibits an intracellular signalling pathway, which is triggered upon binding of these T cell growth factors to their respective receptors, and which normally leads to cell proliferation. The blockage of this signal by everolimus leads to an arrest of the cells at the G1 stage of the cell cycle.
At the molecular level, everolimus forms a complex with the cytoplasmic protein FKBP-12. In the presence of everolimus, the growth factor-stimulated phosphorylation of the p70 S6 kinase is inhibited. Since p70 S6 kinase phosphorylation is under the control of FRAP (also called mTOR), this finding suggests that the everolimus-FKBP-12 complex binds to and thus interferes with the function of FRAP. FRAP is a key regulatory protein that governs cell metabolism, growth and proliferation; disabling FRAP function thus explains the cell cycle arrest caused by everolimus.
Everolimus, if used as mTOR inhibitor, is in addition an anticancer substance used in solid tumours, including patients with tuberous sclerosis complex (TSC).
This MAA concerns everolimus used as selective immunosuppressant where everolimus is used typically at lower doses and in combination with a calcineurin inhibitor (CNI). The indications applied for, thus, are:
Kidney and heart transplantation
Everolimus Ascend 0.25, 0.5, 0.75 and 1 mg Tabletten is indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving an allogeneic renal or cardiac transplant. In kidney and heart transplantation, <Invented name> should be used in combination with ciclosporin for microemulsion and corticosteroids.
Liver transplantation
Everolimus Ascend 0.25, 0.5, 0.75 and 1 mg Tabletten is indicated for the prophylaxis of organ rejection in adult patients receiving a hepatic transplant. In liver transplantation, Everolimus Ascend 0.25, 0.5, 0.75 and 1 mg Tabletten should be used in combination with tacrolimus and corticosteroids.
II.3 General comments on the submitted dossier
This decentralised application concerns a generic version of everolimus. Claim is based on article 10(1) of Directive 2001/83/EC making reference to Certican (0.25 mg, 0.5 mg, 0.75 mg & 1 mg tablets) by Novartis Pharma GmbH, registered since 18.07.2003.
Based on the registration date of the reference, RMS does not consider everolimus as a NAS.
The updated document in the dossier summarizing the grounds and evidence used for demonstrating that the medicinal products are essentially similar to Certican (0.25 mg, 0.5 mg, 0.75 mg & 1 mg tablets) is discussing this generic application in relation to the product specific European BE guideline EMA/CHMP/151597/2015 (Everolimus tablets 0.25 mg, 0.5 mg, 0.75 mg and 1 mg; 2.5 mg, 5 mg and 10 mg, dispersible tablets 0.1 mg and 0.25 mg; 2 mg, 3 mg and 5 mg). Accordingly, the RMS is of the opinion that the bio-waiver of strength as applied for, and the number of 2 BE trials submitted, is well justified in the dossier as updated on request of the RMS.
A similarity report has not been provided because applicant considers such a report as not applicable. According to the application form and a check of the Community Register of orphan medicinal products there is no medicinal product designated as an orphan medicinal product for a condition relating to the indication proposed in this application.
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(s) responsible for manufacture of the finished product and batch release situated in the EU.
GCP
The applicant informs in the dossier that the clinical and analytical sites of both BE trials have been inspected. The outcomes of these inspections have been reported as requested (no critical findings).
III.1 Quality aspects
The chemical-pharmaceutical documentation in the dossier is of sufficient quality in view of the present European regulatory requirements.
Open Part
The active ingredient of Fehler! Verweisquelle konnte nicht gefunden werden. is Fehler! Verweisquelle konnte nicht gefunden werden. which is monographed in the European Pharmacopoeia.
The ASMF holder has submitted an Active Substance Master File (ASMF), consisting of an applicant’s and restricted Part.
Sirolimus is correctly defined as an intermediate, as it does not meet the ICH Q11 definition for a starting material. The details can be found in the restricted part. The information on the manufacturing process, as provided in the applicant’s part of the ASMF is considered sufficient.
Satisfactory details related to the elucidation of structure and other characteristics have been provided.
All impurities of the manufacturing process have been discussed in detail.
The analytical methods for routine control of the active substance are adequately described in the dossier. Results of forced degradation studies have been provided in the dossier; from the provided results it can be concluded that the methods for assay, related substances and BHT content, are stability indicating (purity threshold > purity angle) and a good mass balance was observed.
The determined LOQs for the specified impurities and unidentified impurities by the HPLC method for related substances are below the reporting threshold of 0.05% and are acceptable.
All batches comply with the proposed specification as presented in S.4.1. The drug substance manufacturer demonstrated that Everolimus is consistently manufactured within tight quality margins. The batches manufactured with modified manufacturing process in 2021 comply with specifications.
Specifications have been sufficiently justified based on the Ph. Eur. Monograph. Additional in-house specifications have been established for identification, content of BHT, residual solvents, and microbial limits and are considered acceptable.
The content of BHT is higher than the content of BHT (0.2% according to the EPAR) in the drug substance used for the reference product Afinitor. The applicant confirmed that the amount of BHT is critical for the stability of the drug substance in the response to previous ASMF versions and in the restricted part. The content of 2% BHT is accepted.
CoAs for the Laboratory standard and the impurity standards have been included in this section. The provided information on the reference standards is sufficient.
The primary packaging material and procedure is described in detail, specifications of all components are provided and compliance certificates are presented. The suitability of the container closure system is confirmed by stability studies.
No clear up- or downward trends are observed for any of the parameters, up to 24 months at all storage temperatures up to 25°C, only at higher temperatures (30°C and 40°C) increases in water content (OOS results) and unknown impurities are observed. Therefore the proposed retest period of two years, with the storage condition: “Store under Nitrogen in an air tight container protected from light below 25°C” can be accepted.
Nevertheless, present stability data of batches used to demonstrate stability after 24 months storage should be provided.
The post-approval stability commitment to submit ongoing stability data and place one batch per year on long-term stability studies is provided and accepted.
The open part of the ASMF is considered acceptable.
The composition of the drug product is satisfactorily described.
The drug substance is shortly described in the dossier. The excipients used are standard and commonly used in the pharmaceutical industry. Their chose have been justified.
A drug excipients compatibility study has been conducted with the result that no significant difference in assay and total impurity in drug excipient combination at 40°C/75%RH up to 4 week at open and closed condition could be observed.
The drug product has been developed as a generic version of the originator product Certican® from Novartis Pharma GmbH. (MA no.: 58387.01.00, 04.02.2004 (DE)).
The development of the formulation has been sufficiently described. The dissolution method has been investigated sufficiently, the discriminatory power of the method used in the QC has been shown.
The choice of the bio batch is acceptable. The development of the formulation has been sufficiently described. The acceptance of a biowaiver has been investigated. The extrapolation of the results from the bioequivalence studies performed to the lower strengths is accepted.
The development of the formulation has been described in detail.
The batch formulas provided are in accordance with the composition documented in the dossier. The manufacturing process and the stability performance of the formulation do not require the use of an overage. The manufacturing process is described including conditions/parameters and equipment used. Holding times have been addressed; stability data are not necessary. A statement about the start of the shelf-life has been provided.
The process validation data provided for three commercial batches of each strength indicate a robust and reproducible manufacturing process.
All excipients used in manufacturing of Everolimus tablets are standard excipient in manufacturing of tablets and of compendial (Ph. Eur.) grade and will be tested according the current edition of the Ph. Eur. Based on the information provided together with the CoAs, some specific functional parameters have been additionally specified by the manufacturer of the final medicinal product or the supplier of the excipient. The specifications have been adequately addressed.
The release and shelf life specifications presented cover relevant parameters for this dosage forms and are suitable to control the quality of the drug products.
Analytical methods for the test parameters have been described in detail methods including the principle of the method, the equipment parameters, the sample and standard preparation, the calculation formula, and a System Suitability Test. The applied methods are in accordance with current technical and scientific requirements.
Chromatograms have been presented which show the specificity/selectivity of the chromatographic methods used.
The precision of the assay method (variation coefficient) should be lower than 1/6 of the variation coefficient of the assay. The criterion of precision in the assay method has been set to 1.7 %, the SST is therefore sufficient.
The validation data provided are in accordance with the requirements of the relevant ICH guidelines. Additionally, sufficient results of the SST used have been presented for all validated methods. Satisfactory batch analyses have been presented. The batch analyses data together with the results obtained from the validation of the manufacturing process, stability testing confirm consistency and uniformity of the product based on the parameters tested and indicate the reproducibility of the manufacturing process for the drug product.
The degradation impurities have been sufficiently characterized.
An Elemental Impurities Risk Assessment performed by the proposed Drug Product Manufacturer, in line with the guideline ICH Q3D – Guideline “For Elemental Impurities” has been presented.
After a product risk assessment, one batch of each strength have been tested for metals. All batches comply with specification that each elemental impurity is below the 30% of the PDE. The results of the analysis of the batches (drug product approach) are in concordance with the component approach estimated calculation. Once completed the risk assessment, no extra controls or actions are required.
A Nitrosamine Risk assessment of Everolimus tablets is carried out based on evaluation of drug substance, inactive ingredients and container closure system and assessment report is provided. The conclusion is that Everolimus Tablets is free from Nitrosamine impurities.
The suitability of the reference standards has been shown.
The applied primary packaging systems are standard for solid oral formulations. The provided specifications and information for the proposed container closure systems are considered as sufficient.
The conditions used in the stability studies are according to the ICH stability guideline. The drug products control tests and specifications are adequately set.
Data of stability testing in accordance with ICH requirements at long-term, and accelerated conditions have been provided for min. three validation scale batches. Additionally, for one batch, results obtained under intermediate conditions have been presented. The tablets are packed in Alu-Alu desiccant blisters; and additionally for 1 mg tablets in Alu-Alu blisters and HDPE bottles.
So far, stability data up to 24 at long term and 6 months at accelerated conditions are available. Stability studies at long-term conditions are ongoing.
No significant change can be observed at each storage condition. Stability results for all tablet strengths are comparable and remain well within their specified limits, with the exception of one results for Everolimus-19-ene open ring. The justification is acceptable.
Based on the outcome of photo-stability studies in compliance with CPMP/ICH/279/95, the DPM considers that Everolimus tablets are photo-stable.
For in-use testing, results of one 1 mg batch at long-term conditions for 90 days are provided. The testing scheme is acceptable. During the testing period, no significant change of any parameter tested can be observed. Whereas, in-use stability has been demonstrated for samples at conditioned conditions (long-term conditions) in-use stability at humid conditions (e.g. simulating storage in bathroom, kitchen) is not demonstrated. Therefore, the following specific instruction after first opening has been inlcuded: „After first opening keep the bottle tightly closed and store at dry conditions”.
III.2 Non clinical aspects
Pharmacodynamic, pharmacokinetic and toxicological properties of everolimus are well known. As everolimus is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate.
Since Everolimus Ascend 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.
III.3 Clinical aspects
The analytical method to quantify everolimus concentration in plasma by using a validated method was developed and validated for at the bioanalytical. The analytical method for the determination of everolimus was overall adequately validated and conducted.
Results of 2 BE trials (Study 1 [fast] and Study 2 [fed]) have been submitted and are summarized below:
Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max
median, range); fast (study 1)
| Treatment | AUC 0–72h ng/ml/h | AUC 0-∞ xg/ml/h | C max xg/ml | t max h |
| Test | 81.5004 | See AUC0–72h | 11.1156 | 0.750 (0.50 – 2.00) |
| Reference | 81.5996 | See AUC0–72h | 11.5915 | 0.750 |
| (0.50 – 2.50) | ||||
| *Ratio (90% CI) | 99.88 (94.83–105.19) | See AUC0–72h | 95.89 (90.45–101.66) | Not calculated |
| AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0–72h canbe reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products AUC 0-∞ Area under the plasma concentration curve extrapolated to infinite time. AUC0-∞ does not need to be reported when AUC0–72h is reported instead of AUC0-t C max Maximum plasma concentration t max Time until Cmax is reached | ||||
*ln-transformed values
Table 2. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max
median, range); fed (study 2)
| Treatment | AUC 0–72h ng/ml/h | AUC 0-∞ xg/ml/h | C max ng/ml | t max h |
| Test | 83.4245 | See AUC0–72h | 5.2422 | 3.165 (1.00 – 7.00) |
| Reference | 83.2079 | See AUC0–72h | 5.3442 | 3.330 (1.00 – 5.00) |
| *Ratio (90% CI) | 99.88 (94.76–102.19) | See AUC0–72h | 98.43 (92.56– 104.67) | Not calculated |
| AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0–72h canbe reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products AUC 0-∞ Area under the plasma concentration curve extrapolated to infinite time. AUC0-∞ does not need to be reported when AUC0–72h is reported instead of AUC0-t C max Maximum plasma concentration t max Time until Cmax is reached | ||||
*ln-transformed values
On request, the applicant has provided median and range for tmax (test and reference). Median (and range) for the ratios can be but can be extracted from tables 3 and 4 of the response to this clarification request.
With reference to the product specific BE guideline EMA/CHMP/151597/2015 it is agreed that the results of study 1 and 2 with 1.0 mg formulation can be extrapolated to other (immediate release) strengths (i.e. 0.25, 0.5, and 0.75 mg). The applicant has made this clear in an updated dossier.
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The Applicant has submitted a signed Summary of the Applicant'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 MAA 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 the medicinal product(s) applied for authorisation.
Safety SpecificationAccording to the Applicant, the safety specification is in full accordance with the current safety specification agreed and published for a similar product/similar products, which is acceptable.
Pharmacovigilance planAccording to the Applicant, the pharmacovigilance plan is in full accordance with already authorised RMP(s), which is acceptable.
Plans for post-authorisation efficacy studiesAccording to the Applicant, there are no plans for post-authorisation efficacy studies, which is acceptable.
Risk minimisation measuresAccording to the Applicant, the risk minimisation measures are in full accordance with already authorised RMP(s), which is acceptable.
Summary of activities in the risk management plan by medicinal productAccording to the Applicant, the provided summary of activities in the risk management plan by medicinal product is in full accordance with already authorised RMP(s), which is acceptable.
The submitted Risk Management Plan is considered acceptable.
After approval, the 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.
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.
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.
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.
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.Everolimus Ascend
DE/H/7213/001–004/DC Public Assessment Report Page 10/11
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.Common renewal date
The common renewal date is 13.01.2028.
Legal Status
Medicinal product subject to medical prescription.
User Testing
The user testing is accepted.