Zusammenfassung der Merkmale des Arzneimittels - Dapagliflozin Ascend 5 mg Filmtabletten
Decentralised Procedure
Dapagliflozin Ascend 5 mg Filmtabletten Dapagliflozin Ascend 10 mg Filmtabletten Procedure-Number: DE/H/6969/001–002/DC
Active Substance: Dapagliflozin
Dosage Form:
Film-coated tablet
Applicant:
Ascend GmbH
Publication:
Xxxxxxxx
This module reflects the scientific discussion for the approval of the above-mentioned procedure. The procedure was finalised on 23.08.2023.
V RECOMMENDED CONDITIONS FOR MARKETING AUTHORISATION AND PRODUCT
V.1 Proposed list of recommendations not falling under Article 21a/22 of Directive
| Proposed name of the medicinal product in the RMS | Dapagliflozin Ascend 5 mg Filmtabletten; Dapagliflozin Ascend 10 mg Filmtabletten |
| Name of the drug substance (INN name): | Dapagliflozin |
| Pharmaco-therapeutic group (ATC Code): | A10BK01 |
| Pharmaceutical form(s) and strength(s): | 5 mg & 10 mg film coated tablet |
| Reference Number(s) for the Decentralised Procedure | DE/H/6969/001–002/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 Dapagliflozin Ascend 5 mg and 10 mg Filmtabletten in the treatment of (indication wording as currently proposed by the Applicant)
For 5 mg and 10 mg strength:
Type 2 diabetes mellitus: Dapagliflozin is indicated in adults for the treatment of insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise
- as monotherapy when metformin is considered inappropriate due to intolerance.
- in addition to other medicinal products for the treatment of type 2 diabetes.
is approved.
II.1 Problem statement
For generic application, this section is not applicable.
II.2 About the product
Dapagliflozin is an anti-diabetic. It is a reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2) that improves glycaemic control in patients with type 2 diabetes mellitus by reducing renal glucose reabsorption leading to urinary excretion of excess glucose (glucuresis).
Dapaglifozin is classified under blood glucose lowering drugs / Sodium-glucose co-transporter 2 (SGLT2) inhibitors (ATC code: A10BK01).
Dapagliflozin is recommended for treatment of Type 2 (5 mg and 10 mg strength) diabetes mellitus:
Type 2 diabetes mellitus: Dapagliflozin is indicated in adults and children aged 10 years and above for the treatment of insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise – as monotherapy when metformin is considered inappropriate due to intolerance.
- in addition to other medicinal products for the treatment of type 2 diabetes.
For more detailed information on Dapagliflozin, e.g. posology and recommendation for use, the reader is kindly referred to the clinical assessment report as well as the clinical overview submitted by the applicant.
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 RMS and with Malta as CMS.
The active substance is not considered a new active substance.
In the dossier, the applicant states that the product applied for is a generic version of the reference medicinal product Forxiga, showing the same qualitative and quantitative composition in terms of active substance(s) and the same pharmaceutical form (immediate release tablets).
AstraZeneca has taken the decision to remove the T1DM indication for dapagliflozin. Other dapagliflozin 5 mg and 10 mg indications are not affected by this licensing change. Dapagliflozin remains authorised in adults for the treatment of type 2 diabetes mellitus, and for the treatment of symptomatic chronic heart failure with reduced ejection fraction.
The CHMP agreed to the removal of the T1DM indication in the type II variation procedure (EMEA/H/C/002322/II/0071; opinion 16.9.2021), which was also adopted for the generic product.
One (1) bioequivalence study was conducted. The study was an open label, balanced, pivotal, laboratory blinded, randomized, four period, two treatment, two sequence, single dose, fully replicated crossover, bioequivalence study of Dapagliflozin tablets 10 mg with Forxiga 10 mg (Dapagliflozin) tablets in healthy adult male human subjects under fasting condition.
A biowaiver for an additional 5 mg strength was requested based on linearity of PK of dapagliflozin in line with “Guideline on the Investigation on Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **), 2010, Committee for Medicinal Products for Human Use CHMP), European Medicines Agency, London, UK.
No scientific advice has been given related to this product. For a generic application, a PIP is not required.
The applicant has not provided a similarity report in the dossier. 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.
The applicant has submitted an RMP for dapagliflozin.
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.
Clinical GCP/GLP:
According to the applicant, the bioequivalence study was performed according to GCP and GLP standards. The assessment did not reveal concerns that might trigger an inspection.
III.1 Quality aspects
Drug substance
The drug substance dapagliflozin used for the manufacture of the drug product Dapagliflozin 5 mg Filmtabeltten; 10 mg Filmtabletten is not monographed in the Ph. Eur..
The active substance Dapagliflozin is a known active substance, which is not the subject of a pharmacopoeial monograph. The ASMF procedure has been used for this application.
The quality of the drug substances is confirmed by the ASMF of the ASMF holder and by the applicant’s drug substance dossier.
Dapagliflozin Ascend
DE/H/6969/001–002/DC Public Assessment Report Page 5/11
Regarding ASMF, all major objections and other concerns have been resolved meanwhile. Stability studies have been performed with the drug substance by the ASM. One significant change for the parameter content of water under accelerated conditions was observed.
Drug ProductThe drug product is a film-coated tablet.
The development of the product has been described, the choice of excipients is justified and their functions explained. The applicant has based their formulation on that of the reference product; Forxiga® 10 mg (Dapagliflozin) film coated tablets. The excipients used are well known, Ph. Eur. Grade excipients with the exception of the film-coating. The drug product is manufactured using wet granulation followed by drying, lubrication, compression and film-coating.
The manufacturing process has been outlined and validated for three batches of each strength at the proposed industrial scale.
The product specifications cover appropriate parameters for this dosage form. The requirement of an assay 95%-105% according with the directive 2001/83/EC has been presented after request.
Description and validations of the analytical methods have been presented. Batch analysis has been performed on three batches of each strength. The batch analysis results show that the finished products meet the specifications proposed.
The container closure system is an Alu-Alu blister and is similar to that of the reference product. Appropriate specification is in place for the packaging materials. The applicant has confirmed that nitrocellulosefree packaging material will be used in the future.
The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for drug product are adequately drawn up. The proposed shelf-life of 36 months can be accepted. The proposed storage statement that the product does not require any special storage conditions is endorsed.
III.2 Non clinical aspectsPharmacodynamic, pharmacokinetic and toxicological properties of dapagliflozin are well known. As dapagliflozin 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.
Environmental Risk Assessment (ERA):
Since Dapagliflozin Ascend 5 mg and 10 mg Filmtabletten 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 Dapagliflozin Ascend 5 mg and 10 mg Filmtabletten from a non-clinical point of view.
III.3 Clinical aspects
Pharmacokinetics
SmPC and PL are in accordance with the innovator’s SmPC (Forxiga, AstraZeneca GmbH).
Clinical Studies:
To support the application, the applicant has submitted the results of one (1) bioequivalence (BE) study comparing the applicant’s product with the corresponding originator product of AstraZeneca GmbH:
The study was an open label, balanced, pivotal, laboratory blinded, randomized, four period, two treatment, two sequence, single dose, fully replicated crossover, bioequivalence study of Dapagliflozin tablets 10 mg with Forxiga 10 mg (Dapagliflozin) tablets in healthy adult male human subjects under fasting condition.
Results of the clinical study
Based on the results provided in the submitted BE study, Dapagliflozin tablets 10 mg and Forxiga® 10 mg (Dapagliflozin) tablets, Marketing Authorisation Holder AstraZeneca are considered bioequivalent with respect to the rate and extent to absorption in healthy adult male human subjects under single dose fasted condition (as set by EMA, Note for Guidance on The Investigation Of Bioequivalence, Committee for Medicinal Products for Human Use [CHMP], August, 2010).
Study (10 mg, fasted)
Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max median, range) (n=23)
*ln-
| Treatment | AUC0–48 h ng/ml | AUC0-∞ h ng/ml | C max ng/ml | t max h |
| Test | 599.86 ± 157.50 | 630.96 ± 159.63 | 119.92 ± 47.31 | 1.50 (0.33 – 4.50) |
| Reference | 597.51 ± 133.94 | 632.35 ± 138.33 | 107.22 ± 35.06 | 1.33 (0.33 – 4.50) |
| *Ratio (90% CI) | 99.52 (96.18 – 102.97) | --- | 108.73 (97.99 – 120.64) | --- |
| AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC 0-∞ Area under the plasma concentration curve extrapolated to infinite time. C max Maximum plasma concentration t max Time until Cmax is reached | ||||
transformed values
Figure 1: Linear (left) and semi log (right) graph depicting dapagliflozin plasma concentrations (ng/ml) from 0 to 48 h post-administration of 10 mg of dapagliflozin under fasted conditions (n=23)
The ratio AUC0-t/AUC0-∞ was >0.8 in all of the subjects. No pre-dose concentrations > 5% of Cmax were observed. In subjects 06 (period IV, reference), 21 (period IV, reference) and 27 (period I ,test), Cmax was the first point. A re-analysis of PK parameters Cmax and AUC0-t, excluding those three participants, provided results within 80% – 125% for Cmax and AUC0-t. Cmax was within the validated range for all subjects. No significant period, treatment, sequence or subject (sequence) effect was observed.
Biowaiver for the 5 mg strength formulation
The applicant claims for biowaiver for the dapagliflozin 5 mg formulation.
Comparative in-vitro dissolution studies were conducted under experimental conditions recommended by the EU bioequivalence guideline, i.e. use of a paddle apparatus with a volume of 900 ml and an agitation speed of 50 rpm, use of three different dissolution media at pH 1.2 , 4.5 and 6.8.
The provided in vitro release data suggest a sufficient similarity between the test product Dapagliflozin 5 mg tablets and the test product Dapagliflozin 10 mg tablets as well as the test product Dapagliflozin 10 mg tablets compared to the reference product Forxiga® (dapagliflozin) tablets 10 mg, since f2 is >50 in all cases.
Thus, the biowaiver for the 5 mg strength can be accepted.
For more details, the reader is kindly referred to the non-clinical/clinical AR.
PharmacodynamicsNo data were submitted. No data are demanded
Clinical efficacy
No data were submitted. No data are demanded.
Clinical safetyOne (1) adverse event (Sore Throat) was recorded in one (1) subject (#20), leading to the withdrawal of the subject from the study. The adverse event was moderate in intensity, considered not related to study drug and resolved without sequel. One (1) laboratory adverse event was observed (subject 28, high total white blood cell count). Lab adverse event was resolved in follow-up. No severe, serious or life-threatening adverse events were reported during the course of the study.
For more details, the reader is kindly referred to the study reports as well as the clinical assessment report.
No new safety information emerged during the study. No relevant imbalance in number and type of AEs was observed between the test and the reference arms.
Summary Pharmacovigilance systemThe 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/Rapporteur considers the Summary acceptable.
Risk Management PlanThe MAH has submitted an updated risk management plan for Dapagliflozin 5 mg and 10 mg Filmtabletten.
The RMP covers two products.
Safety specification
The MAH provided the following summary of safety concerns:
| Important identified risks | Diabetic Ketoacidosis including events with atypical presentation |
| Important potential risk | Liver injury Bladder cancer Breast cancer Prostate cancer Lower limb amputation |
| Missing information | Use in patients with NYHA class IV Long-term safety in the paediatric population (aged 10 years and above) |
The applicant revised the list of safety concerns as requested now including the missing information about use in patients with NYHA class IV and long-term safety in the paediatric population age 10 years and above.
Pharmacovigilance Plan
Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.
Specific adverse reaction follow-up questionnaires as part of the routine pharmacovigilance has been added for bladder cancer, breast cancer, prostate cancer, lower limb amputations, and ketoacidosis as requested and in line with the reference RMP.
Risk minimisation measures
Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed.
Summary of the RMP
The submitted Risk Management Plan is acceptable.
Periodic Safety Update Report (PSUR)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.Common Renewal DateThe commom renewal date is 23.08.2023.
Legal StatusMedicinal product subject to medical prescription.
User TestingThe applicant has provided an acceptable readability test.
Based on the results provided in the submitted BE study, Dapagliflozin tablets 10 mg are considered bioequivalent to Forxiga® 10 mg (Dapagliflozin) film coated tablets.
The Biowaiver for the 5 mg strength has been appropriately justified and can be granted.
From a clinical point of view, benefit-risk assessment for the 5 mg and 10 mg strength is positive.
The RMP version is acceptable.
For the quality documentation all concerns have been resolved. From a quality point of view, benefit-risk assessment for the 5 mg and 10 mg strength is positive.
The application is approved. For intermediate amendments, see the current product information.