Zusammenfassung der Merkmale des Arzneimittels - Tolvaptan Ascend 15 mg Tabletten
ADMINISTRATIVE INFORMATION
| Proposed name of the medicinal product(s) in the RMS | Tolvaptan Ascend 15 mg; 30 mg Tabletten |
| Name of the drug substance (INN name): | Tolvaptan |
| Pharmaco-therapeutic group (ATC Code): | C03XA01 |
| Pharmaceutical form(s) and strength(s): | Tablet |
| Reference Number(s) for the Decentralised Procedure | DE/H/6698/001–002/DC |
| Reference Member State: | DE |
| Member States concerned: | UK(NI) |
| 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 manufacturer(s) responsible for batch release in the EEA | MSK Pharmalogistic GmbH Donnersbergstraße 4 64646 Heppenheim (Bergstraße) Germany Interpharma Services Ltd. 43A Cherni Vrach Blvd Sofia, 1407 Bulgaria |
Based on the review of the data and the Applicant’s response to the questions raised by RMS and CMSs on quality, safety and efficacy, the RMS considers that the application for Tolvaptan Ascend 15 mg; 30 mg Tabletten in the indication
“Tolvaptan is indicated in adults for the treatment of hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion (SIADH)”
is approved provided that the applicant commits to perform a number of post authorisation follow- up measures to be reported back to the Member States within predefined timeframes.
A preliminary list of such follow-up measures are in section V of this report.
II.1 Problem statement
This is a generic application pursuant to Article 10(1) of Directive 2001/83/EC as amended.
II.2 About the product
Tolvaptan is a vasopressin antagonist that specifically blocks the binding of arginine vasopressin (AVP) at the V2 receptors of the distal portions of the nephron.
Claimed indication
“Tolvaptan is indicated in adults for the treatment of hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion (SIADH).”
II.3 General comments on the submitted dossier
The current applications for a marketing authorisation are submitted under Article 10(1) (so called “generic application”) of Directive 2001/83/EC as amended.
With Germany as the Reference Member State in this Decentralized Procedure, Ascend GmbH applied for the Marketing Authorisations for Tolvaptan in UK as CMS.
The originator product is Samsca® 15 mg and 30 mg tablets (tolvaptan 15 mg and 30 mg tablets) by Otsuka Pharmaceutical Netherlands B.V., registered since August 3, 2009 (marketing authorization number: EU/1/09/539/001–002).
Essential similarity between the two products is claimed. The indication applied for is the same as the one approved for the reference product.
One bioequivalence study (Study No: 1) with the tolvaptan 30 mg strength has been performed under fasting conditions. The reference product used in the bioequivalence study is Samsca® (tolvaptan) 30 mg tablets.
The application for marketing authorisation of the generic tolvaptan formulations is based on the submitted bioequivalence study demonstrating bioequivalence of the test product with the approved reference product under fasting conditions and thus to prove the surrogate of equivalent efficacy and safety of both products.
The Applicant has provided a Clinical Overview which is considered adequate and is based on comprehensive literature (18 publications). It provides a review of the findings on the pharmacodynamic and pharmacokinetic properties as well as the efficacy and safety of tolvaptan.
The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is considered adequate.
The active substance is not considered a new active substance.
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, except for the finished Product Manufacturer where the validity of the GMP certificate is still not proven. A commitment is presented in the section V.1 to this issue.
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.
GMP active substance
Regarding the statement on GMP for the active substance, a statement/declaration is provided from the manufacturers responsible for manufacture of the finished product and batch release situated in the EU.
According to the applicant the bioequivalence study (Study Code: 1) was conducted in accordance with IEC approved protocol and the requirements of the CDSCO (Central Drugs Standard Control Organization), New Drugs and Clinical Trials Rules 2019 [Gazette notification G.S.R.227(E), Dated 19.03.2019], Ministery of health and familiy welfare, Government of India, Ethical guidelines for biomedical research on human participants, ICMR (Indian Council of Medical Research (2006), ICH (International Conference on Harmonization) E6 (R2) ”Guideline for Good Clincial Practice”, Declaration of Helsinki (2013, Brazil) and EMA guidelines.
During assessment, no issue of GCP non-compliance was detected.
The clinical, bioanalytical and PK/statistical study sites have been previously inspected by the competent European Authority MHRA-UK.
The applicant has submitted the inspection report concerning clinical, bioanalytical and PK/statistical study sites conducted by the MHRA. There were no critical or major findings identified during this inspection. The data are reliable and can be used for supporting the applications.
III.1 Quality aspects
The applicant Ascend GmbH has filed Tolvaptan ASMF. Previously identified major objections on the AP and RP of the ASMF have been solved so far, but some other concerns on the AP and RP of the ASMF should still be resolved. As requested, molecular identity of the API and of the SM 2-Methyl-4-nitro benzoyl chloride have been proven sufficiently now. Except for minor points on documentation, adequate control strategies for potential mutagenic impurities 4-Nitro-ortho-xylene and MeCl in the SM
2-Methyl-4-nitro benzoyl chloride have been presented as requested. Please refer to the corresponding ARs for detailed information.
Regarding the dossier, no questions remain to be resolved so far.
The chemical-pharmaceutical documentation and Quality Overall Summary in relation to Tolvaptan Ascend 15 mg; 30 mg are of sufficient quality in view of the present European regulatory requirements.
The control tests and specifications for drug substance are adequately drawn up.
Stability studies have been performed with the drug substance showing no significant changes in any parameter so far. Photo-stability study on the API in accordance with the ICH Q1B Guideline has been presented. The proposed retest period of 48 months with the proposed storage condition is justified.
Previously identified major objections in the dossier and on the drug product have been resolved sufficiently. All outstanding issues are resolved for the drug product. Please refer to the corresponding Quality AR for detailed information.
The development of the product has been described, the choice of excipients is justified and their functions explained.
The product specifications do cover all parameters for this dosage form. Residual solvents Ethanol and Dichlormethane are controlled sufficiently by IPC. Validations of the analytical methods have been presented sufficiently so far. Batch analysis has been performed. The batch analysis results show that the finished products meet the specifications proposed so far.
The conditions used in the stability studies are according to the ICH stability guidelines, including photostability. The control tests and specifications for shelf life of the drug product are adequately drawn up with regard control of elemental impurities. Regarding risk evaluation/assessment on N-nitrosamines and on elemental impurities, discrepancies in validation of analytical procedures are acceptable.
The proposed shelf-life of 36 months without specific storage conditions for the drug product is considered justified. The intended in-use stability of 3 months for tablets packed in bottles is acceptable for the 30 mg tablets. Extrapolating in-use stability of 3 months from the 30 mg tablets to the 15 mg strengths has been justified sufficiently.
III.2 Non-clinical aspects
Tolvaptan is a selective V2 receptor antagonist for the oral treatment of hypervolemic and euvolemic hyponatriemia. The Applicant has provided an updated Non-clinical Expert Report on the pharmacology, pharmacokinetic and toxicology of Tolvaptan with 24 publication up to the year 2020. The new pre-clinical Expert Report is considered adequate.
Since Tolvaptan 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
One bioequivalence study (Study No: 1) investigating the 30 mg strength of tolvaptan under fasting conditions has been performed.
The submitted bioequivalence study is an open label, balanced, pivotal, laboratory blind, randomized, two period, two treatment, two sequence, single dose, two way, crossover, bioequivalence study in subjects healthy adult human subjects under fasting conditions.
The aim of the study was to evaluate and compare the bioavailability and therefore to assess the bioequivalence between a test formulation of tolvaptan 30 mg tablets, following 30 mg oral doses versus an equal dose of one tablet formulation used as reference medication (Samsca® 30 mg tablets, manufactured by Otsuka Pharmaceutical Netherlands B.V.), each administered twice to fasting healthy volunteers.
The study conduct, bioanalytical methods and statistical analyses are considered appropriate.
The results are summarized below:
| Treatment | AUC 0-t ng/ml/h | AUC 0-∞ ng/ml/h | C max ng/ml | t max h |
| Test | 3739.4314 + 1526.14148 | 3796.3811 + 1537.35968 | 363.1662 + 110.40209 | 2.500 (0.67–5.00) |
| Reference | 3845.2098 + 1551.75813 | 3908.5911 + 1561.87747 | 417.4961 + 139.23191 | 2.750 (1.00–6.00) |
| *Ratio (90% CI) | 96.45 90.91 – 102.32 | 87.37 80.09 – 95.32 | ||
| 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
The 90% confidence intervals calculated for AUC0-t and Cmax for tolvaptan consistently fall within the 80–125% acceptance range after single dose administration under fasting conditions. According to the EU-Guideline “Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**, London, 20 January 2010, section 4.1.6) test formulation (batch No. 7142467) and reference formulation can be considered bioequivalent.
The applicant has confirmed that the test product tolvaptan 30 mg tablets used in the bioequivalence study (Study No: 1) and the product tolvaptan 30 mg tablets intended for marketing authorisation are identical.
The applicant has given the information that the reference product Samsca® is purchased from Germany.
Based on the submitted bioequivalence study (Study No: 1) tolvaptan 30 mg tablets are considered bioequivalent with the originator product Samsca® (tolvaptan) 30 mg tablets under fasting conditions.
No separate bioequivalence studies were performed with the tolvaptan 15 mg strength applied for.
A bio-waiver is requested by the applicant for the tolvaptan 15 mg strength based on the results of the bioequivalence study with the tolvaptan 30 mg strength because the criteria were fulfilled in accordance with the current “Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr**):
– the tolvaptan 15 mg and 30 mg tablets are manufactured by the same manufacturer and manufacturing process
– the qualitative composition of the 15 mg and 30 mg strengths is the same
– the composition of the strengths are quantitatively (dose) proportional, i.e. the ratio between the amount of each excipient to the amount of the active substance is the same for all strengths
– tolvaptan has been shown to be linear over the therapeutic dose range
– the dissolution data demonstrated in vitro similarity between the different strengths.
The justification of the bio-waiver of the additional tolvaptan 15 mg strength applied for can be accepted. The results of the bioequivalence study (Study No: 1) with the 30 mg tolvaptan formulation can be extrapolated to the other strength of 15 mg tolvaptan, according to conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section 4.1.6.
The requirements of the EU-Guideline CPMP/EWP/QWP/1401/98 Rev. 1/Corr* (section 4.1.6) have been fulfilled.
Pharmacodynamic characteristics of tolvaptan are well known. No own data were submitted.
The efficacy of tolvaptan in the proposed indication is established in clinical use. No own data were submitted.
The overall safety profile of tolvaptan is established and generally known. Tolvaptan has an acceptable adverse event profile when contraindications and precautions are considered properly.
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/Proposed Future MAH has submitted an updated 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 Tolvaptan 15mg and 30mg tablets indicated for treatment of SIADH.
Safety specification
| Important identified risks | Too rapid rise of serum sodium and neurologic sequelae (encephalopathy, osmotic demyelination) Interaction with CYP3A4 inhibitors Volume depletion, dehydration and associated sequelae such as renal dysfunction |
| Important potential risks | Raised intraocular pressure/glaucoma |
| Missing information | Paediatric use Pregnancy outcome data Use in breast-feeding Off-label use Use in hepatic impaired patients |
Pharmacovigilance Plan
Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.
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 considered acceptable.
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. 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 19.01.2027.
Medicinal product subject to medical prescription.
The test results showed that 100%% of the participants were able to find the information, 100% of the requested information was understood.
In conclusion, the results of the user testing indicated that the PL of tolvaptan 15 mg and 30 mg tablets is appropriate.
The application contains a review of published non-clinical and clinical data.
The updated non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology as well as the updated clinical overview on the bioavailability of tolvaptan are adequate.
Bioequivalence has been demonstrated for the 30 mg tolvaptan dose strength of the medicinal product applied for and the reference product Samsca® (tolvaptan) 30 mg dose strength under fasting conditions.
No separate bioequivalence studies were performed with the tolvaptan 15 mg strength applied for. A justification of the bio-waiver for the additional dose strength of 15 mg has been submitted. The justification of the bio-waiver of this additional tolvaptan 15 mg strength applied for can be accepted. The requirements of the “Guideline on the Investigation of Bioequivalence” CPMP/EWP/QWP/1401/98 Rev. 1/ Corr**, section 4.1.6, for the requested bio-waiver have been fulfilled.
From a clinical point of view, the application is approvable.
From a pharmaceutical quality point of view, the application is approvable.
The application is approved. For intermediate amendments, see the current product information.