Zusammenfassung der Merkmale des Arzneimittels - Ondansetron Tenshi Kaizen 4 mg Lyophilisat zum Einnehmen
II.4 G eneral comments on compliance with GMP, GLP, GCP, and agreed ethical
| Proposed name of the medicinal product in the RMS | Ondansetron Tenshi Kaizen 4 mg Lyophilisat zum Einnehmen Ondansetron Tenshi Kaizen 8 mg Lyophilisat zum Einnehmen |
| Name of the drug substance (INN name): | Ondansetron |
| Pharmaco-therapeutic group (ATC Code): | A04AA01 |
| Pharmaceutical form(s) and strength(s): | 4 + 8 mg Oral Lyophilisate |
| Reference Number(s) for the Decentralised Procedure | DE/H/7176/001–002/DC |
| Reference Member State: | DE |
| Concerned Member States: | AT |
| Legal basis of application: | Generic Art 10.1 Dir 2001/83/EC |
| Applicant (name and address) | Tenshi Kaizen B.V. Kingsfordweg 151 1043GR Amsterdam Netherlands |
| Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA | SANTA SA Str. Panselohr nr. 25, nr. 27, sin nr.29 Brasov, Jud. Brasov-500419 Romania |
Based on the review of the data on quality, safety, and efficacy, the RMS considers that the application for Ondansetron Tenshi Kaizen 4 mg Lyophilisat zum Einnehmen and Ondansetron Tenshi Kaizen 8 mg Lyophilisat zum Einnehmen
is approved.
II.1 Problem statement
Not applicable
II.2 About the product
The active substance of the applied medicinal products is ondansetron as in the reference products Zofran 4 mg Zydis Lingual and Zofran 8 mg Zydis Lingual.
Ondansetron belongs to the Anatomical Therapeutic Chemical (ATC) Class A04AA01 – Antiemetics and antinauseants, Serotonin (5HT3) antagonists. It is a carbazalone derivative structurally related to serotonin and possesses specific, potent, highly selective 5-hydroxytryptamine (5-HT3) receptor antagonism. Its precise mode of action in the control of nausea and vomiting is not known. The effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to antagonism of 5HT3 receptors on neurons located both in the peripheral and central nervous system. The mechanisms of action in post-operative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting.
For approved indications, see the Summary of Product Characteristics.
II.3 General comments on the submitted dossier
This decentralised application concerns a generic version of ondansetron under two trade names. In this assessment report, the name ondansetron is used.
The originator products are Zofran 4 mg Zydis Lingual and Zofran 8 mg Zydis Lingual (Ondansetron 4 mg and 8 mg, Oral Lyophilisates) by Novartis Pharma GmbH, registered in DE since 30 November 1998, marketing authorisation numbers 41349.00.00 and 41349.01.00 DE as the Reference Member State (RMS) in this Decentralised Procedure (DCP), Tenshi Kaizen B.V. applied for the marketing authorisations (MA) for Ondansetron Tenshi Kaizen 4 mg Lyophilisat zum Einnehmen and Ondansetron Tenshi Kaizen 8 mg Lyophilisat zum Einnehmen in AT.
According to the dossier the clinical overview is dated 23 June 2021 and refers 12 publications up to year 2019.
To support the application, the Applicant has submitted a report of 1 bioequivalence study titled ‘An Open Label, Balanced, Randomized, Two-Treatment, Two-Period, Two-Sequence, Single Dose, Crossover Oral Bioequivalence Study Comparing Ondansetron Orally Disintegrating Tablets 8 mg (Test) with Zofran® 8 Zydis®, Smelttabletten 8 mg (Reference) in, Healthy, Adult Human, Subjects Under Fasting Conditions’.
II.4 General comments on compliance with GMP, GLP, GCP, and agreed ethical principles
GMP
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 the manufacturing site outside the Community a GMP certificate issued by the competent authority is provided.
GMP active substance
Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer responsible for batch release situated in the EU.
GLP
Not applicable since no non-clinical studies have been performed during the development of the applied medicinal products.
GCP
A statement on the application of appropriate GCP standards in the submitted bioequivalence study has been provided. According to the Applicant the latest inspection of the clinical, bioanalytical, pharmacokinetic, and statistical analysis sites has been conducted in 2016 by the MHRA; copies of the inspection reports referred to have been provided.
III.1 Quality aspects
The active substance is Ondansetron. There is no Ph. Eur. monograph for Ondansetron available, but Ondansetron hydrochloride dihydrate is included in the Ph. Eur. The USP includes a monograph for Ondansetron and for Ondansetron orally disintegrating tablets. The ASMF procedure is followed by the ASMF holder.
Characterization data are provided.
A discussion on possible impurities has been provided.
The drug substance is controlled by an in-house specification. The specification includes description, solubility, identification, related compounds.
The batch results of overall eleven production size batches of the drug substance showed compliance with the specification.
Stability studies of production size batches are finalised. The updated stability data justify the claimed retest-period for the drug substance of 5 years.
The proposed drug products are oral lyophilisates, which disperse rapidly in the mouth and contain 4 mg or 8 mg of drug substance per freeze dried tablet.
The quality of the excipients complies with the requirements of the corresponding Ph. Eur. Monographs where applicable. The flavouring agent is tested according to an in-house monograph. Only well-known excipients are used.
Process validation has been performed with submission batches of Ondansetron 4 mg and 8 mg oral lyophilisates.
The product specifications cover relevant parameters for this dosage form. Validation results of the analytical methods have been presented.
Batch analysis results are provided for the three process validation batches for each strength and for one additional batch each of strength 4 mg and 8 mg.
The proposed shelf-life of 2 years is justified.
III.2 Non clinical aspects
Pharmacodynamic, pharmacokinetic, and toxicological properties of ondansetron are well known. As ondansetron is a widely used, well-known active substance, the Applicant has not provided additional studies and further studies are not required. An overview based on a literature review is thus appropriate.
The non-clinical overview is neither signed nor dated. The CV is digitally signed and dated 23 June 2021. The report refers 22 publications up to year 2020.
The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics, and toxicology is adequate.
Since Ondansetron 4 mg and 8 mg Oral Lyophilisate is a generic product, it will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.
III.3 Clinical aspects
To support the application, the Applicant has submitted a report of one bioequivalence study titled ‘An Open Label, Balanced, Randomized, Two-Treatment, Two-Period, Two-Sequence, Single Dose, Crossover Oral Bioequivalence Study Comparing Ondansetron Orally Disintegrating Tablets 8 mg (Test) with Zofran® 8 Zydis®, Smelttabletten 8 mg (Reference) in, Healthy, Adult Human, Subjects Under Fasting Conditions’.
According to the documents provided, the study has been conducted between 05 and 11 April 2021 for the clinical and 09 and 23 April 2021 for the bioanalytical part.
The trial was conducted using a randomised, open label, balanced, two-treatment, two-period, two-sequence, single dose, crossover design. According to the study report an orally disintegrating 8 mg ondansetron tablet (Test) was compared with Zofran 8 Zydis, Smelttabletten 8 mg (Reference), which is acceptable.
The study included 52 normal, healthy, adult, human subjects under fasting conditions.
The bioequivalence design is considered acceptable. The analytical method is considered acceptable as well and adequately validated. Handling of samples is also considered adequate. A statement on GLP compliance has been provided. Standard pharmacokinetic variables have been assessed and standard statistical methods for the assessment of bioequivalence have been applied; both are considered adequate.
Results
Of the 52 subjects enrolled in the study, 49 completed both periods and were considered for the pharmacokinetic and statistical analyses; 3 subjects did not report for the second period.
As regards the statistical evaluation of the pharmacokinetic parameters the geometric least squares means of the test and the reference formulations, ratio (T/R)%, intra-subject variability, 90% confidence intervals of the geometric least square mean ratio (T/R), and power obtained from the analysis of ln-transformed primary pharmacokinetic parameters Cmax and AUC0-t are summarised in the following table:
| PK parameters (Units) | Geometric Least Square Means and Its Ratio (N=49) | 90 % Confidence Interval | ||
| Test Product (T) | Reference Product ® | (T/R)% | ||
| C max (ng/mL) | 31.510 | 34.538 | 91.23 | 84.02% – 99.07% |
| AUC 0-t (hr*ng/mL) | 209.636 | 224.236 | 93.49 | 86.06% – 101.56% |
Conclusion
In summary, based on the pharmacokinetic parameters of ondansetron, the test and reference formulation are considered bioequivalent with respect to the extent and rate of absorption. The 90% confidence intervals calculated for AUC(0-t) and Cmax were inside the normal range of acceptability (80.00–125.00%. ). Ondansetron Orally Disintegrating Tablets 8 mg, are therefore considered bioequivalent with the tested reference Zofran 8 Zydis, Smelttabletten 8 mg (Ondansetron) Orally disintegrating tablet.
Conclusion
The results of the study with the 8 mg formulation can be extrapolated to the 4 mg strength (Ondansetron 4 mg Oral Lyophilisate), according to conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section 4.1.6.
Safety data
The study did not reveal any new or unexpected safety findings. No severe, serious, or life-threatening adverse events were reported during the study.
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/Rapporteur 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.
According 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.
Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.
Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed.
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.
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 theEuropean 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. For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.The common renewal date is 06.01.2028.
Medicinal product subject to medical prescription.
In summary, the test results indicate that the package leaflet is well structured and organised, easy to understand, and written in a comprehensible manner; patients / users are able to act upon the information that it contains. Legal requirements of Art. 59(3) of Directive 2001/83/EC (as amended) are met and the package leaflet is considered acceptable.