Zusammenfassung der Merkmale des Arzneimittels - Aripiprazol HEC Pharm 10 mg Schmelztabletten
| Proposed name of the medicinal product in the RMS | Aripiprazol HEC Pharm 10 / 15 mg Schmelztabletten |
| Name of the drug substance (INN name): | Aripiprazole |
| Pharmaco-therapeutic group (ATC Code): | N05AX12 |
| Pharmaceutical form(s) and strength(s): | Orodispersible tablet; 10 / 15 mg |
| Reference Number(s) for the Decentralised Procedure | DE/H/6343/001–002/DC |
| Reference Member State: | DE |
| Concerned Member States: | ES, FR, IT, UK |
| Legal basis of application: | Article 10(1) Generic application |
| Applicant (name and address) | HEC Pharm GmbH Gabriele-Tergit-Promenade 17 10963 Berlin, Germany |
| Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA | Formula Pharmazeutische und chemische Entwicklungs GmbH Goerzallee 305b 14167, Germany |
Based on the review of the data on quality, safety and efficacy, the application for “Aripiprazol HEC Pharm 10 / 15 mg Schmelztabletten” with the following indication:
Aripiprazole HEC is indicated for the treatment of schizophrenia in adults and in adolescents aged 15 years and older.
Aripiprazole HEC is indicated for the treatment of moderate to severe manic episodes in Bipolar I Disorder and for the prevention of a new manic episode in adults who experienced predominantly manic episodes and whose manic episodes responded to aripiprazole treatment (see section 5.1).
Aripiprazole HEC is indicated for the treatment up to 12 weeks of moderate to severe manic episodes in Bipolar I Disorder in adolescents aged 13 years and older (see section 5.1).
is approved.
II.1 Problem statement
N/A
II.2 About the product
Aripiprazol is an antipsychotic drug (ATC-Code: N05AX12) used for the treatment of schizophrenia and for the treatment and prevention of manic episodes. It has been proposed that aripiprazole’s efficacy in schizophrenia and Bipolar I Disorder is mediated through a combination of partial agonism at dopamine D2 and serotonin 5HT1a receptors and antagonism of serotonin 5HT2a receptors.
In adults, the starting dose is 10 mg to 15 mg/day (dependent also from indication) which may be titrated to a maximum of 30 mg/day. In paediatric patients treatment should be initiated at 2 mg (using aripiprazole oral solution) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. In paediatric patients with schizophrenia the daily dose may be further titrated in 5 mg steps up to a maximum of 30 mg/day.
II.3 General comments on the submitted dossier
The application for Aripiprazole HEC Pharm 10 / 15 mg Schmelztabletten is an abridged application, according to article 10.2(b) so called ’generic application”.
The originator product is ABILIFY (10/ 15/ 30 mg, orodispersible tablets) by Otsuka Pharmaceutical Europe Ltd., registered since 04–06–2004 (EMEA/H/C/0471).
With Germany as the Reference Member State in this Decentralized Procedure, HEC Pharm is applying for the Marketing Authorisations for Aripiprazole HEC Pharm 10 / 15 mg Schmelztabletten in ES, FR, IT and UK.
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.
The applicant assures that the submitted bioequivalence study has been conducted and analysed according GCP- and GLP-standards.
III.1 Quality aspects
Drug Substance
Aripiprazole is included in the European Pharmacopoeia and also described in the USP.
One source of Aripiprazole is proposed: HEC PHARM CO., LTD, China. The drug substance manufacturer holds a valid Certificate of Suitability issued by the EDQM, certifying that the quality of the drug substance is suitably controlled by current version of the Ph. Eur monograph of Aripiprazole. Copy of the valid CEP with filled in declaration of access has been provided.
According to the CEP presented the re-test period of the drug substance is 24 months if stored in a polyethylene terephthalate/aluminum/polyethylene bag.
The information presented is acceptable and sufficient to guarantee the quality of Aripiprazole 10 mg and 15 mg orodispersible tablets.
The data submitted on the quality of the drug substance and drug product reflect well researched and well defined products. The ingredients, the manufacturing process and the in-process controls of the drug product correspond to the current standard of pharmaceutical technology and are suitable to guarantee an appropriate product quality. The description of the analytical test methods is adequate. The validation results are plausible.
All relevant quality criteria are specified in accordance with internationally acknowledged pharmacopoeias. The specified limits are in line with the requirements of the CHMP Guidelines and are guarded by the finished product.
A shelf-life of 24 months for the drug products of the applied formulation has been justified by extrapolation of stability data provided.
III.2 Non clinical aspects
Pharmacodynamic, pharmacokinetic and toxicological properties of aripiprazole are well known. As aripiprazole 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 “Aripiprazol HEC Pharm 10 / 15 mg Schmelztabletten” 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
To support the application, the applicant has submitted as report one bioequivalence study.
The bioequivalence study was performed on Aripiprazole HEC 10 mg Schmelztabletten (# 17-VIN-0269 ) versus the originator product ABILIFY 10 mg orodispersible tablets (by Otsuka Pharmaceutical).
The study was conducted as randomised, open label, balanced, two-treatment, two-period, two-sequence, crossover, single oral dose bioequivalence study in accordance with GCP, relevant regulatory guidance, and written SOPs of the contract research organisation.
Study Results:
Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max median,
Figure 1: Linear plot of mean plasma concentrations versus time for aripiprazole:
Formula tion=R Formula tion=T
range):
| Treatment | AUC 0–72h ng/ml/h | AUC 0-∞ ng/ml/h | C max ng/ml | t max h |
| Test | 1718.320 ± 532.2731 | NA | 42.469 ± 13.9322 | 4.000 (2.00 – 24.00) |
| Reference | 1770.258 ± 499.5850 | NA | 43.494 ± 12.4616 | 4.000 (1.00– 12.00) |
| *Ratio (90% CI) | 96.22 90.46% – 102.35% | 96.34 89.66 % – 103.52% | ||
| AUC 0–72h Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0–72h can be 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; Median (Min – Max) | ||||
*ln-transformed values
The 90% CIs of the ratio of the test to reference product for Cmax and AUC0–72 were within the bioequivalence acceptance range specified in the study protocol (80.00% to 125.00%). The rate and extent
of absorption of aripiprazole from the test (Aripiprazole HEC 10 mg Schmelztabletten) and reference (ABILIFY 10 mg orodispersible tablets) were comparable in healthy volunteers under fasting conditions.
Pharmacokinetik Conclusion
Based on the submitted bioequivalence study Aripiprazole HEC Pharm 10 Schmelztabletten can be considered bioequivalent with Abilify 10 mg orodispersible tablets.
Biowaiver of strength:
Based on the following a biowaiver is requested for the 15 mg strength:
– Both strengths are orodispersible tablets.
– Aripiprazole 10 mg and 15 mg orodispersible tablets are manufactured by the same manufacturing process and the same manufacturer
– The qualitative composition of the different strengths is the same.
– The composition of the strengths is quantitatively proportional.
– Linearity in pharmacokinetics of aripiprazole in the dose range 10 mg to 15 mg.
– Acceptable in vitro dissolution testing of Aripiprazole 10 mg and 15 mg strengths
The results of study 17-VIN-0269 with the 10 mg formulation can be extrapolated to the other strength Aripiprazole HEC Pharm 15 mg Schmelztabletten as the a.m. criteria for a biowaiver are fulfilled.
Medicinal product subject to medical prescription.
Readability testing was conducted on the PIL for “Aripiprazole HEC Pharm 5/ 10 mg Tablet” (Parent PIL). The user testing report for the Parent PIL was assessed during DC procedure DE/H/6356/001–002/DC and the Parent PIL was qualified as acceptable.
In this bridging study, the PIL for “Aripiprazole HEC Pharm 5/ 10 mg Orodispersible Tablet” (Daughter PIL) and the Parent PIL were compared based on:
Visual Presentation: leaflet dimension, font, font size, coloring scheme, spacing, format, organization of sections and any graphics used in the PIL and
Contents: key safety messages including indications, contraindications, side effects, ingredients, storage information, and any other relevant data.
It has been shown that the Daughter PIL and the Parent PIL are very similar in both style and layout. Differences in leaflet content were analysed and were found not to affect readability.
The Daughter PIL contains information not found in the Parent PIL, e.g. because the medicine has a different pharmaceutical form. However, the additional information is clear, was rated easy to understand, and is listed in the same style as the Parent PIL, so no separate testing is regarded as necessary for the Daughter PIL due to these additional details.
Based on the Bridging Report it has been concluded that the Daughter PIL requires no separate user testing due to its similarity to the already tested Parent PIL.
The Applicant has submitted a signed Summary of the Applicant's and/or 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 MAH 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 specification
According to the Applicant the safety specification is in full accordance with the current safety specification agreed and published for a similar product which is acceptable.
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.
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 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 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. 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.