Zusammenfassung der Merkmale des Arzneimittels - Olmesartanmedoxomil HEC Pharm 10 mg Filmtabletten
ADMINISTRATIVE INFORMATION
| Proposed name of the medicinal product(s) in the RMS | Olmesartan medoxomil HEC Pharm 10mg; 20mg; 40mg |
| Name of the drug substance (INN name): | Olmersartan medoxomil |
| Pharmaco-therapeutic group (ATC Code): | C09CA08 |
| Pharmaceutical form(s) and strength(s): | Film coated tablet |
| Reference Number(s) for the Decentralised Procedure | DE/H/4680/001–003/DC |
| Reference Member State: | DE |
| Member States concerned: | no CMS |
| Legal basis of application: | Generic Art 10.1 and 10.2 Dir 2001/83/EC |
| Marketing Authorisation Holder (name and address) | HEC Pharm GmbH Gabriele-Tergit-Promenade 17 D-10963 Berlin Germany |
| Names and addresses of all manufacturer(s) responsible for batch release in the EEA | Formula Pharmazeutische und chemische Entwicklungs GmbH Address: Goerzallee 305 b 14167 Berlin Germany |
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 Olmesartan HEC Pharm 10 mg/20 mg/40 mg film coated tablets in the treatment of essential hypertension, is approved.
EXECUTIVE SUMMARY
I.1 Problem statement
For generic application this section is not applicable.
I.2 About the product
Active Substance
The active drug substance is Olmesartan.
Drug Product
The present formulation is an immediate release formulation for oral use:
Olmesartan HEC Pharm 10 mg film-coated tablets
Olmesartan HEC Pharm 20 mg film-coated tablets
Olmesartan HEC Pharm 40 mg film-coated tablets
Mechanism of action
Olmesartan is a potent, orally active, selective angiotensin II receptor (type AT1) antagonist.
Therapeutic indication
Treatment of essential hypertension
Posology
Adults
The recommended starting dose of olmesartan medoxomil is 10 mg once daily. In patients whose blood pressure is not adequately controlled at this dose, the dose of olmesartan medoxomil may be increased to 20 mg once daily as the optimal dose. If additional blood pressure reduction is required, olmesartan medoxomil dose may be increased to a maximum of 40 mg daily or hydrochlorothiazide therapy may be added.
I.3 General comments on the submitted dossier
This application is an abridged Marketing Authorisation Application (MAA) for generic Olmesartan 10 mg/ 20 mg/ 40 mg film-coated tablets under Article 10(1) of Directive 2001/83/EC as amended.
Reference medicinal product which has been authorised in accordance with Union provisions in force for not less than 10 years in the EEA is:
Olmetec® 10 mg/20 mg/40 mg film-coated tablets, Daiichi Sankyo Europe GmbH (first approved in the EU in 2002).
With Germany as Reference Member State (RMS), HEC Pharm is applying for marketing authorisations for Olmesartan HEC Pharm 10 mg/20 mg/40 mg film coated tablets. No other Concerned Member State (CMS) is involved for this procedure.
I.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.
Fulfilled by providing a current QP declaration and GMP certificates.
The bioequivalence study including the archiving of essential documents has been conducted in accordance with GCP/GLP, relevant regulatory guidance, and written SOPs of the contract research organisation. AXIS Clinicals Ltd. accepts the responsibility for scientific correctness of the project and validity of the data produced in the BE study report. The assessment of the dossier did not reveal concerns regarding GCP/GLP.
II.1 Quality aspects
The active substance olmesartan medoxomil is described in the European Pharmacopoeia. A CEP has been submitted regarding API.
For the manufacturer of the finished product, manufacturing authorisations have been submitted.
The composition of the medicinal products, pharmaceutical development and route of manufacture of the finished products are described sufficiently. Solely concerning the chosen dissolution method the used 0.1N HCl medium is justified and the discriminative power has been shown. In process controls which cover the critical steps of the manufacture process are described. The release specification contains the relevant quality characteristics to describe the finished products. Specifications, batch results and stability tables should be overworked. The analytical methods are described and validated sufficiently. The batch results are in compliance with the given specification.
Stability studies of the finished products have been performed over 12 months at long term and over six months at accelerated conditions. The intended shelf life of two years without storage precaution is acceptable. An extrapolation from 12 to 24 months is acceptable based on the presented stability data.
II.2 Non-clinical aspects
There are no new publications on the pharmacology, pharmacokinetics and toxicology of Olmesartan medoxomil which alter the benefit-to-risk assessment.
II.3 Clinical aspects
To support essential similarity with the reference product Olmetec®, Daiichi Sankyo Europe GmbH, the applicant has submitted a bioequivalence study (268–13):
– An open label, randomized, two treatment, two sequence, two period, crossover, single-dose oral bioequivalence study of Olmesartan Medoxomil 40 mg Film-coated Tablets (EU) (Test) of HEC Pharm GmbH and Olmetec® 40 mg Filmtabletten (Reference) of Daiichi-Sankyo Europe GmbH in healthy, adult, human subjects under fasting conditions.
The in vivo bioequivalence study was conducted in accordance with the Guideline on the Investigation of Bioequivalence for an immediate-release formulation (CPMP/QWP/EWP/1401/98 Rev. 1/ Corr**).
Standard PK parameters and statistical methods were applied. A single-dose study under fasting conditions is considered appropriate since Olmesartan is an immediate release formulation and food does not affect the absorption of Olmesartan.
The analytical methods used in the bioequivalence study (268–13) were validated and suitable to determine Olmesartan in human plasma in a selective and validated manner, provided accurate, precise and reproducible results and fulfilled the acceptance criteria laid down in the Guideline on Bioanalytical method validation (EMEA/CHMP/EWP/192217/2009 Rev.1 Corr.*).
The biowaiver request for the two lower dose strengths (10 mg and 20 mg) was supported by comparative in vitro dissolution testing.
– In 0.1M HCl, Olmesartan medoxomil HEC 10 mg, 20 mg and 40 mg film-coated tablets are rapidly dissolved. More than 85% of olmesartan is dissolved within 15 minutes for all three strengths in 0.1M HCl. The dissolution profiles are considered similar without further f2 evaluation.
– In pH 4.5 Acetate buffer and pH 6.8 Phosphate buffer, the f2 values for dissolution profiles of Olmesartan medoxomil HEC 10 mg and 20 mg compared to Olmesartan medoxomil HEC 40 mg are above 50 and the dissolution profiles are considered similar.
All other conditions for granting a strength waiver as stated in the EU-Guideline on the Investigation of Bioequivalence (Doc. Ref.: CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **) have been fulfilled. The applicant’s justification for not submitting a bioequivalence study for the two lower strengths of Olmesartan 10 mg and 20 mg is accepted.
Bioequivalence Study
Study No.: 268–13
Title of Study:
An open label, randomized, two treatment, two sequence, two period, crossover, single-dose oral bioequivalence study of Olmesartan Medoxomil 40 mg Film-coated Tablets (EU) (Test) of HEC Pharm GmbH and Olmetec® 40 mg Filmtabletten (Reference) of Daiichi-Sankyo Europe GmbH in healthy, adult, human subjects under fasting conditions.
Clinical Phase: 25 May 2015 – 04 June 2014
Analytical Phase: 20 June 2015– 06 July 2014
Olmesartan Medoxomil 40 mg Film-coated Tablets
Batch No.: 1003201401
HEC Pharm GmbH
Olmetec® 40 mg Film-coated Tablets
Batch No. 190641
Daiichi-Sankyo Europe GmbH
Results
Linear Plot of Mean Plasma Concentrations Vs Time profile of Olmesartan
Pharmacokinetic parameters (mean±SD) (%CV) of Olmesartan (N=31)
| Parameter (ijiit) | Mean ± SD (Un-transformed data) | |
| Reference Product ® (N=31) | Test Product (T) (N=31) | |
| ^max(ng/mL) | 1531.864± 428.0258 | 1569.655± 411.8159 |
| AUCo-i (hr. ng/mL) | 12789.399= 4269.6147 | 12663.158±4058.4571 |
| AUCo-^o (hi. ng/mL) | 13116.472± 4524.5272 | 13017.312±4270.9830 |
| AUC 0 Extrapolation | 2.279± 0 9960 | 2.509=1.4246 |
| T™ * (hr) | 2.00 (1.50–4.00) | 2.00 (1.00–4.00) |
| Kel (hr'1) | 0 07497± 0 008651 | 0.07587±0 010974 |
Geometric Least Square Mean, Ratios and 90% Confidence Interval for Olmesartan
| Parameter (Unit) | (Ln-transformed) Geometrie Least Square Mean | 90° o Confidence Interval Tvs R | Intra Subject CV (%) | Power (%) | ||
| Test Product (T) | Reference Product ® | Ratio (TR)°o | ||||
| ^max(ng/mL) | 1515.077 | 1475.658 | 102.67 | 96 3 3–109 43 | 149 | 100 |
| AUCo-t(hr. ng/mL) | 12110.116 | 12192.183 | 99.33 | 94.46–104.45 | 11.7 | 100 |
The 90% confidence intervals for geometric least square means of Ln-transformed data of Cmax and AUC0→t of Olmesartan were within the bioequivalence acceptance range (80.00–125.00%). Based on these results, Olmesartan Medoxomil 40 mg Film-coated Tablets (Test) of HEC Pharm GmbH, Batch No: 1003201401 is bioequivalent with that of Olmetec® 40 mg Filmtabletten (Olmesartan medoxomil) (Reference) of Daiichi-Sankyo Europe GmbH, Lot No.: 190641in healthy, adult, human subjects under fasting conditions.
The applicant has provided documents that set out a detailed description of the system of pharmacovigilance. A statement signed by the applicant and the qualified person for pharmacovigilance has been provided (Module 1.8.1 CTD), indicating that the applicant has the services of a qualified person responsible for pharmacovigilance and the necessary means for the notification of any adverse reaction occurring either in the Community or in a third country.
The applicant has submitted an updated risk management plan (version 03, DLP and date of final sign off 2017/05/11) , 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 olmesartan medoxomil 10mg/20mg/40mg film-coated tablets. The updated RMP is acceptable.
– Summary table of safety concerns as approved in RMP
| Important identified risks | Hypersensitivity reactions Hyperkalaemia Hypotension Foetotoxicity Use in patients with biliary obstruction Sprue-like enteropathy Renal dysfunction as a consequence of dual renin-angiotensin-aldosterone system blockade |
| Important potential risks | Hepatic impairment Increased cardiovascular (CV) mortality in patients with type 2 diabetes Exposure in patients with aortic or mitral valve stenosis or HOCM Drug-drug interactions (e.g. lithium, other hypertensive agents) Rhabdomyolysis |
| Missing information | Exposure in children and adolescents Exposure during the first trimester of pregnancy and in lactation Use in patients with severe renal impairment and renal transplantation Use in patients with severe hepatic impairment |
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, version 03, signed 2017/05/11 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.5 years after the finalisation of the procedure.
Medicinal product subject to medical prescription.
User Test
The package leaflet for generic Olmesartan medoxomil HEC Pharm 10mg; 20mg; 40mg film-coated tablets has been user tested (11 November 2016) and achieved satisfactory results.