Public Assessment Report Scientific discussion
Ésteres etílicos 90 dos ácidos ómega-3 Glenmark 1000 mg, Soft Gel Capsules (Omega-3-Acid Ethyl Esters 90)
PT/H/0779/001/DC
This module reflects the scientific discussion for the approval of Ésteres etílicos 90 dos ácidos ómega-3 Glenmark. The procedure was finalised at 25-07-2013. For information on changes after this date please refer to the module ‘Update’.
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I.
INTRODUCTION
Glenmark Generics (Europe) has applied for a marketing authorisation for Ésteres etílicos 90 dos ácidos ómega-3 Glenmark 1000 mg, Soft Gel Capsules, containing omega-3-acid ethyl esters 90 as the active substance, indicated in: Post Myocardial Infarction Adjuvant treatment in secondary prevention after myocardial infarction, in addition to other standard therapy (e.g. statins, anti-platelet medicinal products, beta-blockers, ACE inhibitors). Hypertriglyceridaemia Endogenous hypertriglyceridaemia as a supplement to diet when dietary measures alone are insufficient to produce an adequate response: - type IV in monotherapy, - type IIb/III in combination with statins, when control of triglycerides is insufficient. This decentralised application concerns a generic version claiming essential similarity with the reference product Omacor, IGM , Capsules by Pronova Biopharma, registered since 1996-10-01. This type of application refers to information that is contained in the pharmacological-toxicological and clinical part of the dossier of the authorisation of the reference product. A reference product is a medicinal product authorised and marketed on the basis of a full dossier, i.e. including chemical, biological, pharmaceutical, pharmacological-toxicological and clinical data. This information is not fully available in the public domain. Authorisations for generic products are therefore only allowed once the data protection time of the dossier of the reference product has expired. For this kind of application, it has to be demonstrated that the pharmacokinetic profile of the product is similar to the pharmacokinetic profile of the reference product. This generic product can be used instead of its reference product. The marketing authorization was granted on 09-08-2013 based on Directive 2001/83/EC article 10.1 (a) (iii) first paragraph. The Concerned Member states for this application were DE and UK.
II. II.1
QUALITY ASPECTS Introduction
Ésteres etílicos 90 dos ácidos ómega-3 Glenmark are slightly yellow soft capsules that contains omega-3-acid ethyl esters 90 as the active substance. This medicine is packed in white (HDPE) bottles containing 20, 28, 30, 60, 100 or 280 soft gelatine capsules. The soft capsule core excipient is alpha-tocopherol (may contain vegetable oil e.g. soya oil). The capsule shell excipients are: gelatin, glycerol, purified water, medium-chain triglycerides, lecithin.
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II.2
Drug Substance
The drug substance is omega-3-acid ethyl esters 90 (Ph. Eur.), which is a mixture of ethyl esters of several fatty acids: alpha-linolenic acid (C18:3 n-3), moroctic acid (C18:4 n-3), eicosatetraenoic acid (C20:4 n-3), eicosapentaenoic acid (C20:5 n-3), heneicosapentaenoic acid (C21:5 n-3), docosapentaenoic acid (C22:5 n-3) and docosahexaenoic acid (C22:6 n-3). The main ingredients of omega-3 acids ethyl esters 90 are: eicosapentaenoic acid ethyl ester (EPA ethyl ester) and docosahexaenoic acid ethyl ester (DHA ethyl ester). According to the Ph. Eur, omega-3-acid ethyl esters are obtained by transesterification of the body oil of fat fish species coming from families such as Engraulidae, Carangidae, Clupeidae, Osmeridae, Salmonidae and Scombridae and subsequent physicochemical purification processes. It is a light yellow clear liquid, practically insoluble in water, very soluble in acetone, in ethanol (96%), in heptane and in methanol. The structural formulas of the main components are the following (Figures 1 and 2):
Figure 1. Structural formulas of EPA and DHA
Figure 2. Structural formulas of other relevant compone nts
The chemical-pharmaceutical documentation and Expert Report in relation to Ésteres etílicos 90 dos ácidos ómega-3 Glenmark are of sufficient quality in view of the present European regulatory requirements. The control tests and specifications for drug substance product are adequately drawn up. The proposed retest period of 1 year for the active substance is acceptable.
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II.3
Medicinal Product
The documentation provided complies with relevant EU guidelines and directives. The development of the product has been described, the choice of excipients is justified and their functions explained. Manufacture is performed in accordance with cGMP and consistency in quality and homogeneity is demonstrated. The product specifications cover appropriate parameters for this dosage form. 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 3 years with do not store above 25ºC and do not freeze storage conditions for the drug product is considered acceptable. The soft gelatin capsules should be used within 100 days of opening the bottle.
III.
NON-CLINICAL ASPECTS
Pharmacodynamic, pharmacokinetic and toxicological properties of omega-3-acid ethyl esters 90 are well known. As omega-3-acid ethyl esters 90 is a widely used, well-known active substance, no further studies are required and the applicant provides none. An overview based on literature review is, thus, appropriate.
IV.
CLINICAL ASPECTS
Introduction EPA and DHA are essential fatty acids because humans do not have the biochemical pathways required to synthesize them. Only a very little amount can be synthesized from linoleic acid. Also they are essential for normal growth and development and for optimal function of body systems. Their source is therefore from external sources, such as plants (for α-linoleic acid) or marine food (for EPA and DHA). EPA and DHA in turns are precursors of a family of eicosanoids that mediate the vasodilatory, anti-inflammatory, anti-thrombotic, and anti-arrhythmic effects of these molecules.
Pharmacokinetics To support the application for the determination of bioequivalence, the applicant submitted a bioequivalence study investigating Ésteres etílicos 90 dos ácidos ómega-3 Glenmark versus the brand leader in Greece (Omacor 1 g capsules). The submitted bioequivalence study showed that Ésteres etílicos 90 dos ácidos ómega-3 Glenmark capsules are bioequivalent with Omacor 1 g and was performed by Algorithme Pharma (no. OEG-P9-470).
Clinical efficacy & Clinical safety omega-3-acid ethyl esters 90 has a well-recognised efficacy and acceptable level of safety in the indications approved for 1000 mg, soft capsules and has been widely used in many countries.
Pharmacovigilance System The RMS considers that the Pharmacovigilance system as described by the applicant fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person
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responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country.
Risk Management Plan This is a generic medicinal product with the same quantitative and qualitative composition in active substance, same pharmaceutical form, same route of administration and same therapeutic indications authorised in the SPC of the reference product. The risk management plan is acceptable.
User consultation The package leaflet has been user tested. The testing was carried out appropriately on a suitable range of participants following the submitted protocol. The listed participants were able to find and understand the requested information and the leaflet was shown to be acceptable.
V.
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION
The application for Ésteres etílicos 90 dos ácidos ómega-3 Glenmark contains adequate quality, non clinical and clinical data and bioequivalence to the reference product, Omacor, has been shown. A benefit/risk ratio comparable to the reference product can therefore be concluded.
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