Public Assessment Report - Medicines and … Desogestrel, Deliges and Desogestrel 75 microgram Film-coated Tablets UK/H/3416, 3418 & 4784/001/DC 1 Public Assessment Report Decentralised

PAR Desogestr el, Deliges and Desogestr el 75 microgram Film-coated Tablets

UK/H/3416, 3418 & 4784/001/DC

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Public Assessment Report

Decentralised Procedure Desogestrel 75 microgram Film-coated Tablets

Deliges 75 microgram Film-coated Tablets

Desogestrel 75 microgram Film-coated tablets

Desogestrel

UK/H/3416/001/DC UK/H/3418/001/DC UK/H/4784/001/DC

UK licence no: PL 34518/0004, 0006 & 0015

Laboratorios Leon Farma S.A.


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LAY SUMMARY

The product name Grystella 75 microgram Film-coated Tablets is used in the main body of this report when referring to PL 34518/0015. It should be noted however that the product name was amended to Desogestrel 75 microgram Film-coated tablets on 7 February 2013. This is a summary of the Public Assessment Report (PAR) for Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets. It explains how the applications for these medicinal products were assessed and their authorisation recommended, as well as their conditions of use. It is not intended to provide practical advice on how to use Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets. For practical information about using the tablets patients should read the package leaflet or contact their doctor or pharmacist. What are Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets and what are they used for? Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets are ‘generic medicines’. This means that they are similar to ‘reference medicines’ already authorised in the European Union (EU) called Cerazette 75 microgram Film-coated Tablets, which have been authorised since 1998. Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets are used to prevent pregnancy. How do Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets work? These medicinal products contain a small amount of one type of female sex hormone, the progestogen desogestrel. For this reason Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets are known as progestogen-only-pills (POP), or mini-pills. Contrary to the combined pill, mini-pills do not contain an estrogen hormone in combination with the progestogen. Most mini-pills work primarily by preventing the sperm cells from entering the womb but do not always prevent the egg cell from ripening, which is the primary action of a combined pill. Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets are distinct from other mini-pills in having a dose that in most cases is high enough to prevent the egg cell from ripening. As a result, these products provide high contraceptive efficacy. In contrast to the combined pill, these mini-pills can be used by women who do not tolerate estrogens and by women who are breastfeeding. The disadvantage is that vaginal bleeding may occur at irregular intervals during the use of these mini-pills, although there may not be any bleeding at all. How are Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets used? The pack contains 28 tablets. The days of the week are printed in the blister and also arrows are printed indicating the order to take the tablets. Each day correspond with one tablet. Every time that a new pack is started a tablet should be taken from the top row. One tablet a day should be taken until the pack is empty, following the direction indicated by the arrows. Tablets should be taken at about the same time each day.


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The tablets should be swallowed whole with water. Bleeding may occur during the use of the tablets but use should be continued as normal. When a pack is empty a new pack should be started on the next day without interruption and without waiting for a bleed. Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets can only be obtained with a prescription. What benefits of Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets have been shown in studies? Because Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets are generic medicines, studies in patients have been limited to tests to determine that the tablets are bioequivalent to the reference medicine, Cerazette 75 microgram Film-coated Tablets. Two medicines are bioequivalent when they produce the same levels of active substance in the body. What are the possible side effects of Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets? Because Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets are generic medicines and are bioequivalent to the reference medicines, their benefits and possible side effects are taken as being the same as those of the reference medicines. Why are Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets approved? It was concluded that, in accordance with EU requirements, Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets have been shown to have comparable quality and to be bioequivalent to Cerazette 75 microgram Film-coated Tablets. Therefore, the MHRA decided that, as for Cerazette 75 microgram Film-coated Tablets, the benefits of Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets are greater than their risks and recommended that they can be approved for use. What measures are being taken to ensure the safe and effective use of Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets? Safety information has been included in the Summaries of Product Characteristics and the package leaflet for Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets, including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored and reviewed continuously. Other information about Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets Marketing Authorisations were granted in the UK for Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets on 20 September 2012. The full PAR for Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets follows this summary. For more information about treatment with Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets, read the package leaflet or contact your doctor or pharmacist. This summary was last updated in October 2015.


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TABLE OF CONTENTS

I Introduction Page 5 II Quality aspects Page 6 III Non-clinical aspects Page 16 IV Clinical aspects Page 16 V User consultation Page 17 VI Overall conclusion, benefit/risk assessment and recommendation Page 17 Annex 1 - Table of content of the PAR update for MRP and DCP Page 19


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I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Reference Member State (RMS) and Concerned Member States (CMSs) consider that the applications for Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets, used as hormonal contraceptive for systemic use, could be approved. These applications were submitted under Article 10.1 of Directive 2001/83/EC, as amended for Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets, claiming to be generic medicinal products of Cerazette 75 microgram Film-coated Tablets (PL 00065/0159), which was first licensed to Organon Laboratories Ltd, on 9th November 1998. With UK as the RMS in these Decentralised Procedures (UK/H/3416, 3418 & 4784/001/DC), Laboratorios Leon Farma S.A. applied for the Marketing Authorisations for Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets in the following CMSs: UK/H/3416/001/DC: Bulgaria, Czech Republic, Estonia, Hungary, Germany, Lithuania, Latvia, Poland, Romania, Slovenia and Slovak Republic. UK/H/3418/001/DC: Austria, Belgium, Germany and Luxemburg UK/H/4784/001/DC: Austria, France, Germany, Poland and Spain Desogestrel/ Deliges/ Grystella is a progestogen-only pill, which contains the progestogen desogestrel. Like other progestogen-only pills, these products are best suited for use during breast feeding and for women who may not or do not want to use estrogens. In contrast to traditional progestogen-only pills, the contraceptive effect of Desogestrel/ Deliges/ Grystella is achieved primarily by inhibition of ovulation. Other effects include increased viscosity of the cervical mucus. No new non-clinical or clinical studies were conducted, which is acceptable given that the applications were based on being generic medicinal products of an originator product that has been licensed for over 10 years. A bioequivalence study was carried out in accordance with Good Clinical Practice (GCP). The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for these product types at all sites responsible for the manufacture and assembly of these products. 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. 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 responsible for pharmacovigilance and the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. A suitable justification has been provided for non-submission of a Risk Management Plan.


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All member states agreed to grant respective Marketing Authorisations for the above products at the end of procedure (Day 210 – 27th June 2012). After a subsequent national phase, the UK granted a Marketing Authorisation for these products on 20th September 2012 (PL 34518/0004, 0006 and 0015). II Quality aspects DRUG SUBSTANCE INN: Desogestrel Chemical Names: 13-Ethyl-11-methylidene-18,19-dinor-17α-pregn-4-en-20-yn-17-ol Structure:

Molecular Formula: C22H30O Molecular Weight: 310.5 General Properties: Desogestrel is a white to off-white crystalline powder, which is practically insoluble in water and slightly soluble in ethanol (96%) and ethyl acetate. All aspects of the manufacture and control of the active substance are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability. DRUG PRODUCT Other Ingredients Other ingredients consist of the pharmaceutical excipients lactose monohydrate, maize starch, povidone K30, all rac α-tocopherol, silica, colloidal anhydrous, stearic acid making up the tablet core, the coating is consisted of hypromellose 2910, polyethylene glycol and titanium dioxide (E 171). All excipients comply with their respective European Pharmacopoeia monographs. Satisfactory Certificates of Analysis have been provided for all excipients. None of the excipients are sourced from animal or human origin. Confirmation has been provided that the lactose monohydrate is sourced from healthy animals under the same conditions as milk for human consumption. Pharmaceutical Development The objective of the development programme was to formulate robust, stable tablets that contain the same active ingredient as Cerazette 75 microgram Film-coated Tablets (Organon Laboratories Ltd). Comparative impurity and dissolution profiles have been presented for the test and reference products.


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Manufacture A satisfactory batch formula has been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated and shown satisfactory results. Satisfactory process validation data have been provided. Finished Product Specification The finished product specification is satisfactory. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of Analysis have been provided for any working standards used. Container-Closure System The finished product is packed in blisters of aluminium push-through foil and polyvinylchloride (PVC)/ polyvinyldichloride (PVDC) film. The pack sizes are: 1 x 28 film-coated tablets 3 x 28 film-coated tablets 6 x 28 film-coated tablets Specifications and Certificates of Analysis for all packaging materials have been provided. These are satisfactory. All primary packaging complies with EU legislation regarding contact with food. Stability Finished product stability studies have been conducted in accordance with current guidelines and in the packaging proposed for marketing. Based on the results, a shelf-life of 2 years with no special storage condition have been set for these products. These are acceptable. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SPCs, PIL and labels are pharmaceutically acceptable. The Marketing Authorisation Holder has committed to submitting mock-ups for unmarketed pack sizes to the relevant regulatory authorities for approval before those packs are commercially marketed. The following product labelling was approved for use in the UK:


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Blister:


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Carton:

Marketing Authorisation Application (MAA) Forms The MAA forms are pharmaceutically satisfactory. Expert report The pharmaceutical expert report has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Conclusion There are no objections to the approval of these products from a pharmaceutical point of view.


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III Non-clinical aspects The pharmacodynamic, pharmacokinetic and toxicological properties of desogestrel are well known. No new non-clinical data have been supplied with these applications and none are required for applications of this type. The non-clinical expert report has been written by an appropriately qualified person and is a suitable summary of the non-clinical aspects of the dossier. A detailed environmental risk assessment has been provided. This is satisfactory. There are no objections to the approval of these products from a non-clinical point of view. IV Clinical aspects Clinical Pharmacology Pharmacokinetics In support of these applications, the Marketing Authorisation Holder has submitted the following bioequivalence study: A single centre, randomised, single-dose, open-label, 2-way crossover bioequivalence study comparing the pharmacokinetics of the test product Desogestrel 75 microgram Tablets (Laboratorios León Farma, S.A., Spain) versus the reference product Cerazette 75 microgram Tablets (Organon Espanola, S.A laboratories, Spain) in female volunteers under fasting conditions. Study drug was administered after an overnight fast with 200 ml water. The blood samples were collected during each period at pre-dose and at 0.33, 0.67, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours post-dose after administration of each product with a washout period of 28 days between study drug administration. The concentration of etonogestrel (2-keto desogestrol) was determined in plasma. The analytical, PK and statistical methods were adequate. Comparisons of pharmacokinetic parameters (Leon Farma test vs Cerazette reference)

Ratio LSM T/R (%) 90% Geometric CI (%) ISCV (%)

AUC0-72 104.18 98.59-110.09 14.87 Cmax 100.54 92.09-109.76 23.85 T: Leon FARMA Test; R:Cerazette Reference LSM: least squares mean; CI: confidence interval; ISCV: intra-subjects coefficient of variation

The 90% confidence intervals for AUC 0-72 and Cmax were within the pre-defined limits. Bioequivalence has been shown for the test formulation (Desogestrel 75 microgram Tablet) and the reference formulation (Cerazette 75 microgram Tablets).


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Pharmacodynamics No new data have been submitted and none are required for applications of this type. Clinical Efficacy No new data have been submitted and none are required. Clinical Safety No new data have been submitted and none are required. Expert Report The clinical expert report is written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and labelling The SmPCs, PIL and labelling are medically satisfactory and consistent with those for the reference product. Marketing Authorisation Application (MAA) Forms The MAA forms are medically satisfactory. Conclusion There are no objections to the approval of these products from a clinical point of view. V User consultation The package leaflet has been evaluated via a user consultation study, in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC, as amended. The results show that the package leaflet meets the criteria for readability, as set out in the guideline on the readability of the label and package leaflet of medicinal products for human use. VI Overall conclusion, benefit/risk assessment and recommendation QUALITY The important quality characteristics of Desogestrel, Deliges and Grystella 75 microgram Film-coated Tablets are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for applications of these type. EFFICACY Bioequivalence has been demonstrated between the applicant’s Desogestrel 75 microgram Tablet and the reference product, Cerazette 75 microgram Tablets. No new or unexpected safety concerns arise from these applications. The SPCs and PIL are satisfactory and consistent with those of the reference product. Satisfactory labelling has also been submitted.


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RISK-BENEFIT ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with s desogestrel is considered to have demonstrated the therapeutic value of the compound. The risk-benefit is, therefore, considered to be positive.


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Annex 1 Table of content of the PAR update for MRP and DCP

Steps taken after the initial procedure with an influence on the Public Assessment Report

Scope Procedure

number Product Information affected

Date of start of procedure

Date of end of procedure

Approval/ non approval

Assessment report attached

To change the name of the medicinal product to Desogestrel 75 microgram Film-coated tablets (for PL 34518/0015 only).

UK/H/4784/001/IB/002

SmPC, PIL, label

08/01/2013 07/02/2013 Approval N

To add an updated Environmental Risk Assessment (for PL 34518/0015 only).

UK/H/4784/001/IB/006

No 19/08/2015 18/09/2015 Approval Y


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VARIATION ASSESSMENT REPORT Our Reference: PL 34518/0015 - 0013 Product: Desogestrel 75microgram Film-coated Tablets Marketing Authorisation Holder: Laboratorios León Farma, S.A. Active Ingredient: Desogestrel Submission Type: Variation Submission Category: Type IB Submission Complexity: Standard Reason To update the Environmental Risk Assessment report Supporting Evidence As a part of the original assessment the Applicant was asked to conduct a full environmental risk (Phase I & II) assessment, as potential endocrine disruptors need to be addressed irrespective of the quantity released into the environment, as per the CHMP guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00). The Applicant has now provided this assessment. Evaluation The data provided indicate that desogestrel should not pose a significant risk to the aquatic environment. This generic product is unlikely to cause an increase of environmental exposure. There is extensive literature data on the environmental impact of this class of compound and so the value of generating addition in vivo toxicology data (i.e. in fish) is not required. New in vivo toxicology will not provide any more helpful impactful data (than that already in the literature) for the assessment of environmental risk. The Applicant has provided an adequate environmental risk assessment. This variation is therefore approved. Decision - Approve

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Public Assessment Report - Medicines and … Desogestrel, Deliges and Desogestrel 75 microgram Film-coated Tablets UK/H/3416, 3418 & 4784/001/DC 1 Public Assessment Report Decentralised