Public Assessment Report - GOV.UK · On 22 August 2012, ... Module 1: Information about ... used in...

Public Assessment Report

Decentralised Procedure

Telmisartan Egis 20mg film-coated tablets Telmisartan Egis 40mg film-coated tablets Telmisartan Egis 80mg film-coated tablets

(telmisartan)

Procedure No: UK/H/5090/001-3/DC

UK Licence No: PL 03525/0023-5

EGIS Pharmaceuticals PLC

Telmisartan Egis 20mg, 40mg and 80mg film-coated tablets UK/H/5090/001-3/DC

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Lay summary On 22 August 2012, the Medicines and Healthcare products Regulatory Agency (MHRA) granted Marketing Authorisations to EGIS Pharmaceuticals PLC for the medicinal products Telmisartan Egis 20mg, 40mg and 80mg film-coated tablets (PL 03525/0023-5; UK/H/5090/001-3/DC). These are prescription-only medicines used in the treatment of essential hypertension (high blood pressure). ‘Essential’ means that the high blood pressure is not caused by any other condition. High blood pressure, if not treated, can damage blood vessels in several organs, which could lead sometimes to heart attack, heart or kidney failure, stroke, or blindness. There are usually no symptoms of high blood pressure before damage occurs. Thus it is important to regularly measure blood pressure to verify if it is within the normal range. Telmisartan is also used to reduce cardiovascular events (i.e. heart attack or stroke) in patients who are at risk because they have a reduced or blocked blood supply to the heart or legs, or have had a stroke or have high risk diabetes. The active ingredient, telmisartan, belongs to a class of medicines known as angiotensin II receptor antagonists. Angiotensin II is a substance produced in your body which causes your blood vessels to narrow, thus increasing your blood pressure. Telmisartan blocks the effect of angiotensin II so that the blood vessels relax, and your blood pressure is lowered. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of taking Telmisartan Egis 20mg, 40mg and 80mg film-coated tablets outweigh the risks and Marketing Authorisations were granted.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Patient Information Leaflet Page 6 Module 4: Labelling Page 7 Module 5: Scientific discussion Page 16 I Introduction II About the product III Scientific overview and discussion III 1 Quality aspects III 2 Non-clinical aspects III 3 Clinical aspects IV Overall conclusion and benefit/risk assessment Module 6: Steps taken after initial procedure


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Module 1 Information about the initial procedure

Product Names

UK/H/5090/001/DC: Telmisartan Egis 20mg film-coated tablets UK/H/5090/002/DC: Telmisartan Egis 40mg film-coated tablets UK/H/5090/003/DC: Telmisartan Egis 80mg film-coated tablets

Type of Applications Generic, Article 10(1) Active Substance Telmisartan Form Film-coated tablets Strengths 20mg, 40mg and 80mg MA Holder

EGIS Pharmaceuticals PLC H-1106 Budapest, Keresztúri út 30-38. Hungary

Reference Member State (RMS) UK Concerned Member States (CMS) Bulgaria, Czech Republic, Hungary, Latvia, Lithuania,

Poland, Romania and Slovak Republic Procedure Numbers UK/H/5090/001-3/DC Timetable Day 210 – 20 June 2012


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Module 2 Summary of Product Characteristics

In accordance with Directive 2010/84/EU, the Summaries of Product Characteristics (SmPCs) for products granted Marketing Authorisations at a national level are available on the MHRA website.


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Module 3 Patient Information Leaflet

In accordance with Directive 2010/84/EU, the Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are available on the MHRA website.


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Module 4 Labelling

The labelling text below is that agreed at the end of the Decentralised Procedure. The Marketing Authorisation Holder has committed to submit the UK labelling for review to the regulatory authority before marketing any pack size.


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Module 5 Scientific discussion during initial procedure

Based on the review of the data on quality, safety and efficacy, the member states considered that the applications for Telmisartan Egis 20mg, 40mg and 80mg film-coated tablets (PL 03525/0023-5; UK/H/5090/001-3/DC) could be approved. These are prescription-only medicines (POM) indicated in the: • treatment of essential hypertension in adults • reduction of cardiovascular morbidity in patients with manifest atherothrombotic

cardiovascular disease (history of coronary heart disease, stroke, or peripheral arterial disease) or type 2 diabetes mellitus with documented target organ damage.

These applications were submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS), and Bulgaria, Czech Republic, Hungary, Latvia, Lithuania, Poland, Romania and Slovak Republic as Concerned Member States (CMS). The applications were submitted under Article 10(1) of Directive 2001/83/EC, as amended, claiming to be generic medicinal products of the innovator medicinal products Micardis 20 mg, 40 mg and 80 mg tablets (Boehringer Ingleheim, Germany), which were authorised in the EEA via the Centralised Procedure on 16 December 1998. The active ingredient, telmisartan, is an orally active and specific angiotensin II receptor (type AT1) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. In patients with hypertension, telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. No new non-clinical data were submitted, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been in clinical use for over 10 years. Two single-dose, bioequivalence studies were submitted to support these applications, comparing the applicant’s test products Telmisartan 20mg and 80mg Tablets (manufactured by Glenmark Pharmaceuticals Limited, India) with the reference products Micardis 20mg and 80mg Tablets (Boehringer Ingleheim Limited, Germany). The bioequivalence studies were carried out in accordance with Good Clinical Practice (GCP). With the exception of the bioequivalence studies, no new clinical data were submitted, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been in clinical use for over 10 years. The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place at all sites responsible for the manufacture, assembly and batch release of these products. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturing 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, 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.


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The RMS and CMS considered that the applications could be approved at the end of procedure (Day 210) on 20 June 2012. After a subsequent national phase, licences were granted in the UK on 22 August 2012. II. ABOUT THE PRODUCT Name of the product in the Reference Member State

UK/H/5090/001/DC: Telmisartan Egis 20mg film-coated tablets UK/H/5090//002/DC: Telmisartan Egis 40mg film-coated tablets UK/H/5090/003/DC: Telmisartan Egis 80mg film-coated tablets

Name(s) of the active substance (INN) Telmisartan Pharmacotherapeutic classification (ATC code)

Angiotensin II Antagonist, Plain (ATC code: C09CA07)

Pharmaceutical form and strength(s) Film coated tablet; 20mg, 40mg and 80mg

Reference numbers for the Decentralised Procedure

UK/H/5090/001-3/DC

Reference Member State (RMS) United Kingdom Concerned Member States (CMS) Bulgaria, Czech Republic, Hungary, Latvia,

Lithuania, Poland, Romania and Slovak Republic Marketing Authorisation Number(s) PL 03525/0023-5 Name and address of the authorisation holder

EGIS Pharmaceuticals PLC H-1106 Budapest, Keresztúri út 30-38. Hungary

III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS ACTIVE SUBSTANCE INN: Telmisartan Chemical Name: 4’-[[4-Methyl-6-(1-methyl-1H-benzimidazol-2-yl)-2-propyl-

1H-benzimidazol-1- yl]methyl]biphenyl-2-carboxylic acid Molecular formula: C33H30N4O2 Structure:

Molecular mass: 514.6 Appearance: A white or slightly yellowish, crystalline powder. Solubility: Practically insoluble in water, slightly soluble in methanol,

sparingly soluble in methylene chloride. It dissolves in 1M sodium hydroxide.

Telmisartan is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance telmisartan are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability.


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DRUG PRODUCT Other Ingredients Other ingredients consist of the pharmaceutical excipients in the tablet core and film coating, namely sodium hydroxide, povidone (K-25), meglumine, lactose monohydrate, crospovidone, ferric oxide yellow (E172), magnesium stearate, hypromellose, titanium dioxide (E171), macrogol-400 and talc. Appropriate justifications for the inclusion of each excipient have been provided. With the exception of ferric oxide yellow (E172), all excipients comply with their respective European Pharmacopoeia monographs. Ferric oxide yellow (E172) is controlled to the United States Pharmacopoeia - National formulary (USP-NF) specification and the specification is in compliance with current EU Directives concerning the use of colouring agents. Satisfactory Certificates of Analysis have been provided for all excipients, showing compliance with the proposed specifications. With the exception of lactose monohydrate, none of the excipients contain materials of animal or human origin. The supplier of lactose monohydrate has confirmed that the milk used in the production of lactose monohydrate is sourced from healthy animals under the same conditions as that intended for human consumption. In addition, the supplier has confirmed that no ruminant material other than calf rennet is used during the production of lactose monohydrate. No genetically modified organisms (GMO) have been used in the preparation of these excipients. Pharmaceutical Development The objective of the development programme was to formulate safe, efficacious, stable products that could be considered generic medicinal products of the reference products Micardis 20 mg, 40 mg and 80 mg tablets (Boehringer Ingelheim Limited, Germany). Suitable pharmaceutical development data have been provided for these applications. Comparative in-vitro dissolution and impurity profiles have been provided for these products and their respective reference products. Manufacturing Process Satisfactory batch formulae have been provided for the manufacture of all strengths of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated with pilot-scale batches and has shown satisfactory results. The Marketing Authorisation Holder has committed to performing process validation studies on future full-scale production batches. Control of Finished Product The finished product specifications are satisfactory. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specifications. Certificates of Analysis have been provided for any working standards used. Container Closure System The tablets are packaged in aluminium/aluminium blisters-cold formable aluminium foil and hard tempered aluminium foil blisters. These are packed into cardboard cartons with Patient Information Leaflets in pack sizes of 14, 15, 28, 30, 56, 60, 84, 90 and 98 film-coated tablets.


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Not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary packaging complies with current European regulations concerning materials in contact with foodstuff. Stability Finished product stability studies were performed in accordance with current guidelines on batches of finished product packed in the packaging proposed for marketing. Based on the results, a shelf-life of 3 years has been proposed, with the storage conditions ‘Store in the original package in order to protect from moisture.’ Suitable post approval stability commitments have been provided to continue stability testing on batches of finished product. Bioequivalence Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the bioequivalence studies. The bioequivalence studies are discussed in Section III.3, Clinical Aspects. Summaries of Product Characteristics (SmPCs), Patient Information Leaflet (PIL) and Labelling The SmPCs, PIL and labelling are satisfactory from a pharmaceutical perspective. Final text versions of the labelling and PIL have been provided. The Marketing Authorisation Holder has committed to submitting mock-ups to the relevant competent authorities for approval before marketing any pack size. User testing of the package leaflet has been accepted, based on a bridging report provided by the applicant making reference to the user-testing of the PIL for Perindopril Tablets as the ‘parent’ PIL. The products are from the same therapeutic and have similar indications. A critical analysis demonstrated that the key messages for safe and effective use for both leaflets were similar. The justification on the rationale for bridging is accepted. MAA (Marketing Authorisation Application) Forms All aspects of the MAA forms are satisfactory from a pharmaceutical perspective. Expert Report (Quality Overall Summary) The quality overall summary is written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Conclusion The grant of Marketing Authorisations is recommended. III.2 NON-CLINICAL ASPECTS As the pharmacodynamic, pharmacokinetic and toxicological properties of telmisartan are well-known, no further non-clinical studies are required and none have been provided. NON-CLINICAL EXPERT REPORT (NON-CLINICAL OVERVIEW) The non-clinical overview has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the relevant non-clinical pharmacology, pharmacokinetics and toxicology.


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ENVIRONMENTAL RISK ASSESSMENT Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As these products are intended for generic substitution with products that are already marketed, no increase in environmental burden is anticipated. Thus, the justification for non-submission of an Environmental Risk Assessment is accepted. CONCLUSION The grant of Marketing Authorisations is recommended. III.3 CLINICAL ASPECTS The clinical pharmacology of telmisartan is well-known. With the exception of data from the bioequivalence studies detailed below, no new pharmacodynamic or pharmacokinetic data are provided or required for these applications. In support of the applications, the Marketing Authorisation Holder submitted the following bioequivalence studies: Study 1 A randomised, open label, single-dose, two-period, two-treatment, two-sequence, crossover study comparing the pharmacokinetics of the test product Telmisartan 20mg Tablets (manufactured by Glenmark Pharmaceuticals Limited, India) and the reference product Micardis 20mg Tablets (Boehringer Ingelheim Limited, Germany) in healthy, adult male subjects under fasting conditions. The subjects were administered one tablet of either the test or the reference product with 240±2 ml of water, after at least a 10-hour overnight fast. Blood samples were collected before and up to and including 72 hours after each administration. The washout period between the treatment phases was 12 days. The pharmacokinetic results are presented below:

Pharmacokinetic parameters (least square means, ratios and confidence intervals [CI]) of telmisartan Parameters Telmisartan 20mg

(Test) Micardis 20mg

(Reference) Test/Ref Ratio

(%) 90% CI

Cmax (ng/mL)

28.00 29.95 93.49 87.07-100.38

AUC0-t (ng.hr/mL)

398.61 402.95 98.92 94.13–103.96

AUC0-inf (ng.hr/mL)

438.72 445.54 98.47 93.52–103.68

Cmax maximum plasma concentration AUC0-t area under the plasma concentration-time curve from time zero to t hours AUC0-inf area under the plasma concentration-time curve from time zero to infinity Ratios and 90% CI calculated from log-transformed data


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Study 2 A randomised, open label, single-dose, two-period, two-treatment, two-sequence, crossover study comparing the pharmacokinetics of the test product Telmisartan 80mg Tablets (manufactured by Glenmark Pharmaceuticals, India) and the reference product Micardis 80mg Tablets (Boehringer Ingelheim Limited, Germany) in healthy, adult male subjects under fasting conditions. The subjects were administered one tablet of either the test or the reference product with 240±2 ml of water, after at least a 10-hour overnight fast. Blood samples were collected before and up to and including 72 hours after each administration. The washout period between the treatment phases was 12 days. The pharmacokinetic results are presented below:

Pharmacokinetic parameters (least square means, ratios and confidence intervals [CI]) of telmisartan Parameters Telmisartan 80mg

(Test) Micardis 80mg

(Reference) Test/Ref Ratio

(%) 90% CI

Cmax (ng/mL)

338.95 370.09 91.58 82.73-101.38

AUC0-t (ng.hr/mL)

1666.31 1685.13 98.88 94.04–103.98

AUC0-inf (ng.hr/mL)

1841.80 1874.85 98.24 93.67–103.03

Cmax maximum plasma concentration AUC0-t area under the plasma concentration-time curve from time zero to t hours AUC0-inf area under the plasma concentration-time curve from time zero to infinity Ratios and 90% CI calculated from log-transformed data The 90% confidence intervals of the test/reference ratio for AUC0-t, AUC0-inf and Cmax lie within the acceptable limits of 80.00% to 125.00%, in line with the ‘Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**). Thus, the data support the claim that the applicant’s test products Telmisartan 20mg and 80mg Tablets (manufactured by Glenmark Pharmaceuticals Limited, India) are bioequivalent to the reference products Micardis 20mg and 80mg Tablets (Boehringer Ingelheim Limited, Germany) under fasting conditions. A biowaiver has been granted to the 40 mg strength tablet based on the studies conducted, in line with the requirements of the Committee for Proprietary Medicinal Products’ Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**). EFFICACY The efficacy of telmisartan is well-known. No new efficacy data have been submitted and none are required for applications of this type. SAFETY With the exception of the safety data generated during the bioequivalence studies, no new safety data were submitted and none are required for applications of this type. No new or unexpected safety issues arose during the bioequivalence studies. PHARMACOVIGILANCE SYSTEM AND RISK MANAGEMENT PLAN The Pharmacovigilance System, as described by the Marketing Authorisation Holder, fulfils the requirements and provides adequate evidence that the Marketing Authorisation Holder has the services of a qualified person 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.


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Suitable justification has been provided for not submitting a Risk Management Plan for these products. SUMMARIES OF PRODUCT CHARACTERISTICS (SmPCs), PATIENT INFORMATION LEAFLET (PIL) AND LABELLING The SmPCs, PIL and labelling are acceptable from a clinical perspective. The SmPCs are consistent with those for the reference products. The PIL is consistent with the details in the SmPCs and in-line with the current guidelines. The labelling is in-line with the current guidelines. CLINICAL EXPERT REPORT (CLINICAL OVERVIEW) The clinical overview is written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. CONCLUSION The grant of Marketing Authorisations is recommended. IV OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT QUALITY The quality characteristics of Telmisartan Egis 20mg, 40mg and 80mg 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. As the pharmacokinetics, pharmacodynamics and toxicology of telmisartan are well-known, no additional data were required. EFFICACY With the exception of the bioequivalence studies, no new data were submitted and none are required for applications of this type. Bioequivalence has been demonstrated between the applicant’s 20mg and 80mg strength tablets and the reference products Micardis 20 mg and 80 mg Tablets and the results can be extrapolated to the 40mg strength film-coated tablet. SAFETY With the exception of the safety data from the bioequivalence studies, no new data were submitted and none are required for applications of this type. As the safety profile of telmisartan is well known, no additional data were required. No new or unexpected safety concerns arose from the bioequivalence studies. PRODUCT LITERATURE The SmPCs, PIL and labelling are satisfactory, and consistent with those for the reference products, where appropriate, and consistent with current guidelines. BENEFIT/RISK ASSESSMENT The quality of the products is acceptable, and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with telmisartan is considered to have demonstrated the therapeutic value of the products. The benefit/risk balance is, therefore, considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted

Application type

Scope Outcome

Public Assessment Report - GOV.UK · On 22 August 2012, ... Module 1: Information about ... used in...

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