Public Assessment Report Decentralised Procedure - GOV.UK · and angina (chest pain). It works mainly by making your blood vessels wider. This helps to lower your blood pressure

Public Assessment Report

Decentralised Procedure

LOFAMIL XL 200MG PROLONGED-RELEASE CAPSULES LOFAMIL XL 300MG PROLONGED-RELEASE CAPSULES

Procedure No: UK/H/4669/001-2/DC

UK Licence No: PL 00289/1648-9

Teva UK Limited

PAR Lofamil XL 200 & 300mg Prolonged-release Capsules UK/H/4669/001-2/DC

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LAY SUMMARY

On 21 August 2012, Belgium, France, the Netherlands and the UK agreed to grant Marketing Authorisations to Teva UK Limited for the medicinal products Lofamil XL 200 and 300mg Prolonged-release Capsules (PL 00289/1648-9; UK/H/4669/001-2/DC). The licences were granted via the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS). After the national phase, Marketing Authorisations were granted in the UK on 5 October 2012. Lofamil contains a medicine called diltiazem. Diltiazem belongs to a group of medicines called calcium-channel blockers. It is used for mild to moderately increased blood pressure and angina (chest pain). It works mainly by making your blood vessels wider. This helps to lower your blood pressure. It also makes it easier for your heart to pump blood around your body. This helps to prevent the lack of oxygen in the heart muscle and thus to prevent chest pain. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of taking Lofamil XL 200 and 300mg Prolonged-release Capsules outweigh the risks; hence, Marketing Authorisations were granted.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 3 Module 2: Summary of Product Characteristics Page 4 Module 3: Patient Information Leaflets Page 22 Module 4: Labelling Page 24 Module 5: Scientific Discussion Page 28 I Introduction II About the product III.1 Quality aspects III.2 Non-clinical aspects III.3 Clinical aspects IV Overall conclusions Module 6 Steps taken after initial procedure


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Module 1

Product Name

Lofamil XL 200 and 300mg Prolonged-release Capsules

Type of Application

Generic, Article 10(1)

Active Substances

Diltiazem hydrochloride

Form

Prolonged-release Tablets. hard

Strength

200mg and 300mg

MA Holder

Teva UK Limited, Brampton Road, Hampden Park, Eastbourne, East Sussex BN22 9AG, UK

Reference Member State (RMS)

UK

Concerned Member States (CMS)

Belgium, France, the Netherlands

Procedure Number

UK/H/4669/001-2/DC

Timetable

Day 210 – 21 August 2012


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Module 2 Summary of Product Characteristics

The current approved UK versions of the Summaries of Product Characteristics (SmPCs) for these products are available on the MHRA website.

Module 3 Patient Information Leaflet

The current approved UK versions of the Patient Information Leaflets (PILs) for these products are available on the MHRA website.


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Module 4 Labelling


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Module 5 Scientific discussion during initial procedure

I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the member states considered that the applications for Lofamil XL 200 and 300mg Prolonged-release Capsules (PL 00289/1648-9; UK/H/4669/001-2/DC) could be approved. These applications were submitted via the Decentralised Procedure (DCP), with the UK as reference member state (RMS), and Belgium, France and the Netherlands as concerned member states (CMS). These are prescription-only medicines indicated in mild to moderate hypertension and angina pectoris. These applications were made via the decentralised procedure (DCP), according to Article 10(1) of Directive 2001/83/EC, as amended, claiming to be generic medicinal products of Mono Tildiem LP 200 and 300mg, which were granted licences in France on 16 October 1992 to Sanofi-Aventis, France. Diltiazem is a benzothiazepine calcium antagonist. Diltiazem restricts calcium entry into the slow calcium channel of vascular smooth muscle and myocardial muscle fibres in a voltage-dependent manner. By blocking the entry of calcium, diltiazem decreases the force of contraction of the heart and its rate of contraction. It also relaxes the muscles surrounding the arteries, allowing the arteries to dilate. By dilating arteries, diltiazem reduces the pressure in the arteries into which the heart must pump blood and, as a result, the heart needs to work less and requires less oxygen. By reducing the heart's need for oxygen, diltiazem relieves or prevents angina. Dilation of the arteries also reduces blood pressure. No new non-clinical studies were conducted, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been licensed for over 10 years. With the exception of the bioequivalence study, no new clinical studies were conducted, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been licensed for over 10 years. Three bioequivalence studies were performed, which compared the pharmacokinetics of the 300mg prolonged-release capsules (the test product) versus MonoTildiem 300mg Prolonged-release Capsules (the reference product – Sanofi-Aventis, France) as (i) single-dose study in fasted state; (ii) single-dose study in fed state; (iii) multiple-dose study in fasted state. The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP). The RMS has been assured that acceptable standards of Good Manufacturing Practice are in place for these product types at all sites responsible for the manufacture, assembly and batch release of this product. The RMS and CMS considered that the applications could be approved with the end of procedure (Day 210) on 21 August 2012. After a subsequent national phase, the licences were granted in the UK on 5 October 2012.


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II. ABOUT THE PRODUCT Name of the product in the Reference Member State

Lofamil XL 200 & 300mg Prolonged-release Capsules

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

Selective calcium channel blockers with direct cardiac effects - Benzothiazepine derivatives (C08DB01)

Pharmaceutical form and strength(s) 200 & 300mg Prolonged-release Capsules

Reference numbers for the Mutual Recognition Procedure

UK/H/4669/001-2/DC

Reference Member State United Kingdom Member States concerned Belgium, France, the Netherlands Marketing Authorisation Number(s) PL 00289/1648-9 Name and address of the authorisation holder Teva UK Limited, Brampton Road,

Hampden Park, Eastbourne, East Sussex BN22 9AG, UK


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III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS S. Active substance – Diltiazem hydrochloride rINN: Diltiazem hydrochloride Chemical name: - (2S, 3S)-5-[2=(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-

oxo-2,3,4,5-tetrehydro-1,5-benzothiazepin-3-yl acetate hydrochloride

- (+)-5-[2-(Dimethylamino)ethyl]-cis-2,3-dihydro-3-hydroxy-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one acetate(ester) monohydrochloride

Structure:

Molecular formula: C22H26N2O4S.HCl Molecular weight: 451.0 Appearance: White to almost white crystalline powder Solubility: Freely soluble in water, chloroform, methylene chloride, formic acid

and methanol. Sparingly soluble in dehydrated alcohol and practically insoluble in ether.

Diltiazem hydrochloride is the subject of a European Pharmacopoeia monograph. Synthesis of the drug substance from the designated starting material has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents and these are supported by relevant certificates of analysis. An appropriate specification is provided for the active substance that complies with the European Pharmacopoeia monograph for diltiazem. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Certificate of analysis for all working standards have been provided. Batch analysis data are provided and comply with the proposed specification.


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Satisfactory specifications and certificates of analysis have been provided for all packaging used to store active diltiazem. Confirmation has been provided that the primary packaging complies with current guidelines concerning materials in contact with food. Appropriate stability data have been generated, supporting a suitable retest period when the drug substance is stored in the packaging proposed. P. Medicinal Product Other Ingredients Other ingredients consist of the pharmaceutical excipients, povidone, talc, ethylcellulose, stearic acid, gelatin, titanium dioxide (E171). Additionally, the capsule shell of the 300mg capsules contains indigo carmine (E132) and quinoline yellow (E104). All excipients comply with their respective European Pharmacopoeia monographs, with the exception of titanium dioxide, indigo carmine and quinoline yellow (which are controlled to suitable national formulary specifications). Suitable batch analysis data have been provided for all excipients, showing compliance with their respective specifications. With the exception of gelatin, none of the excipients are sourced from animal or human origin. The suppliers of gelatin have provided European Directorate for the Quality of Medicine Certificates of Suitability to show that the gelatin is sourced in-line with current regulations concerning the minimisation of TSE/BSE. No genetically modified organisms (GMO) have been used in the preparation of these products. Pharmaceutical Development The objective of the development programme was to formulate a globally acceptable, stable and bioequivalent products that could be considered a generic medicinal products of the innovator products Mono Tildiem LP 200 and 300mg (Sanofi-Aventis, France). A satisfactory account of the pharmaceutical development has been provided. Comparative in vitro dissolution and impurity profiles have been provided for the proposed products versus each respective innovator product. Manufacturing Process Satisfactory batch formulae have been provided for the manufacture of the finished products. The manufacturing process has been validated and has shown satisfactory results. The marketing authorisation holder has committed to conduct process validation studies on the first full-scale batches and inform of any unexpected findings. Finished Product Specifications The finished product specifications proposed are acceptable. Test methods have been described and have been adequately validated. Batch data have been provided and comply with the release specifications. Certificates of analysis have been provided for all working standards used. Container-Closure System The finished product is packaged in aluminium/polyvinylchloride/polyvinylidene chloride blister packs, which are packed into cartons of 28, 30, 56, 60, 84, 90, 98, 100, 50x1 capsules. It has been stated that not all pack sizes may be marketed, however, the marketing authorisation holder has committed to submitting the mock-ups for any pack size to the relevant regulatory authorities for approval before marketing.


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Satisfactory specifications and certificates of analysis have been provided for all packaging components. All primary packaging complies with the current European regulations concerning materials in contact with food. Stability of the product Stability studies were performed in accordance with current guidelines on batches of finished product packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 36 months, with the storage conditions “Store in the original package”. Bioequivalence/bioavailability Satisfactory certificates of analysis have been provided for the test and reference batches used in the bioequivalence study. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels The SmPCs, PILs and labels are pharmaceutically acceptable. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups (‘user testing’), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. Marketing Authorisation Application (MAA) forms The MAA forms are pharmaceutically satisfactory. Quality Overall Summary (Expert report) The pharmaceutical expert report has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. Conclusion The grant of marketing authorisations is recommended. III.2 NON-CLINICAL ASPECTS As the pharmacodynamic, pharmacokinetic and toxicological properties of diltiazem hydrochloride are well-known, no further non-clinical studies are required and none have been provided. The applicant’s non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the product’s pharmacology and toxicology. Suitable justification has been provided for the non-submission of an environmental risk assessment. As these products are intended for generic substitution with products that are currently marketed, no increase in environmental burden is expected. There are no objections to the approval of these products from a non-clinical viewpoint.


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III.3 CLINICAL ASPECTS Pharmacokinetics In support of these applications, the marketing authorisation holder has submitted the following bioequivalence studies: Study 1: An open-label, randomised, two-period, two-treatment, two-sequence, single-dose, crossover study to compare the pharmacokinetics of the test product diltiazem hydrochloride 300mg prolonged-release capsules versus the reference product MonoTildiem 300mg Prolonged-release Capsules (Sanofi-Aventis, France) in healthy adult subjects under fasted conditions. Volunteers were dosed with either treatment after an overnight fast of at least 10 hours. Blood samples were taken for the measurement of pharmacokinetic parameters at pre- and up to 48 hours post dose. The two treatment arms were separated by a 7-day washout period. The pharmacokinetic results (presented as geometric least-squares means, ratios and 90% confidence intervals) are presented below:

In-transformed Data

Geometric Least Squares Mean

Parameters (Units)

Test Product-B

Reference Product-A

Ratio (B/A)

90% Confidence

Interval

Diltiazem: Cmax (ng/mL) 134.276 131.798 101.88 95.58;108.60 AUC0-t (ng.h/mL) 2488.008 2435.061 102.17 96.95;107.68 AUC0-∞ (ng.h/mL) 2555.501 2504.217 102.05 96.86;107.51

Desacetyldiltiazem: Cmax (ng/mL) 10.465 10.299 101.61 95.57;108.05 AUC0-t (ng.h/mL) 280.499 272.177 103.06 97.56;108.87 AUC0-∞ (ng.h/mL) 316.189 306.520 103.15 97.65;108.96

N-desmethyldiltiazem: Cmax (ng/mL) 49.387 49.057 100.67 95.68;105.92 AUC0-t (ng.h/mL) 1126.924 1087.482 103.63 99.75;107.65 AUC0-∞ (ng.h/mL) 1193.459 1155.866 103.25 99.18;107.49

The 90% confidence intervals for all actives lie within the acceptance criteria specified in the Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98), meaning that bioequivalence has been shown between the test and reference products. Study 2: An open-label, randomised, two-period, two-treatment, two-sequence, single-dose, crossover study to compare the pharmacokinetics of the test product diltiazem hydrochloride 300mg prolonged-release capsules versus the reference product MonoTildiem 300mg Prolonged-release Capsules (Sanofi-Aventis, France) in healthy adult subjects under fed conditions. Volunteers were dosed with either treatment after an overnight fast of at least 10 hours and a high-fat, high-calorie breakfast. Blood samples were taken for the measurement of pharmacokinetic parameters at pre- and up to 48 hours post dose. The two treatment arms were separated by a 7-day washout period.


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The pharmacokinetic results (presented as geometric least-squares means, ratios and 90% confidence intervals) are presented below:

In-transformed Data


Parameters (Units)

Test Product-B

Reference Product-A

Ratio (B/A)

90% Confidence

Interval

Diltiazem: Cmax (ng/mL) 234.692 237.421 98.85 89.82;108.79 AUC0-t (ng.h/mL) 3010.840 3064.403 98.25 93.47;103.28 AUC0-∞ (ng.h/mL) 3068.218 3123.157 98.24 93.53;103.19

Desacetyldiltiazem: Cmax (ng/mL) 12.852 13.159 97.67 92.68;102.93 AUC0-t (ng.h/mL) 285.898 287.537 99.43 95.45;103.57 AUC0-∞ (ng.h/mL) 309.248 311.496 99.28 95.00;103.75

N-desmethyldiltiazem: Cmax (ng/mL) 79.612 81.589 97.58 90.46;105.26 AUC0-t (ng.h/mL) 1368.727 1384.090 98.89 95.27;102.64 AUC0-∞ (ng.h/mL) 1424.942 1442.642 98.77 95.10;102.59

The 90% confidence intervals for all actives lie within the acceptance criteria specified in the Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98), meaning that bioequivalence has been shown between the test and reference products. Study 3: An open-label, randomised, two-period, two-treatment, two-sequence, multiple-dose, crossover study to compare the rate/extent of absorption of the test product diltiazem hydrochloride 300mg prolonged-release capsules versus the reference product MonoTildiem 300mg Prolonged-release Capsules (Sanofi-Aventis, France) in healthy adult subjects under fasting conditions. Volunteers were dosed for three consecutive days with either treatment after an overnight fast of at least 10 hours. Blood samples were taken for the measurement of pharmacokinetic parameters over 24 hours on a clinic day post the final dose. The two treatment arms were separated by a 7-day washout period.


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The pharmacokinetic results (presented as geometric least-squares means, ratios and 90% confidence intervals) are presented below:

In-transformed Data


Parameters (Units)

Test Product-B

Reference Product-A

Ratio (B/A)

90% Confidence

Interval

Diltiazem: Cmax,ss (ng/mL) 180.160 182.913 98.49 88.13;110.08 AUCss (ng.h/mL) 2877.361 2795.391 102.93 91.01;116.41 Cmin,ss (ng/mL) 60.653 58.040 104.50 87.11;125.37

Desacetyldiltiazem: Cmax,ss (ng/mL) 16.536 17.043 97.02 89.76;104.88 AUCss (ng.h/mL) 322.412 333.668 96.63 88.98;104.92 Cmin,ss (ng/mL) 10.249 10.301 99.50 89.41;107.48

N-desmethyldiltiazem: Cmax,ss (ng/mL) 61.957 62.821 98.62 92.52;105.14 AUCss (ng.h/mL) 1125.252 1108.293 101.53 94.71;108.84 Cmin,ss (ng/mL) 29.653 28.505 104.03 92.89;116.50

With the exception of the Cmin,ss values, the 90% confidence intervals for all actives lie within the acceptance criteria specified in the Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98). One Cmin,ss value was outside the upper range of the 90% confidence interval for diltiazem (125.37%). This value was not considered to be of clinical significance, based on the large variation in Cmin,ss values. Also the mean values for the test product were higher than the reference, and the observed deviation concerns the upper limit of the 90% CI. Therefore, there is no particular concern about drug concentrations falling below the expected levels (compared to the originator). So overall, this finding is of little clinical relevance. Therefore, bioequivalence has been shown between the test and reference products. As these products meet all the criteria as specified in the Note for Guidance on the investigation of bioavailability and bioequivalence (CPMP/EWP/QWP/1401/98), the results and conclusions of the bioequivalence study on the 300mg strength can be extrapolated to the 200mg strength tablets. Efficacy No new data on the efficacy have been submitted and none are required for these types of applications. Safety With the exception of the data submitted during the bioequivalence study, no new safety data were submitted and none were required. No new or unexpected safety issues were raised by the bioequivalence data. SmPC, PIL and Labels The SmPCs, PILs and labels are medically acceptable. The SmPCs are consistent with those for the originator product. Pharmacovigilance System and Risk Management Plan 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. Suitable justification has been provided for not submitting a risk management plan for these products. Clinical Expert Report The clinical expert report has been 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 important quality characteristics of Lofamil XL 200 and 300mg Prolonged-release Capsules 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 this type. CLINICAL Bioequivalence has been demonstrated between the applicant’s products and the reference products. No new or unexpected safety concerns arose from these applications. The SmPCs, PILs and labelling are satisfactory and consistent with those for the reference products. BENEFIT-RISK ASSESSMENT The quality of the products is acceptable, and no new non-clinical or clinical safety concerns have been identified. The bioequivalence study supports the claim that the applicant’s products and the originator products are interchangeable. Extensive clinical experience with diltiazem hydrochloride is considered to have demonstrated the therapeutic value of the compound. The benefit-risk is therefore considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted

Application type

Scope Outcome

Documents

Public Assessment Report Decentralised Procedure - GOV.UK · and angina (chest pain). It works mainly by making your blood vessels wider. This helps to lower your blood pressure