SUMMARY OF PRODUCT CHARACTERISTICS - Medicines and Healthcare

Lisinopril 2.5 mg, 5 mg 10 mg and 20 mg Tablets PL 16363/0182-4 and 0187

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LISINOPRIL 2.5 MG TABLETS LISINOPRIL 5 MG TABLETS

LISINOPRIL 10 MG TABLETS LISINOPRIL 20 MG TABLETS

PL 16363/0182 PL 16363/0183 PL 16363/0184 PL 16363/0187

UKPAR

TABLE OF CONTENTS Lay Summary

Page 3

Scientific discussion

Page 4

Steps taken for assessment

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Steps taken after authorisation – summary

Summary of Product Characteristics Page 13

Product Information Leaflet

Page 14

Labelling Page 15




PL 16363/0182-4 and 0187

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Milpharm Limited, UK Marketing Authorisations for the medicinal products Lisinopril 2.5 mg, 5 mg, 10 mg and 20 mg Tablets (PL 16363/0182-4 and 0187) on 28 June 2012. These are prescription-only medicines (POM). Lisinopril belongs to a group of medicines called Angiotensin-Converting Enzymes (ACE) inhibitors. These work by expanding your blood vessels and making it easier for your heart to pump blood to all parts of your body. Lisinopril is used in the treatment of high blood pressure (hypertension), heart failure, kidney problems caused by Type II diabetes in people with high blood pressure and patients who have recently had a heart attack (myocardial infarction). No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of taking Lisinopril 2.5 mg, 5 mg, 10 mg and 20 mg Tablets outweigh the risks; hence Marketing Authorisations were granted.

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PL 16363/0182-4 and 0187

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 4

Pharmaceutical assessment

Page 5

Non-clinical assessment

Page 8

Clinical assessment

Page 9

Overall conclusions and risk assessment Page 11

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INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted Milpharm Limited Marketing Authorisations for the medicinal products Lisinopril 2.5 mg, 5 mg, 10 mg and 20 mg Tablets (PL 16363/0182-4 and 0187) on 28 June 2012. These products are prescription-only medicines (POM). These tablets contain the active ingredient lisinopril and are indicated for the following conditions:

• Hypertension • Heart failure • Acute myocardial infarction • Renal disease in hypertensive patients with Type 2 diabetes mellitus and incipient

nephropathy. These applications were submitted under Article 10(1) of Directive 2001/83/EC, as amended, claiming to be generic medicinal products of Acerbon 2.5 mg, 5mg, 10mg, 20 mg Tablets, (AstraZeneca, Germany), which were first authorised on 13 December 1997. The corresponding reference products in the UK Zestril 2.5 mg, 5 mg , 10 mg and 20 mg Tablets (AstraZeneca Limited, UK), which were first authorised in the UK on May 1988). Lisinopril non-competitively inhibits ACE, a dipeptidyl dipeptidase that generates vasoactive peptide angiotensin II from angiotensin I. This mechanism inhibits production of Angiotensin II with reduction in plasma renin activity. Lisinopril also exhibits antihypertensive effects in low renin population as well. No new non-clinical data have been submitted, which is acceptable given that the applications were based on being generic versions of the originator products that have been in clinical use for over 10 years. A single-dose, bioequivalence study carried out under fasting conditions was submitted to support these applications, comparing the pharmacokinetic profile of the test product, Lisinopril 20 mg Tablets (Milpharm Limited, UK), versus the reference product, Acerbon 20 mg Tablets (AstraZeneca, Germany). The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP). With the exception of the bioequivalence study, no new clinical studies were performed, which is acceptable given that the applications were based on being generic versions of the originator products which have been in clinical use for over 10 years. No new or unexpected safety concerns arose during review of information provided by the Marketing Authorisation Holder and it was, therefore, judged that the benefits of taking Lisinopril 2.5 mg, 5 mg, 10 mg and 20 mg Tablets outweigh the risks; hence the Marketing Authorisations were granted.

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Lisinopril 2.5 mg, 5 mg 10 mg and 20 mg Tablets PL 16363/0182-4 and 0187 PHARMACEUTICAL ASSESSMENT ACTIVE SUBSTANCE INN: Lisinopril

Chemical names: (2S)-1-[(2S)-6-amino-2-[[(1S)-1-carboxy-3-phenylpropyl] amino]hexanoyl]pyrrolidine-2- carboxylic acid dihydrate.

Structure:

Molecular Formula: C21H31N3O52H2O Molecular Weight: 441.5Appearance: A white or almost white crystalline powder. Solubility: Soluble in water, sparingly soluble in methanol and practically

insoluble in acetone and in anhydrous ethanol. Lisinopril is the subject of a European Pharmacopoeia monograph at the time of assessment. All aspects of the manufacture and control of the active substance lisinopril are covered by European Directorate for the Quality of Medicines (EDQM) Certificates of Suitability. Suitable specifications have been provided for all packaging used. The primary packaging has been shown to comply with current guidelines concerning contact with foodstuff. Appropriate stability data have been generated to support a suitable retest periods for the active substance when stored in the proposed packaging. DRUG PRODUCT Other Ingredients Other ingredients consist of pharmaceutical excipients, namely Mannitol, calcium hydrogen phosphate dihydrate, , maize starch, pregelatinised starch, magnesium stearate and colloidal anhydrous silica. Appropriate justifications for the inclusion of each excipient have been provided. All excipients comply with their respective European Pharmacopoeia monograph. Certificates of Analysis have been provided for all excipients, showing compliance with the proposed specifications. The applicant has provided a declaration confirming that none of the excipients contain materials of animal or human origin. The supplier of magnesium stearate has provided a TSE Certificate of Suitability to show that appropriate measures are taken to reduce the risk of transmission of BSE/TSE, in line with current EU regulations. No genetically modified organisms (GMO) have been used in the preparation of these excipients.

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Lisinopril 2.5 mg, 5 mg 10 mg and 20 mg Tablets PL 16363/0182-4 and 0187 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, Acerbon 2.5 mg, 5 mg, 10 mg and 20 mg Tablets (AstraZeneca, Germany). Suitable pharmaceutical development data have been provided for these applications. Comparative impurity and dissolution profiles have been provided for batches of the test products and appropriate 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 and has shown satisfactory results. Finished Product Specification The finished product specifications are satisfactory. Test methods have been described and adequately validated, as appropriate. Batch data have been provided for all strengths of the medicinal product 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 blisters constituted from a polyvinylchloride/polyvinylidene chloride (PVC/PVdC) and aluminium foil blisters in packs containing 28 tablets.

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 foodstuffs. Stability Finished product stability studies were performed in accordance with current guidelines on batches of finished products in the packaging proposed for marketing. Based on the results, a shelf life of 36 months with storage condition, ‘Do not store above 25°C. Store in the original package’ has been accepted. Bioequivalence/Bioavailability Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the bioequivalence study. Summaries of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SmPCs, PIL and labelling are satisfactory. 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.

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Lisinopril 2.5 mg, 5 mg 10 mg and 20 mg Tablets PL 16363/0182-4 and 0187 MAA Forms The MAA forms are satisfactory. Expert Report 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.

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Lisinopril 2.5 mg, 5 mg 10 mg and 20 mg Tablets PL 16363/0182-4 and 0187 NON-CLINICAL ASSESSMENT PHARMACODYNAMICS, PHARMACOKINETICS AND TOXICOLOGY As the pharmacodynamic, pharmacokinetic and toxicological properties of lisinopril are well-known, no further non-clinical studies are required and none have been provided. NON-CLINICAL EXPERT REPORT The non-clinical overview has been written by an appropriately qualified person and is a suitable summary of the non-clinical aspects of the dossier. ENVIRONMENTAL RISK ASSESSMENT Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As the products are intended for generic substitution with products that is 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.

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Lisinopril 2.5 mg, 5 mg 10 mg and 20 mg Tablets PL 16363/0182-4 and 0187 CLINICAL ASSESSMENT CLINICAL PHARMACOLOGY The clinical pharmacology of lisinopril is well-known. With the exception of data from the bioequivalence study shown below, no new pharmacodynamic or pharmacokinetic data are provided or required for these applications. Pharmacokinetics In support of these applications, the Marketing Authorisation Holder has submitted the following bioequivalence study: A single-dose, randomized, double-blind, two-period, two-way, crossover study to compare the pharmacokinetics of the test product Lisinopril 20 mg Tablets (Milpharm Limited, UK) versus the reference product, Acerbon 20 mg Tablets (AstraZeneca, Germany) in healthy adult male subjects under fasted conditions. Blood samples were taken for the measurement of pharmacokinetic parameters pre-dose and up to 216 hours post dose. The washout period between the two treatment arms was 28 days. The pharmacokinetic results are presented below: Pharmacokinetic parameters (geometric least squares mean, ratios and confidence intervals [CI]) of lisinopril: Lisinopril 20 mg

(Test) Acerbon 20 mg

(Reference) Test/Ref

Ratio (%) 90% CI

Cmax (ng/ml) 61.60 62.28

0.96 82-114

AUC0-t (ng.h/ml) 103.14

103.14

1.00 89-113

AUC0-inf (ng.h/ml)) 113.07

115.51

0.98 89-115

AUC0-t area under the plasma concentration-time curve from time zero to t hours AUC0-∞ area under the plasma concentration-time curve from time zero to infinity Cmax maximum plasma concentration 90% geometric CI calculated from ln-transformed data The 90% confidence intervals for AUC and Cmax for test versus reference product for lisinopril are within the acceptance criteria specified in the Note for Guidance on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/, Corr), Thus, the data support the claim that the test product Lisinopril 20 mg Tablets (Milpharm Limited, UK) is bioequivalent to the reference product Acerbon 20 mg Tablets (AstraZeneca, Germany). EFFICACY The efficacy of lisinopril 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 study, no new safety data were submitted and none are required for applications of this type. No new or unexpected safety issues were raised by the bioequivalence study.

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Lisinopril 2.5 mg, 5 mg 10 mg and 20 mg Tablets PL 16363/0182-4 and 0187 SUMMARY OF PRODUCT CHARACTERISTICS (SmPC), PATIENT INFORMATION LEAFLET (PIL) AND LABELLING The SmPCs, PIL and labelling are clinically acceptable. 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 The clinical overview is written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. 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 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. CONCLUSION The grant of Marketing Authorisations is recommended.

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Lisinopril 2.5 mg, 5 mg 10 mg and 20 mg Tablets PL 16363/0182-4 and 0187 OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT QUALITY The important quality characteristics of Lisinopril 2.5 mg, 5 mg, 10 mg and 20 mg 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 lisinopril are well-known, no additional data were required. EFFICACY With the exception of the bioequivalence study, no new efficacy data were submitted and none are required for applications of this type. Bioequivalence has been demonstrated between the applicant’s 20 mg tablet strength and the 20 mg strength of reference product, Acerbon. As the 2.5 mg, 5 mg and the 10 mg strengths of the product meet the biowaiver criteria specified in the Guidance on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/, Corr), the results and conclusions from the bioequivalence study with the 20 mg strength tablet can be extrapolated to the 2.5 mg, 5 mg and 10 mg strengths. SAFETY With the exception of the safety data from the bioequivalence study, no new data were submitted and none are required for applications of this type. No new or unexpected safety concerns arose from the bioequivalence study PRODUCT LITERATURE The SmPCs, PIL and labelling are acceptable. 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. BENEFIT/RISK ASSESSMENT The quality of the products is acceptable, and no new non-clinical or clinical safety concerns have been identified. The data provided support the claim that these products are generic medicinal products of the reference products, Acerbon 2.5 mg, 5 mg , 10 mg and 20 mg Tablets (AstraZeneca, Germany). Extensive clinical experience with lisinopril is considered to have demonstrated the therapeutic value of the products. The benefit/risk is, therefore, considered to be positive.

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PL 16363/0182-4 and 0187

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Marketing Authorisation application on 18 June 2004.

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 20 August 2004

3 Following assessment of the application the MHRA requested further information relating on the quality dossier on 01 March 2005, 05 April 2005, 12 July 2006, 03 November 2008, 09 April 2010 and 18 November 2010, and the clinical dossier on 28 February 2005 .

4 The applicant responded to the MHRA’s requests, providing further information on the clinical dossier on 28 October 2010 and on the quality dossier on 13 June 2005, 12 July 2006, 03 July 2007, 03 April 2009, 28 October 2010 and 06 December 2010.

5 The application was determined and granted on 28 June 2012.

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SUMMARY OF PRODUCT CHARACTERISTICS The Summary of Product Characteristics for these products are published on the MHRA website

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MODULE 3

The Patient Information Leaflet for these products is published on the MHRA website.

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MODULE 4

Labelling

Carton

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SUMMARY OF PRODUCT CHARACTERISTICS - Medicines and Healthcare

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