ukpar nifed 30 mg and 60 mg prolonged release tablets … · nifed 60 mg prolonged release tablets...

UKPAR Nifed 30 mg and 60 mg Prolonged Release Tablets PL 20117/0228-9

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NIFED 30 MG PROLONGED RELEASE TABLETS NIFED 60 MG PROLONGED RELEASE TABLETS

Nifedipine

PL 20117/0228-9

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

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Summary of Product Characteristics

Page 16

Patient Information Leaflet

Page 17

Labelling Page 18


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NIDEF 30 MG PROLONGED RELEASE TABLETS NIDEF 30 MG PROLONGED RELEASE TABLETS

Nifedipine

PL 20117/0228-9

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Morningside Healthcare Limited Marketing Authorisations for the medicinal products Nifed 30 mg and 60 mg Prolonged Release Tablets (PL 20117/0228-9) on 29 July 2013. These medicines are only available on prescription from your doctor. Nifed 30 mg and 60 mg Prolonged Release Tablets contain nifedipine, which belongs to a group of medicines called calcium antagonists. Nifed Tablets are used to treat high blood pressure or angina (chest pain). For high blood pressure: Nifed 30 mg and 60 mg Prolonged Release Tablets work by relaxing and expanding the blood vessels. This makes the blood flow more easily and lowers blood pressure. Lower blood pressure reduces the strain on the heart. For angina: Nifed 30 mg and 60 mg Prolonged Release Tablets work by relaxing and expanding the arteries supplying the heart. This allows more blood and oxygen to reach the heart and decrease the strain on it. Angina attacks will be less severe and less frequent if there is less strain on the heart. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of taking Nifed 30 mg and 60 mg Prolonged Release Tablets outweigh the risks and Marketing Authorisations were granted.


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NIDEF 30 MG PROLONGED RELEASE TABLETS NIDEF 30 MG PROLONGED RELEASE TABLETS

Nifedipine

PL 20117/0228-9

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 4

Pharmaceutical assessment

Page 5

Non-clinical assessment

Page 8

Clinical assessment

Page 9

Overall conclusion and risk assessment Page 14


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INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted Morningside Healthcare Limited Marketing Authorisations for the medicinal products Nifed 30 mg and 60 mg Prolonged Release Tablets (PL 20117/0228-9) on 29 July 2013. These products are prescription-only medicines (POM) indicated for the: treatment of all grades of hypertension; prophylaxis of chronic stable angina pectoris either as monotherapy or in combination with a

beta-blocker. The applications were submitted under Article 10(1) of Directive 2001/83/EC, as amended, cross-referring to Adalat LA 30 mg and 60 mg prolonged-release tablets (Bayer plc, UK), authorised in the UK on 16 March 1992. The active ingredient, nifedipine, is a dihydropyridine calcium channel blocker. Four bioequivalence studies were submitted to support these applications, three bioequivalence studies comparing the applicant’s test product Nifedipine 30 mg XL tablets with the reference product Adalat LA 30 mg (Bayer plc, UK) under fed, fasting and steady-state conditions and one bioequivalence study comparing the applicant’s product Nifedipine 60 mg XL Tablets with the reference product Adalat LA 60 mg (Nifedipine 60 mg Tablets; Bayer plc, UK) under fasting conditions. The bioequivalence studies were carried out in accordance with Good Clinical Practice (GCP). With the exception of the bioequivalence studies, no new non-clinical or clinical data were submitted, which is acceptable given that these applications were based on the products being generic medicinal products of originator products that 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 Nifed 30 mg and 60 mg Prolonged Release Tablets outweigh the risks and Marketing Authorisations were granted.


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PHARMACEUTICAL ASSESSMENT ACTIVE SUBSTANCE INN: Nifedipine Chemical name: Dimethyl 1,4 – dihydro – 2,6 – dimethyl – 4 – (o –nitrophenyl) – 3,5 –

pyridinedicarboxylate Structure:

Molecular formula: C17H18N2O6 Molecular weight: 346.33 Appearance: Yellow powder, which is affected by exposure to light. Solubility Freely soluble in acetone, sparingly soluble in ethanol, practically insoluble in

water. Nifedipine is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance nifedipine are covered by a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of Suitability. DRUG PRODUCT Other Ingredients Other ingredients consist of the pharmaceutical excipients in the tablet core, seal coating and film coating, namely polyethylene oxide, hydroxy propyl methyl cellulose (E463), sodium chloride, polyethylene oxide, ferric oxide (E172), magnesium stearate (E572), hypromellose (E464), cellulose acetate, polyethylene glycol (E1521), dichloromethane, methanol, hydroxypropyl cellulose (E463), titanium dioxide (E171), talc (E553b) and iron oxide red (E172). Appropriate justification for the inclusion of each excipient has been provided. With the exception of polyethylene oxide, ferric oxide (E172) and iron oxide red (E172), all excipients comply with their respective European Pharmacopoeia monographs. Polyethylene oxide, ferric oxide (E172) and iron oxide red (E172) are compliant with their United States Pharmacopoeia-National Formulary specifications. Satisfactory Certificates of Analysis have been provided for all excipients, showing compliance with the proposed specifications. None of the excipients contain materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of these excipients. Pharmaceutical Development The objective of the development programmes was to formulate safe efficacious, stable prolonged release tablets that were comparable in performance to the innovator products Adalat LA 30 mg and 60 mg prolonged release tablets (Bayer plc, UK). Suitable pharmaceutical development data have been provided for these applications.


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Comparative in-vitro dissolution profiles have been provided for these products and the reference products. Manufacturing Process Satisfactory batch formulae have been provided for the manufacture of the products, along with an appropriate account of the manufacturing processes. The manufacturing process has been validated with full-scale production-scale batches and has shown satisfactory results. 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 specification. Certificates of Analysis have been provided for any working standards used. Container Closure System The tablets are packaged in polyvinylchloride/polyethylene/polyvinylidene chloride-aluminum blisters, with the Patient Information Leaflet in cartons, in pack sizes of 10, 14, 15, 28, 30, 56, 60, 90 and 112 prolonged release 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 food.

Stability Finished 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 24 months, with the storage conditions ‘Store in the original container.’ Suitable post approval stability commitments have been provided to continue stability studies on batches of finished product. Bioequivalence Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the bioequivalence studies. Summaries of Product Characteristics (SmPCs), Patient Information Leaflets (PILs) and Labelling The SmPCs, PILs and labelling are satisfactory from a pharmaceutical perspective. 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. MAA (Marketing Authorisation Application) Forms The MAA forms are satisfactory from a pharmaceutical perspective.


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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.


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NON-CLINICAL ASSESSMENT PHARMACODYNAMICS, PHARMACOKINETICS AND TOXICOLOGY As the pharmacodynamic, pharmacokinetic and toxicological properties of nifedipine are well-known, no further non-clinical studies are required and none have been provided. NON-CLINICAL EXPERT REPORT (NON-CLINICAL OVERVIEW) The applicant’s 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. ENVIRONMENTAL RISK ASSESSMENT As the products are intended for generic substitution with products that are already marketed, no increase in environmental burden is anticipated. Thus, non-submission of an Environmental Risk Assessment is accepted. CONCLUSION The grant of Marketing Authorisations is recommended.


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CLINICAL ASSESSMENT

CLINICAL PHARMACOLOGY The clinical pharmacology of nifedipine is well-known. With the exception of data from the bioequivalence studies detailed below, no new pharmacodynamic or pharmacokinetic data are provided or are required for these applications. Pharmacokinetics In support of these applications, the applicant submitted the following bioequivalence studies: Study 1 A randomised, open label, two-treatment, two-sequence, two-period, single-dose, crossover study to compare the pharmacokinetics of the test product Nifedipine 30 mg XL Tablets (Cipla Limited, India) versus the reference product Adalat LA 30 (Nifedipine 30 mg tablets; Bayer plc, UK) in healthy adult male and female subjects under fasting conditions. The subjects were administered a single dose (1 tablet) of either the test or the reference product with 240 ml of water, after at least a 10-hour overnight fast. Blood samples were collected before and up to and including 36 hours after each administration. The washout period between the treatment phases was at least 7 days. The pharmacokinetic results are presented below:

Descriptive Statistics for Untransformed parameters

Measures Cmax (ng/mL)

AUC0-t (ng*h/mL

AUC0-inf (ng*h/mL)

Test Product-A

Mean 32.17 570.18 918.06

SD 18.19 355.09 939.93

CV (%) 56.56 62.28 102.38

Reference Product-B

Mean 29.72 527.58 983.11

SD 12.53 299.08 2200.58

CV (%) 42.15 56.69 223.84

Test product-A Nifedipine 30 mg XL Tablets (Cipla Limited, India) Reference product-B Adalat LA 30 (Nifedipine 30 mg tablets; Bayer plc, UK) Cmax maximum plasma concentration AUC0-t area under the plasma concentration-time curve from time zero to t hours AUC0-inf Standard deviation

Pharmacokinetic parameters (geometric means, ratios and confidence intervals [CI]) for nifedipine)

Test product (A) Nifedipine 30 mg XL Tablets (Cipla Limited, India) Reference product (B) Adalat LA 30 (Nifedipine 30 mg tablets; Bayer plc, UK) Cmax maximum plasma concentration AUC0-t area under the plasma concentration-time curve from time zero to t hours * Geometric mean was taken as the antilog (exponential) of the least square mean of the log-transformed data


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The Note for Guidance on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1) defines the confidence limits as 80.00% to 125.00% for AUC and Cmax values. Thus, the data support the claim that the applicant’s test product Nifedipine 30 mg XL Tablets (Cipla Limited, India) is bioequivalent to the reference product Adalat LA 30 (Nifedipine 30 mg tablets; Bayer plc, UK) under fasting conditions. Study 2 A randomised, open label, two-treatment, two-sequence, two-period, single-dose, crossover study to compare the pharmacokinetics of the test product Nifedipine 60 mg XL Tablets (Cipla Limited, India) versus the reference product Adalat LA 60 (Nifedipine 630 mg tablets; Bayer plc, UK) in healthy adult male subjects under fasting conditions. The subjects were administered a single dose (1 tablet) of either the test or the reference product with 240 ml of water, after at least a 10-hour overnight fast. Blood samples were collected before and up to and including 36 hours after each administration. The washout period between the treatment phases was at least 7 days. The pharmacokinetic results are presented below:



AUC0-t (ng*h/mL

AUC0-inf (ng*h/mL)

Test Product-A

Mean 62.70 1212.83 4861.97

SD 28.20 679.88 19904.72

CV (%) 44.97 56.06 409.40

Reference Product-B

Mean 64.49 1140.75 1218.96

SD 28.22 618.89 875.21

CV (%) 43.76 54.25 71.80

Test product-A Nifedipine 60 mg XL Tablets (Cipla Limited, India) Reference product-B Adalat LA 60 (Nifedipine 60 mg tablets; Bayer plc, UK) 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 hours SD standard deviation


Test product (A) Nifedipine 60 mg XL Tablets (Cipla Limited, India) Reference product (B) Adalat LA 60 (Nifedipine 60 mg tablets; Bayer plc, UK) Cmax maximum plasma concentration AUC0-t area under the plasma concentration-time curve from time zero to t hours * Geometric mean was taken as the antilog (exponential) of the least square mean of the log-transformed data.

The 90% confidence intervals of the test/reference ratio for AUC0-t, and Cmax lie within the acceptable limits. Thus, the data support the claim that the applicant’s test product Nifedipine 60 mg XL Tablets (Cipla Limited, India) is bioequivalent to the reference product Adalat LA 60 (Nifedipine 60 mg tablets; Bayer plc, UK) under fasting conditions.


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Study 3 A randomised, open label, two-treatment, two-sequence, two-period, single-dose, crossover study to compare the pharmacokinetics of the test product Nifedipine 30 mg XL Tablets (Cipla Limited, India) versus the reference product Adalat LA 30 (Nifedipine 30 mg tablets; Bayer plc, UK) in healthy adult male and female subjects under fed conditions. The subjects were administered a single dose (1 tablet) of either the test or the reference product with 240 ml of water, 30 minutes after the start of a high-fat, high calorie breakfast. Subjects were fasted for at least 10 hour overnight before breakfast and breakfast was completed within 30 minutes. Blood samples were collected before and up to and including 36 hours after each administration. The washout period between the treatment phases was at least 8 days. The pharmacokinetic results are presented below:



AUC0-t (ng*h/mL

AUC0-inf (ng*h/mL)

Test Product-A

Mean 35.36 610.59 910.63

SD 19.32 383.26 891.92

CV (%) 54.63 62.77 97.95

Reference Product-B

Mean 34.69 574.90 747.36

SD 20.39 424.15 705.13

CV (%) 58.78 73.78 94.35

Test product-A Nifedipine 30 mg XL Tablets (Cipla Limited, India) Reference product-B Adalat LA 30 (Nifedipine 30 mg tablets; Bayer plc, UK) 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 hours SD standard deviation CV coefficient of deviation


Test product (A) Nifedipine 30 mg XL Tablets (Cipla Limited, India) Reference product (B) Adalat LA 30 (Nifedipine 30 mg tablets; Bayer plc, UK) Cmax maximum plasma concentration AUC0-t area under the plasma concentration-time curve from time zero to t hours * Geometric mean was taken as the antilog (exponential) of the least square mean of the log-transformed data

The 90% confidence intervals of the test/reference ratio for AUC0-t, and Cmax lie within the acceptable limits. Thus, the data support the claim that the applicant’s test product Nifedipine 30 mg XL Tablets (Cipla Limited, India) is bioequivalent to the reference product Adalat LA 30 (Nifedipine 30 mg tablets; Bayer plc, UK) under fed conditions.


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Study 4 A randomised, open label, two-treatment, two-sequence, two-period, multiple dose, crossover study to compare the pharmacokinetics of the test product Nifedipine 30 mg XL Tablets (Cipla Limited, India) versus the reference product Adalat LA 30 (Nifedipine 30 mg tablets; Bayer plc, UK) in healthy adult male and female subjects under fasting conditions. The subjects were administered a single dose (1 tablet) of either the test or reference product (as per the randomization schedule) with 240 ml of water, after at least a 10-hour overnight fast on Days 1, 2, 3, 4, 5, 6 and 7 in each period. The washout period between the treatment phases was at least 11 days. Blood samples were collected before administration on Days 1, 2, 3, 4, 5 and 6 and before and up to 24 hours after administration on Day 7. The pharmacokinetic results are presented below:

Test Product A Nifedipine 30 mg XL Tablets (Cipla Limited, India) Reference Product B Adalat LA 30 (Nifedipine 30 mg tablets; Bayer plc, UK) Cmaxss Maximum observed drug concentration between dose time and dose time t Cminss Minimum observed drug concentration after drug reaches steady state AUC0-τ Area under the plasma concentration-time curve measure to the last quantifiable concentration SD standard deviation


Cmaxss Maximum observed drug concentration between dose time and dose time t Cminss Minimum observed drug concentration after drug reaches steady state AUC0-τ Area under the plasma concentration-time curve measure to the last quantifiable concentration * Geometric mean was taken as the antilog (exponential) of the least square mean of the log-transformed data

The 90% confidence intervals of the test/reference ratio for Cminss, Cmaxss and AUC0-τ lie within the acceptable limits. Thus, the data support the claim that the applicant’s test product Nifedipine 30 mg XL Tablets (Cipla Limited, India) is bioequivalent to the reference product Adalat LA 30 (Nifedipine 30 mg tablets; Bayer plc, UK) under steady state conditions.


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Overall Conclusion on Bioequivalence Bioequivalence has been demonstrated between the applicant’s 30 mg and 60 mg strength products and the respective reference products under fasting conditions, and the applicant’s 30 mg strength product and the reference product under fed conditions. At steady state, bioequivalence has been demonstrated between the applicant’s 30 mg strength product and the reference product. Suitable justification has been provided for non-submission of bioequivalence studies for the applicant’s 60 mg strength product under fed and steady state conditions. A biowaiver has been granted to the 60 mg strength tablets under fed and steady state conditions, based on the studies conducted, in line with the current bioequivalence guideline. EFFICACY The efficacy of nifedipine 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 were raised during the bioequivalence studies. 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. The applicant has stated that no special important risks or potential risks have been identified for the originator products which would require additional risk minimization activities; this is acceptable. SUMMARIES OF PRODUCT CHARACTERISTICS (SmPCs), PATIENT INFORMATION LEAFLETS (PILs) AND LABELLING The SmPCs, PILs and labelling are acceptable from a clinical perspective. The SmPCs are consistent with that for the reference products. The PILs are consistent with the details in the SmPCs and in line with the current guidance. The labelling is also in line with current guidance. 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.


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OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT QUALITY The important quality characteristics of Nifed 30 mg and 60 mg Prolonged Release 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 nifedipine 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 30 mg and 60 mg strength products and the reference products under fasting conditions, and the applicant’s 30 mg strength product and the reference product under fed conditions. At steady state, bioequivalence was demonstrated between the applicant’s 30 mg strength product and the reference product. A biowaiver has been granted to the 60 mg strength tablets under fed and steady state conditions, based on the studies conducted, in line with the current bioequivalence guideline.

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 nifedipine is well-known, no additional data were required. No new or unexpected safety concerns arose from the bioequivalence studies. PRODUCT LITERATURE The SmPCs, PILs and labelling are satisfactory and in line with current guidance. BENEFIT/RISK ASSESSMENT The quality of the products are acceptable, and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with nifedipine is considered to have demonstrated the therapeutic value of the compound. The benefit/risk balance is, therefore, considered to be positive.


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NIFED 30 MG PROLONGED RELEASE TABLETS NIFED 60 MG PROLONGED RELEASE TABLETS

Nifedipine

PL 20117/0228-9

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Marketing Authorisation applications on 13 January 2012.

2 Following standard checks and communication with the applicant the MHRA considered the applications valid on 29 March 2013.

3 Following assessment of the applications the MHRA requested further information relating to the clinical dossier on 25 July 2012 and on the quality dossier on 25 July 2012, 11 February 2013 and 20 May 2013

4 The applicant responded to the MHRA’s requests, providing further information on the clinical dossier on 11 December 2012, and the quality dossier on 11 December 2012, 26 February 2013, 17 April 2013, 22 May 2013 and 24 May 2013.

5 The applications were granted on 29 July 2013.


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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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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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LABELLING


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ukpar nifed 30 mg and 60 mg prolonged release tablets … · nifed 60 mg prolonged release tablets...

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