Nifedepine CR UKPAR

UKPAR Nifed 30 mg and 60 mg Prolonged Release Tablets PL 20117/0228-9
NIFED 30 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 Page 15
Summary of Product Characteristics

Page 16
Patient Information Leaflet Page 17
Labelling Page 18
1
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.
2

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
3
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.
4
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.
5
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.
6
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.
7
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
8
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 AUC0-t AUC0-inf
(ng/mL) (ng*h/mL (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)
* Geometric mean was taken as the antilog (exponential) of the least square mean of the log-transformed data
9
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
healthy adult male subjects under fasting conditions.
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:

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
AUC0-inf area under the plasma concentration-time curve from time zero to infinity hours
SD standard deviation
Pharmacokinetic parameters (geometric means, ratios and confidence intervals [CI]) for nifedipine)

* 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.
10
Study 3
healthy adult male and female subjects under fed conditions.
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:

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
AUC0-inf area under the plasma concentration-time curve from time zero to infinity hours
CV coefficient of deviation

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.
11
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
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
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.
12
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
13
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.
14

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.
15
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.
16
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.
17
LABELLING
18
19

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

NIFED 30 MG PROLONGED RELEASE TABLETS

Scientific discussion Page 3

Steps taken for assessment Page 15

Summary of Product Characteristics

NIDEF 30 MG PROLONGED RELEASE TABLETS

NIDEF 30 MG PROLONGED RELEASE TABLETS

Pharmaceutical assessment Page 5

Non-clinical assessment Page 8

Clinical assessment Page 9

Overall conclusion and risk assessment Page 14

The active ingredient, nifedipine, is a dihydropyridine calcium channel blocker.

Molecular formula: C17H18N2O6

Nifedipine is the subject of a European Pharmacopoeia monograph.

None of the excipients contain materials of animal or human origin.

Control of Finished Product

Container Closure System

Summaries of Product Characteristics (SmPCs), Patient Information Leaflets (PILs) and

MAA (Marketing Authorisation Application) Forms

Expert Report (Quality Overall Summary)

NON-CLINICAL EXPERT REPORT (NON-CLINICAL OVERVIEW)

ENVIRONMENTAL RISK ASSESSMENT

Descriptive Statistics for Untransformed parameters

Test product (A) Nifedipine 30 mg XL Tablets (Cipla Limited, India)

The Note for Guidance on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1)

Descriptive Statistics for Untransformed parameters

Test product (A) Nifedipine 60 mg XL Tablets (Cipla Limited, India)

Descriptive Statistics for Untransformed parameters

Test product (A) Nifedipine 30 mg XL Tablets (Cipla Limited, India)

Test Product A Nifedipine 30 mg XL Tablets (Cipla Limited, India)

Overall Conclusion on Bioequivalence

PHARMACOVIGILANCE SYSTEM AND RISK MANAGEMENT PLAN

SUMMARIES OF PRODUCT CHARACTERISTICS (SmPCs), PATIENT INFORMATION

CLINICAL EXPERT REPORT (CLINICAL OVERVIEW)

OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT

NIFED 30 MG PROLONGED RELEASE TABLETS

STEPS TAKEN FOR ASSESSMENT

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

SUMMARY OF PRODUCT CHARACTERISTICS

PATIENT INFORMATION LEAFLET

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