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Public Assessment Report
Scientific discussion
AGEN 5
AGEN 10
Amlodipine besylate
CZ/H/0120/001/MR
CZ/H/0120/002/MR
Applicant: Zentiva, a.s., Prague, Czech Republic
This module reflects the scientific discussion for the approval of Agen 5 and 10 tablets. The
procedures were finalised at 5th June 2006.
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INTRODUCTION
This generic application for marketing authorisation concerns Agen, Zentiva a.s., tablets in
the strengths 5mg and 10mg. These two strengths of Agen, are approved in a Mutual
Recognition Procedure on 5th June 2006. The Concerned Member State were Hungary and
Latvia..
2nd wave of Mutual Recognition Procedure was finished on 5th December 2007, the
Concerned Member State were Romania and Bulgaria.
The tablets are claimed to be essentially similar to Norvasc 5mg/10mg (5mg and 10mg of
amlodipine) tablets marketed in Czech Republic by Pfizer Ltd., Sandwich, Kent, UK.
The product is indicated for the treatment of hypertension and prophylactic treatment of stable
angina pectoris and Prinzmetal variant angina pectoris.
The reference products used in the bioequivalence study was Norvasc 10mg (10mg of
amlodipine) tablets. No new pre-clinical and clinical studies, besides the bioequivalence
study, were conducted. This is acceptable for this abridged application.
QUALITY ASPECTS
Introduction
Agen 5/10 is presented in the form of uncoated tablets containing 5 mg or 10 mg of
amlodipine besilate. The excipients are cellulose microcrystalline, calcium hydrogen phosphate
dihydrate, sodium starch glycolate (typeA) and magnesium stearate.
The product is packed into blisters made of PVC white opaque foil coated with PVDC and aluminium
foil. Blisters are placed, together with a package leaflet, into a paper folding box.
Drug substance
The active substance amlodipine besilate is described in the European Pharmacopoeia. Amlodipine
besilate is a white or almost white powder, slightly soluble in water, freely soluble in methanol,
sparingly soluble in ethanol, slightly soluble in 2-propanol. Amlodipine besilate has one chiral center,
it is a racemic mixture of R and S isomers (1:1), which is routinely controlled by optical rotation (0,10 0 and +0,100). One polymorph form was confirmed by X-ray diffraction, DSC and IR.
The manufacturer possesses CEP (European Pharmacopoeia certificate of suitability),
additional tests on residual solvents and any other impurity are included in the specification.
Satisfactory Certificates of Analysis have been provided which demonstrate compliance with the
stated specification.
Based on stability results, the re-test period (date) was set for 3 years.
Medicinal Product
The development of the medicinal product has been sufficiently described; the essential
similarity, based on comparison of dissolution profiles, impurity profiles and bioequivalence with
brand leader Norvasc 5/10 mg has been documented.
All excipients contained in tablets are described in the current Ph. Eur. It is claimed that the drug
product doesn’t contain any excipient of human or animal origin (magnesium stearate is of vegetable
origin).
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The manufacturing process described is a standard process and all in-process controls are considered
adequate to assure the quality of the product. The validation of manufacturing process confirms
that the process is reproducible, and demonstrates compliance with the specification.
The tests and limits are considered appropriate to justify the quality of the drug product. The
analytical methods have been sufficiently described and validated.
Batch analysis data has demonstrated compliance with the proposed release specification.
The safety of proposed packaging material has been documented.
Stability studies under ICH conditions have been performed and data presented. Based on the
results obtained from this stability study and evaluation of stability data, the shelf life of 3 years can be
approved for Agen 5/10 when stored in the original package (blister and carton) to protect the product
from light.
STEPS TAKEN AFTER AUTHORISATION – SUMMARY
Application type and scope
Variation IA/15a:
Submission of an updated European
Pharmacopoeia certificate of suitability for
an active substance Amlodipini besilas from
a manufacturer currently approved
Variation II:
Change to Module 1- addition of Risk
Managment Plan
Variation IA/15b:
Submission of a new European
Pharmacopoeia certificate of suitability for
an active substance Amlodipini besilas from
a new manufacturer
Variation IB/17a:
Approval of the re-test period of 3 year for
the active substance Amlodipini besilas from
a new manufacturer
Variation IA/38a:
Change in the test procedure of finished
product - minor change to an approved test
procedure with consequent change IA/37a
Change in the specification of finished
product (5.2.2008)
Variation II:
Change to Module 1 - Correction of SPC,
PIL and LAB during 2nd wave of MRP
(5.2.2008)
Variation IA/15a:
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Submission of an updated European
Pharmacopoeia certificate of suitability for
an active substance Amlodipini besilas from
a manufacturer currently approved (5.2.2008)
Variation IB/17a:
Change in the re-test period of the active
substance Amlodipine besilate from 3 to 5
years (19.3.2008)
Variation IA/15a:
Submission of an updated European
Pharmacopoeia certificate of suitability for
an active substance Amlodipini besilas from
a manufacturer currently approved
(20.10.2008)
Discussion on chemical and pharmaceutical aspects
Information on development, manufacture and control of the drug substance and drug product
has been presented in a satisfactory manner. The results of tests carried out indicate
satisfactory consistency and uniformity of important product quality characteristics, and these
in turn lead to the conclusion that the product should have a satisfactory and uniform
performance in the clinic.
CLINICAL ASPECTS
It’s acceptable that specific studies have not been performed, as the application is submitted in
accordance with Article 10.1 of Directive 2001/83/EC.
Amlodipine is a long-acting dihydropyridine calcium channel-blocking agent used in
treatment of hypertension and angina pectoris. Amlodipine is a peripheral arterial vasodilator
that acts directly on vascular smooth muscle to cause a reduction in blood pressure. In
subjects with exertional angina, amlodipine reduces the total peripheral resistance against
which the heart works and reduces the rate pressure product and thus myocardial oxygen
demand. The effectiveness of amlodipine in vasospastic angina is based on blocking the
constriction and restoring the blood flow in coronary arteries and arterioles.
Amlodipin has demonstrated efficacy in the treatment of hypertension and prophylactic
treatment of stable angina pectoris and Prinzmetal (variant) angina pectoris.
Amlodipine is gradually but completely absorbed from the gastrointestinal tract, with peak
serum levels occurring in 6 to 12 hours following oral administration. Absolute bioavailability
ranges from 64% to 80% and the absorption is not influenced by food.
Approximately 97,5% of circulating amlodipine is bound to plasmatic proteins. Distribution
volume is approximately 21.0 l/kg.
Mean peak serum levels are linear and age-independent after 5 and 10 mg oral dose.
The drug is extensively metabolised to inactive metabolites in liver.
The primary elimination route is oxidation to the pyridine analogue, with subsequent
oxidative de-amination of the 2-aminoethoxymethyl side chain or de-esterification at the 5methoxycarbonyl group.
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Elimination half-life is 35 to 50 hours. 10 percent are eliminated by urine in form of an
unchanged substance and 60 percent in form of metabolites in the urine.
In support of this application one study on strength 10 mg was submitted.
Randomised, two-way, two-period, single dose crossover study in healthy male volunteers.
Each subject received one tablet of 10 mg on two occasions with 14 days wash-out period.
Number of subjects: 26 healthy subjects were included. 26 persons finished the study and
evaluated.
Methods of analysis: Blood samples were sufficient for accurate Cmax estimation and
analysed using HPLC. The validation of the method is satisfactory.
Data analysis: Is performed using the ANOVA on log transformed AUC, Cmax.
Twenty six healthy volunteers completed the study. The wash out period was 14 days. Blood
samples were taken before administration and up to 132 hours post dose (acceptable since
AUCt / AUCinf > 0.8). The protocol defines acceptance criteria of 0.8 – 1.25 for AUC and 70 143% for Cmax. This is satisfactory.
The reported values for Tmax and T1/2 are in line with published data.
All plasma levels of amlodipine were above the assay lower limit of quantification for all
subjects. Baseline plasma levels at period 2 were below the assay lower limit of quantification
for all subjects.
Analyses of variance model included sequence, subject nested within sequence, period, and
formulation as effects. Analyses were performed on ln-transformed main pharmacokinetic
parameters AUC(0-inf.), and Cmax.
ANOVA was carried out on log transformed Cmax and AUC values and 90% confidence
intervals were calculated. The treatment, period, sequence and subject in sequence terms were
included in the model. Computer output corresponds with that model. There were no
significant sequence or period effects for AUCinf and Cmax.
Twenty six subjects have regularly completed both study periods. Their samples were
analysed and statistically evaluated. There are no procedures for protocol deviations and
missing data in the study protocol. There were no other major protocol deficiencies.
The values and variability of the individual data and the appearance of the individual plots are
in line with published data for this product.
No serious or unexpected adverse events were reported during the study.
The linear kinetic justifies the approach of only performing the bioequivalence on the highest
strength.
Bioequivalence between Agen 5/10(Zentiva) and Norvasc 5mg/10mg(Pfizer) has been
demonstrated.
Since this product has been shown to be essentially similar and refer to a product approved
based on a full application with regard to clinical efficacy/safety data, no further such data
have been submitted or are considered necessary.
The SPC of product Agen 5/10, tablets corresponds to the SPC of reference product Norvasc
5/10mg and is in compliance with the latest pharmacovigilance information. The Package
leaflet has been shown to provide the tested consumers with all required information in a clear
and comprehensive form and the Readability testing was performed according to the
guidelines.
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The quality of the product Agen 5/10, tablets, is satisfactory in relation to its safety and
efficacy.
The risk/benefit ratio is considered positive and Agen 5/10 tablets are recommended for
approval.
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