Download Public Assessment Report Scientific discussion Citalopram Jubilant

Public Assessment Report
Scientific discussion
Citalopram Jubilant 10 mg, 20 mg,
30 mg and 40 mg, film-coated tablets
(citalopram)
NL/H/2919/001-004/DC
Date: 28 October 2014
This module reflects the scientific discussion for the approval of Citalopram Jubilant
10 mg, 20 mg, 30 mg and 40 mg, film-coated tablets. The procedure was finalised at 22
April 2014. For information on changes after this date please refer to the module
‘Update’.
This report includes a summary, on pages 9-11.
I.
INTRODUCTION
Based on the review of the quality, safety and efficacy data, the Member States have granted a
marketing authorisation for Citalopram Jubilant 10 mg, 20 mg, 30 mg and 40 mg, film-coated tablets
from Jubilant Pharmaceuticals N.V.
The product is indicated for:
 Treatment of episodes of major depression.
 Treatment of panic disorder with or without agoraphobia.
A comprehensive description of the indications and posology is given in the SmPC.
This decentralised procedure concerns a generic application claiming essential similarity with the
innovator products Cipramil 10, 20 and 40 mg tablets (NL License RVG 19592- 19594) which were
first registered in the Netherlands in 1997 by Lundbeck B.V. The 10 mg strength is no longer
registered.
The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC.
For Citalopram Jubilant 30 mg the application is based on legal basis Article 10(3) Directive 2001/83,
a hybrid application because it concerns a different strength. Reference is made to Cipramil 20 mg
tablets.
The concerned member states (CMS) involved in this procedure were Cyprus (20 mg only), Denmark,
Germany, Sweden and the United Kingdom (10, 20, 40 mg).
II.
QUALITY ASPECTS
II.1
Introduction
Citalopram Jubilant 10 mg is a white, round, film-coated tablet debossed with ‘F7’ on one side and
plain on the other side.
Citalopram Jubilant 20 mg is a white oval shaped, biconvex, film-coated tablet with a scoreline on one
side, debossed with ‘F’ on the left side and ‘8’ on the right side of the scoreline and plain on the other
side. The tablet can be divided into equal doses.
Citalopram Jubilant 30 mg is a white, modified capsule shaped, biconvex, film-coated tablet with a
scoreline on both sides, debossed with ‘F’ and ‘9’ on either side of the scoreline on one side of the
tablet. The tablet can be divided into equal doses.
Citalopram Jubilant 40 mg is a white oval shaped, biconvex, film-coated tablet with a scoreline on one
side, debossed with ‘G’ on the left side and ‘1’ on the right side of the scoreline and plain on the other
side. The tablet can be divided into equal doses.
The tablets are packed in Alu/PVC/PVdC or Alu/Alu blisters.
The excipients are:
Tablet core - microcrystalline cellulose (E460), lactose monohydrate, copovidone (E1201),
croscarmellose sodium (E468), maize starch, magnesium stearate (E470b), hypromellose (E464),
glycerol (E422)
Tablet coating – hypromellose, titanium dioxide (E171), macrogol (E1521)
The tablet strengths are fully dose proportional.
II.2
Drug Substance
The active substance is citalopram hydrobromide, an established active substance described in the
European Pharmacopoeia (Ph.Eur.). It is a white or almost white crystalline powder which is sparingly
soluble in water. Existence of polymorphism was not reported in the literature for this active
substance. Citalopram contains one asymmetric carbon; hence, two enantiomers are possible.
The CEP procedure is used for the active substance. Under the official Certification Procedures of the
EDQM of the Council of Europe, manufacturers or suppliers of substances for pharmaceutical use can
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apply for a certificate of suitability concerning the control of the chemical purity and microbiological
quality of their substance according to the corresponding specific monograph, or the evaluation of
reduction of Transmissible Spongiform Encephalopathy (TSE) risk, according to the general
monograph, or both. This procedure is meant to ensure that the quality of substances is guaranteed
and that these substances comply with the European Pharmacopoeia.
Manufacturing process
A CEP has been submitted; therefore no details on the manufacturing process have been included.
Quality control of drug substance
The active substance specification is considered adequate to control the quality. Analytical methods
are validated where necessary. Batch analysis showed satisfactory results.
Stability of drug substance
Stability data on the active substance have been provided. Assessment thereof was part of granting
the CEP and has been granted by the EDQM. A retest period of 4 or 5 years is applied.
II.3
Medicinal Product
Pharmaceutical development
The development of the product has been described, the choice of excipients is justified and their
functions explained. The objective was to develop a product having pharmaceutical quantities as close
as possible to the innovator product, Cipramil. The choices of the packaging and manufacturing
process are justified in relation to the innovator. The manufacture and composition of the bio-batch
used in the bioequivalence study is identical to the proposed marketed product. The dissolution tests
are in conformity with the bioequivalence guideline. At pH 1.5, 4.5 and 6.8, dissolution profiles of the
lower tablet strengths are similar to the 40 mg batch used in the bioequivalence study, since more
than 85% of the drug is released in 15 minutes. Dissolution profiles of the Citalopram Jubilant tablets
were demonstrated to be similar to the innovator product. The MAH used the test as described in the
Ph.Eur. for testing breakability of the 20 mg, 30 mg and 40 mg tablets. Results for these three tablet
strengths show the efficacy of the break marks. The pharmaceutical development of the product has
been adequately performed.
Manufacturing process
The tablets are manufactured by wet granulation. The manufacturing process is considered a standard
process and has been adequately validated according to relevant European guidelines. Validation
data on the product has been presented for 3 pilot-scale batches.
Control of excipients
The excipients comply with the Ph.Eur. These specifications are acceptable.
Quality control of drug product
The product specification includes tests for appearance, identification of active substance and
colorant, assay, uniformity of dosage units (by content uniformity), subdivision (20, 30 and 40 mg),
water content, dissolution, related substances and microbiological quality. The analytical methods are
adequately described and validated. Where relevant, the stability indicating nature of analytical
procedures is demonstrated. Batch analytical data from the proposed production site have been
provided on two pilot/production-scale batches of each tablet strength, demonstrating compliance with
the release specification.
Stability of drug product
Stability data on the product has been provided for two pilot-scales batches of each tablet strength,
stored at 25°C/60%RH (12 months) and 40°C/75%RH (6 months). The conditions used in the stability
studies are according to the ICH stability guideline. The batches were stored in the proposed package.
No significant changes or trends were observed in any of the parameters. Based on the data of 12
months, the claimed shelf life of 2 years is acceptable. No special storage condition is needed.
Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies
Lactose monohydrate is prepared from milk and calf rennet. Milk is sourced from healthy animals in
the same conditions as milk collected for human consumption (Complies EU food hygiene
regulations). The production of calf rennet complies with the requirements defined in regulation
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999/2001 and other applicable EU legislation. The excipients have been declared by the respective
supplier to be without risk of TSE/BSE contamination.
Magnesium stearate is manufactured from fatty acid derived from vegetable sources. However,
magnesium stearate that is manufactured from fatty acids derived from animal sources may also be
used provided the material complies with the recommendations outlined in current version of EMA’s
“Note for guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via
human and veterinary medicinal products (EMA/410/01)”. The TSE/BSE declarations are added.
II.4
Discussion on chemical, pharmaceutical and biological aspects
Based on the submitted dossier, the member states consider that Citalopram Jubilant has a proven
chemical-pharmaceutical quality. Sufficient controls have been laid down for the active substance and
finished product.
No post-approval commitments were made.
III.
III.1
NON-CLINICAL ASPECTS
Ecotoxicity/environmental risk assessment (ERA)
Since Citalopram Jubilant is intended for generic substitution, this will not lead to an increased
exposure to the environment. An environmental risk assessment is therefore not deemed necessary.
III.2
Discussion on the non-clinical aspects
This product is a generic formulation of Cipramil, which is available on the European market.
Reference is made to the preclinical data obtained with the innovator product. A non-clinical overview
on the pharmacology, pharmacokinetics and toxicology has been provided, which is based on up-todate and adequate scientific literature. The overview justifies why there is no need to generate
additional non-clinical pharmacology, pharmacokinetics and toxicology data. Therefore, the member
states agreed that no further non-clinical studies are required.
IV.
IV.1
CLINICAL ASPECTS
Introduction
Citalopram is a well-known active substance with established efficacy and tolerability.
A clinical overview has been provided, which is based on scientific literature. The overview justifies
why there is no need to generate additional clinical data. Therefore, the member states agreed that no
further clinical studies are required.
For this generic application, the MAH has submitted a bioequivalence study, which is discussed
below.
IV.2
Pharmacokinetics
The MAH conducted a bioequivalence study in which the pharmacokinetic profile of the test product
Citalopram Jubilant 40 mg (Jubilant Pharmaceuticals N.V., Belgium) is compared with the
pharmacokinetic profile of the reference product Cipramil 40 mg tablets (H. Lundbeck A/S-Kobenhavn,
Denmark).
The choice of the reference product in the bioequivalence study has been justified by comparison of
compositions of reference products in different member states. The formula and preparation of the
bioequivalence batch is identical to the formula proposed for marketing.
Biowaiver
Based on the data submitted the following requirements for waiving additional strengths were met:
 The pharmaceutical products are manufactured by the same manufacturing process.
 The qualitative composition of the different strengths is the same.
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

The composition of the strengths are quantitatively proportional.
The dissolution profiles of the additional 10, 20 and 30 mg strengths are similar to the profiles
of the biobatch 40 mg as a dissolution of ± 85% was achieved within 15 minutes in the
relevant pH of 1.5, 4.5 and 6.8.
In addition, bioequivalence was shown between the test 40 mg and reference 40mg (see below). A
waiver for the additional strengths, Citalopram Jubilant 10 mg, 20 mg and 30 mg, can therefore be
granted.
Bioequivalence study
Design
A single-dose, randomised, two-period, two-treatment, two-sequence, crossover bioequivalence study
was carried out under fasted conditions in 28 healthy male subjects, aged 20-41 years. Each subject
received a single dose (40 mg) of one of the 2 citalopram formulations. The tablet was orally
administered with 240 ml water after an overnight fast. There were 2 dosing periods, separated by a
washout period of 15 days.
Blood samples were collected pre-dose and at 0.50, 1.00, 1.50, 2.00, 2.33, 2.67, 3.00, 3.33, 3.67,
4.00, 4.33, 4.67, 5.00, 5.33, 5.67, 6.00, 7.00, 8.00, 12.00, 18.00, 24.00, 48.00 and 72.00 hours after
administration of the products.
The design of the study is acceptable. A study in the fasting condition is appropriate as citalopram can
be taken with or without food. The wash-out period of 15 days (i.e. at least 5 terminal half-lives to
exclude carry-over effects) is agreed.
Analytical/statistical methods
The analytical method has been adequately validated and is considered acceptable for analysis of the
plasma samples. The methods used in this study for the pharmacokinetic calculations and statistical
evaluation are considered acceptable.
Citalopram is a racemic mixture of 50% S-enantiomer and 50% R-enantiomer. However, only the Senantiomer is pharmacologically active. According to guideline, if one enantiomer is pharmacologically
active and the other is inactive or has a low contribution to activity, it is sufficient to demonstrate
bioequivalence for the active enantiomer. Both enantiomers were measured in the study.
Bioequivalence was based on the S-citalopram and results from R-citalopram were reported as
supportive information. This is agreed.
Results
One subject was withdrawn prior to dosing in period II and one subject dropped out of the study.
Twenty-six subjects completed the study and were eligible for pharmacokinetic analysis.
Table 1.
Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
(median, range)) of S-citalopram under fasted conditions.
Treatment
N=26
Test
AUC0-72
Cmax
tmax
ng.h/ml
ng/ml
h
t1/2
h
1141 ± 339
43.4 ± 8.5
2.7
(1.5 – 5.0)
28.6 ± 8
Reference
1158 ± 331
43.2 ± 9.1
30.8 ± 11
*Ratio (90% CI)
0.98
(0.95 –1.02)
1.00
(0.96 – 1.05)
2.7
(1.5 – 7)
--
--
AUC0-72 area under the plasma concentration-time curve from time zero to 72 hours
Cmax
maximum plasma concentration
tmax
time for maximum concentration
t1/2
half-life
*ln-transformed values
Table 2.
Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
(median, range)) of R-citalopram under fasted conditions.
Treatment
AUC0-72
Cmax
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tmax
t1/2
N=26
Test
ng.h/ml
ng/ml
h
h
1483 ± 229
46.1 ± 7.6
2.7
(1.5 – 5.0)
41.3 ± 6.7
Reference
1507 ± 245
46.1 ± 9.5
44.6 ± 11.1
*Ratio (90% CI)
0.98
(0.96 –1.01)
1.00
(0.96 – 1.04)
2.8
(1.5 – 7.0)
--
--
AUC0-72 area under the plasma concentration-time curve from time zero to 72 hours
maximum plasma concentration
Cmax
time for maximum concentration
tmax
t1/2
half-life
*ln-transformed values
Conclusion on bioequivalence study:
The 90% confidence intervals calculated for AUC0-72 and Cmax are within the bioequivalence
acceptance range of 0.80-1.25. Based on the submitted bioequivalence study Citalopram Jubilant 40
mg is considered bioequivalent with Citapramil 40 mg tablets.
The MEB has been assured that the bioequivalence study has been conducted in accordance with
acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good
Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC).
IV.3
Risk Management Plan
The MAH has submitted a risk management plan, in accordance with the requirements of Directive
2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to
identify, characterise, prevent or minimise risks relating to Citalopram Jubilant.
No additional risk management measures are required, which is in line with the innovator product.
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IV.4
Discussion on the clinical aspects
For this authorisation, reference is made to the clinical studies and experience with the innovator
product Cipramil tablets. No new clinical studies were conducted. The MAH demonstrated through a
bioequivalence study that the pharmacokinetic profile of the product is similar to the pharmacokinetic
profile of this reference product. Risk management is adequately addressed. This generic medicinal
product can be used instead of the reference product.
V.
USER CONSULTATION
The package leaflet has been evaluated via a user consultation study in accordance with the
requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The testing method included 22
participants. The initial testing involved 2 participants to identify any major changes needed to the PIL.
The 1st round of testing involved the initial interviewing and testing of 10 participants. The 2nd round
of testing involved the interviewing and testing of 10 additional participants.
The questionnaire included 22 questions (19 specific to the medicine and 3 general questions about
the format of the leaflet).
Both rounds of testing showed that 100% of the participants were able to trace the information for the
questions 100% of the time.
The results show that the package leaflet meets the criteria for readability as set out in the Guideline
on the readability of the label and package leaflet of medicinal products for human use.
VI.
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
Citalopram Jubilant 10 mg, 20 mg and 40 mg, film-coated tablets have a proven chemicalpharmaceutical quality and are generic forms of Cipramil 10, 20 and 40 mg tablets, a well-known
medicinal product with an established favourable efficacy and safety profile. Citalopram Jubilant 30 mg
is approved following a hybrid application.
Bioequivalence has been shown to be in compliance with the requirements of European guidance
documents.
There was no discussion in the CMD(h). Agreement between member states was reached during a
written procedure. The member states, on the basis of the data submitted, considered that essential
similarity has been demonstrated for Citalopram Jubilant 10 mg, 20 mg and 40 mg film-coated tablets
with the reference product, and have therefore granted a marketing authorisation. The decentralised
procedure was finalised with a positive outcome on 22 April 2014.
There were no post-approval commitments made during the procedure.
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STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY
Scope
Procedure
number
Type of
modification
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Date of start
of the
procedure
Date of
end of the
procedure
Approval/
non
approval
Assessment
report
attached
Summary Public Assessment Report
Generics
Citalopram Jubilant 10 mg, 20 mg,
30 mg and 40 mg, film-coated tablets
(citalopram)
NL/H/2919/001-004/DC
Date: 28 October 2014
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Summary Public Assessment Report
Generics
Citalopram Jubilant 10 mg, 20 mg, 30 mg and 40 mg, film-coated tablets
Active substance: citalopram
This is a summary of the public assessment report (PAR) for Citalopram Jubilant 10 mg, 20 mg, 30 mg
and 40 mg, film-coated tablets. It explains how this medicine was assessed and its authorisation
recommended as well as its conditions of use. It is not intended to provide practical advice on how to
use Citalopram Jubilant.
For practical information about using this medicine, patients should read the package leaflet or contact
their doctor or pharmacist.
What is Citalopram Jubilant and what is it used for?
Citalopram Jubilant is a ‘generic medicine’. This means that it is similar to a ‘reference medicine’
already authorised in the European Union (EU) called Cipramil tablets.
This medicine is used in the treatment of episodes of major depression. Citalopram is also beneficial in
relieving symptoms of patients who tend to suffer from panic attacks.
How does this medicine work?
Citalopram is a Selective Serotonin Reuptake Inhibitor (SSRI) and belongs to a group of medicines
known as antidepressants. These medicines help to correct certain chemical imbalances in the brain
that are causing the symptoms of major depression or panic disorders.
How is this medicine used?
The pharmaceutical form of Citalopram Jubilant is a film-coated tablet and the route of administration
is oral. The medicine can only be obtained with a prescription.
Please read section 3 of the PL for detailed information on dosing recommendations, the route of
administration, and the duration of treatment.
How has this medicine been studied?
Because this is a generic medicine, studies in patients have been limited to tests to determine that it is
bioequivalent to the reference medicine, Cipramil. Two medicines are bioequivalent when they
produce the same levels of the active substance in the body.
What are the possible side effects of this medicine?
Because Citalopram Jubilant is a generic medicine and is bioequivalent to the reference medicine, its
benefits and possible side effects are taken as being the same as the reference medicine.
For the full list of all side effects reported with this medicine, see section 4 of the package leaflet.
Why is this medicine approved?
It was concluded that, in accordance with EU requirements, this medicine has been shown to have
comparable quality and to be bioequivalent to the reference medicine Cipramil. Therefore, the
Medicines Evaluation Board of the Netherlands decided that, as for the reference medicine, the
benefits are greater than its risk and recommended that it can be approved for use.
What measures are being taken to ensure the safe and effective use of this medicine?
A risk management plan has been developed to ensure that Citalopram Jubilant is used as safely as
possible. Based on this plan, safety information has been included in the summary of product
characteristics and the package leaflet for this medicine, including the appropriate precautions to be
followed by healthcare professionals and patients.
Known side effects are continuously monitored. Furthermore new safety signals reported by
patients/healthcare professionals will be monitored/reviewed continuously as well.
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Other information about this medicine
In the Netherlands, the marketing authorisation for Citalopram Jubilant 10 mg, 20 mg, 30 mg and 40
mg, film-coated tablets was granted on 19 June 2014.
The full PAR for this medicine can be found on the website http://mri.medagencies.org/Human. For
more information about treatment with this medicine, read the package leaflet
(http://mri.medagencies.org/download/NL_H_2919_001_FinalPL.pdf) or contact your doctor or
pharmacist.
This summary was last updated in October 2014.
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