Public Assessment Report
Scientific discussion
CITALEC 10 ZENTIVA
CITALEC 20 ZENTIVA
CITALEC 40 ZENTIVA
Citalopram hydrobromide
CZ/H/0127/001/MR
CZ/H/0127/002/MR
CZ/H/0127/003/MR
Applicant: Zentiva a.s., Hlohovec, Slovak Republic
This module reflects the scientific discussion for the approval of Citalec 10mg, 20mg and 40mg.
The procedures were finalised at 25-07-2006.
INTRODUCTION
This mutual recognition application concerns a generic version of citalopram, under three
trade names: Citalec 10, 20 and 40 Zentiva, film-coated tablets. In this Assessment Report,
the names Citalopram 10, 20 and 40 Slofa coated tablets are used, because the documentation
of the product was assessed before the change of the product name from Citalopram Slofa to
Citalec Zentiva after change of marketing authorisation holder from Slovakofarma a.s.
Slovakia to Zentiva a.s., Slovak Republic.
QUALITY ASPECTS
Introduction
Citalec 10, 20, 40 Zentiva is presented in the form of film-coated tablets containing 10 mg,
20 mg or 40 mg of citalopram as the active substance. The excipients are lactose
monohydrate, microcrystalline cellulose, pregelatinized maize starch, croscarmellose sodium,
colloidal silicon dioxide, magnesium stearate, Sepifilm 752 White as film coated agent
containing hydroxypropylmethylcellulose, microcrystalline cellulose, polyoxyl 40 stearate
and titanium dioxidum and macrogol 6000.
Resp.
Citalec 10 – 12,49 mg citalopram hydrobromid (10 mg citalopram)
Citalec 20 – 24,98 mg citalopram hydrobromid (20 mg citalopram)
Citalec 40 – 49,96 mg citalopram hydrobromid (40 mg citalopram)
The packaging for marketing of the product is white, non-transparent PVC/PVDC/Al blister.
The materials comply with the Ph.Eur. Blisters are placed, together with a package leaflet,
into a paper folding box.
Active Substance
The active substance is not described in any Pharmacopoiea. It is a white to almost white
crystalline powder, it is sparingly soluble in water, soluble in methanol. The substance does
not show any polymorphism. The drug substance shows optical isomerism but the compound
is commercially available as a racemic mixture.
The scientific information has been submitted in form of an Active Substance Master File
from both manufactures. The Letters of Access from the manufacturers were provided. The
manufacture has been described in detail in both ASMF. Both manufacturers produce the
same racemic mixture.
An appropriate in-house specification for citaloprame hydrobromide has been proposed.
Certificates of analysis have been provided. Results comply with the proposed specifications
and confirm the consistency of the manufacturing process.
Appropriate stability studies according to ICH guidelines have been carried out. Results
showed no significant change and remained within the specification. Therefore the proposed
re-test periods for citalopram hydrobromide from both sources are justified based on the
stability results when substance is kept in the proposed packaging. No special storage
conditions are required.
Medicinal Product
The qualitative and quantitative composition of Citalec 10, 20 and 40, film-coated tablets is
detailed including composition of film-coating agents. All excipients are commonly used in
the pharmaceutical industry and are described in the Ph.Eur. The film coating agent
corresponds to the in-house specification.
Pharmaceutical Development
The aim was to develop a stable immediate release tablets that are comparable with the
reference product Cipramil tablets (Lundbeck). The essential similarity, based on comparison
of dissolution profiles, impurity profiles and bioequivalence, with Cipramil has been
documented.
Satisfactory Certificates of Analysis of all excipients have been provided.
The applicant states that none of the ingredients are of animal origin, except lactose, which is
manufactured only from milk sourced for human consumption. For the magnesium stearate a
statement from the supplier confirms vegetable origin and for the Sepifil’s component
Polyoxyl 40 stearate vegetable or synthetic origin is confirmed.
Manufacturing of the product
The manufacturing process is stated as standard. Satisfactory controls of the manufacturing
process are described in the specifications, which are considered adequate to assure the
quality of the product. A prospective validation of manufacturing process has been conducted
on three consecutive pilot batches. A satisfactory scheme for validation proposed for fullscale batches has been provided.
Product specification
Satisfactory control tests are applied at time of release and during the shelf-life. Release and
shelf-life limits for the assay of citalopram hydrobromide are in line with batch data and
stability data. Limits for related substances are in line with ICH guidelines and stability data.
Analytical methods have been satisfactorily described and validated in accordance with
regulatory requirements.
Batch data are provided for three pilot scale batches of Citalec 10 and for two pilot scale
batches of Citalec 20 and 40. The source of active substance used for manufacture of batch
has been provided in Certificates of Analysis. The batches were manufactured at the proposed
site and are considered to adequately represent the product to be marketed. The data comply
with the proposed specification and demonstrate consistent manufacture.
Stability of the product
Stability trials were performed on the drug product according to the stability protocols and
ICH guidelines. These data support the proposed shelf-life of 2 years for the finished product
with restriction of storage conditions Store at temperature of not more than 30°C.
In addition, the in-bulk stability data have been provided for three batches, the packaging
material used for bulk packaging complies with Commission Directive 2002/72/EC.
Discussion on chemical and pharmaceutical aspects
Information on development, manufacture, control of the drug substance and drug product
and stability 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.
STEPS TAKEN AFTER AUTHORISATION – SUMMARY
Application type and scope
Variation II
Change to Module 3 – submission of an updated
version of DMF from an approved manufacturer
Variation IA5 – change in the name of a
manufacturer of an excipient
Variation IA36b – change in dimensions of a
blister and paper folding box
(Citalec 10 Zentiva only)
Variation II
Change to Module 1 – change in SPC and PIL
CLINICAL ASPECTS
Based on the review of data on quality, safety and efficacy, the Reference Member State
considered that the application for CITALEC 10, 20, 40 ZENTIVA, film-coated tablets, in the
treatment of depression, could be approved. The national marketing authorisation was granted
on 14th December 2005.
This is an abridged application. The applicant claims essential similarity, under article 10.1
a)(iii) of Directive 2001/83/EC, to Cipramil tablets, Lundbeck, authorized for more than 6
years in the EU. The innovator product Cipramil carries various trade names e.g. Seropram.
Seropram 10, 20, 40 film-coated tablets, was authorised in the Czech Republic in 1991 (MA
No 30/122/91-C, marketing authorisation holder – H.Lundbeck A/S)
The citalopram is an antidepressant. Citalopram belongs to Selective Serotonin Reuptake
Inhibitors. Citalopram has place in the treatment of depressive, panic and obsessivecompulsive disorders.
No new preclinical studies and no clinical studies were conducted, which is acceptable given
that the applications were based on essential similarity to a product that has been licensed for
more than 10 years. The application contains an adequate review of published clinical data.
One single-dose bioequivalence study at fasted state has been conducted for 40 mg strength.
Given the linear pharmacokinetics of citalopram, and the dose proportionality between the 10,
20 and 40 mg film-coated citalopram tablet, the results obtained for the 40 mg film-coated
tablet can be extrapolated to the 10 and 20 mg film-coated tablet.
Essential similarity has been sufficiently proven by the bioequivalence study that complies
with current requirements and by comparison of dissolution and impurity profiles.
Quality of the product Citalec 10, 20 and 40 Zentiva, film-coated tablets and GMP standards
of manufacture have been sufficiently demonstrated.
The SmPC of product Citalec 10, 20 and 40 Zentiva, film-coated tablets corresponds to the
SmPC of reference product and is in compliance with the latest pharmacovigilance
information. The Package leaflet has been shown to provide the tested potential consumers
with all required information in a clear and comprehensive form and the Readability testing
was performed according to the guidelines.
The quality of the Citalec 10, 20 and 40 Zentiva, film-coated tablets, is satisfactory in relation
to its safety and efficacy. The data have demonstrated the efficacy and safety of Citalec 10, 20
and 40 Zentiva, film-coated tablets, to the extent that the overall risk/benefit of the products is
favourable for the proposed indications.
The Package leaflet for CITALEC 10, 20 and 40 ZENTIVA, film-coated tablets in the Czech
language has been shown to provide the tested potential consumers with all required
information in a clear and comprehensive manner and the Readability testing was performed
according to the guidelines.
To support the application, the applicant has submitted as report one bioequivalence study. As
mentioned above, in this Assessment Report the name Citalopram Slofa is used for the test
product:
Bioequivalence study with two preparations containing Citalopram 40 mg coated tablets:
Citalopram 40-Slofa, (Slovakofarma, a.s, Slovakia) and Cipramil 40 (Lundbeck, GmbH &Co,
Germany) after single dose to healthy volunteers. The test product Citalopram 40-Slofa is
identical to the formulation intended to be marketed Citalec 40 Zentiva.
The study was randomised, two-way, single-dose, fasted, balanced cross-over study with a
wash-out period of 14 days, conducted in healthy volunteers. Each subject received a single
dose of corresponding formulation in each period with 200 ml of water, on an empty stomach,
each treatment once according to a randomisation list. Food and fluid intake was standardised
during the whole clinic stay. Minimum 14 days passed between drug administrations. A series
of 19 × 8 ml of venous blood samples of each subject (predose, 1; 2; 3; 4; 5; 6; 8; 12; 18; 24;
36; 48; 60; 72; 84; 96; 108 and 132 hours) were collected over a 132 hours period of time
after a drug administration. The plasma concentration of citalopram was determined by
HPLC.
Twenty six (26) normal, healthy, Caucasian, male (13) and female (13) subjects were enrolled
in the study. One volunteer discontinued the study due to acute bronchitis. Several adverse
events were observed but were not serious. Volunteers after being dismissed from the medical
facility were in good health status.
The plasma concentration of citalopram was determined by high performance liquid
chromatography. Validated method allows determination of citalopram concentration over the
range 3 – 75 ng/ml. The LOQ was 2.89 ng/ml.
ANOVA was carried out on log transformed AUC0-last, AUC0-∞, Cmax 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.
26 subjects were enrolled. One subject discontinued the study due to acute bronchitis.
According to the protocol, samples of first 24 included subjects who completed the study
were analyzed. Therefore the final statistical analysis was performed on 24 subjects.
The extrapolated part of AUC did not exceed 20% in any subject. The 90% confidence
intervals for AUC0-last, AUC0-∞ and Cmax lie within acceptable limits (0.80-1.25). There
were significant period effects for AUC0-last and AUC0-∞ in ANOVA analysis. There was no
significant sequence effect. Bearing in mind that the point estimates and ANOVA based 90%
AUC and Cmax were fully satisfied, a significant period effect does not disqualify the
conclusion of bioequivalence.
Based on the presented bioequivalence study, Citalopram 40-Sofa (identical to Citalec 40
Zentiva) coated tablets is considered bioequivalent to Cipramil 40 coated tablets.