Public Assessment Report
Scientific discussion
YASNAL 5 mg
YASNAL 10 mg
Donepezil hydrochloride
CZ/H/0145/001/MR
CZ/H/0145/002/MR
Applicant: Krka, d.d., Novo mesto, Slovenia
This module reflects the scientific discussion for the approval of Yasnal 5 and 10mg. The
procedures were finalised at 03-10-2007.
QUALITY ASPECTS
Introduction
Yasnal 5mg a 10mg is presented in the form of film-coated tablets containing 5 mg or 10 mg of
donepezil hydrochloride as the active substance. The excipients are lactose monohydrate,
microcrystalline cellulose, maize starch, hydroxypropylcellulose, magnesium stearate and Opadry Y1-7000 in 5 mg tablets and Opadry 02B22462 Yellow in 10 mg tablets as film-coated agent. Opadry
Y-1-7000 contains hypromellose 5 cP, titanium dioxide and macrogol/PEG 400. Opadry 02B22462
Yellow contains hypromellose 5 cP, titanium dioxide, macrogol/PEG 400 and iron oxide yellow.
The tablets are packed in a OPA/Al/PVC//Al blister. The materials comply with the Ph.Eur. and with
EU directives. 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 odorless crystalline
substance in the form of hydrate, it is sparingly soluble in water. It shows polymorphism.
The scientific information has been submitted in form of an Active Substance Master File from the
manufacturer. The Letter of Access from the manufacturer was provided. The manufacture has been
described in detail.
An appropriate in-house specification for donepezil hydrochloride has been proposed. Certificates of
analysis have been provided. Results comply with the proposed specification and confirm the
consistency of the 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 period is
justified based on the stability results when substance is kept in the proposed packaging (laminated
PET/Al/PE foil). No special storage condition is required.
Medicinal Product
The qualitative and quantitative composition of Yasnal 5 mg and 10 mg, film-coated tablets is detailed
including composition of film-coating agents. Most of excipients are commonly used in the
pharmaceutical industry and are described in the Ph.Eur. The coating agents correspond to the inhouse specification, this is acceptable.
Pharmaceutical Development
The aim was to develop a stable immediate release tablets that are comparable with the reference
product Aricept. The essential similarity, based on comparison of dissolution profiles, impurity
profiles and bioequivalence, with Aricept has been documented.
Satisfactory Certificates of Analysis of all excipients have been provided.
Magnesium stearate is of vegetal origin. Lactose monohydrate is of the animal origin. The suppliers
have submitted statements concernig information about safety of this excipient.
Manufacturing of the product
The manufacturing process can be stated as standard.
Satisfactory controls of the manufacturing process are described with specifications, which are
considered adequate to assure the quality of the product The process was validated according to
satisfactory validation plan.
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 donepezil hydrochloride are in line with batch 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.
Stability of the product
Stability trials were performed on the drug product according to the stability protocols and ICH
guidelines. The shelf-life of 36 months without special storage conditions is in compliance with
stability data and are acceptable.
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
This mutual recognition application concerns a generic version of donepezil, under two trade names:
Yasnal 5 mg and Yasnal 10 mg, film-coated tablets.
Donepezil is a reversible acetylcholine esterase inhibitor used in the treatment of mild to moderate
dementia of Alzheimer’s type.
The recommended initial dose is 5 mg of donepezil once daily in the evening prior to retiring. After a
subsequent clinical evaluation, the daily dose may be increased to 10 mg donepezil daily. The duration
of the treatment has not been established yet.
To support the application, the applicant has submitted as report one bioequivalence study.
The study was a single-dose, randomised, two-period, two-sequence, fasted, cross-over study,
conducted in healthy volunteers.
Twenty-two healthy male subjects, Caucasian race, non smokers, were included in the study. Their
mean age was 24 years (range 21-26 years) and mean weight 79 kg (range 63-97kg).
One volunteer did not come to the part I of the study, therefore 21 completed the study.
Each subject received a single dose of respective formulation in each period with 240 ml of tap water
after an overnight fast. Each treatment was administered once according to a randomisation list.
Standardised meals were served during each study phase.
Sixteen (16) blood samples were collected over 288 hours in each period. There was a 4 weeks
washout interval between the two periods.
The plasma concentration of donepezil was determined by LC-MS/MS method. A full validation
report of the analytical technique is provided.
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.
Results
The final statistical analysis was performed on 19 subjects because two subjects experienced emesis
before Tmax and were excluded from statistical analysis. The vomiting in both cases have occurred
1,5 hour after the ingestion of the reference formulation. Their pharmacokinetic parameters are also
presented. The exclusion of two subjects from statistical analysis is acceptable.
The ratio (AUC0-last/AUC0-∞) of all subjects was above 80% for test and reference formulations.
The 90% confidence intervals for AUC0-last, AUC0-∞ and Cmax lie within acceptable limits (0.801.25).
No serious or unexpected adverse events were reported during the study.
Pharmacokinetic conclusion
Based on the presented bioequivalence study, Donepezil 10 mg coated tablets are considered
bioequivalent to Aricept 10 mg coated tablets.
The results of study with 10mg formulation can be extrapolated to other strength 5 mg, according to
conditions in Note for Guidance on the Investigation of Bioavailability and Bioequivalence
CPMP/EWP/QWP/1401/98, section 5.4.