Download III. Non-clinical aspects

Public Assessment Report
Scientific discussion
Rispemar 1, 2, 3 & 4mg
film-coated tablets
(risperidone)
CZ/H/177/01-04/MR
This module reflects the scientific discussion for the approval of Rispemar 1, 2, 3 & 4mg filmcoated tablets. The procedure was finalised at 2 October 2008. For information on changes after
this date please refer to the module ‘Update’.
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I.
INTRODUCTION
These mutual recognition procedures concern a generic version of risperidone film-coated tablets.
National marketing authorisations for Rispemar 1/2/3/4 mg, film coated tablets were granted on 14
February 2007. The applicant claims essential similarity, under Article 10.1 a)(iii) of Directive
2001/83/EC, to innovator product Risperdal 1/2/3/4 mg, film coated tablets, Janssen-Cilag Ltd.,
United Kingdom, authorised more then 10 years in Europe. Risperdal 1/2/3/4 mg has been authorised
in the Czech Republic since 22 March 1995 (MANo 68/185/95-A-D/C, marketing authorisation holder
Janssen-Cilag s.r.o, Czech Republic).
With the Czech Republic as the Reference Member State in this Mutual Recognition Procedure, ICN
Polfa Rzeszów S.A., Poland is applying for the Marketing Authorisations for Rispemar 1/2/3/4 mg
film-coated tablets in Romania.
There were no withdrawals during the procedure.
II.
QUALITY ASPECTS
II.1
Introduction
Rispemar 1/2/3/4 mg are presented in the form of film-coated tablets containing risperidone as the
active substance. The excipients used are: lactose monohydrate, maize starch, microcrystalline
cellulose, hypromellose, magnesium stearate, silicon dioxide colloidal, sodium lauryl sulphate and
coating film (1 mg: Opadry white, 2 mg: Opadry orange, 3 mg: Opadry yellow, 4 mg: Opadry green).
The products are packed into transparent PVC-PVDC/Alu blisters. They are placed in the paper
folding box together with their information leaflet.
II.2
2.2
Drug Substance
Risperidone is a benzisoxazol derivative with antipsychotic properties. The precise mechanism by
which this selective monoaminergic antagonist acts is unknown.
Risperidone shows a high affinity for the serotonine-5-HT2- and dopamine D2 receptors. Risperidone
binds to the α1-adrenergic receptor and, with a lower affinity to the histamine-H1 and α2-adrenergic
receptor. Risperidone does not have any affinity for the cholinergic receptor. Risperidone is effective
on positive symptoms and seems to be associated with the possible effect on negative symptoms.
The drug products contain Risperidone as the active substance. For this substance, Ph. Eur. monograph
exists. Two source of Risperidone are presented.
The first source of Risperidone: data supporting the suitability of the drug substance have been
provided by way of a Certificate of Suitability. Satisfactory and current copy has been provided. The
re-test period of 3 years if stored in a double polyethylene bag kept in a fibre drum is stated on the
Certificate of Suitability. Two tests are added in the Ph. Eur.specifications – the test for particle size
and the test for residual solvents.
The second source of Risperidone: data supporting the suitability of the drug substance have been
provided by way the DMF. Based on stability data, 2 years re-test period is acceptable for the product
packed in clear virgin foodgrade double PE bags inserted in black PE bags and finally placed in fibre
drums. Two tests are added in the Ph. Eur.specification – the test for particle size and the test for
residual solvents.
Satisfactory specification of active substance as used by finished product manufacturer has been
provided. Risperidone is a white or almost white powder practically insoluble in water, freely soluble
in methylene chloride, sparingly soluble in ethanol. It dissolves in dilute acid solutions.
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II.3
Medicinal Product
Satisfactory chemical and pharmaceutical data have been submitted for marketing authorization. There
are no significant deviations from EU and ICH quality guidelines.
The product was developed as a generic equivalent to the German brand Risperdal®, adopting the
same pharmaceutical form and qualitative composition.
.
Rispemar film-coated tablets are available in four strengths, 1mg, 2 mg, 3 mg and 4 mg. The product
does not contain any novel excipient. The inactive ingredients are all standard excipients commonly
used in the pharmaceutical industry and they are controlled according to the Ph.Eur. Coating layers
(Opadry) are controlled according to an in-house specification. All colorants used in the coating layers
(Opadry) comply with the directive 95/45/EC [titanium dioxide (E 171), FD&C Yellow #6/Sunset yellow
FCF Aluminium Lake (E110), Quinoline yellow Aluminium Lake (E104)].
Lactose monohydrate is the only material of animal origin used in manufacture of film-coated tablets.
TSE risk is minimised in line with the Public Statement EMEA/CPMP/571/02.
Pharmaceutical development
Pharmaceutical development has been appropriately described. The formulation was intended to be a
film-coated tablet with an immediate drug release similar to that of the innovator product.
To demonstrate the equivalence to innovator product, the comparative dissolution profiles have been
presented. The dissolution method has been described in detail.
The comparative impurity profile was also provided and was found to be the same for the innovator
and generic product.
Manufacturing of the product
The manufacturing process is standard according to the NfG CPMP/QWP/848/96.
The batch formula, manufacturing process and in process controls were described in adequate details.
Satisfactory process validation protocol for the drug products (for the 1, 2, 3, 4 mg strengths) has been
provided. This protocol has been included and is satisfactory – includes description of manufacturing
steps, tested parameters, sampling requirements, validation equipment description and specification
limits. The validation of production batches is planned to be carried out on three consecutive
production batches.
Product specification
Specification at release and shelf life is acceptable. Release and shelf life limits are in line with
stability data. Limits for impurities comply with ICH guidelines with consideration of maximum daily
dose.
Analytical methods are satisfactorily described and validated according to ICH requirements or follow
Ph.Eur. methods.
Satisfactory certificates of analysis of the batches are provided for all strengths. The data comply with
the specifications and demonstrate consistent manufacture.
Packaging
Risperidone film-coated tablets are packed into transparent PVC/PE/PVDC//Alu blisters. Packaging
materials conform to European requirements. PVC and PVDC comply with the requirements of
Ph.Eur. and Directive 2002/72/EC.
Stability of the product
Stability studies under ICH conditions have been performed and data presented. The quality
specification and the range of tests and limits for these tests are considered acceptable. The test
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methods have been described. All the physical and chemical characteristics of film-coated tablets
remained within the established specification. The data support the shelf life proposed in the SPC, 3
years when stored in the original package in order to protect from light.
II.4
Discussion on chemical, pharmaceutical and biological aspects
III.
NON-CLINICAL ASPECTS
III.1
Introduction
Pharmacodynamic, pharmacokinetic and toxicological properties of risperidone are well known. As
risperidone is widely used, well-known active substances, no further studies are required and the
applicant provides none. Also the excipients are widely used and well-known substances. Overview
based on literature review is, thus, appropriate.
The non-clinical overview has been written by an expert Louizos Poulos, M.D., B.Pharm., Ph.D., and
dated on the 26th July 2007.
III.2
Pharmacology
N/A
III.3
Pharmacokinetics
N/A
III.4
Toxicology
N/A
III.5
Ecotoxicity/environmental risk assessment
N/A
III.6
Discussion on the non-clinical aspects
No objections to the approval of risperidone film-coated tablets were raised by the RMS or CMS from
a non-clinical point of view.
IV.
CLINICAL ASPECTS
IV.1
Introduction
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.
The clinical overview has been written by an expert Louizos Poulos, M.D., B.Pharm., Ph.D., and dated
on the 26th July 2007.
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IV.2
Pharmacokinetics
One bioequivalence study with two preparations containing 1 mg Risperidone tablets: Risperidone 1
mg tablets (manufactured by Specifar Pharmaceuticals, Greece) and Risperdal 1 mg tablets
(manufactured by Janssen-Cilag GmbH, Germany), was performed. It was an open-label, single-dose,
randomized, two-way, cross-over, fasted study with wash-out period of 14 days. Twenty-eight healthy
male (25) and female (3 surgically sterile or post-menopausal) subjects were enrolled and the first
twenty-four subjects were included into PK and statistical evaluation.
The clinical part of the study was carried at the Anapharm Inc., Canada. Plasma concentrations of
risperidone and 9-OH-risperidone were detarmined at the bioanalytical division of Anapharm Inc. by
LC/MS/MS method. There is no concern regarding to the validity of the data.
The 90% CIs for the ratios of the test to reference formulations for the parameters AUC0-t, AUC0-∞
and Cmax after single dosing with the 1 mg tablets were entirely within the bioequivalence acceptance
range (0.80-1.25).
Based on the presented bioequivalence study Risperidone/Specifar 1 mg is considered bioequivalent to
Risperdal.
The results of study with 1 mg formulation can be extrapolated to the higher strengths 2, 3 and 4
mg because all points required by guideline CPMP/EWP/QWP/1401/98 have been fulfilled:
 the pharmaceutical products are manufactured by Specifar SA using the same manufacturing
process
 the drug input is linear over the therapeutic dose range
 the qualitative composition of the different strengths is the same
 the product contains a low concentration of active substance and the amounts of excipients
contained within each tablet strength is the same
 the dissolution profiles of all strengths are similar under identical conditions
IV.3
Pharmacodynamics
N/A
IV.4
Clinical efficacy
N/A
IV.5
Clinical safety
Pharmacovigilance issues
Pharmacovigilance system
After the requested amendment of some part of description, the RMS considers that the
Pharmacovigilance system fulfils the legislative 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.
Risk Management Plan
The RMS considers that routine pharmacovigilance activities are sufficient to identify actual or
potential risks. RMS does not consider a detailed EU-RMP necessary for risperidone products.
Further requirements:
The PSUR should be submitted according the agreed HBD.
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IV.6
Discussion on the clinical aspects
No other clinical studies were conducted to support this application.
V.
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
The bioequivalence with the innovator has been sufficiently demonstrated for 1 mg, 2 mg, 3 mg and 4
mg strengths.
User consultation
The user consultation on PL was done with PL for Risperidone Dival 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg,
6 mg and 8 mg Film Coated Tablet. Testing was done with potential consumers. The range of subjects
was felt to be representative of the population of the whole, given the age and educational range of the
subjects. A pilot study carried out with 2 interviews was followed by two phases each with 10
subjects. Twenty questions were phrased. Correct answers represented 96.5% in Phase 1 and 94.5 % in
Phase 2. Tested Package leaflet for Risperidone 0.5/1/2/3/4/6/8 mg Film Coated Tablet 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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