2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg film-coated

Public Assessment Report
Scientific discussion
Olanzapin “Actavis”
2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg
film-coated tablets
Olanzapine
DK/H/1495/001-006/DC
This module reflects the scientific discussion for the approval of Olanzapin “Actavis”. The
procedure was finalised on 5 October 2009. For information on changes after this date please
refer to the module ‘Update’.
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I. INTRODUCTION
Based on the review of the quality, safety and efficacy data, the Member States have granted a
marketing authorisation for Olanzapin “Actavis” 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg filmcoated
tablets, from Actavis Group PTC ehf. The product was authorised in Denmark on 23 July 2010.
The product is indicated for the following conditions in adults:
Olanzapine is indicated for the treatment of schizophrenia.
Olanzapine is effective in maintaining the clinical improvement during continuation therapy in
patients who have shown an initial treatment response.
Olanzapine is indicated for the treatment of moderate to severe manic episode.
In patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated for the
prevention of recurrence in patients with bipolar disorder.
Olanzapine is a thienobenzodiazapine derivative belonging to the relatively new class of second
generation derivative antipsychotic agents, known as atypical antipsychotics. Atypical antipsychotics
generally applies to drugs that in contrast to classical antipsychotics have a greater affinity for
serotonin 5-HT 2A receptors than for dopamine D 2 receptors and cause fewer extrapyramidal symptoms
and improve negative symptoms.
This decentralised procedure concerns a generic application claiming essential similarity with the
reference product Zyprexa coated tablets, Eli Lilly, authorised by the Community in 1996.
The marketing authorisation is granted based on article 10.1 of Directive 2001/83/EC.
II.
II.1
QUALITY ASPECTS
Introduction
Each film-coated tablet contains 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg of olanzapine.
The 2.5 mg tablets are round, biconvex, white film-coated tablet 6 mm in diameter, marked with “O”
on one side.
The 5 mg tablets are round, biconvex, white film-coated tablet 8 mm in diameter, marked with “O1”
on one side.
The 7.5 mg tablets are round, biconvex, white film-coated tablet 9 mm in diameter, marked with “O2”
on one side.
The 10 mg tablets are round, biconvex, white film-coated tablet 10 mm in diameter, marked with “O3”
on one side.
The 15 mg tablets are oval, biconvex, light blue film-coated tablet 7.35 x 13.35 mm in diameter,
marked with “O” on one side.
The 20 mg tablets are oval, biconvex, light pink film-coated tablet 7.5 x 14.5 mm in diameter, marked
with “O” on one side.
The tablets are packed in blister packs (aluminium/aluminium) in various pack sizes.
The excipients in the tablet core are: Lactose anhydrous; microcrystalline cellulose; crospovidone and
magnesium stearate.
The coating consists of: Polyvinyl alcohol; titanium dioxide (E171); talc; lecithin soya (E322);
xanthan gum (E415); indigo carmine (E132) (in 15 mg film-coated tablet only) and iron oxide red
(E172) (in 20 mg film-coated tablet only).
Compliance with Good Manufacturing Practice
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The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place
for this product type at all sites responsible for the manufacturing of the active substance as well as for
the manufacturing and assembly of this product prior to granting its national authorisation.
II.2
Drug Substance
INN: Olanzapine (Form I)
Chemical name: 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine
Molecular formula: C 17 H 20 N 4 S
Molecular weight: 312.44 g/mol
Structural formula:
Olanzapine is a pale yellow to yellow crystalline powder. The substance is freely soluble in
chloroform and sparingly soluble in acetic acid.
The drug substance olanzapine is not described in any pharmacopoeia. The DMF procedure is used for
the documentation on the drug substance. A DMF has been provided from each of the two drug
substance suppliers.
The manufacturing process has been adequately described in the restricted part of the DMFs.
The control tests and specifications for the drug substance are in accordance with in-house
requirements and justified according to the EU/ICH guidelines.
Based on the presented data appropriate retest periods have been set.
II.3
Medicinal Product
The development of the drug product has been adequately described. Dissolution testing has been
performed comparing the product applied for with the brand leader in media with different pH and
comparing each of the strengths applied for.
The manufacturing process is a standard direct compression process. The validation on production
scale batches has been performed for all strength.
The excipients used in the tablets are well known and meet the Ph. Eur. monograph requirements,
except the pigment blends, which comply with in-house requirements.
Stability studies have been carried out in accordance with ICH recommendations, justifying the
proposed shelf-life 24 months and the special precaution for storage “store in the original package in
order to protect from light and moisture”.
III.
NON-CLINICAL ASPECTS
This product is a generic formulation of Zyprexa, which is available on the European market. No new
preclinical data have been submitted, and therefore the application has not undergone preclinical
assessment. This is acceptable for this type of application
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Environmental risk assessment
The product is intended as a substitute for other identical products on the market. The approval of this
product will not result in an increase in the total quantity of olanzapine released into the environment.
It does not contain any component, which results in an additional hazard to the environment during
storage, distribution, use and disposal.
IV.
CLINICAL ASPECTS
IV.1
Introduction
Olanzapine is a well-known active substance with established efficacy and tolerability.
For this generic application, the MAH has submitted one bioequivalence study in which the
pharmacokinetic profile of Olanzapin “Actavis” 5 g film-coated tablets is compared with the
pharmacokinetic profile of the reference product Zyprexa 5 mg coated tablets, Eli Lilly.
The application concerns 6 dosage strengths, 2.5, 5, 7.5, 10, 15 and 20 mg. The study was carried out
with the 5 mg strength. Justification for biowaivers for the other strengths has been provided.
The study was an open-label, randomized, two-treatment, two-sequence, two-period, two-way
crossover, single-dose bioavailability study conducted under fasting conditions with a wash out period
of 21 days between the two administrations. 5 mg was administered in each period.
Blood samples were collected pre-dosing and at 0.75, 1.25, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10, 14, 24,
48, 72, 96, 120 and 144 hours post administration of a single-dose 5 mg tablet with 240 ml of water
for the analyses of olanzapine.
The subjects were housed from the evening before dosing until the 48-hour blood draw and they
returned for the 72-, 96-, 120- and 148-hour blood draws.
24+2 healthy non-smoking (9 male and 17 female subjects (21-45 years) participated in the study. All
subjects completed the study; there were no drop-outs. The data from subject no. 1-24 were included
in the pharmacokinetic and statistical analysis, in accordance with the protocol.
Pharmacokinetic variables
Choice of primary variables and secondary PK variables:
The parameters calculated were AUC 0-t , AUC 0-inf , AUC 0-t /AUC 0-inf , C max , t max , K el and t ½ el .
Primary variables: AUC 0-t , AUC 0-inf and C max .
The 90% confidence interval of the relative mean AUC 0-t , AUC 0-inf and C max of olanzapine of the test
and reference formulation should be within 80-125% in order to conclude bioequivalence.
Results
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The 90% confidence intervals for the primary variables AUC 0-t , AUC 0-inf and C max are within the
acceptance range of 80-125%.
Based on the submitted bioequivalence study Olanzapin “Actavis” film-coated tablets are considered
bioequivalent with Zyprexa coated tablets, Eli Lilly.
The RMS 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.2
Risk management plan & Pharmacovigilance system
Olanzapine was first approved in 1996, and there is now more than 10 years post-authorisation
experience with the active substance. The safety profile of olanzapine can be considered to be well
established and no product specific pharmacovigilance issues were identified pre- or postauthorisation
which are not adequately covered by the current SPC. Additional risk minimisation activities have not
been identified for the reference medicinal product. The MAH has a pharmacovigilance system at their
disposal, which is based on the current European legislation.
The Pharmacovigilance system described fulfils the 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 identification and notification of any potential risks occurring either in the
Community or in a third country.
V. PRODUCT INFORMATION
SmPC and Package leaflet
The content of the SmPC and package leaflet approved during the decentralised procedure is in
accordance with that accepted for the reference product Zyprexa.
Readability test
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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 language used for the purpose
of user testing the package leaflet was English. The test consisted of two rounds with 10 participants
each. The questions covered the following areas sufficiently: traceability, comprehensibility and
applicability.
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
Olanzapin “Actavis” 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg film-coated tablets has a proven
chemical-pharmaceutical quality and is a generic form of Zyprexa. Zyprexa is a well-known medicinal
product with an established favourable efficacy and safety profile.
Bioequivalence has been shown to be in compliance with the requirements of European guidance
documents.
The MAH has provided written confirmation that systems and services are in place to ensure
compliance with their pharmacovigilance obligations.
The SmPC, package leaflet and labelling are in the agreed templates and the content of the SmPC and
package leaflet approved during the decentralised procedure is in accordance with that accepted for the
reference product Zyprexa.
Agreement between Member States was reached during a written procedure. There was no discussion
in the CMD(h). The Concerned Member States, on the basis of the data submitted, considered that
essential similarity has been demonstrated for Olanzapin “Actavis” with the reference product, and
have therefore granted a marketing authorisation. The decentralised procedure was finalised on 5
October 2009. Olanzapin “Actavis” was authorised in Denmark on 23 July 2010.
The applicant has agreed to follow the PSUR submission schedule for Zyprexa.
The following post-approval commitments have been made during the procedure:
Drug Substance
• The ASM commits to provide the updated Active Substance Master File within three months
of the completion date of the procedure.
• The entire synthetic process for Olanzapine is being re-evaluated for the presence of structural
alerts for potential genotoxicity and subsequently, the data would be provided by end
September 2009.
• The ASM commits to update the DMF once the procedure has been completed. The updated
ASMF will contain responses from all approved European procedures up to the last
completion date of the above mentioned procedure. The updated ASMF will also contain an
audit table, tracking changes to each CTD section and the corresponding procedure number for
the change and also commit to provide the updated ASMF within 3 months of the completion
date of the last procedure.
Drug Product
• The enclosed stability studies will be continued.
• The first 3 production batches of each strength will be put on stability and tested according to
the stability protocol as presented in section P.8.1.
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