Public Assessment Report
Scientific discussion
Dolocodon 5, 10, 20, 40 mg
prolonged-release tablets
(oxycodone hydrochloride)
This module reflects the scientific discussion for the approval of Dolocodon 5, 10, 20, 40mg
prolonged-release tablets. The procedure was finalised at 24 June 2010. For information on
changes after this date please refer to the module ‘Update’.
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I.
INTRODUCTION
This decentralised application concerned a generic version of oxycodone tablets under trade name
Dolocodon, 5/10/20/40/80 mg prolonged-release tablets.
The applicant has decided to withdraw the application for 80 mg strength in all MS before the Day
120.
The legal basis of this decentralised application is article 10(1) of Directive 2001/83/EC as amended
for Dolocodon 5, 10, 20 and 40 mg, prolonged-release tablets claiming essential similarity to the
respective strength of Oxygesic (Oxycontin) prolonged release film-coated tablets manufactured by
Mundipharma GmbH.
The originator product used for data protection is OxyContin 20 mg prolonged release film-coated
tablets by Mundipharma Oy, registered on the 8th January 1996 in Finland.
The reference product is “OxyContin”, prolonged release tablet”, MUNDIPHARMA GES.M.B.H,
authorized since the 26th April 2000 in the Czech Republic.
The bioequivalence has been demonstrated to Oxygesic 10 mg, Oxygesic 20 mg Oxygesic 40 mg
prolonged release tablet from the German market.
With the Czech Republic as the Reference Member State in this Decentralised Procedure, ZENTIVA,
k.s., the Czech Republic is applying for the Marketing Authorisations for Dolocodon 5/10/20 a 40 mg
prolonged-release tablets in EE, LT, LV, RO, SK and UK.
The applicant has decided to withdraw the application from FI and FR due to marketing reasons before
the Day 120.
II.
QUALITY ASPECTS
II.1
Introduction
The oxycodone prolonged release tablets are multiple unit formulations containing 5, 10, 20, 40 mg of
the drug substance (the highest strength of 80 mg has been withdrawn before of the procedure restart).
All formulations contain oxycodone-coated sugar beads which are further coated with a polymer film
providing controlled release of the drug substance.
II.2
Drug Substance
Oxycodone (ATC classification code N02AA05) is a widely used and well established opioid
analgesic. It has been shown to be as effective as morphine in the management of severe to most
severe pain, i.e. for the treatment of cancer pain, post-operative pain and non-malignant pain.
Oxycodone hydrochloride is a pure agonist opioid, whose principal therapeutic action is analgesia. It is
a subject of the Ph. Eur.
The AS is sourced from 2 sources. The DMF procedure is used for the AS from the first source and
the adequate quality of the DMF submitted was already assessed as it was employed during other
DCPs.
II.3
Medicinal Product
The development of the product has been described in detail, the choice of excipients justified and
their functions explained, dissolution data and comparative impurity profiles have been supplemented.
The manufacturing process has been adequately described, appropriate in-process controls are in
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place, maximum holding times for intermediates I, II and tablet cores have been given and justified.
Satisfactory process validation studies performed by both manufacturers have been provided. The
applicant has committed to performing full process validation studies on the first three production
batches of each strength and at each manufacturing site. The product specifications cover appropriate
parameters, which are controlled by validated methods. The stability data provided justify the
proposed shelf life of 2 years.
The chemical-pharmaceutical documentation is well-arranged and of sufficient quality. Based on the
assessment, the product is approvable from the quality point.
II.4
Discussion on chemical, pharmaceutical and biological aspects
III.
NON-CLINICAL ASPECTS
III.1
Introduction
As oxycodone is a widely used, well-known active substance, no further studies are required.
Overview based on literature review is, thus, appropriate.
The non-clinical overview has been written by relevant expert.
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 oxycodone prolonged-release tablets. were raised by the RMS or
CMSs from a non-clinical point of view.
IV.
CLINICAL ASPECTS
IV.1
Introduction
This assessment report represents an evaluation of the key elements of the information provided by the
company in the dossier.
As oxycodone is a widely used, well-known active substance, no further studies are required.
Overview based on literature review is, thus, appropriate.
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IV.2
Pharmacokinetics
This application initially concerned 5 strengths containing 5, 10, 20, 40 and 80 mg of the active
substance oxycodone in prolonged-release tablets, however the applicant has decided to withdraw the
application for 80 mg strength in all MS before the Day 120, therefore only 4 strengths are discussed.
To support the application, the applicant has submitted initially six bioequivalence studies.
During stop clock one new single dose bioequivalence study with 40 mg strength under fasting
conditions has been performed and submitted. Consequently these seven bioequivalence studies were
considered:
Three BEQ studies with 10mg strength.
1) single dose under fasting conditions
2) single dose administration under fed conditions
3) multiple dose administration (fasting conditions).
Three BEQ studies with 20mg strength.
1) single dose under fasting conditions
2) single dose administration under fed conditions
3) single dose and multiple dose administration (fasting conditions).
One BEQ study with 40mg strength.
1) single dose under fasting conditions
Each bioequivalence study was 2-way cross-over study with 36 healthy adult subjects. Each subject
received a single/multiple dose of both test (Oxycodone HCl SR Tablets - Develco Pharma Schweiz
AG) and reference oxycodone formulation(s) (Oxygesic - Mundipharma GmbH, Germany) in
fasting/fed conditions, according to the design of the study.
The clinical part of all studies were carried out in Hungary at the same clinical site and under the same
principal investigator; plasma concentrations of oxycodone were determined in the same laboratory in
Germany 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 10 mg / 20mg tablets were entirely within the bioequivalence
acceptance range (0.80-1.25) in both fasted and fed state.
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 40 mg tablets were entirely within the bioequivalence
acceptance range (0.80-1.25) in fasted state.
The 90% CIs for the ratios of the test to reference formulations for the parameters AUCt, CmaxSS,
and CminSS after multiple dosing with the 10 mg / 20mg tablets were within the specified
bioequivalence ranges of 0.8-1.25
Bioequivalence criteria have been demonstrated for the 10 mg, 20 strengths as well for the 40 mg
strength.
The results of study with 10 mg formulation can be extrapolated to the 5mg strength according to
conditions in Note for Guidance on the Investigation of Bioavailability and Bioequivalence
CPMP/EWP/QWP/1401/98, section 5.4, since the Applicant provided comparative dissolution data at
pH 1.5, 4.5 and 6.8.
Biowaiver concept for 40 mg strength based on studies with 20mg strength could not be accepted
because dissolution profiles were not similar between 20mg and 40 mg strengths in all three pH.
Nevertheless, the results of the new submitted single dose fasting study with 40 mg strength, together
with additional dissolution data provided by the applicant were considered enough for the acceptance
of 40mg strength.
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Consequently, the bioequivalence with the innovator has been sufficiently demonstrated for 5mg,
10mg, 20mg, and 40 mg strengths.
IV.3
Pharmacodynamics
N/A
IV.4
Clinical efficacy
N/A
IV.5
Clinical safety
Pharmacovigilance issues
Pharmacovigilance system
The RMS considers that the Pharmacovigilance system as described by the applicant 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 Dolocodon product.
Further requirements:
The PSUR should be provided to the Czech Institute for Drug Control every 3 years since the date of
product authorisation.
Other issues:
A question about a possible risk of dose dumping in presence of ethanol (for modified release opioids)
was raised.
The drug release characteristics of the tested Oxycodone HCl PR Tablet formulations (5, 10, 20 and
80mg) are considered not significantly altered in presence ethanol as similarity factors above 50% for
different ethanol concentrations (5, 10, 20 and 40%) vs. 0.1 HCl were shown. Therefore, a risk of dose
dumping in presence of ethanol was excluded for the applicant's formulation.
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 5mg, 10mg, 20mg, and
40 mg strengths.
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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 language used for the purpose
of user testing the PIL was Czech.
The questionnaire included 12 questions about the product, and general question designed to obtain
user comments on the format of the PL and comprehensibility. The questions are considered relevant
and appropriate for testing readability and include warnings, information how to use Dolocodon and
what is it used for, and questions concerning adverse drug reactions. Questions were posed to the
subjects in random.
Before actual testing a pilot test was performed with four subjects.
The test consisted of two test rounds of 10 subjects each. The range of subjects chosen over the two
phases is considered to be representative of the population that would have needed to use this product.
No changes were considered necessary and no changes were introduced.
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.
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