Summary Public Assessment Report
Generics
Levodopa + Carbidopa + Entacapona Tecnigen
50 mg + 12.5 mg + 200 mg;
100 mg + 25 mg + 200 mg;
150 mg + 37.5 mg + 200 mg;
200 mg + 50 mg + 200 mg
Film-coated Tablets
(Levodopa + Carbidopa + Entacapone)
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Scientific discussion
Summary Public Assessment Report
Generics
Levodopa + Carbidopa + Entacapona Tecnigen
50 mg + 12.5 mg + 200 mg; 100 mg + 25 mg + 200 mg; 150 mg + 37.5 mg + 200 mg; 200 mg + 50
mg + 200 mg, Film-coated Tablets
This is a summary of the public assessment report (PAR) for Levodopa + Carbidopa + Entacapona
Tecnigen. It explains how Levodopa + Carbidopa + Entacapona Tecnigen was assessed and its
authorisation recommended as well as its conditions of use. It is not intended to provide practical
advice on how to use Levodopa + Carbidopa + Entacapona Tecnigen.
For practical information about using Levodopa + Carbidopa + Entacapona Tecnigen, patients should
read the package leaflet or contact their doctor or pharmacist.
What is Levodopa + Carbidopa + Entacapona Tecnigen and what is it used for?
Levodopa + Carbidopa + Entacapona Tecnigen is a ‘generic medicine’. This means that Levodopa +
Carbidopa + Entacapona Tecnigen is similar to a ‘reference medicine’ already authorised in the
European Union (EU) called Stalevo.
Levodopa + Carbidopa + Entacapona Tecnigen contains contains three active substances (levodopa,
carbidopa and entacapone) in one film-coated tablet and is used for the treatment of Parkinson’s
disease. Parkinson’s disease is caused by low levels of a substance called dopamine in the brain.
How does Levodopa + Carbidopa + Entacapona Tecnigen work?
Levodopa increases the amount of dopamine and hence reduces the symptoms of Parkinson’s disease.
Carbidopa and entacapone improve the antiparkinson effects of levodopa.
How is Levodopa + Carbidopa + Entacapona Tecnigen used?
The pharmaceutical form of Levodopa + Carbidopa + Entacapona Tecnigen is film coated tablets and
the route of administration is oral.
Please read section 3 of the PL for detailed information on dosing recommendations, the route of
administration, and the duration of treatment.
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What benefits of Levodopa + Carbidopa + Entacapona Tecnigen have been shown in studies?
Because Levodopa + Carbidopa + Entacapona Tecnigen is a generic medicine, studies in patients have
been limited to tests to determine that it is bioequivalent to the reference medicine, Stalevo. Two
medicines are bioequivalent when they produce the same levels of the active substance in the body.
What are the possible side effects of Levodopa + Carbidopa + Entacapona Tecnigen?
Because Levodopa + Carbidopa + Entacapona Tecnigen is a generic medicine and is bioequivalent to
the reference medicine, its benefits and possible side effects are taken as being the same as the
reference medicine. For the full list of restrictions, see the package leaflet.
Why is Levodopa + Carbidopa + Entacapona Tecnigen approved?
It was concluded that, in accordance with EU requirements, Levodopa + Carbidopa + Entacapona
Tecnigen has been shown to have comparable quality and to be bioequivalent to Stalevo. Therefore,
the Infarmed decided that, as for Stalevo, the benefits are greater than its risk and recommended that it
can be approved for use.
Other information about Levodopa + Carbidopa + Entacapona Tecnigen
The marketing authorisation for Levodopa + Carbidopa + Entacapona Tecnigen was granted on 23-
02-2016.
The full PAR for Levodopa + Carbidopa + Entacapona Tecnigen can be found on the website
www.infarmed.pt/infomed . For more information about treatment with Levodopa + Carbidopa +
Entacapona Tecnigen, read the package leaflet or contact your doctor or pharmacist.
This summary was last updated in.
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Public Assessment Report
Scientific discussion
Levodopa + Carbidopa + Entacapona Tecnigen
50 mg + 12.5 mg + 200 mg;
100 mg + 25 mg + 200 mg;
150 mg + 37.5 mg + 200 mg;
200 mg + 50 mg + 200 mg
Film-coated Tablets
(Levodopa + Carbidopa + Entacapone)
PT/H/1200/001-004/DC
This module reflects the scientific discussion for the approval of Levodopa + Carbidopa +
Entacapona Tecnigen. The procedure was finalised at 01-04-2015. For information on changes
after this date please refer to the module ‘Update’.
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I.
INTRODUCTION
Verum Pharma has applied for a marketing authorization for levodopa/carbidopa/entacapone,
indicated in the treatment of adult patients with Parkinson’s disease and end -of-dose motor
fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor treatment, in PT and ES.
The application is an abridged application according to Directive 2001/83/EC article 10.1 (a) (iii)
first paragraph, claiming essential similarity. The Marketing Authorization was granted on 23-022016.
The originator product is Stalevo 50 mg + 12,5 mg + 200 mg, 100 mg + 25 mg + 200 mg, 150 mg +
37,5 mg + 200 mg, 200 mg + 50 mg + 200 mg film-coated tablet by Orion Corporation, registered
since 17 October 2003.
This type of application refers to information that is contained in the pharmacological-toxicological
and clinical part of the dossier of the authorisation of the reference product. A reference product is a
medicinal product authorised and marketed on the basis of a full dossier, i.e. including chemical,
biological, pharmaceutical, pharmacological-toxicological and clinical data. This information is not
fully available in the public domain. Authorisations for generic products are therefore linked to the
‘original’ authorized medicinal product, which is legally allowed once the data protection time of the
dossier of the reference product has expired. For this kind of application, it has to be demonstrated
that the pharmacokinetic profile of the product is similar to the pharmacokinetic profile of the
reference product. This generic product can be used instead of its reference product.
II.
QUALITY ASPECTS
II.1
Introduction
50 mg + 12.5 mg + 200 mg, Film-coated tablets: Elliptic, shallow convex, dark-pink to red filmcoated tablet embossed with a “5” on one side.
100 mg + 25 mg + 200 mg, Film-coated tablets: Elliptic, shallow convex, dark-pink to red filmcoated tablet embossed with a “10” on one side.
150 mg + 37.5 mg + 200 mg, Film-coated tablets: Oblong, convex, dark-pink film-coated tablet
embossed with a “15” on one side.
200 mg + 50 mg + 200 mg, Film-coated tablets: Oblong, shallow convex, red film-coated tablet
embossed with a “20” on one side.
The excipients are
Tablet core: croscarmellose sodium, magnesium stearate, maize starch, mannitol, povidone K 30
Film-coating:
50 mg + 12.5 mg + 200 mg, Film-coated tablets: glycerol, hypromellose, magnesium stearate,
polysorbate 80, red iron oxide (E172), sucrose, titanium dioxide (E171), yellow iron oxide (E172)
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100 mg + 25 mg + 200 mg, Film-coated tablets: glycerol, hypromellose, magnesium stearate,
polysorbate 80, red iron oxide (E172), sucrose, titanium dioxide (E171), yellow iron oxide (E172)
150 mg + 37.5 mg + 200 mg, Film-coated tablets: glycerol, hypromellose, magnesium stearate,
polysorbate 80, red iron oxide (E172), sucrose, titanium dioxide (E171), yellow iron oxide (E172)
200 mg + 50 mg + 200 mg, Film-coated tablets: glycerol, hypromellose, magnesium stearate,
polysorbate 80, red iron oxide (E172), sucrose, titanium dioxide (E171), yellow iron oxide (E172),
black iron oxide (E172)
II.2
Drug Substance
Levodopa
Carbidopa
Entacapone
The drug substance Levodopa, is a white or almost white crystalline powder, slightly soluble in water,
practically insoluble in ethanol (96%), freely soluble in 1M HCl and sparingly soluble in 0.1M HCl.
Potential hygroscopicity = Levodopa is non-hygroscopic Isomerism = The molecule of Levodopa
displays an optical activity due to an asymmetrical carbon atom. The active ingredient is the
levorotatory form. Polymorphism = This medicine contains consistently the only know crystalline
form of levodopa.
The drug substance Carbidopa, is a white or yellowish-white powder, slightly soluble in water, very
slightly soluble in ethanol (96%), practically soluble in methylene chloride, and it dissolves in diluted
solutions of mineral acids. Potential hygroscopicity = Not hygroschopic (monohydrate); Isomerism =
None; and Polymorphism = As monohydrate it does not show polymorphism.
The drug substance Entacapone, is a greenish-yellow or yellow powder, practically insoluble in water,
soluble or sparingly soluble in acetone, slightly soluble in anhydrous ethanol. Potential hygroscopicity
= Not hygroschopic; Isomerism = Entacapone is not having any chiral carbon in its chemical
structure; hence it does not possess optical isomerism; and Polymorphism = Anhydrous crystalline
form ‘A’.
II.3
Medicinal Product
The documentation provided complies with relevant EU guidelines and directives. Manufacture is
performed in accordance with cGMP and consistency in quality and homogeneity is demonstrated.
The finished product specification is based on relevant development and stability studies. The
development of the product has been described, the choice of excipients is justified and their functions
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explained.
Appropriate validation data have been provided for the analytical methods. Batch analyses data
support the proposed finished product specification.
Stability studies were performed in line with the ICH guidance.
The proposed shelf-life of 24 months without any special conditions in HDPE container with child
proof closure is considered acceptable for 50 mg + 12.5 mg + 200 mg, 100 mg + 25 mg + 200 mg and
200 mg + 50 mg + 200 mg. The proposed shelf-life of 36 months without any special conditions in
HDPE container with child proof closure is considered acceptable for 150 mg + 37.5 mg + 200 mg.
These film-coated tablets are stable for 100 days after first opening.
100 film-coated tablets for HDPE bottles
III.
NON-CLINICAL ASPECTS
Pharmacodynamic, pharmacokinetic and toxicological properties of levodopa + carbidopa +
entacapone are well known. As levodopa + carbidopa + entacapone are widely used, well-known
active substances, the applicant has not provided additional studies and further studies are not
required. Overview based on literature review is, thus, appropriate.
Environmental Risk Assessment (ERA)
An Environmental Risk Assessment has not been performed as the product is intended for generic
substitution. No information is available about the fate and effect of this product in environment, thus
a disposal advice was added to the SmPC.
IV.
CLINICAL ASPECTS
To support the application, the applicant has submitted the report of three bioequivalence studies on
the highest and lowest strengths and 150 mg + 37.5 mg + 200 mg strength. The results presented
herein show that the criteria used to assess bioequivalence between the Test and Reference
formulations were all fulfilled for levodopa, carbidopa and entacapone. Hence:
- the Test formulation of Levodopa 200mg, Carbidopa· 50mg and Entacapone 200mg tablet is
bioequivalent with the Reference formulation Stalevo® tablet containing Levodopa 200mg, Carbidopa
50mg and Entacapone 200mg in healthy volunteers under fasting condition.
- the Test formulation of Levodopa 50mg, Carbidopa· 12.5mg and Entacapone 200mg tablet is
bioequivalent with the Reference formulation Stalevo® tablet containing Levodopa 50mg, Carbidopa
12.5mg and Entacapone 200mg in healthy volunteers under fasting condition.
- the Test formulation of Levodopa 150mg, Carbidopa· 37.5mg and Entacapone 200mg tablet is
bioequivalent with the Reference formulation Stalevo® tablet containing Levodopa 150mg, Carbidopa
37.5mg and Entacapone 200mg in healthy volunteers under fasting condition.
Pharmacovigilance system
Marketing Authorisation Application section 1.8.1 Summary of Pharmacovigilance System includes a
statement of the Marketing Authorisation Applicant and the Qualified Person for Pharmacovigilance
Regarding their Availability and the Means for the Notification of Adverse Reactions signed by Maria
do Carmo Neves (Vice-President Administration Board, Verum Pharma - Produtos Farmacêuticos,
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Unipessoal Lda.), and the European Qualified Person responsible for Pharmacovigilance (Augusto
Filipe, Tecnimede Sociedade Técnico-Medicinal, S.A.) on behalf of MAA, dated as version 2:
01-10-2012.
Summary of the Pharmacovigilance System gives the following information: contact details of the
Qualified Person for pharmacovigilance ( Augusto Filipe, Tecnimede Sociedade TécnicoMedicinal, S.A.) and the location of the Pharmacovigilance System Master File ( Tecnimede
Sociedade Técnico-Medicinal, S.A. Zona Industrial da Abrunheira, R Tapada Grande, 2
Abrunheira, 2710-089 Sintra Portugal).
Risk Management Plan
The Applicant provided the information requested for generic applications only. The RMP as provided
is considered acceptable.
User testing
The readability of the PL has been accepted by the RMS.
V.
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
The application for Levodopa + Carbidopa + Entacapona Tecnigen contains adequate quality, non
clinical and clinical data and the bioequivalence has been shown. A benefit/risk ratio comparable to
the reference product can therefore be concluded.
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