Download Public Assessment Report Decentralised Procedure Trazodone hydrochloride 50 mg/5 ml Oral

PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
UK/H/5221/001/DC
Public Assessment Report
Decentralised Procedure
Trazodone hydrochloride 50 mg/5 ml Oral
Solution
(Trazodone hydrochloride)
UK/H/5221/001/DC
UK licence no: PL 21834/0003
RMR Pharmaceuticals Ltd.
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PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
UK/H/5221/001/DC
LAY SUMMARY
Trazodone hydrochloride 50 mg/5 ml Oral Solution
(Trazodone hydrochloride)
This is a summary of the Public Assessment Report (PAR) for Trazodone hydrochloride 50
mg/5 ml Oral Solution (PL 21834/0003). It explains how Trazodone hydrochloride 50 mg/5
ml Oral Solution was assessed and authorisation recommended, as well as its conditions of
use. It is not intended to provide practical advice on how to use Trazodone hydrochloride 50
mg/5 ml Oral Solution. For practical information about using Trazodone hydrochloride 50
mg/5 ml Oral Solution, patients should read the package leaflet or contact their doctor or
pharmacist.
What are Trazodone hydrochloride 50 mg/5 ml Oral Solution and what it is used for?
Trazodone hydrochloride 50 mg/5 ml Oral Solution contains the active substance trazodone
hydrochloride. Trazodone hydrochloride belongs to a group of medicines called
antidepressants.
Trazodone hydrochloride 50 mg/5 ml Oral Solution is used to treat depression, including
depression accompanied by feelings of anxiety.
How is Trazodone hydrochloride 50 mg/5 ml Oral Solution used?
Trazodone hydrochloride 50 mg/5 ml Oral Solution is taken by mouth. This medicine can
only be obtained on prescription from the doctor.
Always take Trazodone Oral Solution exactly as the doctor has prescribed. The patient
should check with the doctor or pharmacist if they are not sure. The doctor may tell the
patient to take the medicine, either in divided doses, after food, or as a single dose before
going to bed.
A 20 ml measuring cup is provided with the medicine
• The required amount of liquid can be dispensed using the measuring cup provided.
• The measuring cup should be washed after use and kept safe for the next dose
Adults
• The usual starting dose is 15 ml (150 mg trazodone hydrochloride) daily;
• This may be increased to 30 ml (300 mg trazodone hydrochloride) daily;
• If the patient is in hospital he/she may be given a higher dose, of up to 60 ml (600 mg
trazodone hydrochloride) daily.
Elderly or frail
• The usual starting dose is 10 ml (100 mg trazodone hydrochloride) daily;
• This may be increased to a maximum of 30 ml (300 mg trazodone hydrochloride)
daily.
Children and adolescents under 18 years of age
• Trazodone Oral Solution should not be given to children and adolescents under 18
years of age.
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PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
UK/H/5221/001/DC
It may take 1 to 2 weeks of treatment before the patient begins to feel better. This is normal
for this type of medicine. The doctor should see the patient 3 to 4 weeks after he/she starts
taking the medicine. The patient should consult the doctor if he/she does not feel any better.
The patient must continue taking the medicine until they are told to stop by the doctor; this
may be for several months after they start to feel better.
The patient should not stop taking Trazodone Oral Solution suddenly. The doctor will tell the
patient how to reduce the dose gradually to help lower the chance of getting withdrawal
symptoms.
Stopping Trazodone Oral Solution suddenly can lead to withdrawal symptoms such as feeling
sick, headaches and feeling generally unwell.
How does Trazodone hydrochloride 50 mg/5 ml Oral Solution work?
Trazodone hydrochloride is a triazolopyridine derivative which differs chemically from other
currently available antidepressants. Trazodone hydrochloride inhibits serotonin uptake into
brain synaptosomes and by platelets at relatively high concentrations and inhibits brain
uptake of noradrenaline in vitro only at very high concentrations. It possesses antiserotoninadrenergic blocking and analgesic effects.
How has Trazodone hydrochloride 50 mg/5 ml Oral Solution been studied?
The product is an oral solution; the applicant has not performed any clinical trials. No
additional studies were needed as Trazodone hydrochloride 50 mg/5 ml Oral Solution is a
generic medicine that is given orally and contains the same active substance and content as
the reference medicine, Trazodone hydrochloride 50 mg/5 ml Oral Solution (PL 17780/0542)
(formerly known as Molipaxin Liquid 50 mg/5 ml oral solution).
What are the benefits and risks of Trazodone hydrochloride 50 mg/5 ml Oral Solution?
As Trazodone hydrochloride 50 mg/5 ml Oral Solution is a generic medicinal product of
Trazodone hydrochloride 50 mg/5 ml Oral Solution (PL 17780/0542) (formerly known as
Molipaxin Liquid 50 mg/5 ml oral solution), their benefit and risks are taken as being the
same.
Why is Trazodone hydrochloride 50 mg/5 ml Oral Solution approved?
No new or unexpected safety concerns arose from this application. It was, therefore,
considered that the benefits of Trazodone hydrochloride 50 mg/5 ml Oral Solution (PL
21834/0003) outweigh the risks; and the grant of a Marketing Authorisation was
recommended.
What measures are being taken to ensure the safe and effective use of Trazodone
hydrochloride 50 mg/5 ml Oral Solution?
A risk management plan has been developed to ensure that Trazodone hydrochloride 50 mg/5
ml Oral Solution is used as safely as possible. Based on this plan, safety information has been
included in the summary of product characteristics and the package leaflet for Trazodone
hydrochloride 50 mg/5 ml Oral Solution, including the appropriate precautions to be
followed by healthcare professionals and patients.
Other information about Trazodone hydrochloride 50 mg/5 ml Oral Solution
A Marketing Authorisation for Trazodone hydrochloride 50 mg/5 ml Oral Solution was
granted on 8th November 2013.
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PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
UK/H/5221/001/DC
The full PAR for Trazodone hydrochloride 50 mg/5 ml Oral Solution follows this summary.
For more information about treatment with Trazodone hydrochloride 50 mg/5 ml Oral
Solution, read the package leaflet or contact your doctor or pharmacist.
This summary was last updated in 01-2014.
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PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
UK/H/5221/001/DC
TABLE OF CONTENTS
Module 1: Information about initial procedure
Page 6
Module 2: Summary of Product Characteristics
Page 7
Module 3: Patient Information Leaflet
Page 8
Module 4: Labelling
Page 9
Module 5: Scientific Discussion
Page 13
I. Introduction
II. About the Product
III. Scientific Overview and Discussion
III.1. Quality aspects
III.2. Non-clinical aspects
III.3. Clinical aspects
IV. Overall conclusion and Benefit-Risk Assessment
Module 6
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Steps taken after initial procedure
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PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
Module 1
Information about initial procedure
Product Name
Trazodone hydrochloride 50 mg/5 ml Oral Solution
Type of Application
Article 10(1), Generic application
Active Substance
Trazodone hydrochloride
Form
Oral Solution
Strength
50 mg/5 ml
MA Holder
RMR Pharmaceuticals Ltd.
Unit 5, Faraday Court
First Avenue, Centrum 100
Burton upon Trent
Staffordshire
DE14 2WX
RMS
UK
CMSs
Cyprus and Greece
Procedure Number
UK/H/5221/001/DC
Timetable
Day 210: 16th October 2013
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UK/H/5221/001/DC
PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
UK/H/5221/001/DC
Module 2
Summary of Product Characteristics
In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs)
and Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a
national level are available on the MHRA website.
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PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
UK/H/5221/001/DC
Module 3
Patient Information Leaflet
In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs)
and Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a
national level are available on the MHRA website.
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PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
Module 4
Labelling
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UK/H/5221/001/DC
PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
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UK/H/5221/001/DC
PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
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UK/H/5221/001/DC
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PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
UK/H/5221/001/DC
Module 5
Scientific discussion during initial procedure
I
INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the Reference Member State
(RMS) and Concerned Member States (CMSs) considered that the application for Trazodone
hydrochloride 50 mg/5 ml Oral Solution for the relief of symptoms in all types of depression
including depression accompanied by anxiety could be approved.
This application was submitted according to Article 10(1) of 2001/83/EC, as amended, as a
generic application. The reference medicinal product for this application is Molipaxin Liquid
50 mg/5 ml oral solution, which was first authorised to Roussel Laboratories Limited (PL
00109/0045), on 11th July 1980. The reference licence has under gone a Change of
Ownership (COA) procedure to Aventis Pharma Limited (PL 04425/0326) on 1st September
2009 and then to the current Marketing Authorisation holder Zentiva (previously known as
Winthrop Pharmaceuticals Limited) (PL 17780/0542) on 3rd September 2010 which is
currently marketed under the generic name “Trazodone hydrochloride 50 mg/5 ml Oral
Solution”.
With UK as the RMS in this Decentralised Procedure (UK/H/5221/001/DC), RMR
Pharmaceuticals Ltd applied for the Marketing Authorisation for Trazodone hydrochloride 50
mg/5 ml Oral Solution in Cyprus and Greece.
Trazodone is a triazolopyridine derivative which differs chemically from other currently
available antidepressants. Although trazodone bears some resemblance to the
benzodiazepines, phenothiazines and tricyclic antidepressants, its pharmacological profile
differs from each of these classes of drugs. The basic idea for the development of trazodone
was the hypothesis that depression involves an imbalance of the mechanism responsible for
the emotional integration of unpleasant experiences.
No new clinical or non-clinical studies were conducted, which is acceptable given that this is
a generic application, which refers to an originator product that has been licensed for over 10
years. Bioequivalence studies are not necessary to support this application for an oral
solution.
The RMS has been assured that acceptable standards of GMP are in place for this product
type at all sites responsible for the manufacture and assembly of this product.
For manufacturing sites within the Community, the RMS has accepted copies of current
manufacturer authorisations issued by inspection services of the competent authorities as
certification that acceptable standards of GMP are in place at those sites.
The RMS considers that the Pharmacovigilance System as described by the applicant 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
notification of any adverse reaction suspected of occurring either in the Community or in a
third country. A Risk Management Plan has been submitted and it is satisfactory.
All member states agreed to grant a licence for the above product at the end of the procedure
(Day 210 – 16th October 2013). After a subsequent national phase, the UK granted a licence
for this product on 8th November 2013 (PL 21834/0003).
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PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
II.
UK/H/5221/001/DC
ABOUT THE PRODUCT
Name of the product in the Reference
Member State
Name(s) of the active substance(s)
(USAN)
Pharmacotherapeutic classification
(ATC code)
Pharmaceutical form and strength(s)
Trazodone hydrochloride 50 mg/5 ml Oral Solution
Reference numbers for the Decentralised
Procedure
Reference Member State
Concerned Member States
UK/H/5221/001/DC
Marketing Authorisation Number(s)
Name and address of the authorisation
holder
PL 21834/0003
RMR Pharmaceuticals Ltd.
Unit 5, Faraday Court
First Avenue, Centrum 100
Burton upon Trent
Staffordshire
DE14 2WX
14
Trazodone hydrochloride
N06A X05
Other antidepressant
Oral Solution
United Kingdom
Cyprus and Greece
PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
UK/H/5221/001/DC
III
SCIENTIFIC OVERVIEW AND DISCUSSION
III.1 QUALITY ASPECTS
DRUG SUBSTANCE
INN: Trazodone hydrochloride
Chemical Names: 2,3-[4-(3-chloro)phenylpiperazin-1-yl]propyl-1,2,4-triazolo[4,3-a] pyridin3(2H)-one hydrochloride
Structure:
Molecular formula: C19H22ClN5O, HCl
Molecular weight: 408.3 g/mol
Physical form: white or almost white crystalline powder.
Solubility: It is soluble in water, sparingly soluble in ethanol (96%), practically insoluble in
ether.
The drug substance is the subject of active substance master file (ASMF). A letter of access
has been provided by the drug substance manufacturer.
Synthesis of the drug substance from the designated starting material has been adequately
described and appropriate in-process controls and intermediate specifications are applied.
Satisfactory specifications are in place for all starting materials and reagents and these are
supported by relevant Certificates of Analysis. Appropriate proof-of-structure data have been
supplied. All potential known impurities have been identified and characterised.
An appropriate specification is provided for the active substance. Analytical methods have been
appropriately validated and are satisfactory for ensuring compliance with the relevant specifications.
Batch analysis data are provided and comply with the proposed specification.
Satisfactory Certificates of Analysis have been provided for working standards used by the drug
substance manufacturer and finished product manufacturer.
The active substance is stored in appropriate packaging. The specifications and typical analytical test
reports are provided and are satisfactory.
Appropriate stability data have been generated, supporting a suitable retest period when the
drug substance is stored in the packaging proposed.
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PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
UK/H/5221/001/DC
DRUG PRODUCT
Other Ingredients
Other ingredients consist of the pharmaceutical excipients glycerol (E422), sorbitol (E420),
benzoic acid (E210), saccharin sodium (E954), orange flavour 14104/04 (includes ethanol
96%, benzyl alcohol (E1519), propylene glycol (E1520)), sodium hydroxide solution and
purified water. A rationale for the inclusion of each excipient is provided.
All excipients comply with the relevant European Pharmacopoeia monographs with the
exception of orange flavour 14104/04 which complies with an in-house specification.
Satisfactory Certificates of Analysis have been provided for these excipients.
The above excipients do not contain materials of animal or human origin. No genetically
modified organisms (GMO) have been used in the preparation of this product.
Pharmaceutical Development
The objective of the pharmaceutical development programme was to obtain a stable oral
solution containing trazodone hydrochloride that could be considered a generic medicinal
product of Molipaxin Liquid 50 mg/5 ml oral solution (Zentiva).
Suitable pharmaceutical development data have been provided for this application.
Comparative impurity profiles have been provided for the proposed and originator products.
Manufacture
Satisfactory batch formula has been provided for the manufacture of the product, along with
an appropriate account of the manufacturing process. The manufacturing process has been
validated using commercial scale batch sizes and has shown satisfactory results. The
applicant has committed to perform further process validation on three consecutive full scale
commercial size batches.
Finished Product Specification
The finished product specification is satisfactory. Test methods have been described and
adequately validated. Batch data have been provided and comply with the release
specifications. Certificates of Analysis have been provided for any working standards used.
Container Closure System
The finished product is supplied in a type III amber glass container of 125 ml nominal
capacity suitable for pharmaceutical solutions containing 120 ml of medicine. A childresistant high density polyethylene (HDPE) screw cap with PEBD seal and tamper evident
closure constitutes integral part of the primary container.
A 20 ml, CE marked polypropylene homopolymer (PPH) measuring cup with intermediate
graduations is also provided.
Specifications and Certificates of Analysis for the primary packaging material have been
provided. These are satisfactory. All primary packaging is controlled to European
Pharmacopoeia standards and complies with relevant guidelines.
Stability
Finished product stability studies have been conducted in accordance with current guidelines
and in the packaging proposed for marketing.
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PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
UK/H/5221/001/DC
Based on the results, shelf-lives of 24 months for unopened bottles and 1 month after opening
have been set. The proposed storage conditions are “Do not store above 25°C” and “Keep
bottle in the outer carton in order to protect from light”. These are satisfactory.
Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and
Labelling
The SmPC, PIL and labelling are pharmaceutically satisfactory.
User testing of the package leaflet has been accepted, based on a bridging report provided by
the applicant. The justification on the rationale for bridging is accepted.
The Marketing Authorisation holder has stated that not all packs are intended to be marketed.
However, they have committed to submit mock-ups of any pack size to the relevant
regulatory authorities before marketing.
Marketing Authorisation Application (MAA) Form
The MAA form is pharmaceutically satisfactory.
Expert Report/Quality Overall Summary
A quality overall summary has been written by an appropriately qualified person and is a
suitable summary of the pharmaceutical aspects of the dossier.
Conclusion
There are no objections to the approval of this product from a pharmaceutical point of view.
III.2 NON-CLINICAL ASPECTS
PHARMACODYNAMICS, PHARMACOKINETICS, TOXICOLOGY
The pharmacological, pharmacokinetic and toxicological properties of trazodone
hydrochloride are well-known.
No new non-clinical data have been supplied with this application and none are required for
applications of this type. The non-clinical expert report has been written by an appropriately
qualified person and is a suitable summary of the non-clinical aspects of the dossier.
A suitable justification has been provided for the non-submission of the environmental risk
assessment.
There are no objections to the approval of this product from a non-clinical point of view.
III.3 CLINICAL ASPECTS
CLINICAL PHARMACOLOGY
Pharmacokinetics
In accordance with Note for Guidance on the investigation of bioequivalence
(CPMP/EWP/QWP/1401/98 Rev 1), a bioequivalence study is not requested if the test
product is an oral solution containing the same active substance in the same concentration as
the reference product. In addition the excipients and levels present are adequately justified.
No bioequivalence studies have been submitted with this application and none are required.
No new data have been submitted and none are required for applications of this type.
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PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
UK/H/5221/001/DC
EFFICACY
No new efficacy data have been submitted and none are required for this application.
SAFETY
No new safety data have been submitted and none are required for this application.
EXPERT REPORT
The clinical overview is written by an appropriately qualified physician and is a suitable
summary of the clinical aspects of the dossier.
SUMMARY OF PRODUCT CHARACTERISTICS
The SmPC is medically satisfactory and consistent with that for the reference product.
PATIENT INFORMATION LEAFLET
The PIL is medically satisfactory and consistent with the SmPC.
LABELLING
The labelling is medically satisfactory.
MAA FORM
The MAA form is medically satisfactory.
CONCLUSIONS
There are no objections to the approval of this product from a clinical point of view.
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PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
UK/H/5221/001/DC
IV
OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT
QUALITY
The important quality characteristics of Trazodone hydrochloride 50 mg/5 ml Oral Solution
are well-defined and controlled. The specifications and batch analytical results indicate
consistency from batch to batch. There are no outstanding quality issues that would have a
negative impact on the benefit/risk balance.
NON-CLINICAL
No new non-clinical data were submitted and none are required for applications of this type.
CLINICAL
No new efficacy data were submitted and none are required for applications of this type. As
the safety profile of trazodone hydrochloride is well-known, no additional data were required.
No new or unexpected safety concerns arose from this application.
PRODUCT LITERATURE
The SmPC and PIL are satisfactory and consistent with those of the reference product.
Satisfactory labelling has also been submitted.
RISK-BENEFIT ASSESSMENT
The quality of the product is acceptable and no new non-clinical or clinical concerns have
been identified. Extensive clinical experience with trazodone hydrochloride is considered to
have demonstrated the therapeutic value of the compound. The risk-benefit is, therefore,
considered to be positive.
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PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution
UK/H/5221/001/DC
Module 6
STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY
Date
submitted
20
Application
type
Scope
Outcome