Post on 27-May-2018
Public Assessment Report
UKPAR
Trazodone Hydrochloride 100mg/5ml Oral Solution
(Trazodone hydrochloride)
UK Licence No: PL 31862/0027
Creo Pharma Limited
Trazodone Hydrochloride 100mg/5ml Oral Solution
PL 31862/0027
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LAY SUMMARY
Trazodone Hydrochloride 100mg/5ml Oral Solution
(Trazodone hydrochloride)
The product may be called ‘Trazodone Oral Solution’ in this lay summary.
This is a summary of the Public Assessment Report (PAR) for Trazodone Hydrochloride 100mg/5ml
Oral Solution (PL 31862/0027, previously PL 41344/0038). It explains how the application for
Trazodone Oral Solution was assessed and its authorisation recommended, as well as the conditions of
use. It is not intended to provide practical advice on how to use Trazodone Oral Solution.
For practical information about using Trazodone Oral Solution, patients should read the package leaflet
or contact their doctor or pharmacist.
What is Trazodone Oral Solution and what is it used for?
Trazodone Oral Solution is a ‘hybrid medicine’. This means that Trazodone Oral Solution is similar to
reference medicine already authorised in the UK called Molipaxin Liquid 50mg/5ml Oral solution
(PL 17780/0542; Winthrop Pharmaceuticals UK Limited, UK).
Trazodone Oral Solution contains the same active substance trazodone hydrochloride as the reference
medicines, however it differs in the strength of active substance from the reference product. Trazodone
Oral Solution contains 100 mg of trazodone hydrochloride per 5 ml of oral solution, while Molipaxin
Liquid 50mg/5ml Oral solution (PL 17780/0542; Winthrop Pharmaceuticals UK Limited, UK) contains
50 mg trazodone hydrochloride per 5 ml of oral solution.
For ease of reading, Molipaxin Liquid 50mg/5ml Oral solution will be referred to as ‘Molipaxin Oral
solution’ in this lay summary.
Trazodone Oral Solution can be used to treat anxiety and depression.
How does Trazodone Oral Solution work?
Trazodone Oral Solution contains the active substance, trazodone (as trazodone hydrochloride), which
belongs to a group of medicines called antidepressants.
How is Trazodone Oral Solution used?
Trazodone Oral Solution is available as an oral solution and is taken by mouth (swallowed).
This medicine can be taken with or after food. This can help lower the chances of side effects.
Trazodone Oral Solution can only be obtained on prescription. The patient should always take this
medicine exactly as advised by his/her doctor. The patient should check with his/her doctor or
pharmacist if he/she is not sure.
Note:
If necessary, Trazodone Oral Solution can be administered via a nasogastric, nasoduodenal or
nasojejunal feeding tube that should be rinsed twice with 10ml of water immediately after
administration.
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Children and adolescents
Trazodone Oral Solution should not be used in children and adolescents under 18 years of age.
Please read section 3 of the package leaflet for detailed information on dosing recommendations, the
route of administration and the duration of treatment.
What benefits of Trazodone Oral Solution have been shown in studies?
Studies in patients have been limited to tests to determine that Trazodone Oral Solution is bioequivalent
to an equivalent dose of the reference medicine, Molipaxin Oral solution (Winthrop Pharmaceuticals UK
Limited, UK). Two medicines are bioequivalent when they produce the same levels of the active
substance in the body.
What are the possible side effects of Trazodone Oral Solution?
Like all medicines, Trazodone Oral Solution used can cause side effects, although not everybody gets
them.
For the full list of all side effects reported with Trazodone Oral Solution, see section 4 of the package
leaflet.
For the full list of restrictions, see the package leaflet for Trazodone Oral Solution.
Why is Trazodone Oral Solution approved?
It was concluded that, in accordance with EU requirements, Trazodone Oral Solution has been shown to
have comparable quality and is comparable to Molipaxin Oral solution (Winthrop Pharmaceuticals UK
Limited, UK). Therefore, the view was that, as for Molipaxin Oral solution (Winthrop Pharmaceuticals
UK Limited, UK), the benefits outweigh the identified risks.
What measures are being taken to ensure the safe and effective use of Trazodone Oral Solution?
A Risk Management Plan has been developed to ensure that Trazodone 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 Oral Solution, including the appropriate
precautions to be followed by healthcare professionals and patients.
Other information about Trazodone Oral Solution
A Marketing Authorisation was granted in the UK to Colonis Pharma Limited on 27 November 2017.
Subsequent to a Change of Authorisation (COA) procedure, a Marketing Authorisation was granted in
the UK to Creo Pharma Limited on 15 December 2017.
The full Public Assessment Report approved for Trazodone Oral Solution follows this summary.
For more information about treatment with Trazodone Oral Solution, read the package leaflet, or contact
your doctor or pharmacist.
This summary was last updated in January 2018.
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SCIENTIFIC DISCUSSION
TABLE OF CONTENTS
I Introduction Page 5
II Quality aspects Page 6
III Non-clinical aspects Page 8
IV Clinical aspects Page 8
V User consultation Page 11
VI Overall conclusion, benefit/risk assessment and recommendation Page 11
Steps taken after the initial procedure - summary Page 14
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Scientific discussion
I. INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the MHRA considered that the
application for Trazodone Hydrochloride 100mg/5ml Oral Solution (PL 31862/0027, previously
PL 41344/0038) could be approved. The product is a Prescription Only Medicine (POM) indicated for
the relief of symptoms in all types of depression including depression accompanied by anxiety.
Symptoms of depression likely to respond in the first week of treatment include depressed mood,
insomnia, anxiety, somatic symptoms and hypochondriasis. The product may be called ‘Trazodone
Hydrochloride Oral Solution’ ‘in this scientific discussion.
The application was submitted under Article 10(3) of Directive 2001/83/EC, as amended, claiming to be
a hybrid application. For the purposes of satisfying data exclusivity, the application refers to the
originator medicinal product Molipaxin 50mg Capsules/Trazodone Hydrochloride 50mg Capsules (PL
00109/0045; Roussel Laboratories Limited, UK), which was authorised in the UK on 11 July 1980. The
originator reference product is currently authorised to Zentiva, previously known as Winthrop
Pharmaceuticals UK Limited (PL 17780/0617; Molipaxin 50mg Capsules/Trazodone Hydrochloride
50mg Capsules), following a series of Change of Ownership (CoA) procedures, the last being granted on
03 September 2012.
The application also refers to the medicinal product Trazodone hydrochloride 50mg/5ml oral solution
(PL 17780/0542; Zentiva, UK). Trazodone hydrochloride 50mg/5ml Oral Solution (PL 17780/0542;
Zentiva UK) was granted on 27 October 2010, following a series of CoA procedures of Molipaxin
Liquid (50mg/5ml) (PL 00109/0117; Roussel Laboratories Limited, trading as Sanofi-aventis).
Molipaxin Liquid (50mg/5ml) (PL 00109/0117; Roussel Laboratories Limited, trading as
Sanofi-aventis) was first authorised in the UK on 06 January 1983.
The active substance, trazodone (as trazodone hydrochloride), 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.
One bioequivalence study, comparing the applicant’s test product Trazodone Hydrochloride 100mg/5ml
Oral solution (5ml) with the reference product Trazodone Hydrochloride 50mg/5ml Oral Solution
(10ml; Winthrop Pharmaceuticals UK Limited) under fed conditions, was submitted to support the
application. It is stated that the the bioequivalence study was conducted in accordance with Good
Clinical Practice (GCP).
With the exception of the bioequivalence study, no new non-clinical or clinical studies were conducted,
which is acceptable given that this was a hybrid application of a medicinal reference product that has
been in clinical use for over 10 years.
The MHRA has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in
place at all sites responsible for the manufacture, assembly and batch release of this product.
No new or unexpected safety concerns arose during review of information provided by the Marketing
Authorisation Holder and it was, therefore, judged that the benefits of Trazodone Oral Solution
outweigh the risks, and a Marketing Authorisation (PL 41344/0038) was granted to Colonis Pharma
Limitedon 27 November 2017.
Subsequent to a Change of Authorisation procedure, a Marketing Authorisation (PL 31862/0027) was
granted in the UK to Creo Pharma Limited on 15 December 2017.
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II. QUALITY ASPECTS
II.1 Introduction
The submitted documentation concerning the proposed product is of sufficient quality and meets the
current EU regulatory requirements.
The quality overall summary has been written by an appropriately qualified person and is a suitable
summary of the pharmaceutical aspects of the dossier.
The product is a clear, colourless to yellowish solution with characteristic orange odour.
Each 5ml of oral solution contains 100mg of trazodone hydrochloride, as the active substance.
The products also contain pharmaceutical excipients, namely sorbitol solution 70% (E 420), glycerol
(E 422), sodium benzoate (E 211), saccharin sodium (E 954), hydrochloric acid solution 1.0 N, purified
water, nitrogen and orange flavour (14104/04; containing ethyl alcohol). Appropriate justification for the
inclusion of each excipient has been provided.
Trazodone Oral Solution is packed in Ph Eur, Type III, amber glass containers containing 120 ml of oral
solution. Each bottle has a child-resistant high density polyethylene (HDPE) screw cap with low density
polyethylene seal and tamper evident closure. Each bottle is package in a carton box. The pack also
contains a 15 ml CE marked plastic (polypropylene(PP)) dosing cup with intermediate graduations.
Satisfactory specifications and Certificates of Analysis for the primary packaging material have been
provided. All primary packaging is controlled to European Pharmacopoeia standards that comply with
guidance concerning materials in contact with foodstuff.
II.2 DRUG SUBSTANCE
Trazodone hydrochloride
INN: Trazodone hydrochloride
Chemical name 2,3-[4-(3-chloro)phenylpiperazin-1-yl]propyl-1,2,4-triazolo[4,3-a]
pyridin-3(2H)-one hydrochloride
Molecular formula: C19H22ClN5O, HCl
Structure:
Mr: 408.3
Appearance: White or almost white crystalline powder
Solubility: Soluble in water and methanol, sparingly soluble in chloroform, slightly
soluble in acetone.
Trazodone hydrochloride is the subject of a British Pharmacopoeia monograph.
Synthesis of the active substance from the designated starting materials has been adequately described
and appropriate in-process controls and intermediate specifications are applied. Satisfactory
specification tests are in place for all starting materials and reagents, and these are supported by relevant
Certificates of Analysis.
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Appropriate proof-of-structure data have been supplied for the active substance. 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 analyses data are provided that comply with the proposed specification.
Satisfactory Certificates of Analysis have been provided for all working standards used.
Suitable specifications have been provided for all packaging used. The primary packaging has been
shown to comply with current guidelines concerning contact with food.
Appropriate stability data have been generated supporting a suitable retest period when stored in the
proposed packaging.
II.3 MEDICINAL PRODUCT
Pharmaceutical Development
The objective of the development programme was to produce a safe, efficacious, stable oral solution that
was equivalent to the reference product Trazodone hydrochloride 50mg/5ml Oral Solution (Winthrop
Pharmaceuticals UK Limited, UK). Suitable pharmaceutical development data have been provided for
this application.
With the exception of orange flavour, which is controlled to a suitable in-house specification, all the
excipients comply with their respective European Pharmacopoeia monographs. Certificates of Analysis
have been provided for all excipients, showing compliance with their respective specifications.
None of the excipients contain materials of animal or human origin .
This product does not contain or consist of genetically modified organisms (GMO).
Manufacturing Process
A 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 with
minimum production-scale batches that have shown satisfactory results. The Marketing Authorisation
Holder has committed to performing process validation studies on future full production-scale batches.
Control of Finished Product
The finished product specification is acceptable. Test methods have been described that have been
validated adequately. Batch data have been provided that comply with the release specification.
Certificates of Analysis have been provided for all working standards used.
Stability of the Product
Finished product stability studies were performed in accordance with current guidelines on batches of
finished product in the packaging proposed for marketing. Based on the results, a shelf-life of 2 years for
the unopened product, with the special storage conditions ‘Keep bottle in the outer carton in order to
protect from light’, has been accepted. After first opening the product should be used within a month
and not be stored above 25oC.
Suitable post approval stability commitments have been provided to continue stability testing on batches
of finished product.
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Bioequivalence/Bioavailability
Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the
bioequivalence study. The bioequivalence study is discussed in Section IV, Clinical Aspects.
Discussion on chemical, pharmaceutical and biological aspects
It is recommended that a Marketing Authorisation is granted, from a quality point of view.
III NON-CLINICAL ASPECTS
III.1 Introduction
As the pharmacodynamic, pharmacokinetic and toxicological properties of trazodone hydrochloride are
well-known, no new non-clinical data have been submitted and none are required.
The applicant’s non-clinical overview has been written by an appropriately qualified person and is
satisfactory, providing an appropriate review of the relevant non-clinical pharmacology,
pharmacokinetics and toxicology.
III.2 Pharmacology
No new data have been submitted and none are required for an application of this type. Refer to Section
III.1 Introduction, above.
III.3 Pharmacokinetics
No new data have been submitted and none are required for an application of this type. Refer to Section
III.1 Introduction, above.
III.4 Toxicology
No new data have been submitted and none are required for an application of this type. Refer to Section
III.1 Introduction, above.
III.5 Ecotoxicity/Environmental Risk Assessment (ERA)
Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As
the application is for a generic version of an already authorised product, it is not expected that
environmental exposure will increase following approval of the Marketing Authorisation for the
proposed product.
III.6 Discussion of the non-clinical aspects
No new non-clinical studies were conducted, which is acceptable given that the application was based
on being a generic medicinal product of reference product that has been licensed for over 10 years.
It is recommended that a Marketing Authorisation is granted, from a non-clinical point of view.
IV. CLINICAL ASPECTS
IV.1 Introduction
The clinical pharmacology, safety and efficacy profiles of trazodone hydrochloride are
well-known.
The clinical overview has been written by an appropriately qualified person and is a suitable summary of
the clinical aspects of the dossier.
In accordance with the regulatory requirements CPMP/EWP/QWP/1401/98 Rev 1/Corr**, Guideline on
the Investigation of Bioequivalence, the Marketing Authorisation Holder submitted a bioequivalence
study to support the application.
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With the exception of data from the bioequivalence study detailed in Section IV.2, Pharmacokinetics
below, no new pharmacodynamic or pharmacokinetic data are provided and none are required for this
type of application.
IV.2 Pharmacokinetics
The pharmacokinetic properties of trazodone are well known.
In support of the application, the applicant submitted the following bioequivalence study:
An open-label, randomised, two-treatment, two-period, two-sequence, single-dose, crossover,
bioequivalence study comparing the pharmacokinetics of the applicant’s test product Trazodone
Hydrochloride 100mg/5ml Oral solution (5 ml) versus the reference product Trazodone
Hydrochloride 50mg/5ml Oral Solution (10ml; Winthrop Pharmaceuticals UK Limited) in healthy
adult subjects, under fed conditions.
The subjects were administered a single dose (100 mg) of either the test product (5ml]) or the reference
product (10ml). Either treatment was administered, with approximately 240 ml of water 30 minutes after
a high fat, high calorie breakfast, after at least a 10-hour overnight fast. Blood samples were collected
before, up to and including 48 hours after each administration. The washout period between the
treatment phases was 16 days. A summary of the pharmacokinetic results of the study are presented
below.
Table: The statistical results for primary pharmacokinetic parameters of trazodone
Cmax maximum plasma concentration
AUC0-t area under the plasma concentration-time curve from time zero to time t hours
AUC0-∞ area under the plasma concentration-time curve from time zero to time infinity hours
Conclusion
The 90% confidence intervals of the test/reference ratio for AUC and Cmax values lie within the
acceptable limits of 80.00% to 125.00%, in line with the ‘Guideline on the Investigation of
Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr**). Thus, the data support the claim that 5ml of
the applicant’s test product (100mg/5ml) is bioequivalent, in terms of rate and extent of absorption, to
the 10ml of the reference product Trazodone Hydrochloride 50mg/5ml Oral Solution (Winthrop
Pharmaceuticals UK Limited, UK) in healthy subjects after a single, oral dose under fed conditions.
IV.3 Pharmacodynamics
The clinical pharmacodynamic properties of trazodone hydrochloride are well-known. No new
pharmacodynamic data were submitted and none are required for this type of application.
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IV.4 Clinical Efficacy
The clinical efficacy of trazodone hydrochloride is well-known. No new efficacy data are presented or
are required for this type of application.
IV.5 Clinical Safety
The safety profile of trazodone hydrochloride is well known. No new safety data have been submitted
with this application and none are required. No new or unexpected safety concerns arose from this
application.
IV.6 Risk Management Plan
The MAH has submitted a Risk Management Plan, in accordance with the requirements of Directive
2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to
identify, characterise, prevent or minimise risks relating to Trazodone Oral Solution.
A summary of safety concerns is listed in the table below:
Table: Summary of safety concerns
Routine pharmacovigilance and risk minimisation measures are proposed. This is acceptable.
IV.7 Discussion of the clinical aspects
It is recommended that a Marketing Authorisation is granted, from a clinical point of view.
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V. USER CONSULTATION
A 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 pack leaflet was English.
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
The quality of the product is acceptable, and no new non-clinical safety concerns have been identified.
Extensive clinical experience with trazodone hydrochloride in the proposed indications is considered to
have demonstrated the therapeutic value of the compound. The proposed product is considered
therapeutically equivalent to the reference product. The overall benefit/risk balance is, therefore,
considered to be positive.
The grant of a Marketing Authorisation is recommended.
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In accordance with Directive 2010/84/EU, the current version of the SmPC and package leaflet is
available on the MHRA website. The current labelling is presented below:
Trazodone Hydrochloride 100mg/5ml Oral Solution
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Trazodone Hydrochloride 100mg/5ml Oral Solution
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Trazodone Hydrochloride 100mg/5ml Oral Solution
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STEPS TAKEN AFTER THE INITIAL PROCEDURE - SUMMARY
Date
submitted
Application
type
Scope Outcome