Public Assessment Report UKPAR Trazodone … · the UK to Creo Pharma Limited on 15 December 2017. The full Public Assessment Report approved for Trazodone Oral Solution follows this

Public Assessment Report

UKPAR

Trazodone Hydrochloride 100mg/5ml Oral Solution

(Trazodone hydrochloride)

UK Licence No: PL 31862/0027

Creo Pharma Limited


PL 31862/0027

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LAY SUMMARY


(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



III.4 Toxicology



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:


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PL 31862/0027

STEPS TAKEN AFTER THE INITIAL PROCEDURE - SUMMARY

Date

submitted

Application

type

Scope Outcome

Documents

Public Assessment Report UKPAR Trazodone … · the UK to Creo Pharma Limited on 15 December 2017. The full Public Assessment Report approved for Trazodone Oral Solution follows this