public assessment report - gov.uk · par trazodone hydrochloride 50 mg/5 ml oral solution...

PAR Trazodone hydrochloride 50 mg/5 ml Oral Solution UK/H/5221/001/DC

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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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LAY SUMMARY


(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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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 antiserotonin-adrenergic 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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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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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 Steps taken after initial procedure Page 20


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Module 1

Information about initial procedure

Product Name


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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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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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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Module 4

Labelling


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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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II. ABOUT THE PRODUCT Name of the product in the Reference Member State


Name(s) of the active substance(s) (USAN)

Trazodone hydrochloride

Pharmacotherapeutic classification (ATC code)

N06A X05 Other antidepressant

Pharmaceutical form and strength(s) Oral Solution

Reference numbers for the Decentralised Procedure

UK/H/5221/001/DC

Reference Member State United Kingdom Concerned Member States

Cyprus and Greece

Marketing Authorisation Number(s) PL 21834/0003 Name and address of the authorisation holder

RMR Pharmaceuticals Ltd. Unit 5, Faraday Court First Avenue, Centrum 100 Burton upon Trent Staffordshire DE14 2WX


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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] pyridin-3(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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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 child-resistant 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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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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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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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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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted

Application type

Scope Outcome

public assessment report - gov.uk · par trazodone hydrochloride 50 mg/5 ml oral solution...

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