Public Assessment Report Decentralised Procedure … · Public Assessment Report Decentralised...

Public Assessment Report

Decentralised Procedure

Buspirone hydrochloride 5 and 10 mg Tablets

(buspirone hydrochloride)

Procedure No: UK/H/5429/001-02/DC

UK Licence No: PL 28176/0153-0154

Strides Arcolab International Ltd.

PAR Buspirone hydrochloride 5 and 10 mg Tablets

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LAY SUMMARY Buspirone hydrochloride 5 and 10 mg Tablets

(buspirone hydrochloride)

This is a summary of the public assessment report (PAR) for Buspirone hydrochloride 5 and 10 mg

Tablets (PL 28176/0153-0154; UK/H/5429/001-02/DC). It explains how Buspirone hydrochloride 5 and

10 mg Tablets were assessed and their authorisations recommended as well as their conditions of use. It

is not intended to provide practical advice on how to use Buspirone hydrochloride 5 and 10 mg Tablets.

For practical information about using Buspirone hydrochloride 5 and 10 mg Tablets, patients should

read the package leaflet or contact their doctor or pharmacist.

What are Buspirone hydrochloride 5 and 10 mg Tablets and what are they used for?

Buspirone hydrochloride 5 and 10 mg Tablets are medicines that contain the active substance buspirone

(as hydrochloride). Buspirone Tablets may be used for the:

• short term management of anxiety disorders;

• relief of symptoms of anxiety with or without symptoms of depression.

Buspirone hydrochloride 5 and 10 mg Tablets are generic medicines. This means that Buspirone

hydrochloride 5 and 10 mg Tablets are similar to ‘reference medicines’ already authorised in the

European Union (EU) called Buspar Tablets 5 mg and 10 mg (Actavis Group PTC EHF; PL

30306/0320-0321).

How are Buspirone hydrochloride 5 and 10 mg Tablets used?

Buspirone hydrochloride 5 and 10 mg Tablets are taken by mouth. The whole tablet should be

swallowed with some water, at the same time each day with or without food.

The starting dose in adults is 5 mg two to three times a day, which may be increased every two to three

days. The usual dose a patient will be maintained on is 15 mg to 30 mg a day up to a maximum dose of

45 mg a day in divided doses.

These medicinal products are not recommended for use in children.

Buspirone hydrochloride 5 and 10 mg Tablets can only be obtained on prescription from a doctor.

For further information on how Buspirone hydrochloride 5 and 10 mg Tablets are used, please see the

Summaries of Product Characteristics and package leaflet available on the MHRA website.

How do Buspirone hydrochloride 5 and 10 mg Tablets work?

The active substance in Buspirone hydrochloride Tablets, buspirone hydrochloride, belongs to a group

of medicines called anxiolytics. These medicines work on the central nervous system, altering levels of

chemicals in the brain.

How have Buspirone hydrochloride 5 and 10 mg Tablets been studied?

Buspirone hydrochloride 5 and 10 mg Tablets are generic medicines. Buspirone hydrochloride was

designated as a Biopharmaceutics Classification System (BCS) Class I drug based on its properties

(highly soluble, highly permeable). With these applications the applicant claimed BCS biowaiver.

What are the benefits and risks of Buspirone hydrochloride 5 and 10 mg Tablets?

As Buspirone hydrochloride 5 and 10 Tablets are generic medicines of the reference medicines, Buspar

Tablets 5 mg and 10 mg (Actavis Group PTC EHF), their benefits and risks are taken as being the same


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as those for Buspar Tablets 5 mg and 10 mg (Actavis Group PTC EHF).

Why are Buspirone hydrochloride 5 and 10 Tablets approved?

It was concluded that, in accordance with EU requirements, Buspirone hydrochloride 5 and 10 mg

Tablets have been shown to have comparable quality and bioequivalent to Buspar Tablets 5 mg and 10

mg (Actavis Group PTC EHF). Therefore, the view was that, as for Buspar Tablets 5 mg and 10 mg

(Actavis Group PTC EHF), the benefit outweighs the identified risk.

What measures are being taken to ensure the safe and effective use of Buspirone hydrochloride 5

and 10 mg Tablets?

A risk management plan has been developed to ensure that Buspirone hydrochloride 5 and 10 mg

Tablets are used as safely as possible. Based on this plan, safety information has been included in the

Summaries of Product Characteristics and the package leaflet for Buspirone hydrochloride 5 and 10 mg

Tablets, including the appropriate precautions to be followed by healthcare professionals and patients.

Other information about Buspirone hydrochloride 5 and 10 mg Tablets

Luxemburg and the UK agreed to grant Marketing Authorisations for Buspirone hydrochloride 5 and 10

mg Tablets on 24th

November 2014. Marketing Authorisations were granted in the UK on 30th

January

2015.

The full PAR for Buspirone hydrochloride 5 and 10 mg Tablets follows this summary. For more

information about treatment with Buspirone hydrochloride 5 and 10 mg Tablets, read the package leaflet

or contact your doctor or pharmacist.

This summary was last updated in April 2015.


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TABLE OF CONTENTS

I Introduction Page 5

II Quality aspects Page 6

III Non-clinical aspects Page 7

IV Clinical aspects Page 8

V User consultation Page 24

VI Overall conclusion, benefit/risk assessment and Page 24

recommendation

Table of content of the PAR update for MRP 0

and DCP


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I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the Reference Member State (RMS) and

Concerned Member State (CMS) considered that the applications for Buspirone hydrochloride 5 and 10

mg Tablets for the treatment of short-term management of anxiety disorders and the relief of symptoms

of anxiety with or without accompanying symptoms of depression, is approvable.

The applications were submitted using the Decentralised Procedure (DCP) with the UK as the RMS and

Luxemburg as CMS. The applications were submitted under Article 10(1) of Directive 2001/83/EC, as

amended and cross referred to Buspar Tablets 5 mg and 10 mg, which were originally authorised to

Bristol-Myers Squibb Holdings Limited (PL 00125/0162-0163) on 11th

June 1987. These reference

licences underwent change of ownership procedures to the currently Marketing Authorisation holder,

Actavis Group PTC EHF (PL 30306/0320-0321), on 15th

September 2010.

Buspirone is an azaspirodecanedione. The exact mechanism of buspirone’s anxioselective action is not

fully known. It does not act on benzodiazepine receptor sites and lacks sedative, anticonvulsant and

muscle relaxant properties. From animal studies it is known to interact with serotonin, noradrenaline

(norepinephrine), acetylcholine and dopamine systems of the brain. Buspirone enhances the activity of

specific noradrenergic and dopaminergic pathways, whereas the activity of serotonin and acetylcholine

are reduced.

No bioequivalence study was submitted and these applications are based on Biopharmaceutics

Classification System (BCS) class I biowaiver.

The RMS has been assured that acceptable standards of Good Manufacturing Practice are in place for

this product type at all sites responsible for the manufacture, assembly and batch release of these

products.

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.

For manufacturing sites outside the community, the RMS has accepted copies of current GMP

Certificates or satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’

issued by the inspection services of the competent authorities (or those countries with which the EEA

has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards

of GMP are in place at those non-Community sites.

All involved Member States agreed to grant Marketing Authorisations for the above products at the end

of the procedure (Day 210 – 24th

November 2014). After a subsequent national phase, the UK granted

Marketing Authorisations (PL 28176/0153-0154) for these products on 30th

January 2015.


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II QUALITY ASPECTS

II.1 Introduction

These products are tablets and contain 5 mg and 10 mg buspirone hydrochloride, as active ingredient.

The excipients present are lactose monohydrate, microcrystalline cellulose (Avicel-PH-101), sodium

starch glycolate, microcrystalline cellulose (Avicel-PH-200), colloidal silicon dioxide and magnesium

stearate.

All excipients used comply with their respective European Pharmacopoeia monographs.

The only excipient used that contains material of animal or human origin is lactose monohydrate. The

applicant has provided a declaration that the milk used in the production of lactose monohydrate is

sourced from healthy animals under the same conditions as that for human consumption. Confirmation

has also been given that the magnesium stearate used in the tablets is of vegetable origin.

The finished product is packaged in blister packs of white opaque polyvinylchloride (PVC) film and

plain aluminium blister foil containing 20, 30, 40, 50, 60, 90 and 100 tablets. Not all pack sizes may be

marketed.

Satisfactory specifications and Certificates of Analysis have been provided for all packaging

components. All primary packaging complies with the current European regulations concerning

materials in contact with food.

II.2 Drug Substance

INN: Buspirone hydrochloride

Chemical name(s): 8-[4-[4-(Pyrimidin-2-yl)- piperazin-1-yl]butyl]-8-azaspiro[4,5]decane-7,9-dione

hydrochloride

Structure:

Molecular formula: C21H32ClN5O2

Molecular weight: 421.97 g/mol

Appearance: White or almost white crystalline powder.

Solubility: Freely soluble in water and in methanol, practically insoluble in acetone.

Buspirone hydrochloride is the subject of an active substance master file (ASMF).

Synthesis of the drug 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.

An appropriate specification is provided for the drug substance. Analytical methods have been

appropriately validated and are satisfactory for ensuring compliance with the relevant specifications.

Certificates of Analysis for all working standards have been provided.

Batch analyses data are provided that comply with the proposed specification.


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Satisfactory specifications and Certificates of Analysis have been provided for all packaging used to

store the drug substance. Confirmation has been provided that the primary packaging complies with

current guidelines concerning materials in contact with food.

Appropriate stability data have been generated, supporting a suitable retest period when the drug

substance is stored in the packaging proposed.

II.3 Medicinal Product

Pharmaceutical Development

The objective of the development programme was to formulate robust, stable, tablets, bioequivalent to

Buspar Tablets 5 mg and 10 mg (Actavis Group PTC EHF).

Comparative in-vitro studies have been performed with UK generic products, Buspirone 5 mg and 10

mg tablets (PL 00142/0455 - 0456), as the reference products are no longer marketed in the EU.

Comparative dissolution and impurity profiles have been presented for the proposed and reference

products.

Manufacture of the product Satisfactory batch formulae have been provided for the manufacture of the products, along with an

appropriate account of the manufacturing processes. The manufacturing processes have been validated

and have shown satisfactory results. The manufacturing process has been validated using two pilot scale

batches and committed to producing a third pilot-scale batch and conducting process validation on three

full scale commercial batches of each tablet strength post approval.

Finished Product Specifications

The finished product specifications are satisfactory. The test methods have been described and

adequately validated. Batch data have been provided that comply with the release specifications.

Certificates of Analysis have been provided for any working standards used.

Stability of the product

Finished product stability studies have been conducted in accordance with current guidelines and in the

packaging proposed for marketing.

Based on the results, a shelf-life of 3 years with no special storage conditions has been set. This is

satisfactory.

II.3 Discussion on chemical, pharmaceutical and biological aspects

The grant of Marketing Authorisations is recommended.

III NON-CLINICAL ASPECTS

The pharmacodynamic, pharmacokinetic and toxicological properties of buspirone hydrochloride are

well known.

No new non-clinical data have been supplied with these applications and none are required for

applications of this type. The non-clinical overview 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 not submitting an environmental risk assessment. As these

products are intended for generic substitution with products that are currently marketed, no increase in

environmental burden is expected.


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There are no objections to the approval of these products from a non-clinical point of view.

IV CLINICAL ASPECTS

IV.1 Introduction

For these generic applications, the Applicant applied for Biopharmaceutics Classification System (BCS)

based biowaiver. No bioequivalence study was performed.

No new clinical data have been submitted and none are required for applications of this type. A clinical

overview has been submitted to justify the biowaiver. The applicant’s clinical overview has been written

by an appropriately qualified person and is considered acceptable.

IV.2 BCS Biowaiver

The Applicant applied for Biopharmaceutics Classification System (BCS) based biowaiver for both

tablet strengths. In line with the ‘Note for Guidance on the investigation of bioavailability and

bioequivalence’ (CPMP/EWP/QWP/1401/98 Rev 1/ Corr**), this was considered acceptable as

buspirone hydrochloride is highly soluble with complete absorption, high permeability (BCS class I) and

is not considered to be a narrow-therapeutic drug and the products are immediate release solid dose

preparations for oral use with the same pharmaceutical form as the reference products. Satisfactory data

has been submitted to justify the BCS biowaiver.

IV.3 Pharmacokinetics

No new data have been submitted and none are required for applications of this type.

IV.4 Pharmacodynamics

No new data have been submitted and none are required for applications of this type.

IV.5 Clinical efficacy

No new data on efficacy have been submitted and none are required for this type of applications.

IV.6 Clinical safety

No new safety data were submitted and none are required.

IV.7 Risk Management Plan (RMP)

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 Buspirone hydrochloride 5 mg and 10 mg

Tablets.


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Summary table of Safety concerns


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Summary table of risk minimisation measures


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IV.8 Discussion on the clinical aspects

The grant of Marketing Authorisations is recommended.

V User consultation The 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, as amended. The language used for

the purpose of user testing the PIL 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 AND BENEFIT-RISK ASSESSMENT AND

RECOMMENDATION

The quality of the products is acceptable, and no new non-clinical or clinical concerns have been

identified. The data provided by the applicant showed that the test product is comparable to the


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reference product. Extensive clinical experience with buspirone hydrochloride is considered to have

demonstrated the therapeutic value of the compound. The benefit-risk assessment is, therefore,

considered to be positive.


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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and labelling

In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and

Patient Information Leaflets (PILs) for products that are granted Marketing Authorisations at a national

level are available on the MHRA website.

Labelling


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Table of content of the PAR update for MRP and DCP

Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II

variations, PSURs, commitments)

Scope Procedure

number

Product

information

affected

Date of

start of the

procedure

Date of end

of

procedure

Approval/

non

approval

Assessment

report

attached

Y/N

(version)

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