Public Assessment Report Decentralised Procedure … · PAR Tramadol Hydrochloride/Paracetamol 37.5...

PAR Tramadol Hydrochloride/Paracetamol 37.5 mg/325 mg Film-coated Tablets UK/H/5925/001/DC

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Public Assessment Report

Decentralised Procedure

Tramadol Hydrochloride/Paracetamol 37.5 mg/325 mg

Film-coated Tablets

(tramadol hydrochloride and paracetamol)

Procedure No: UK/H/5925/001/DC

UK Licence No: PL 30464/0170

Athlone Pharmaceuticals Limited


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LAY SUMMARY Tramadol Hydrochloride/Paracetamol 37.5 mg/325 mg Film-coated Tablets

(tramadol hydrochloride and paracetamol)

This is a summary of the Public Assessment Report (PAR) for Tramadol Hydrochloride/Paracetamol

37.5 mg/325 mg Film-coated Tablets (UK/H/5925/001/DC; PL 30464/0170). Tramadol

Hydrochloride/Paracetamol 37.5 mg/325 mg Film-coated Tablets will be referred to as Tramadol

hydrochloride/Paracetamol tablets throughout this lay summary, for ease of reading.

This summary explains how Tramadol hydrochloride/Paracetamol tablets were assessed and their

authorisation recommended, as well as the conditions of use. It is not intended to provide practical

advice on how to use Tramadol hydrochloride/Paracetamol tablets.

For practical information about using Tramadol hydrochloride/Paracetamol tablets, patients should read

the Patient Information Leaflet (PIL) or contact their doctor or pharmacist.

What are Tramadol hydrochloride/Paracetamol tablets and what are they used for?

Tramadol hydrochloride/Paracetamol tablets are a ‘generic medicine’. This means that this product is

similar to a ‘reference medicine’, already authorised in the European Union (EU) called Tramacet 37.5

mg/325 mg film-coated tablets (PL 21727/0039; Grünenthal Limited).

Tramadol hydrochloride/Paracetamol tablets are used to treat moderate to severe pain.

How do Tramadol hydrochloride/Paracetamol tablets work?

Tramadol hydrochloride/Paracetamol tablets contain the active ingredients tramadol hydrochloride and

paracetamol. Tramadol is an opioid analgesic that acts on the central nervous system. The precise

mechanism of the analgesic properties of paracetamol is not fully understood but is thought to involve

central and peripheral effects.

How are Tramadol hydrochloride/Paracetamol tablets used?

Tramadol hydrochloride/Paracetamol tablets should be swallowed whole with liquid. These tablets

should not be broken or chewed.

Please read Section 3 of the PIL for detailed information on dosing recommendations, the route of

administration and the duration of treatment.

Tramadol hydrochloride/Paracetamol tablets should be taken for as short a time as possible, and for no

longer than instructed by a doctor. For adults and adolescents over 12 years of age, the recommended

dosage is to start with 2 tablets, unless otherwise prescribed by a doctor. The shortest time between

doses must be at least 6 hours and no more than 8 tablets should be taken per day.

Tramadol hydrochloride/Paracetamol tablets are not recommended in children under 12 years of age.

This medicine can only be obtained with a prescription from a doctor.

How has Tramadol hydrochloride/Paracetamol tablets been studied?

Because Tramadol hydrochloride/Paracetamol tablets are a generic medicine, studies in patients have

been limited to tests to determine that it is bioequivalent to the reference medicine, Tramacet 37.5

mg/325 mg film-coated tablets. Two medicines are bioequivalent when they produce the same levels of

the active substance in the body.


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What are the benefits and risks of Tramadol hydrochloride/Paracetamol tablets?

Because Tramadol hydrochloride/Paracetamol tablets are a generic medicine, and are bioequivalent to

the reference medicine, Tramacet 37.5 mg/325 mg film-coated tablets, their benefits and risks are taken

as being the same as the reference medicine.

Why are Tramadol hydrochloride/Paracetamol tablets approved?

It was concluded that, in accordance with EU requirements, Tramadol hydrochloride/Paracetamol tablets

have been shown to have comparable quality and to be bioequivalent to Tramacet 37.5 mg/325 mg film-

coated tablets. Therefore, the view was that, as for Tramacet 37.5 mg/325 mg film-coated tablets, the

benefits outweigh the identified risks.

What measures are being taken to ensure the safe and effective use of Tramadol

hydrochloride/Paracetamol tablets?

A risk management plan has been developed to ensure that Tramadol hydrochloride/Paracetamol tablets

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

of Product Characteristics (SmPC) and the PIL for Tramadol hydrochloride/Paracetamol tablets,

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

Known side effects are continuously monitored. Furthermore new safety signals reported by patients and

healthcare professionals will be monitored and reviewed continuously as well.

Other information about Tramadol hydrochloride/Paracetamol tablets The Republic of Ireland and the UK agreed to grant a Marketing Authorisation for Tramadol

hydrochloride/Paracetamol tablets on 21 April 2016. A Marketing Authorisation was granted in the UK

on 18 May 2016.

The full PAR for Tramadol hydrochloride/Paracetamol tablets follows this summary.

For more information about treatment with Tramadol hydrochloride/Paracetamol tablets, read the PIL or

contact your doctor or pharmacist.

This summary was last updated in July 2016.


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TABLE OF CONTENTS

I Introduction Page 5

II Quality aspects Page 7

III Non-clinical aspects Page 9

IV Clinical aspects Page 9

V User consultation Page 12

VI Overall conclusion, benefit/risk assessment and

recommendation

Page 12

Table of content of the PAR update for MRP and

DCP

Page 16


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I Introduction Based on the review of the data on quality, safety and efficacy the Member States considered that the

application for Tramadol Hydrochloride/Paracetamol 37.5mg/325mg Film-Coated Tablets

(UK/H/5925/001/DC; PL 30464/0170), is approvable. This product is a prescription only medicine

(POM), indicated for the symptomatic treatment of moderate to severe pain.

The use of Tramadol Hydrochloride/Paracetamol should be restricted to patients whose moderate to

severe pain is considered to require a combination of tramadol and paracetamol.

The application was submitted using the Decentralised Procedure (DCP), with the UK as Reference

Member State (RMS), and Republic of Ireland as Concerned Member State (CMS). The application was

submitted under Article 10(1) of Directive 2001/83/EC, as amended, as a generic application. The

reference medicinal product, which has been authorised in accordance with Community provisions in

force for not less than 10 years in the European Economic Area (EEA), is Primiza 37.5 mg/325 mg film-

coated tablets; this product was authorised to Laboratoires Grünenthal in France on 05 April 2002. The

licence for Primiza 37.5 mg/325 mg film-coated tablets subsequently underwent a Mutual Recognition

procedure and, following agreement between the RMS (France) and CMSs, was granted a Marketing

Authorisation (MA) in the UK to Janssen-Cilag Limited (PL 00242/0384) on 25 September 2003, under

the product name Tramacet 37.5 mg/325 mg film-coated tablets. This UK licence subsequently

underwent a change of ownership procedure to the current MA holder, Grünenthal Limited (PL

21727/0039), on 01 April 2009.

Tramadol hydrochloride/Paracetamol tablets contain the active ingredients tramadol hydrochloride and

paracetamol.

Tramadol is an opioid analgesic that acts on the central nervous system. Tramadol is a pure, non-

selective agonist of the µ, δ and κ opioid receptors, with a higher affinity for the µ receptor. Other

mechanisms which contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline

and enhancement of serotonin release. Tramadol has an antitussive effect. Unlike morphine, a broad

range of analgesic doses of tramadol has no respiratory depressant effect. Similarly, the gastrointestinal

motility is not modified. The cardiovascular effects are generally slight. The potency of tramadol is

considered to be one-tenth to one-sixth that of morphine.

The precise mechanism of the analgesic properties of paracetamol is unknown and may involve central

and peripheral effects.

No new non-clinical studies were conducted, which is acceptable given that the application was based on

being a generic medicinal product of an originator product that has been licensed for over 10 years.

Since Tramadol hydrochloride/Paracetamol tablets are intended for generic substitution, their use will

not lead to an increased exposure to the environment. An Environmental Risk Assessment (ERA) is,

therefore, not deemed necessary.

With the exception of one bioequivalence study, no new clinical data were provided with this

application. A bioequivalence study was submitted to support this application, comparing the applicant’s

test product Tramadol hydrochloride/Paracetamol 37.5 mg/325 mg Tablets with the reference product

Tramacet 37.5 mg/325 mg film-coated tablets (Grünenthal Limited) in healthy adult subjects, under

fasting conditions. The bioequivalence study was conducted in line with current Good Clinical Practice

(GCP).

A summary of the pharmacovigilance system and a detailed risk management plan have been provided

with this application and these are satisfactory.


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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 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.

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.

Both Member States agreed to grant a Marketing Authorisation for the above product at the end of the

procedure (Day 210 – 21 April 2016). After a subsequent national phase, the UK granted a Marketing

Authorisation (PL 30464/0170) for this product on 18 May 2016.


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II Quality Aspects II.1 Introduction Tramadol hydrochloride/Paracetamol tablets are formulated as Pale yellow film-coated tablets, marked

with “325” on one side and ’37.5’ on the other side.

Each film-coated tablet contains 37.5 mg tramadol hydrochloride and 325 mg paracetamol, as active

ingredients. The excipients present in the tablet core are: pregelatinised starch, sodium starch glycolate

(Type A), microcrystalline cellulose, magnesium stearate making up the tablet core, and the film coat

Opadry yellow 15B82958 (hypromellose, titanium dioxide (E171), macrogol 400, yellow iron oxide and

polysorbate 80).

All excipients comply with their respective European Pharmacopoeia monographs with the exception of

Opadry yellow 15B82958 which complies with an in-house specification. Satisfactory Certificates of

Analysis have been provided for all excipients showing compliance with their proposed specifications.

None of the excipients are sourced from animal or human origin. The magnesium stearate used in the

tablets is of vegetable origin.

No genetically modified organisms (GMO) have been used in the preparation of these excipients.

The tablets are packaged in polyvinylchloride-polyvinylidene chloride/aluminium (PVC-PVdC/Al)

blister packs. Tramadol hydrochloride/Paracetamol tablets are available in a box of 60 tablets.

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

components.

II.2. Drug Substance

Tramadol hydrochloride

INN: Tramadol hydrochloride

Chemical Name: (1RS,2RS)-2-[(dimethyl amino)methyl]-1-(3-methoxyphenyl) cyclohexanol,

hydrochloride

Structure:

Molecular formula: C16H26ClNO2

Molecular weight: 299.8 g/mol

Appearance: white to almost white crystalline powder.

Solubility: Tramadol hydrochloride is freely soluble in water and in methanol and very

slightly soluble in acetone.

Tramadol hydrochloride is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance, tramadol hydrochloride, are covered

by a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of

Suitability.

http://www.pharmacopoeia.co.uk/bp2015updated/ixbin/bp.cgi?a=imagezoom&file=bp2015_v2_11_medicinal_and_pharmaceutical_substances_08/large/tramadol_hydrochloride_cf1681-e.png


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Paracetamol

INN: Paracetamol

Chemical Name: 4-acetamidophenol, p-acetamidophenol, n-(4-hydroxyphenyl) acetamide

Structure:

Molecular formula: C8H9NO2

Molecular weight: 151.2 g/mol

Appearance: white to almost white crystalline powder.

Solubility: Sparingly soluble in water, freely soluble in alcohol and very slightly soluble in

methylene chloride.

Paracetamol is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance, paracetamol, are covered by an

EDQM Certificate of Suitability.

II.3. Medicinal Product

Pharmaceutical Development

The objective of the development programme was to formulate safe, efficacious tablets containing 37.5

mg of tramadol hydrochloride and 325 mg of paracetamol per tablet, that are generic versions of the

reference product Tramacet 37.5 mg/325 mg film-coated tablets (Grünenthal Limited).

Comparative in vitro dissolution and impurity profiles have been provided for the proposed and

originator products.

Manufacture of the product

A satisfactory batch formula has been provided for the manufacture of the product, along with an

appropriate account of the manufacturing process. A validation report for commercial scale batches has

been provided. The process validation data provided is satisfactory.

Finished Product Specification

The finished product specification proposed is acceptable. The test methods have been described that

have been adequately validated. 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. The data from these studies support a

shelf-life of 3 years with no special storage conditions.

Suitable post approval stability commitments have been provided to continue stability testing on batches

of finished product.

II.4 Discussion on chemical, pharmaceutical and biological aspects

There are no objections to the approval of this application from a pharmaceutical viewpoint.

http://www.pharmacopoeia.co.uk/bp2015updated/ixbin/bp.cgi?a=imagezoom&file=bp2015_v2_11_medicinal_and_pharmaceutical_substances_04/large/paracetamol_cf0049-b.png


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III Non-Clinical Aspects III.1 Introduction

As the pharmacodynamic, pharmacokinetic and toxicological properties of tramadol and paracetamol are

well-known, no new non-clinical studies are required and none have been provided. An overview based

on the literature review is, thus, appropriate.

The applicant’s non-clinical expert report 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

Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above.

III.3 Pharmacokinetics


III.4 Toxicology


III.5 Ecotoxicity/environmental risk assessment (ERA)

Since Tramadol hydrochloride/Paracetamol tablets are intended for generic substitution, their use will

not lead to an increased exposure to the environment. An environmental risk assessment is therefore not

deemed necessary.

III.6 Discussion on 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 the originator product that has been licensed for over 10 years.

There are no objections to the approval of this application from a non-clinical viewpoint.

IV Clinical Aspects IV.1 Introduction

For this generic application, the Applicant applied for a Biopharmaceutics Classification System (BCS)

based biowaiver. Therefore, 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 a BCS based biowaiver for the product. 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 tramadol hydrochloride is highly soluble with complete absorption, high

permeability (BCS class I) and paracetamol is highly soluble with limited absorption (BCS class III),

and the product is an immediate release solid dose preparation for oral use with the same pharmaceutical

form as the reference product. 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 pharmacodynamics data are required for this application and none have been submitted.


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IV.5 Clinical efficacy

No new clinical efficacy data are required for this application and none have been submitted.

IV.5 Clinical safety

No new clinical safety data are required for this application and none have been submitted.

IV.6 Risk Management Plan (RMP) and Pharmacovigilance system

The Marketing Authorisation Holder (MAH) has submitted an RMP, 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 Tramadol

hydrochloride/Paracetamol 37.5 mg/325 mg Film-coated Tablets.

A summary of safety concerns and planned risk minimisation activities, as approved in the RMP,

is listed below:


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IV.7 Discussion on the clinical aspects The grant of a Marketing Authorisation is recommended for this application.

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, benefit/risk assessment and recommendation The quality of the product 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 reference

product. Extensive clinical experience with tramadol hydrochloride and paracetamol is considered to

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

considered to be positive.


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

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

Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are

available on the MHRA website.

The approved labelling for Tramadol hydrochloride/Paracetamol 37.5 mg/325 mg Film-coated Tablets is

presented below:


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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)

Public Assessment Report Decentralised Procedure … · PAR Tramadol Hydrochloride/Paracetamol 37.5...

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