bosentan dr. reddy's 62.5 mg and 125 mg film-coated tablets

Public Assessment Report

Decentralised Procedure

Bosentan Dr. Reddy’s 62.5 mg and 125 mg Film-coated

Tablets

(bosentan monohydrate)

Procedure No: UK/H/5750/001-02/DC

UK Licence No: PL 08553/0514-0515

Dr. Reddy’s Laboratories (UK) Ltd

Bosentan Dr. Reddy’s 62.5 mg and 125 mg Film-coated Tablets

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Lay Summary Bosentan Dr. Reddy’s 62.5 mg and 125 mg Film-coated Tablets

(bosentan monohydrate)

This is a summary of the public assessment report (PAR) for Bosentan Dr. Reddy’s 62.5 mg

and 125 mg Film-coated Tablets (PL 08553/0514-0515; UK/H/5750/001-02/DC). Bosentan

Dr. Reddy’s 62.5 mg and 125 mg Film-coated Tablets will be referred to as Bosentan Tablets

throughout this summary, for ease of reading.

This summary explains how Bosentan 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 Bosentan Tablets.

For practical information about using Bosentan Tablets, patients should read the patient

information leaflet (PIL) or contact their doctor or pharmacist.

What are Bosentan Tablets and what are they used for?

Bosentan Tablets are ‘generic medicines’. This means that they are similar to ‘reference

medicines’, already authorised in the European Union (EU) called Tracleer® 62.5 mg and 125

mg Film-coated Tablets (Actelion Registration Limited).

Bosentan Tablets are used to treat pulmonary arterial hypertension (PAH). PAH is a disease

of severe narrowing of the blood vessels in the lungs resulting in high blood pressure in the

blood vessels (the pulmonary arteries) that carry blood from the heart to the lungs. This

pressure reduces the amount of oxygen that can get into the blood in the lungs, making

physical activity more difficult. The ‘class’ of PAH reflects the seriousness of the disease.

Bosentan Tablets are used to treat class III PAH, which is a condition that involves marked

limitation of physical activity. These medicines are also effective in treating class II PAH,

which is a condition that involves slight limitation of physical activity. There are several

different types of PAH but Bosentan Tablets are used to treat PAH, which is either:

primary (with no identified cause or familial (i.e. inherited)

caused by scleroderma (also called systemic sclerosis, a disease where there is

abnormal growth of the connective tissue that supports the skin and other organs)

or

caused by congenital (inborn) heart defects, with shunts (abnormal passageways)

causing abnormal flow of blood through the heart and lungs.

How do Bosentan Tablets work?

Bosentan Tablets contain the active substance bosentan (as bosentan monohydrate), which

belongs to the class of medicines called “endothelin receptor antagonists”. These block a

naturally occurring hormone called endothelin-1 (ET-1). ET-1 normally causes blood vessels

to narrow and, therefore, the blocking action of bosentan causes blood vessels to expand.


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How are Bosentan Tablets used?

Bosentan Tablets are taken by mouth. The whole tablet should be swallowed with water, in

the morning and evening, and can be taken with or without food.

Treatment with Bosentan Tablets should only be started and monitored by a doctor who has

experience in the treatment of PAH. The treatment in adults is usually started, for the first 4

weeks, with 62.5 mg twice daily (morning and evening). The prescribing doctor will usually

advise the patient to take the higher strength (125 mg) tablet twice daily depending on how

the patient reacts to the 62.5 mg strength tablet.

For children 2 years and older, treatment is usually started with 2 mg per kg bodyweight

twice daily (morning and evening). The prescribing doctor will advise on the correct dosing.

These medicinal products are also available as a dispersible 32 mg tablet formulation to make

correct dosing easier for children and patients with low body weight or difficulties

swallowing tablets.

Bosentan Tablets can only be obtained with a prescription from a doctor.

Please read Section 3 of the patient information leaflet (PIL) for detailed information on

dosing recommendations, the route of administration and the duration of treatment.

How have Bosentan Tablets been studied?

Because Bosentan Tablets are generic medicines, studies in patients have been limited to tests

to determine that they are bioequivalent to the reference medicines, Tracleer® 62.5 mg and

125 mg Film-coated Tablets. Two medicines are bioequivalent when they produce the same

levels of the active substance in the body.

What are the possible side effects of Bosentan Tablets?

As Bosentan Tablets are generic medicines, their benefits and possible side effects are taken

as being the same as those of the reference medicines, Tracleer® 62.5 mg and 125 mg Film-

coated Tablets.

For further information, please see the PIL.

Why are Bosentan Tablets approved?

It was concluded that, in accordance with EU requirements, Bosentan Tablets have been

shown to have comparable quality and are bioequivalent to Tracleer® 62.5 mg and 125 mg

Film-coated Tablets. Therefore, the view was that, as for Tracleer® 62.5 mg and 125 mg

Film-coated Tablets, the benefits outweigh the identified risks.

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

Tablets?

A risk management plan has been developed to ensure that Bosentan Tablets are used as

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

of Product Characteristics (SmPCs) and the PIL for Bosentan 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.


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Other information about Bosentan Tablets Germany and the UK agreed to grant Marketing Authorisations to Dr. Reddy’s Laboratories

(UK) Ltd for Bosentan Tablets on 5th

February 2015. Marketing Authorisations were granted

in the UK On 2nd

March 2015.

The full PAR for Bosentan Tablets follows this summary.

For more information about treatment with Bosentan Tablets, read the PIL or contact your

doctor or pharmacist.

This summary was last updated in May 2015.


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Table of Contents

I Introduction Page 6

II Quality aspects Page 8

III Non-clinical aspects Page 10

IV Clinical aspects Page 11

V User consultation Page 15

VI Overall conclusion, benefit/risk assessment and

recommendation

Page 15

Table of content of the PAR update for MRP and DCP

Page 20


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I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Member States have

granted Marketing Authorisations to Dr. Reddy’s Laboratories (UK) Ltd for the medicinal

products Bosentan 62.5 mg and 125 mg Tablets (PL 08553/0514-0515; UK/H/5750/001-

02/DC).

These products are prescription-only medicines (POM) indicated for the treatment of

pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in

patients with WHO functional class III. Efficacy has been shown in:

Primary (idiopathic and heritable) pulmonary arterial hypertension

Pulmonary arterial hypertension secondary to scleroderma without significant

interstitial pulmonary disease

Pulmonary arterial hypertension associated with congenital systemic-to-pulmonary

shunts and Eisenmenger’s physiology

Some improvements have also been shown in patients with pulmonary arterial hypertension

WHO functional class II.

These applications were submitted using the Decentralised Procedure (DCP), with the UK as

Reference Member State (RMS) and Germany as Concerned Member State (CMS).

These applications were made under Article 10.1 of Directive 2001/83/EC, as amended. The

applicant has cross referred to Tracleer® 62.5 mg and 125 mg Film-coated Tablets, originally

authorised to Actelion Registration Limited (EU/1/02/220/001-005) on 15th

May 2002 via the

Centralised procedure.

Bosentan 62.5 mg and 125 mg Tablets contain the active ingredient bosentan (as bosentan

monohydrate). Bosentan is a dual endothelin receptor antagonist (ERA) with affinity for both

endothelin A and B (ETA and ETB) receptors. Bosentan decreases both pulmonary and

systemic vascular resistance resulting in increased cardiac output without increasing heart

rate. The neurohormone endothelin-1 (ET-1) is one of the most potent vasoconstrictors

known and can also promote fibrosis, cell proliferation, cardiac hypertrophy and remodelling,

and is pro-inflammatory. These effects are mediated by endothelin binding to ETA and ETB

receptors located in the endothelium and vascular smooth muscle cells. ET-1 concentrations

in tissues and plasma are increased in several cardiovascular disorders and connective tissue

diseases, including pulmonary arterial hypertension, scleroderma, acute and chronic heart

failure, myocardial ischaemia, systemic hypertension and atherosclerosis, suggesting a

pathogenic role of ET-1 in these diseases. In pulmonary arterial hypertension and heart

failure, in the absence of endothelin receptor antagonism, elevated ET-1 concentrations are

strongly correlated with the severity and prognosis of these diseases.

Bosentan competes with the binding of ET-1 and other ET peptides to both ETA and ETB

receptors, with a slightly higher affinity for ETA receptors (Ki = 4.1–43 nanomolar) than for

ETB receptors (Ki = 38–730 nanomolar). Bosentan specifically antagonises ET receptors and

does not bind to other receptors.

No new non-clinical studies were conducted, which is acceptable given that the applications

were based on being generic medicinal products of the originator products that have been

licensed for over 10 years.


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A suitable justification for not submitting the Environmental Risk Assessment (ERA) has

been provided.

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

these applications. A bioequivalence study was performed, which compared the

pharmacokinetics of the applicant’s Bosentan 125 mg Tablets with that of the reference

product, Tracleer® 125 mg film-coated Tablets, in healthy subjects under fasting conditions.

The bioequivalence study was conducted in line with current Good Clinical Practice (GCP).

The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP)

are in place for these product types 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 a manufacturing sites outside the Community, the RMS has accepted copies of current

GMP Certificates of 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.

A Risk Management Plan (RMP) and a summary of the pharmacovigilance system have been

provided with these applications and are satisfactory.

Both involved Member States agreed to grant Marketing Authorisations for the above

products at the end of the procedure (Day 210 – 5th

February 2015). After a subsequent

national phase, the UK granted Marketing Authorisations (PL 08553/0514-0515) for these

products on 2nd

March 2015.


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II QUALITY ASPECTS

II.1 Introduction The applications are submitted according to Article 10.1 of Directive 2001/83/EC, as

amended. The applicant has specified Tracleer® 62.5 mg and 125 mg Film-coated Tablets as

the reference medicinal products (Actelion Registration Limited).

Bosentan 62.5 mg Tablets are formulated as light orange, round, approximately 6 mm in

diameter, biconvex film-coated Tablets, debossed with “62.5” on one side and plain on the

other side.

Bosentan 125 mg Tablets are formulated as light orange, oval, approximately 11.00 mm in

length, 5.00 mm in width, biconvex, film-coated Tablets debossed with “125” on one side

and plain on the other side.

The excipients are qualitatively identical in both products. The excipients in the tablet core

are: maize starch, pregelatinised starch, sodium starch glycolate, povidone, glycerol

dibehenate and magnesium stearate. The film-coat consists of Opadry yellow (hypromellose

(E464), titanium dioxide (E171), triacetin, talc, ethylcellulose, cetyl alcohol, sodium lauryl

sulfate, yellow Iron oxide (E172) and red iron oxide (E172)).

All excipients used comply with their respective European Pharmacopoeia monographs with

the exception of Opadry yellow which complies with an in-house specification. Confirmation

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

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. No genetically modified

organisms (GMO) have been used in the preparation of these excipients.

The finished product is packaged in aluminium-aluminium (oriented

polyamide/aluminium/polyvinylchloride-aluminium (OPA/Alu/PVC-Alu)) or Triplex

polyvinylchloride/polyethylene/polyvinylidene chloride (PVC/PE/PVDC)-aluminium blister.

Packs of 62.5 mg tablets contain 14, 56 or 112 tablets and packs of 125 mg tablets contain

28, 56 or 112 tablets. Not all pack sizes may be marketed.

II.2 Drug Substance Bosentan monohydrate

INN: Bosentan monohydrate

Chemical Name: 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-

(pyrimidin-2-yl) pyrimidin-4-yl] benzene-1-sulfonamide monohydrate

4-(1,1-Dimethylethyl)-N-(6-(2-hydroxyethoxy)-5-(2-

methoxyphenoxy)(2,2'-bipyrimidin)-4-yl) benzenesulfonamide

monohydrate

Structure:


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Molecular formula: C27H29N5O6S.H20

Molecular weight: 569.64 g/mol

Appearance: White to yellowish colour powder.

Solubility: Bosentan monohydrate is soluble in dimethylformamide and

acetonitrile.

Bosentan monohydrate 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.

Appropriate proof-of-structure data have been supplied for the active pharmaceutical

ingredient. 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.

Satisfactory Certificates of Analysis have been provided for all working standards. Batch

analysis data are provided and comply with the proposed specification.

Suitable specifications have been provided for all packaging used to contain the active

substance. The primary packaging has been shown to comply with current guidelines

concerning contact with food.

Appropriate stability data have been provided 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 obtain stable Film-coated Tablets

containing bosentan monohydrate that could be considered as generic medicinal products of

the reference products, Tracleer® 62.5 mg and 125 mg film-coated Tablets (Actelion

Registration Limited).

The development of the products has been adequately described. Comparative dissolution

and impurity profiles have been demonstrated between Bosentan 62.5 mg and 125 mg Film-


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coated Tablets and the reference medicinal products, Tracleer® 62.5 mg and 125 mg film-

coated Tablets.

Manufacture of the product s

Satisfactory batch formulae have been provided for the manufacture of the finished products,

together with an appropriate account of the manufacturing processes. The manufacturing

processes have been validated using a pilot scale batches and have shown satisfactory results.

A commitment has been provided that process validation will be performed on commercial

scale batches of each tablet strength.

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 products

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 2 years with no special storage conditions has been set.

This is satisfactory.

Suitable post approval stability commitments have been provided.

II.4 Discussion on chemical, pharmaceutical and biological aspects The grant of Marketing Authorisations is recommended.

III NON-CLINICAL ASPECTS

III.1 Introduction These generic applications have been submitted in accordance with Article 10.1 of Directive

2001/83/EC, as amended.

The pharmacodynamic, pharmacokinetic and toxicological properties of bosentan

monohydrate are well known. As bosentan monohydrate is a widely used, well-known active

substance, no new non-clinical data have been supplied 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.

III.2 Pharmacology No new data have been submitted and none are required for applications of this type.

III.3 Pharmacokinetics No new data have been submitted and none are required for applications of this type.

III.4 Toxicology No new data have been submitted and none are required for applications of this type.

III.5 Ecotoxicity/environmental risk assessment (ERA)


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Since the proposed products are intended for generic substitution, these 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 There are no objections to the approval of these products from a non-clinical point of view.

IV CLINICAL ASPECTS IV.1 Introduction The pharmacodynamic, pharmacokinetic, clinical efficacy and safety properties of bosentan

monohydrate are well known. As bosentan monohydrate is a widely used, well-known active

substance, the applicant has not provided additional studies and further studies are not

required. An overview based on literature review is considered appropriate.

With the exception of bioequivalence data, no new clinical data have been submitted and

none are required for applications of this type. The applicant’s clinical overview has been

written by an appropriately qualified person and is considered acceptable.

IV. 2 Pharmacokinetics In support of these applications, the Marketing Authorisation holder has submitted the

following bioequivalence study:

An open-label, balanced, randomized, two-treatment, two-period crossover oral

bioequivalence study, comparing the pharmacokinetics of the test product Bosentan 125

mg Tablets (Dr Reddy’s Laboratories Ltd) versus the reference product Tracleer®

125

mg Film-coated Tablets (Actelion Registration Limited) in healthy, adult, subjects

under fasting conditions.

Volunteers received the test or reference treatment after an overnight fast of at least 10 hours.

Blood samples were taken for the measurement of pharmacokinetic parameters pre-dose and

at 0.500, 1.000, 1.500, 2.000, 2.500, 3.000, 3.500, 4.000, 4.500, 5.000, 5.500, 6.000, 7.000,

8.000, 10.000, 12.000, 14.000, 16.000, 24.000 and 36.000 hours following drug

administration in each period. The minimum washout period between studies was 10 days.

The main pharmacokinetic results are presented below:

Bioequivalence results for ln-transformed test/reference ratios with 90% Confidence

Intervals

Parameters Test

Product - T Reference

Product - R

90% Confidence

Interval

Ratio %

(T/R)%

Cmax (ng/ml)

2329.531 2378.243 87.40 – 109.77 98.0

AUC0-t (ng/ml/h)

11923.750 12065.745 91.55 – 106.68 98.8

AUC0-∞ (ng/ml/h)

12118.835 12237.569 91.92 – 106.69 99.0

The 90% confidence intervals for Cmax and AUC were within the pre-defined limits.

Bioequivalence has been shown for the test formulation (Bosentan 125 mg Tablets) and the


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reference formulation (Tracleer® 125 mg Film-coated Tablets). According to the Committee

for Proprietary Medicinal Products Notes for Guideline on “Guideline on the Investigation of

Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev.1 Corr**), the results of the studies for

125 mg formulation can be extrapolated to the other strength i.e. 62.5 mg Fil-coated Tablets.

IV.3 Pharmacodynamics No new pharmacodynamics data are required for these applications and none have been

submitted.

IV.4 Clinical efficacy No new clinical efficacy data are required for these applications and none have been

submitted.

IV.5 Clinical safety No new clinical safety data are required for these applications and none have been submitted.

IV.6 Risk Management Plan (RMP) 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 Bosentan 62.5 mg and 125 mg Film-coated Tablets.

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

RMP, are listed below:

Summary table of safety concerns


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Planned risk minimisation activities


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V.7 Discussion on the clinical aspects The grant of Marketing Authorisations is recommended for these applications.


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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 patient information leaflet (PIL) was English.

The results show that the PIL 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 applications include an adequate review of published non-clinical and

clinical data concerning the efficacy and safety of bosentan monohydrate. The test product

Bosentan 125 mg Tablets can be considered bioequivalent with the reference product

Tracleer® 125 mg Film-coated Tablets. As the biowaiver criteria are satisfied, these results

can also be extrapolated to conclude that Bosentan 62.5 mg Tablets are also bioequivalent to

Tracleer® 62.5 mg Film-coated Tablets. 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

The Summaries of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and

labelling are satisfactory, in line with current guidelines and consistent with the reference

products. In accordance with Directive 2012/84/EU, the current approved UK versions of the

SmPCs and PILs for these products are available on the MHRA website.

The currently approved labelling are listed 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)

bosentan dr. reddy's 62.5 mg and 125 mg film-coated tablets

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