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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2
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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Bosentan Dr. Reddy’s 62.5 mg and 125 mg Film-coated Tablets
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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)