Postadress/Postal address: P.O. Box 26, SE-751 03 Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0)18 17 46 00 Fax: +46 (0)18 54 85 66 Internet: www.lakemedelsverket.se E-mail: registrator@lakemedelsverket.se

Swedish MPA template version: 2020-03-13 PAR Generics

Public Assessment Report

Scientific discussion

Bosentan Actavis

bosentan (anhydrous), bosentan monohydrate

SE/H/2157/01-02

This module reflects the scientific discussion for the approval of Bosentan Actavis. The Public

Assessment Report was written in August 2015 by the previous RMS IS after initial procedure

IS/H/0236-9/001-002/DC and is attached at the end of this document. RMS transfer from IS to

SE was completed 2021-05-07. For information on changes after this date please refer to the

module ‘Update’.

Active substance bosentan (anhydrous), bosentan monohydrate

Pharmaceutical form Film-coated tablets

Strength 62,5 mg ; 125 mg

Applicant Actavis Group PTC ehf

EU-Procedure number (original) IS/H/0236/001-002

Postadress/Postal address: P.O. Box 26, SE-751 03 Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0)18 17 46 00 Fax: +46 (0)18 54 85 66 Internet: www.lakemedelsverket.se E-mail: registrator@lakemedelsverket.se

Swedish MPA template version: 2020-03-13 PAR Generics

Public Assessment Report – Update

Procedure number* Scope Product

Information

affected

(Yes/No)

Date of

end of

procedure

Approval/

non approval

Summary/

Justification

for refuse

*Only procedure qualifier, chronological number and grouping qualifier (when applicable)

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Public Assessment Report

Scientific discussion

Bosentan Actavis

Trocordis

Tansnura

Bosenzpen

Bosentan monohydrate

4/22

IS/H/0236-9/001-002/DC

Date: 31.8.2015

This module reflects the scientific discussion for the approval of Bosentan Actavis, Trocordis, Tansnura and Bosenzpen. The procedure was

finalised at 28.7.2015. For information on changes after this date please refer to the module ‘Update’.

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I. INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted marketing authorisations for Bosentan Actavis,

Trocordis, Tansnura and Bosenzpen film-coated tablets 62.5mg and 125mg from Actavis and Sigillata.

The product is indicated for:

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) PAH

• PAH secondary to scleroderma without significant interstitial pulmonary disease

• PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger’s physiology

Some improvements have also been shown in patients with PAH WHO functional class II.

The products are also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital

ulcer disease.

A comprehensive description of the indications and posology is given in the SmPC.

The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC.

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.

Pharmacotherapeutic group: other antihypertensives, ATC code: C02KX01.

No discussion took place in CMDh during the procedure.

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II. QUALITY ASPECTS

II.1 Introduction

Each 62.5 mg film-coated tablet contains 64.541 mg bosentan monohydrate corresponding to 62.5 mg bosentan. The film-coated tablets are

pale yellow coloured, (6 mm), round, biconvex, debossed with “111” on one side and “A” on the other side.

Each 125 mg film-coated tablet contains 129.082 mg bosentan monohydrate corresponding to 125 mg bosentan. The film-coated tablets are

pale yellow coloured, (10.7 mm x 5.1 mm) capsule shaped, biconvex, debossed with “117” on one side and “A” on the other side.

The tablets contain the following excipients:

Tablet core:

Maize starch

Starch, pregelatinised

Sodium starch glycolate

Povidone

Glycerol dibehenate

Magnesium stearate

Film coat:

Poly(vinyl alcohol) (E1203)

Titanium dioxide (E171)

Macrogol (E1521)

Talc (E553b)

Iron oxide yellow (E172)

Iron oxide red (E172)

The tablets are packaged into PVC/Aclar /Alu blister packs.

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II.2 Drug Substance

Bosentan does not contain any chiral centre; hence it does not exhibit optical isomerism. Bosentan does exhibit polymorphism. It is not

described in an individual monograph in the Ph.Eur.

The active substance specification includes relevant tests and the acceptance limits have been appropriately justified. The analytical

methods applied are suitably described and validated.

Stability studies have been conducted and the data provided is sufficient to support the proposed retest period.

II.3 Medicinal Product

The development of the drug product formulation is well described. The excipients used in the product are all standard in the manufacture

of film-coated tablets and are compliant with European Pharmacopoeia (or equivalent) requirements.

The standard manufacturing process has been sufficiently described and critical steps were identified. Results from the process validation

studies confirm that the process is under control and ensure both batch to batch reproducibility and compliance with the product

specification.

The tests and limits in the finished products specifications are considered appropriate to control the quality of the finished product in relation

to its intended purpose. Comparative in vitro dissolution profiles of the products and the reference product support the claim for similarity.

Stability studies under ICH conditions have been performed in the commercial packaging and data presented support the shelf life claimed

in the SPC (18 months not above 30°C).

The pharmaceutical quality of the products has been adequately demonstrated.

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II.4 Discussion on chemical, pharmaceutical and biological aspects

Information on development, manufacture and control of active substance and medicinal product has been presented in a satisfactory

manner. The results of tests carried out indicate satisfactory consistency and uniformity of important product quality characteristics.

III. NON-CLINICAL ASPECTS

III.1 Introduction

Abridged applications avoid the need for repetitive tests on animals and humans.

III.2 Pharmacology

Pharmacodynamic, pharmacokinetic and toxicological properties of bosentan are well known. As bosentan is a widely used, well-known

active substance, the applicant has not provided additional studies and further studies are not required. Overview based on literature review

is, thus, appropriate.

The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.

III.3 Ecotoxicity/environmental risk assessment (ERA)

Since the products are intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental

risk assessment is therefore not deemed necessary.

III.4 Discussion on the non-clinical aspects

Bosentan Actavis, Trocordis, Tansnura and Bosenzpen film-coated tablets from Actavis and Sigillata are generic to Tracleer® film-coated

tablets from Actelion Registration Ltd. Abridged applications avoid the need for repetitive tests on animals and humans.

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IV. CLINICAL ASPECTS

IV.1 Introduction

Abridged applications avoid the need for repetitive tests on animals and humans apart from a conduction of bioequivalence studies to

confirm that the applied product is bioequivalent to the reference medicinal product.

The clinical overview on the clinical pharmacology, efficacy and safety is adequate.

The SmPC is in line with the text of the reference product, Tracleer® 62.5 and 125 mg film-coated tablets, Centralised product,

EMEA/H/C/000401 from Actelion Registration Ltd.

IV.2 Pharmacokinetics

Biowaiver

A bioequivalence study for the higher strength (125 mg) was submitted. A biowaiver for the 62.5 mg strength is requested. The results of

study BE-0904-12 with 125 mg formulation CAN be extrapolated to other strengths 62.5 mg, according to conditions in Guideline on the

Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section 4.1.6.

Bioequivalence studies

To support the application, the applicant has submitted as report one (1) bioequivalence study.

The study was an open label, randomised, single dose, two treatments, four periods, two sequences, fully replicated crossover bioequivalence

study comparing two 125 mg bosentan tablet formulations in forty (40) healthy adult male subjects under fasting conditions. The study was

conducted under standardised conditions. Bosentan was measured in human plasma using a validated LC/MS/MS method. The test to

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reference ratio of geometric LSmeans and corresponding 90% confidence interval for the Cmax and AUC0-t were all within the acceptance

range of 80.00 to 125.00%. The drugs were generally safe and well tolerated by the subjects included in the study.

Table 1. Pharmacokinetic parameters for Bosentan (N=38) (non-transformed values; arithmetic mean ± SD, tmax median, range)

Treatment AUC0-t

ng/ml/h

AUC0-∞

ng/ml/h

Cmax

ng/ml

tmax

h Test

12131.69±6108.63

12660.73±6145.04

2395.87±1432.57 4.00

(2.00-4.50)

Replicate Test 12072.58±5609.23

**

12641.24±5658.91

**

2160.45±1169.33

**

4.50

(2.50-16.00) **

Reference

12406.46±5803.44

12956.70±5961.65 2453.65±1364.12 4.50

(2.00-4.50)

Replicate

Reference

12170.05±5581.10 12418.92±5566.00 2379.67±1429.63 4.50

(2.00-7.00)

*Ratio (90% CI)

97.24%

(90.40%-104.59%)

***

97.47%

(90.98%-104.43%)

****

94.25%

(85.40%-104.01%)

***

-

AUC0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0-72h can be reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable.

Only for immediate release products

AUC0-∞ Area under the plasma concentration curve extrapolated to infinite time. AUC0-∞ does not need to be reported when AUC0-72h

is reported instead of AUC0-t

Cmax Maximum plasma concentration

tmax Time until Cmax is reached *ln-transformed values

**N=34

***N=31

****N=29; no value of AUC0-∞, Kel and t1/2 was reported for subject no. 124 in Period 3, since their respective Rsq_adjusted value was less than 0.8000 and also for subject no. 131

in Period 4 as their respective Rsq_adjusted value was missing.

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Figure 1: Linear plot of mean bosentan plasma concentrations versus time in healthy adult male subjects.

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Figure 2: Semi-log plot of mean bosentan plasma concentrations versus time in healthy adult male subjects.

Conclusion on bioequivalence studies

Based on the submitted bioequivalence study Bosentan Actavis 125 mg film-coated tablet is considered bioequivalent with Tracleer® 125

mg film-coated tablet.

The results of study BE-0904-12 with 125 mg formulation CAN be extrapolated to other strengths 62.5 mg, according to conditions in

Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section 4.1.6.

IV.3 Pharmacodynamics

No new pharmacodynamic studies were presented and no such studies are required for this application.

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IV.4 Clinical efficacy

No new clinical efficacy studies were presented and no such studies are required for this application.

IV.5 Clinical safety

No new clinical safety studies were presented and no such studies are required for this application.

IV.6 Risk Management Plan

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 Bosentan Actavis,

Trocordis, Tansnura and Bosenzpen.

Summary of safety concerns

Important Identified Risks • Hepatotoxicity

• Teratogenicity

• Decrease in haemoglobin concentration

• Decrease of sperm count

Important Potential Risks • Pulmonary oedema associated with pulmonary venoocclusive

disease (PVOD)

• Interaction with substrates, inducers or inhibitors, of cytochrome

P450 isoenzymes CYP3A4 and CYP2C9 ( including hormonal

contraceptives, sildenafil and antiretrovirals)

• Testicular disorders and male infertility

• Respiratory tract infection in children

Missing Information • Use of bosentan with addition of sildenafil

• Use in children with renal function impairment

This product has special conditions and restrictions for its safe and effective use. The MAH will implement educational materials nationally

as additional risk minimisation measures for the following risks:

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Table of on-going and planned additional PhV studies/activities in the Pharmacovigilance Plan:

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The MAH will also set up a surveillance programme/registry to collect information on the demographics, safety and outcome data from

patients prescribed bosentan to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease

as additional pharmacovigilance activities

IV.7 Discussion on the clinical aspects

Bosentan Actavis, Trocordis, Tansnura and Bosenzpen film-coated tablets from Actavis and Sigillata are generics to Tracleer® film-coated

tablets from Actelion Registration Ltd. Abridged applications avoid the need for repetitive tests on animals and humans apart from a

conduction of bioequivalence studies to confirm that the applied product is bioequivalent to the reference medicinal product.

The application contains an adequate review of published clinical data and the bioequivalence has been shown between the applied products

and Tracleer®.

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. 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

Based on the review of the data on quality, safety and efficacy, the risk-benefit ratio for application for Bosentan Actavis, Trocordis,

Tansnura and Bosenzpen film-coated tablets from Actavis and Sigillata in 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:

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• Primary (idiopathic and heritable) PAH

• PAH secondary to scleroderma without significant interstitial pulmonary disease

• PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger’s physiology

Some improvements have also been shown in patients with PAH WHO functional class II.

The products are also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer

disease.

is considered positive and marketing authorisation can be recommended.

The marketing authorisation has been granted pursuant to Article 10(1), generic application, of Directive 2001/83/EC.

There was no discussion in CMDh.

Conditions or restrictions with regard to the safe and effective use of the product

• Risk Management Plan (RMP)

• Additional Risk Minimisation Measures

Controlled Distribution system:

- Prescriber Kit containing the following:

o Information about Bostentan

o Patient Alert Card

o Patient Information Booklet (decided on a national level)

A surveillance programme/registry:

The MAH shall set up a surveillance programme/registry to collect information on the demographics, safety and outcome data from patients

prescribed the product to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease. The

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data to be collected and the details of the operation of the surveillance programme/registry should be further discussed with the RMS before

marketing of the product.

• Obligation to conduct post-authorisation measures in accordance with Article 21a of Directive 2001/83

The MAH shall complete, within the stated timeframe, the below measures:

Description Due date

A surveillance programme/registry to collect information on the demographics, safety and outcome data from

patients prescribed bosentan to reduce the number of new digital ulcers in patients with systemic sclerosis and

ongoing digital ulcer disease: a multicentre, prospective, observational, non-interventional programme to

document adherence to SmPC requirements for liver function, pregnancy testing

Yearly submission

cycle with PSUR