Bosentan BASICS 62.5 Mg & 125Mg

PUBLIC ASSESSMENT REPORT

Decentralised Procedure

Bosentan BASICS 62.5 mg & 125mg Procedure Number: DE/H/4181/001-002/DC

Active Substance Bosentan

Dosage Form Film Coated Tablets

Marketing Autorisation Holder Basics GmbH, Hemmelrather Weg 201 D- 51377 Leverkusen, Germany

Publication: 12.10.2016 TABLE OF CONTENTS

I. EXECUTIVE SUMMARY...... 3 I.1 Problem statement ...... 3 This is a generic application ...... 3 I.2 About the product ...... 3 I.3 General comments on the submitted dossier...... 4 I.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.4 II. SCIENTIFIC OVERVIEW AND DISCUSSION ...... 5 II.1 Quality aspects ...... 5 II.2 Non-clinical aspects ...... 5 II.3 Clinical aspects ...... 7 III. BENEFIT RISK ASSESSMENT ...... 12 IV. PROPOSED LIST OF OUTSTANDING ISSUES ...... 12 IV.1 Quality aspects ...... 12 IV.2 Non-clinical aspects ...... 12 IV.3 Clinical aspects ...... 13 V. PROPOSED CONDITIONS FOR MARKETING AUTHORISATION AND PRODUCT INFORMATION ...... 13 V.1 Legal Status...... 13 V.2 (Draft) final list of recommendations not falling under Article 21a/22 of Directive 2001/83 in case of a positive benefit risk assessment ...... 13 V.3 Proposed list of conditions pursuant to Article 21a or 22 of Directive 2001/83/EC ...... 13 V.4 Summary of Product Characteristics (SmPC) ...... 14 V.5 Package Leaflet (PL) ...... 14 V.5.1 Package Leaflet...... 14 V.5.2 Assessment of User Testing ...... 14 V.6 Labelling ...... 14 VI. APPENDIX ...... 15 QRD GUIDANCE AND CHECKLIST FOR THE REVIEW OF USER TESTING RESULTS ...... 15 Guidance regarding Recruitment ...... 18

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RECOMMENDATION

Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Bosentan Basics, in the treatment of

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 (see section 5.1). Bosentan film-coated tablets are also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease (see section 5.1) is approvable provided that the applicant commits to perform a number of post authorisation follow- up measures to be reported back to the RMS and CMS within predefined timeframes.

A list of such follow-up measures is in section VI of this report.

There is no need for an additional expert involvement or a GCP inspection.

I. EXECUTIVE SUMMARY

I.1 Problem statement

This is a generic application

I.2 About the product

This decentralised application concerns a generic version of Bosentan, under 1 trade name (Bosentan Basics 62,5mg & 125 mg). In this Assessment Report, the name Bosentan Basics is used.

The originator product is Tracleer (62.5 and 125 mg film-coated tablets) by Actelion Pharmaceuticals, registered since 2002-05-15.

With Germany as the Reference Member State in this Decentralized Procedure, Basics GmbH is applying for the Marketing Authorisations for Bosentan Basics in FR, IT, ES.

Bosentan 62.5/125 mg film-coated tablets is a dual endothelin A and B (ETA and ETB) receptor antagonist that is indicated for the treatment of patients with primary or secondary pulmonary arterial hypertension.

Endothelin 1 (ET 1) is a potent vascular paracrine and autocrine peptide whose actions are mediated through ETA receptors present on smooth muscle cells and endothelin B (ETB) receptors present on endothelial cells. Predominant actions of ET 1 binding to ETA receptors are vasoconstriction and vascular remodeling, while binding to ETB receptors results in ET 1 clearance and vasodilatory and antiproliferative effects due in part to nitric oxide and prostacyclin release. ET 1 concentrations are DE/H/4148/001-002/DC Public Assessment Report Page 3/21 elevated in plasma and lung tissue of patients with PAH. ETA and ETB receptors play a key role in regulating vascular resistance in the lung by directly stimulating vasoconstriction and pulmonary vascular remodeling and this ultimately leads to progressive right heart failure.

The proposed indications are:

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 (see section 5.1). Bosentan film-coated tablets are also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease (see section 5.1)

I.3 General comments on the submitted dossier

This decentralised application concerns a generic version of Bosentan, under one trade name. The originator product is Tracleer (62.5 and 125 mg film-coated tablets) by Actelion Pharmaceuticals, registered since 2002-05-15.

With Germany as the Reference Member State in this Decentralized Procedure, Basics GmbH is applying for the Marketing Authorisations for Bosentan Basics in FR, IT, ES.

No scientific advice has been given. The strategy was in accordance with the relevant guideline CPMP/QWP/EWP/1401/98 Rev. 1, January 2010 (bioequivalence guideline).

Sections 1.6.1-3 of the paediatric regulation EC No 1901/2006 are not applicable for a generic medicinal product. No PIP has been submitted

I.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.

According to the Applicant the bioequivalence study and the validation of the methods were conducted in accordance to the principles of GCP and GLP. The BE study has been approved by a local ethics committee prior to the conduct of the study.

The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. Valid GMP certificates for all proposed manufacturing sites, which are responsible for bulk manufacture, packaging step, testing and batch release, are presented.

A QP declaration is applicable to the following registered MIAH(s), that use the active substance as a starting material and/or is responsible for QP certification of the finished batch of a human or veterinary medicinal product, where the active substance is registered as a starting material and is manufactured at the sites listed in Part A.

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II. SCIENTIFIC OVERVIEW AND DISCUSSION

This is a generic application.

II.1 Quality aspects

Drug substance Bosentan monohydrate contained in the drug products applied for is manufactured by Ranbaxy Laboratories Limited, India. A complete ASMF (Applicant’s and Restricted Parts) has been submitted in support of the application. A suitable declaration by the Qualified Person from the site responsible for batch release in DE regarding the GMP compliance of the drug substance manufacturer has been provided. The name and address of the DMF Holder have been changed.

Bosentan monohydrate does not have a monograph in the Ph.Eur. The proposed limits for the identified and unknown individual impurities were set according to ICH Q3A and are acceptable. The limit for total impurities is in line with data from batch analysis and the stability program and reflects drug substance behaviour. Limits for residual solvents, including ethylene glycol are according to the batch results and are lower than the levels stated in ICH Q3C. Bosentan exhibits polymorphism and to monitor consistency in the API manufacture, the drug substance manufacturer included a test for polymorphic identity into the drug substance specification.

The drug substance specification is considered acceptable so far. The analytical in-house methods for control of Bosentan monohydrate have been validated. The retest period of the drug substance is set on 36 months without any storage conditions.

Drug Product The choice of excipients is acceptable and their functions explained. All excipients are well known and of appropriate quality. The requested biowaiver for the Bosentan 62.5 mg film-coated tablet product is acceptable from the pharmaceutical point of view. The name of the drug product manufacturer has been changed.

The manufacturing process has been suitably validated at the pilot scale (115,000 tablets) and has been shown to be capable of consistently producing drug products of acceptable quality. A validation protocol for the manufacture of the drug products at the commercial scale has been submitted. The applicant has committed to validate the first three commercial scale batches according to the validation scheme.

The drug product specification generally covers appropriate parameters for this type of dosage form. Validation of the analytical method is acceptable. Batch analysis has been performed and the results show that the drug products meet the specifications proposed by the applicant. Sufficient stability data have been submitted and a shelf-life of 24 months without any storage conditions is acceptable for both products.

II.2 Non-clinical aspects

Pharmacology Bosentan is a competitive endothelin receptor antagonist (ERA) with affinity for both endothelin A and B (ETA and ETB) receptors. Bosentan has a slightly higher affinity for ETA receptors (Ki = 4.1—43 nM) than for ETB receptors (Ki = 38—730 nM) as determined in human smooth muscle cells (ETA) and human placenta and porcine trachea (ETB) (Clozel et al. 1994). Bosentan has a high selectivity for ETA and ETB receptors against other receptors (Clozel et al. 1994). Bosentan inhibits the ET-1-induced proliferarion of pulmonary artery smooth muscle cells (Yang et al. 1999). ET-1- induced contractions in rat aorta and sarafotoxin S6C (a selective ETB receptor agonist)-induced DE/H/4148/001-002/DC Public Assessment Report Page 5/21 contractions in rat trachea were competitively inhibited by bosentan with pA values of 7.2 and 6.0, respectively, and the endothelium-dependent relaxation to sarafotoxin S6C in rabbit superior mesenteric artery was inhibited by bosentan with a pA value of 6.7 (Clozel et al. 1994). In vivo, bosentan at doses of 3 – 30 mg/kg p.os and 10 mg/kg i.v. inhibits the pressor response effects of ET-1; bosentan has no intrinsic agonist activity (Clozel et al. 1994). Bosentan (100 mg/kg/die p.os for 2 days) inhibited the pulmonary vasoconstrictor response to acute hypoxia in the rat, and chronic bosentan administration (100 mg/kg/die p.os) prevented the development of pulmonary hypertension and attenuated right heart hypertrophy; administration of bosentan after hypoxia reversed hypoxia-induced pulmonary hypertension (Chen et al. 1995). Bosentan has been shown to improve survival rate and ameliorate end-organ damage in homozygous rats transgenic for the mouse Ren-2 renin gene without lowering blood pressure, and proteinuria, glomerulosclerosis and cardiac hypertrophy as well as ET-1 content in left ventricular tissue were reduced (Vaneckova et al. 2005).

Pharmacokinetics In humans, the absolute bioavailability of bosentan is approximately 50%. Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. The volume of distribution (Vss) is about 18 l, and the clearance is 8.2 l/h. The terminal elimination half- life (t½) is 5.4 hours. Bosentan is eliminated by biliary excretion following metabolism in the liver by the cytochrome P450 isoenzymes CYP2C9 and CYP3A4. Bosentan forms three metabolites and only one of these is pharmacologically active. This metabolite is mainly excreted unchanged via the bile. Upon multiple dosing, plasma concentrations of bosentan decrease to 50%—65% of those seen after single dose administration. This decrease is probably due to auto-induction of metabolising liver enzymes, because bosentan is an inducer of CYP2C9 and CYP3A4. In vitro data demonstrated that bosentan had no relevant inhibitory effect on the CYP isoenzymes tested (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4). Bosentan increases plasma concentrations of ET-1 (Weber et al. 1996, Dingemanse and van Giersbergeb 2004, SPC).

Toxicology Some ERAs (e.g. sitaxsentan, bosentan) induce hepatotoxicity in humans. It has been discussed that these effects are mediated by an inhibition of the bile salt export pump (BSEP) which exports bile salts out of hepatocytes into the bile, inducing bile salt accumulation in liver cells and cytolysis. In December 2010, sitaxsentan (Thelin®) was withdrawn due to its hepatotoxicity (EMA/CHMP/821121/2010). In rats, bosentan induces increases in plasma bile salt concentration. In dogs, cholestasis was observed after the administration of bosentan. In a 4 week study, bosentan induced increases in serum liver enzymes, bile duct proliferation and single cell necrosis at doses of 500 and 1000 mg/kg/die. In a 12 months study, bosentan induced pigment deposits in the liver and increased serum bile salts at a dose of 500 mg/kg/die. In humans, bosentan induces increases in bile salt concentrations followed by increases in liver enzymes.

A 2-year carcinogenicity study in mice showed an increased combined incidence of hepatocellular adenomas and carcinomas in males, but not in females, at plasma concentrations about 2 to 4 times the plasma concentrations achieved at the therapeutic dose in humans. In rats, oral administration of bosentan for 2 years produced a small, significant increase in the combined incidence of thyroid follicular cell adenomas and carcinomas in males, but not in females, at plasma concentrations about 9 to 14 times the plasma concentrations achieved at the therapeutic dose in humans. Bosentan was negative in tests for genotoxicity. There was evidence of a mild thyroid hormonal imbalance induced by bosentan in rats. However, there was no evidence of bosentan affecting thyroid function (thyroxine, TSH) in humans. Bosentan has been shown to be teratogenic in rats at plasma levels higher than 1.5 times the plasma concentrations achieved at the therapeutic dose in humans. Teratogenic effects, including malformations of the head and face and of the major vessels, were dose dependent. The similarities of the pattern of malformations observed with other ET receptor antagonists and in ET knock-out

DE/H/4148/001-002/DC Public Assessment Report Page 6/21 mice indicate a class effect. Appropriate precautions must be taken for women of child-bearing potential. In fertility studies in male and female rats at plasma concentrations 21 and 43 times, respectively, the expected therapeutic level in humans, no effects on sperm count, motility and viability, or on mating performance or fertility were observed, nor was there any adverse effect on the development of the pre-implantation embryo or on implantation (section 5.3 of the SPC).

In conclusion, from a toxicological point of view, the major issues regarding bosentan are hepatotoxicity and teratogenicity.

II.3 Clinical aspects

The applicant has applied for two strengths, Bosentan 62.5/125 mg film-coated tablets, mainly based on one bioequivalence study with the 125 mg strength. A waiver for the lower strength was accepted based on the following considerations and in accordance with the requirements of the Guideline on investigation of bioequivalence (CPMP/ EWP/QWP/1401/98 Rev. 1, January 2010): a) the pharmaceutical products are manufactured by the same manufacturing process. b) the qualitative composition of the different strengths is the same, c) the composition of the strengths are quantitatively proportional d) appropriate in vitro dissolution data should confirm the adequacy of waiving additional in vivo bioequivalence testing. In vitro dissolution using surfactant was similar for the 62.5 and the 125 mg strength. The applicant has provided a justification to use surfactant. e) absorption of Bosentan is dose proportional up to 500 mg.

The results of one BE study were provided as a report. PROTOCOL NO.: 1031_BOSEN_14 Single-dose crossover fully replicate bioequivalence study on Bosentan 125 mg tablets in healthy adult human male subjects under fasting condition. Study design, pharmacokinetic parameters and statistical analyses were in line with the Guideline on investigation of bioequivalence. 36 healthy male subjects were included, 34 subjects completed the study and were included in the PK evaluations. The key results of the statistical analyses for Bosentan are summarized in table 1:

Table 1: Ratios of LSM for log transformed pharmacokinetic parameters (Cmax, AUC0-t and AUC0-) for Bosentan (90% Confidence Interval) Bosentan Parameter Test (T) vs Reference (R) ln Cmax 103.15% (93.88 % – 113.33 %) ln AUC0-t 103.89% (96.90% – 111.38%) ln AUC0- 103.47% (96.77% – 110.65%)

The results were consistent with the assumption of bioequivalence between test and reference. Pharmacodynamics No data were submitted. Clinical efficacy No data were submitted. Clinical safety A total of 03 adverse events (AE) were reported during the BE study. The study did not indicate safety concerns particularly related to the Test medicinal product.

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The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.

Risk Management Plan At the start of this decentralised procedure the applicant submitted the first Risk Management Plan (RMP version 1, date of final sign off 27-June-2014) which has been subsequently updated to version 1.2 (date of final 16-July-2015) and further to version 1.3 (date of final sign off 13-Nov-2015) according to the comments and questions raised by the RMS and the CMS FR in the course of this decentralised procedure. Details are given in the accompanying Clinical Assessment Report. The updated RMP is now acceptable. The applicant has submitted the 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 Basics film-coated tablets. The following table presents the updated safety concerns:

- Summary table of safety concerns as approved in RMP Important identified risks  Hypersensitivity reactions  Teratogenicity  Hepatotoxicity  Decrease in haemoglobin concentration  Interaction with hormonal contraceptives  Interaction with cyclosporine A  Concomitant use with substrates, inducers or inhibitors of P450 isoenzymes- CYP3A4 and CYP2C9  Pulmonary oedema associated with veno-occlusive disease  Decrease of sperm count Important potential risks  Use in patients with PAH and left ventricular failure  Concomitant use with antiretrovirals  Testicular disorders and male infertility  Respiratory tract infection in children Missing information  Use in patients with severe PAH  Use in pregnancy and during breastfeeding  Use in children with renal function impairment  Use of Bosentan with addition of sildenafil

- Summary of Safety Concerns and Planned Risk Minimisation Activities as proposed/approved in RMP

Safety Concern Routine Risk Minimisation Measures Additional Risk Minimisation Measures

Important Identified Risks

Hypersensitivity Information regarding this safety concern is None proposed reactions provided in the following sections of SmPC: section 4.3-Contraindications in patients with known hypersensitivity to active substance or other product excipient. labelled in section 4.8 under Immune system disorders. section 6.1 a detailed list of product excipients. Teratogenicity Information regarding this safety concern is Controlled distribution

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Safety Concern Routine Risk Minimisation Measures Additional Risk Minimisation Measures provided in the following sections of SmPC: system to identify all section 4.3- Contraindications: in pregnancy prescribers in the EEA in and in women of childbearing potential who are order that they can be not using reliable methods of contraception. informed about the sections 4.4 and 4.6 Warning and appropriate use of recommendations so that Bosentan treatment bosentan. Educational should not be initiated in women of childbearing material supplied as potential unless they practice reliable methods of Prescriber Kit contraception and the result of pregnancy test is to prescribers and negative . Also appropriate advice in given in patients (patient these sections regarding reliable methods of brochure) as detailed in contraception along with recommendation for Pregnancy Prevention Plan. monthly pregnancy test during therapy. Patient Reminder Card sections 4.4, 4.5 and 4.6: Patients and specifically aimed at prescribers must be aware that, due to potential informing patients of the pharmacokinetic interactions, Bosentan may need to avoid pregnancy render hormonal contraceptives ineffective. and to ensure effective Therefore, women of child-bearing potential must contraceptive measures not use hormonal contraceptives (including oral, are used. injectable, transdermal, and implantable forms) as the sole method of contraception but should use an additional or an alternative reliable method of contraception. section 5.3 –Preclinical safety data suggests that Bosentan like other ET receptor antagonists has teratogenic effect in animal studies. Hepatotoxicity Information regarding this safety concern is Controlled distribution provided in the following sections of SmPC: system to identify all section 4.3-Contraindications in patients with prescribers in the EEA in moderate to severe hepatic impairment and with order that they can be baseline transaminases more than 3 times ULN. informed about the section 4.4-Warnings that elevation of liver appropriate use of function test may be dose depended and may bosentan. typically occur within the first 26 weeks of Educational material treatment, but may also occur late in treatment. supplied as Prescriber Kit Recommendations on liver aminotransferase to prescribers and patients levels monitoring prior to initiation and at (patient brochure). Patient monthly intervals during treatment with Bosentan Reminder Card specifically along with necessary dose adjustment or aimed at facilitating discontinuation. sections 4.4 and 4.5 -information on possible patient’s awareness of the need for regular monitoring mechanisms of liver function tests elevation of liver function. provided and warning that the risk may be increased if inhibitors of bile export pumps are co-administered. labelled in section 4.8 under hepatobiliary disorders. section 5.2 -there are details on Bosentan hepatic metabolism and elimination. Restricted medical prescription. Decrease in Information regarding this safety concern is Controlled distribution haemoglobin provided in the following sections of SmPC: system to identify all concentration section 4.4 Warning that treatment with prescribers in the EEA in Bosentan is associated with a dose-related order that they can be decrease in haemoglobin concentration and informed about the proposals for monitoring. appropriate use of labelled in section 4.8 under blood and bosentan. Educational lymphatic system disorders. 4.8. material supplied as Restricted medical prescription. Prescriber Kit to prescribers and patients (patient brochure). Patient Reminder Card specifically aimed at facilitating DE/H/4148/001-002/DC Public Assessment Report Page 9/21

Safety Concern Routine Risk Minimisation Measures Additional Risk Minimisation Measures patient’s awareness of the need for regular blood tests. Interaction with Information regarding this safety concern is Controlled distribution hormonal provided in the following sections of SmPC: system to identify all contraceptives sections 4.4 and 4.5 and 4.6: Patients and prescribers in the EEA in prescribers must be aware that, due to potential order that they can be pharmacokinetic interactions, Bosentan may informed about the render hormonal contraceptives ineffective. appropriate use of Hormonal contraceptives (including oral, bosentan. Educational injectable, transdermal, and implantable forms) material supplied as should not be used as the sole method of Prescriber Kit to contraception. Women of child-bearing potential prescribers and patients must use an additional or an alternative reliable (patient brochure), as method of contraception. detailed in Pregnancy section 5.2 -there are details on Bosentan Prevention Plan. hepatic metabolism and elimination. Patient Reminder Card Restricted medical prescription. specifically aimed at informing patients of the need to avoid pregnancy and to ensure effective contraceptive measures are used. Interaction with Information regarding this safety concern is None proposed cyclosporine A provided in the following sections of SmPC: • section 4.3-concomitent use with Cyclosporine is contraindicated. sections 4.4 and 4.5: Patients and prescribers must be aware that, due to inhibition of the bile salt export pump Cyclosporine may alter Bosentan elimination and increase the risk of liver dysfunction. section 5.2- there are details on Bosentan hepatic metabolism and elimination. Concomitant use Information regarding this safety concern is None proposed with substrates, provided in the following sections of SmPC: inducers or section 4.4 and 4.5: information on possible inhibitors of P450 interaction with other medicinal products that are isoenzymes- substrate, inducers or inhibitors of P450 CYP3A4 and isoenzymes CYP2C9 section 5.2- PK properties: there are details on Bosentan hepatic metabolism and elimination. Pulmonary Information regarding this safety concern is None proposed oedema provided in the following section of SmPC: associated with section 4.4:Warning that pulmonary oedema veno-occlusive has been reported with vasodilators (mainly disease prostacyclins), when used in patients with PVOD disease and to consider PVOD if pulmonary oedema occurs. Decrease of Information regarding this safety concern is None proposed sperm count provided in the following section of SmPC: section 4.6 and 5.3: The results observed in the juvenile rat toxicity studies (reduced testis weight associated with reduced number of sperms , reduced epididymides weights, increased incidence of testicular tubular atrophy) and from clinical study in humans (decreased sperm concentration) suggest testicular effects of Bosentan. Therefore it cannot be excluded that bosentan has an effect on spermatogenesis in human. Important Potential Risks DE/H/4148/001-002/DC Public Assessment Report Page 10/21

Safety Concern Routine Risk Minimisation Measures Additional Risk Minimisation Measures

Use in patients Information regarding this safety concern is None proposed with PAH and left provided in the following sections of SmPC: ventricular failure section 4.4: Warning that fluid retention and oedema has been reported when Bosentan was used in patients with left ventricular dysfunction and that appropriate diuretic treatment should be considered in patients with evidence of fluid retention. labelled in section 4.8 under General disorders and administration site conditions. Concomitant use Information regarding this safety concern is None proposed with provided in the following sections of SmPC: antiretrovirals section 4.4- Warnings regarding the use of bosentan in patients with PAH associated with HIV infection, treated with antiretrovirals. section 4.5 details regarding interactions with lopinavir + ritonavir and other antiretroviral agents. section 5.2- there are details on Bosentan hepatic metabolism and elimination. Testicular Information regarding this safety concern is None proposed disorders and provided in the following sections of SmPC: male infertility • section 4.6 and 5.3: The results observed in the juvenile rat toxicity studies (reduced testis weight associated with reduced number of sperms , reduced epididymides weights, increased incidence of testicular tubular atrophy) and from clinical study in humans (decreased sperm concentration) suggest testicular effects of Bosentan. Therefore it cannot be excluded that Bosentan has an effect on spermatogenesis in human. Respiratory tract Information regarding this safety concern is None proposed infection in provided in the following sections of SmPC: children section 4.8: Prescriber to be informed that infection of respiratory tract was more frequently reported in children studies that in adults studies. Missing Information Use in patients Information regarding this safety concern is None proposed with severe PAH provided in the following sections of SmPC: section 4.1 and 4.2 :information on Bosentan use in several forms of PAH and class indication and therapy management during clinical deterioration section 4.4: Prescribers must be aware that therapy efficacy has not been established in patients with severe PAH and switch to other therapy should be considered in these cases. Use in pregnancy Information regarding this safety concern is None proposed and during provided in the following sections of SmPC: breastfeeding section 4.6 and 5.3: Inform that teratogenic effects of Bosentan were observed in animals and its potential risk for humans is still unknown, therefore Bosentan is contraindicated in pregnancy (see section 4.3). section 4.6 – Inform that breastfeeding is not recommended during Bosentan as it is unknown whether Bosentan is excreted into human breast milk. Use in children Information regarding this safety concern is None proposed with renal provided in the following sections of SmPC : function section 4.2 and 5.2: Inform prescribers that DE/H/4148/001-002/DC Public Assessment Report Page 11/21

Safety Concern Routine Risk Minimisation Measures Additional Risk Minimisation Measures impairment there are limited data on the safety and efficacy in patients under the age of 18 years and that optimal maintenance dose has not been defined. However paediatric pharmacokinetic data have shown that Bosentan plasma concentrations in children were on average lower than in adult patients. The recommended starting and maintenance dose is 2 mg/kg morning and evening in children 2 years and older. section 4.5; Results of the study with Bosentan in combination with eporostenol in children section 5.1 and 5.2. provides details on Bosentan efficacy in several paediatric pharmacokinetic studies Use of Bosentan Information regarding this safety concern is None proposed with addition of provided in the following sections of SmPC: sildenafil section 4.5: Interaction between Bosentan and sildenafil in healthy volunteers leading to 63% decrease in the sildenafil AUC and a 50% increase in the bosentan AUC. section 5.1: Efficacy in clinical studies in adult patients with PAH when Bosentan was used alone and/or in combination with sildenafil.

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted: - At the request of the RMS; - Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

Periodic Safety Update Report (PSUR) The next PSUR should be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal.

III. BENEFIT RISK ASSESSMENT

Bioequivalence of Bosentan Basics to the reference medicinal product Tracleer® (62.5 and 125 mg film-coated tablets) by Actelion Pharmaceuticals has been demonstrated for both strengths. B/R can be considered positive.

IV. PROPOSED LIST OF OUTSTANDING ISSUES

IV.1 Quality aspects

None

IV.2 Non-clinical aspects

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None

IV.3 Clinical aspects

None

V. PROPOSED CONDITIONS FOR MARKETING AUTHORISATION AND PRODUCT INFORMATION

V.1 Legal Status

Medical Prescription

V.2 (Draft) final list of recommendations not falling under Article 21a/22 of Directive 2001/83 in case of a positive benefit risk assessment

Post approval Commitment have been raised.

V.3 Proposed list of conditions pursuant to Article 21a or 22 of Directive 2001/83/EC Additional risk minimisation measures (including educational material)

Controlled Distribution system: The MAH shall agree the details of a controlled distribution system with the National Competent Authorities and must implement such programme nationally to ensure that prior to prescribing all health care professionals who intend to prescribe and/or dispense Bosentan are provided with a Prescriber Kit containing the following: • Information about Bosentan • Patient Information Booklet/Patient Alert Card The information provided about Bosentan shall contain the following key elements: • That Bosentan is teratogenic in animals o Use in pregnant women is contraindicated o The need for effective contraception o That there is an interaction with hormonal contraceptives o Monthly pregnancy tests in women of child bearing potential are recommended. • That Bosentan is hepatotoxic o Bosentan should not be used in Child Pugh Class B or C, ie moderate to severe hepatic impairment. o Need for liver function tests to be measured:

rease. o Need for close monitoring and dosage adjustment if levels rise above 3 x upper limit normal (ULN):

treatment and monitor liver function at least every 2 weeks. and ≤ 8 x ULN: Confirm levels and if confirmed stop treatment and monitor liver function at least every 2 weeks. In the above circumstances, if the levels return to pre-treatment values, continuing or re-introducing Bosentan may be considered. or any of the above with associated clinical symptoms of liver injury: Treatment must be stopped and re-introduction of Bosentan is not to be considered. • That treatment with Bosentan is associated with a decrease in haemoglobin. o Need for blood monitoring

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• That co-administration of Bosentan with cyclosporine is contraindicated. • That the safety database of Bosentan in the indication to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease is limited and physicians are encouraged to enrol patients in the surveillance programme/registry to further increase knowledge about the product. The surveillance programme/registry should prompt doctors to report adverse reactions. The patient information shall contain the following information: • That Bosentan is teratogenic in animals • That pregnant women must not take Bosentan • That women of child bearing potential must use effective contraception • That hormonal contraceptives on their own are not effective • The need for regular pregnancy tests • That Bosentan causes a decrease in haemoglobin and the need for regular blood tests • That Bosentan is hepatotoxic and the need for regular monitoring of liver function.

The Patient Alert Card: • Patient Alert Card specifically aimed at facilitating patients’ awareness of the need for regular blood tests for liver function. • Patient Alert Card specifically aimed at informing patients of the need to avoid pregnancy and to ensure effective contraceptive measures are used.

Surveillance programme/Registry The MAH shall set up or participate in a multicentre, prospective, observational, non-interventional surveillance programme/registry to document adherence to SmPC requirements for liver function, pregnancy testing and the use of adequate contraception in in DU/ SSC patients; Details of the operation of/participating in the surveillance programme/registry shall be agreed with the National Competent Authorities in each Member State.

Other conditions and requirements of the marketing Periodic safety update reports (PSURs) The marketing authorisation holder shall submit periodic safety update reports including liver reports for this product in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c (7) of Directive 2001/84/EC and published on the European medicines web-portal.

V.4 Summary of Product Characteristics (SmPC)

None

V.5 Package Leaflet (PL)

V.5.1 Package Leaflet

None

V.5.2 Assessment of User Testing

Assessment of the User Testing is attached in the ‘QRD Guidance and Checklist for the Review of User Testing Results’.

V.6 Labelling

None

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VI. APPENDIX

QRD GUIDANCE AND CHECKLIST FOR THE REVIEW OF USER TESTING RESULTS

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London,

QRD GUIDANCE AND CHECKLIST FOR THE REVIEW OF USER TESTING RESULTS

[Disclaimer: This guidance has been set up to provide practical information on how to evaluate user testing reports which are based on the readability testing method as described in Annex 1 of the EC Readability Guideline. This does not exclude the submission and evaluation of user testing reports based on methods other the one outlined above, for which specific assessment guidance may be issued once experience has been gained

Useful links: More detailed practical guidance can be found in the following documents: - EC Readability Guideline [link to be inserted] - “Operational procedure on Handling of “Consultation with target patient groups” on Package Leaflets (PL) for Centrally Authorised Products for Human Use [link to be inserted - [MRP/DCP relevant document – link to be inserted]

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PRODUCT INFORMATION

Name of the medicinal product:

Name and address of the applicant:

Name of company which has performed the user testing:

Type of Marketing Authorisation Application:

Active substance:

Pharmaco-therapeutic group (ATC Code):

Therapeutic indication(s):

- Report provided x yes no

- Justification for not submitting report: extensions for the same route of administration ref to test on same class of medicinal product ref to test with same safety issues other ______

- Is the justification for not submitting a report acceptable? yes no

Reasons [assessor’s views on acceptability or not of the justification – assessment of justification] ______

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1 TECHNICAL ASSESSMENT

1.1 Recruitment

 Is the interviewed population acceptable? x yes no