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Updated on 29 May 2024

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IE-Tracleer-PIL-16May2024-1738-IG.pdf

Reasons for updating

  • Change to section 6 - what the product looks like and pack contents
  • Change to section 6 - date of revision

Updated on 29 May 2024

File name

IE Tracleer 62.5mg and 125mg SmPC -16May2024-1738-IG-clean.pdf

Reasons for updating

  • Change to section 3 - Pharmaceutical form
  • Change to section 10 - Date of revision of the text

Legal category:Product subject to medical prescription which may not be renewed (A)

Updated on 29 March 2024

File name

Tracleer-SPC-08Feb2024-WS-2583.pdf

Reasons for updating

  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 10 - Date of revision of the text

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Section 4.6 – Fertility, pregnancy and lactation: Breast Feeding

Updated on 29 March 2024

File name

IE-Tracleer-PIL-08Feb2024-WS-2583.pdf

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 6 - date of revision

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Section 2- Breast feeding concerns updated

EDM Updated on 05 December 2023

File name

Tracleer Patient Card.pdf

Reasons for updating

  • Add New Doc

Updated on 17 February 2023

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IE Tracleer 62.5mg-125 mg PIL 09Feb23 IB-WS-PIL-Combination and storage condition update.pdf

Reasons for updating

  • Change to section 6 - what the product contains
  • Change to section 6 - what the product looks like and pack contents
  • Correction of spelling/typing errors

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Approval EMEA/H/C/xxxx/WS/2404 - Update to the storage conditions and combination of differing strengths into one PIL for film coated tablets. 

Updated on 17 February 2023

File name

IE Tracleer 62.5mg and 125mg SmPC - 09Feb23 IB-WS-Combination and storage condition update.pdf

Reasons for updating

  • Change to section 6.4 - Special precautions for storage
  • Correction of spelling/typing errors

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Approval of EMEA/H/C/xxxx/WS/2404 - Update to the storage conditions and combination of differing strengths into one PIL for film coated tablets.

Updated on 21 July 2021

File name

NI and IE Tracleer 62.5mg and 125mg SmPC C02 Day27 21July21 Clean EDMS-ERI-205912247 V19.pdf

Reasons for updating

  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 10 - Date of revision of the text
  • Updated inline with QRD template and/or excipient guideline

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Correction of male fertility wording and QRD update

Updated on 21 July 2021

File name

NI and IE Tracleer 62.5mg PIL C02 Day27 21July21 Clean EDMS-ERI-205912247 V19.pdf

Reasons for updating

  • Change to section 6 - manufacturer
  • Change to section 6 - date of revision

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Removal of DE batch release site, changes in local representatives and QRD update

Updated on 02 March 2020

File name

Tracleer 62.5 & 125mg SmPC C01 CHMP 26 Feb 2020 - clean.pdf

Reasons for updating

  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors

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Editorial changes.

Updated on 02 March 2020

File name

Tracleer 62.5mg PIL C01 CHMP 26 Feb 2020 - clean.pdf

Reasons for updating

  • Change to section 6 - manufacturer
  • Change to section 6 - date of revision
  • Correction of spelling/typing errors

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Change to manufacturing site responsible for batch release.

Updated on 17 October 2019

File name

Tracleer-62.5 & 125 mg-SmPc-Sep 2019.pdf

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration

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update of the excipients wording according to the Revised Annex to the European Commission guideline on ‘Excipients in the labelling and package leaflet of medicinal products for human use’ (EMA/CHMP/302620/2017).

Updated on 17 October 2019

File name

Tracleer-62.5 mg-PIL_Sep-Ireland 2019.pdf

Reasons for updating

  • Change to section 2 - what you need to know - contraindications

Updated on 18 December 2018

File name

Tracleer 62.5 mg PIL.pdf

Reasons for updating

  • Change to section 6 - date of revision
  • Change to other sources of information section

Updated on 21 November 2018

File name

EN_Tracleer_H-401_MAH transfer_clean_AppV_PI-I-III_November2018 PIL 62.5 mg.pdf

Reasons for updating

  • Change to section 4 - how to report a side effect
  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - date of revision

Updated on 19 November 2018

File name

EN_Tracleer_H-401_MAH transfer_clean_AppV_PI-I-III_November2018 SPC.pdf

Reasons for updating

  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

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Summary of Changes

Section 4.8:

Addition of:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed below.

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

Section 7:

Removal of:

Actelion Registration Ltd

Chiswick Tower 13th Floor

389 Chiswick High Road

London W4 4AL

United Kingdom

Addition of:

Janssen-Cilag International NV

Turnhoutseweg 30

B 2340 Beerse

Belgium

Section 10:

Date of revision of text: November 2018

 

 

Updated on 17 September 2018

File name

Tracleer 62.5-125 mg SmPC.pdf

Reasons for updating

  • Change to section 10 - Date of revision of the text

Legal category:Product subject to medical prescription which may not be renewed (A)

Updated on 03 September 2018

File name

Tracleer PIL 62.5 mg.pdf

Reasons for updating

  • Change to section 6 - date of revision

Updated on 14 August 2018

File name

Tracleer Package leaflet_62.5 mg_23October2017.pdf

Reasons for updating

  • New PIL for new product

Updated on 13 August 2018

File name

Tracleer SmPC_23October2017.pdf

Reasons for updating

  • File format updated to PDF

Legal category:Product subject to medical prescription which may not be renewed (A)

Updated on 01 December 2017

Reasons for updating

  • New SPC for new product

Legal category:Product subject to medical prescription which may not be renewed (A)

Updated on 01 December 2017

Reasons for updating

  • Change to section 10 - Date of revision of the text

Legal category:Product subject to medical prescription which may not be renewed (A)

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Addition of site batch release

Updated on 01 December 2017

Reasons for updating

  • Change to section 10 - Date of revision of the text

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Addition of site batch release

Updated on 12 October 2017

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category:Product subject to medical prescription which may not be renewed (A)

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$0Tadalafil: Bosentan (125 mg twicedaily) reduced tadalafil (40 mg once per day) systemic exposure by 42% and Cmaxby 27% following multiple dose co-administration. Tadalafil did not affect theexposure (AUC and Cmax) of bosentan or its metabolites. $0

Updated on 12 October 2017

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Free text change information supplied by the pharmaceutical company

$0Tadalafil: Bosentan (125 mg twicedaily) reduced tadalafil (40 mg once per day) systemic exposure by 42% and Cmaxby 27% following multiple dose co-administration. Tadalafil did not affect theexposure (AUC and Cmax) of bosentan or its metabolites. $0

Updated on 30 May 2017

Reasons for updating

  • Correction of spelling/typing errors

Legal category:Product subject to medical prescription which may not be renewed (A)

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linguistic improvements and editorial corrections. 

Updated on 30 May 2017

Reasons for updating

  • Correction of spelling/typing errors

Free text change information supplied by the pharmaceutical company

linguistic improvements and editorial corrections. 

Updated on 10 October 2016

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 8 - MA number

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4.2 Patientsshould be advised not to swallow the desiccant found in the white high-densitypolyethylene bottles.$0$0$04.7 Blurred vision$0$0$0$0$06.3 For white high-density polyethylene bottles, usewithin 30 days after the first opening.$0$0$0$0$06.4 For PVC/PE/PVDC/aluminium-blisters$0$0$0$0$06.5 White high-densitypolyethylene bottles with a silica gel desiccant containing 56film-coated tablets. Cartonscontain 56 film-coated tablets.$0$0$0$0$08. MA numbers$0$0$0$0$0$0

Updated on 10 October 2016

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 8 - MA number

Free text change information supplied by the pharmaceutical company

4.2 Patientsshould be advised not to swallow the desiccant found in the white high-densitypolyethylene bottles.$0$0$04.7 Blurred vision$0$0$0$0$06.3 For white high-density polyethylene bottles, usewithin 30 days after the first opening.$0$0$0$0$06.4 For PVC/PE/PVDC/aluminium-blisters$0$0$0$0$06.5 White high-densitypolyethylene bottles with a silica gel desiccant containing 56film-coated tablets. Cartonscontain 56 film-coated tablets.$0$0$0$0$08. MA numbers$0$0$0$0$0$0

Updated on 30 March 2016

Reasons for updating

  • Change to joint SPC covering all presentations

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Merged 62.5mg and 125mg strenghts

Updated on 30 March 2016

Reasons for updating

  • Change to joint SPC covering all presentations

Free text change information supplied by the pharmaceutical company

Merged 62.5mg and 125mg strenghts

Updated on 02 September 2015

Reasons for updating

  • Change to section 4.8 - Undesirable effects

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

$0$0Add “nasal congestion” to the ADR table as “common” event event under the “Respiratory, thoracic and mediastinal disorders”$0$0Update ADR table where hepatitis and jaundice are listed under the ‘Hepatobiliary disorders’ SOC, further specifying as follows (new text in brackets): “Aminotransferase elevations associated with hepatitis (including possible exacerbation of underlying hepatitis) and/or jaundice”$0$0

Updated on 02 September 2015

Reasons for updating

  • Change to section 4.8 - Undesirable effects

Free text change information supplied by the pharmaceutical company

$0$0Add “nasal congestion” to the ADR table as “common” event event under the “Respiratory, thoracic and mediastinal disorders”$0$0Update ADR table where hepatitis and jaundice are listed under the ‘Hepatobiliary disorders’ SOC, further specifying as follows (new text in brackets): “Aminotransferase elevations associated with hepatitis (including possible exacerbation of underlying hepatitis) and/or jaundice”$0$0

Updated on 18 June 2015

Reasons for updating

  • Change to section 10 - Date of revision of the text

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

change to the local representatives contact details

Updated on 18 June 2015

Reasons for updating

  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

change to the local representatives contact details

Updated on 28 April 2015

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Paediatric population$0$0In children, the optimal maintenance dose has not been defined in well-controlled studies. However, paediatric Paediatric pharmacokinetic data have shown that bosentan plasma concentrations in childrenwith PAH aged from 1 year to 15 years were on average lower than in adult patients and were not increased by increasing the dose of Tracleer above 2 mg/kg body weight or by increasing the dosing frequency from twice daily to three times daily (see section 5.2). Increasing the dose or the dosing frequency will likely not result in additional clinical benefit.$0$0Based on these pharmacokinetic results, higher doses are unlikely to be more effective, and greater adverse reaction rates cannot formally be excluded in young children if the dose is increased. Whenwhen used in children with PAH 21 years and older, the recommended starting and maintenance dose is therefore 2 mg/kg morning and evening. No clinical study has been conducted to compare the efficacy/safety ratio of 2mg/kg to 4 mg/kg body weight twice daily in children.$0$0There is only limited clinical experience in paediatric patients under 2 years of age.$0$0In neonates with persistent pulmonary hypertension of the newborn (PPHN), the benefit of bosentan has not been shown in the standard-of-care treatment. No recommendation on a posology can be made (see sections 5.1 and 5.2).$0$0$0$0$0$0$0Paediatric population$0$0Interaction studies have only been performed in adults.$0$0$0$0$0$0$0Fertility$0$0Fertility studies in rats showed no effects on sperm parameters or fertility (see section 5.3).$0$0Animal studies showed testicular effects (see section 5.3). In a study investigating the effects of bosentan on testicular function in male PAH patients, 8 out of 24 patients showed a decreased sperm concentration from baseline of at least 42% after 3 or 6 months of treatment with bosentan. Based on these findings and preclinical data, it cannot be excluded that bosentan may have a detrimental effect on spermatogenesis in men. In male children, a long-term impact on fertility after treatment with bosentan cannot be excluded.$0$0$0$0$0$0$0Paediatric population$0$0Uncontrolled studies in paediatric patients with PAH (AC-052-356 [BREATHE-3]; AC-052-365 [FUTURE 1])$0$0Uncontrolled clinical studies in paediatric patients:$0$0The safety profile in this population the first paediatric uncontrolled study performed with the film-coated tablet (BREATHE-3: n = 19, median age 10 years [range 3–15 years], open-label bosentan 2mg/kg twice daily; treatment duration 12 weeks; FUTURE 1: n = 36, bosentan 2 mg/kg twice daily for 4 weeks followed by 4 mg/kg twice daily; treatment duration 12 weeks) was similar to that observed in the pivotal trials in adult patients with PAH. In BREATHE-3, the most frequent adverse reactions were flushing (21%), headache, and abnormal liver function test (each 16%). In FUTURE 1, the most frequent adverse reactions were infections (33%) and abdominal pain/discomfort (19%). There were no cases of liver enzyme elevations in the FUTURE 1 study.$0$0A pooled analysis of uncontrolled paediatric studies conducted in PAH with the bosentan 32 mg dispersible tablet formulation (FUTURE 1/2, FUTURE 3/Extension) included a total of 100 children treated with bosentan 2 mg/kg twice daily (n = 33), 2 mg/kg three times daily (n = 31), or 4 mg/kg twice daily (n = 36). At enrolment, six patients were between 3 months and 1 year old, 15 children were between 1 and less than 2 years old, and 79 were between 2 and 12 years old. The median treatment duration was 71.8 weeks (range 0.4–258 weeks).$0$0The safety profile in this pooled analysis of uncontrolled paediatric studies was similar to that observed in the pivotal trials in adult patients with PAH except for infections, which were more frequently reported than in adults (69.0% vs 41.3%).This difference in infection frequency may in part be due to the longer median treatment exposure in the paediatric set (median 71.8 weeks) compared to the adult set (median 17.4 weeks). The most frequent adverse events were upper respiratory tract infections (25%), pulmonary (arterial) hypertension (20%), nasopharyngitis (17%), pyrexia (15%), vomiting (13%), bronchitis (10%), abdominal pain (10%), and diarrhoea (10%). There was no relevant difference in adverse event frequencies between patients above and below the age of 2 years, however this is based on only 21 children less than 2 years, including 6 patients between 3 months to 1 year of age. Adverse events of liver abnormalities and anaemia/haemoglobin decrease occurred in 9% and 5% of patients, respectively.$0$0In a randomised placebo-controlled study, conducted in PPHN patients (FUTURE-4), a total of 13 neonates were treated with the bosentan dispersible tablet formulation at a dose of 2 mg/kg twice daily (8 patients were on placebo). The median bosentan and placebo treatment duration was, respectively, 4.5 days (range 0.5–10.0 days) and 4.0 days (range 2.5-6.5 days). The most frequent adverse events in the bosentan- and the placebo-treated patients were, respectively, anaemia or haemoglobin decrease (7 and 2 patients), generalised oedema (3 and 0 patients), and vomiting (2 and 0 patients).$0$0Laboratory abnormalities$0$0$0$0In the pooled analysis of 100 PAH patients from uncontrolled paediatric studies FUTURE 1/2 and FUTURE 3/Extension, elevations in liver aminotransferases ≥ 3 × ULN were observed in 2% of patients.$0$0In the FUTURE-4 study including 13 neonates with PPHN treated with bosentan 2 mg/kg twice daily for less than 10 days (range 0.5–10.0 days) there were no cases of liver aminotransferases ≥ 3 × ULN during treatment, but one case of hepatitis occurred 3 days after the end of bosentan treatment.$0$0Haemoglobin$0$0A In the adult placebo-controlled studies, a decrease in haemoglobin concentration to below 10 g/dL from baseline was reported in 8.0% of bosentan-treated patients and 3.9% of placebo-treated patients (see section 4.4).$0$0$0$0$0$0$0In the pooled analysis of 100 PAH children from uncontrolled paediatric studies FUTURE 1/2 and FUTURE 3/Extension, a decrease in haemoglobin concentration from baseline to below 10 g/dL was reported in 10.0% of patients. There was no decrease to below 8 g/dL.$0$0In the FUTURE-4 study, 6 out of 13 bosentan-treated neonates with PPHN experienced a decrease in haemoglobin from within the reference range at baseline to below the lower limit of normal during the treatment.$0$0$0$0$0$0Efficacy$0$0$0$0$0$0Studiesy performed in children with pulmonary arterial hypertension$0$0One study has been conducted in children with pulmonary hypertension.$0$0BREATHE-3 (AC-052-356)$0$0Bosentan film-coated tablets were evaluated in an open-label non-controlled uncontrolled study in 19 paediatric patients with pulmonary arterial hypertension aged (AC-052-356 [BREATHE-3]:aged 3-–to 15 years. This study was primarily designed as a pharmacokinetic study (see section 5.2). Patients had primary pulmonary hypertension, (10 patients) , andor pulmonary arterial hypertension related to congenital heart diseases, (9 patients). This study was primarily designed as a pharmacokinetic study (see section 5.2) and were in WHO functional class II (n = 15 patients, 79%) or class III (n = 4 patients, 21%) at baseline. Patients were divided into and dosed according to three body-weight groups and dosed with bosentan at approximately 2 mg/kg twice daily for 12 weeks. Half of the patients in each group were already being treated with intravenous epoprostenol and the dose of epoprostenol remained constant for the duration of the study. The age range was 3–15 years. Patients were in WHO functional class II (n = 15 patients, 79%) or class III (n = 4 patients, 21%) at baseline.$0$0$0$0$0$0$0FUTURE 1/2 (AC-052-365/AC-052-367)$0$0FUTURE 1 was an open-label, uncontrolled study that was conducted with the dispersible tablet formulation of bosentan administered at a maintenance dose of 4 mg/kg twice daily to 36 patients from 2 to 11 years of age. It was primarily designed as a pharmacokinetic study (see section 5.2). At baseline, patients had idiopathic (31 patients [86%]) or familial (5 patients [14%]) PAH, and were in WHO functional class II (n = 23 patients, 64%) or class III (n = 13 patients, 36%). In the FUTURE 1 study, the median exposure to study treatment was 13.1 weeks (range: 8.4 to 21.1). 33 of these patients were provided with continued treatment with bosentan dispersible tablets at a dose of 4 mg/kg twice daily in the FUTURE 2 uncontrolled extension phase for a median overall treatment duration of 2.3 years (range: 0.2 to 5.0 years). At baseline in FUTURE 1, 9 patients were taking epoprostenol. 9 patients were newly initiated on PAH-specific medication during the study. The Kaplan-Meier event-free estimate for worsening of PAH (death, lung transplantation, or hospitalisation for PAH worsening) at 2 years was 78.9%. The Kaplan-Meier estimate of overall survival at 2 years was 91.2%.$0$0FUTURE 3 (AC-052-373)$0$0In this open-label randomised study with the bosentan 32 mg dispersible tablet formulation, 64 children with stable PAH from 3 months to 11 years of age were randomised to 24 weeks bosentan treatment 17$0$02 mg/kg twice daily (n = 33) or 2 mg/kg three times daily (n = 31). 43 (67.2%) were ≥ 2 years to 11 years old, 15 (23.4%) were between 1 and 2 years old, and 6 (9.4%) were between 3 months and 1 year old. The study was primarily designed as a pharmacokinetic study (see section 5.2) and efficacy endpoints were only exploratory. The aetiology of PAH, according to Dana Point classification, included idiopathic PAH (46%), heritable PAH (3%), associated PAH after corrective cardiac surgery (38%), and PAH-CHD associated with systemic-to-pulmonary shunts, including Eisenmenger syndrome (13%). Patients were in WHO functional class I (n = 19 patients, 29 %), class II (n = 27 patients, 42%) or class III (n = 18 patients, 28%) at start of study treatment. At study entry, patients were treated with PAH medications (most frequently PDE-5 inhibitor [sildenafil] alone [35.9%], bosentan alone [10.9%], and a combination of bosentan, iloprost, and sildenafil in 10.9% of patients) and continued their PAH treatment during the study.$0$0At study start, less than half of the patients included (45.3% = 29/64) had bosentan treatment alone not combined with other PAH-medication. 40.6% (26/64) remained on bosentan monotherapy during the 24 weeks of study treatment without experiencing PAH worsening. The analysis on the global population included (64 patients) showed that the majority had remained at least stable (i.e., without deterioration) based on non-paediatric-specific WHO functional class assessment (97% twice daily, 100% three times daily) and physicians’ global clinical impression (94% twice daily, 93% three times daily) during the treatment period. The Kaplan-Meier event-free estimate for worsening of PAH (death, lung transplantation, or hospitalisation for PAH worsening) at 24 weeks was 96.9% and 96.7% in the twice daily and three times daily groups, respectively.$0$0There was no evidence of any clinical benefit with 2 mg/kg three times daily as compared to 2 mg/kg twice daily dosing.$0$0$0$0Study performed in neonates with persistent pulmonary hypertension of the newborn (PPHN):$0$0FUTURE 4 (AC-052-391)$0$0This was a double-blind, placebo-controlled, randomised study in pre-term or term neonates (gestational age 36–42 weeks) with PPHN. Patients with suboptimal response to inhaled nitric oxide (iNO) despite at least 4 hours of continuous treatment were treated with bosentan dispersible tablets at 2 mg/kg twice daily (N = 13) or placebo (N = 8) via nasogastric tube as add-on therapy on top of iNO until complete weaning of iNO or until treatment failure (defined as need for extra-corporeal membrane oxygenation [ECMO] or initiation of alternative pulmonary vasodilator) and for a maximum of 14 days.$0$0The median exposure to study treatment was 4.5 (range: 0.5–10.0) days in the bosentan group and 4.0 (range: 2.5–6.5) days in the placebo group.$0$0The results did not indicate an additional benefit of bosentan in this population:$0$0• The median time to complete weaning from iNO was 3.7 days (95% CLs 1.17, 6.95) on bosentan and 2.9 days (95% CLs 1.26, 4.23) on placebo (p = 0.34).$0$0• The median time to complete weaning from mechanical ventilation was 10.8 days (95% CLs 3.21, 12.21 days) on bosentan and 8.6 days (95% CLs 3.71, 9.66 days) on placebo (p = 0.24).$0$0• One patient in the bosentan group had treatment failure (need for ECMO as per protocol definition), which was declared based on increasing Oxigenation Index values within 8 h after the first study drug dose. This patient recovered within the 60-day follow-up period. AC-052-356 was an open-label, non- uncontrolled study;$0$0$0$0$0$0$0Pharmacokinetics in special populations$0$0Based on the investigated range of each variable, it is not expected that the pharmacokinetics of bosentan will be influenced by gender, body weight, race, or age in the adult population to any relevant extent. No pharmacokinetic data are available in children under 2 years.$0$0Children$0$0Pharmacokinetics were studied in paediatric patients in 4 clinical studies (BREATHE-3, FUTURE 1, FUTURE-3 and FUTURE-4 see section 5.1). Due to limited data in children below 2 years of age, pharmacokinetics remain not well characterised in this age category.$0$0TheStudy AC-052-356 [BREATHE-3]) evaluated the pharmacokinetics of single and multiple oral doses of the film-coated tablet formulation of bosentan were studied in paediatric patients 19 children aged from 3 to 15 years with pulmonary arterial hypertension (PAH) who were dosed on the basis of body weight (see section 5.1, AC-052-356 [BREATHE-3]). Thewith 2 mg/kg twice daily. In this study, the exposure to bosentan decreased with time in a manner consistent with the known auto-induction properties of bosentan. The mean AUC (CV%) values of bosentan in paediatric patients treated with 31.25, 62.5 or 125 mg twice daily were 3,496 (49), 5,428 (79), and 6,124 (27) ng·h/mL, respectively, and were lower than the value of 8,149 (47) ng·h/mL observed in adult patients with pulmonary arterial hypertension PAH receiving 125 mg twice daily. At steady state, the systemic exposures in paediatric patients weighing 10–20 kg, 20–40 kg and > 40 kg were 43%, 67% and 75%, respectively, of the adult systemic exposure.$0$0In a second pharmacokinetic study (study AC-052-365 [FUTURE 1]), dispersible tablets were administered in 36 paediatric patients PAH children aged from 2– to 11 years. with PAH were treated at 2 and 4 mg/kg twice daily with the dispersible tablet. No dose proportionality was observed . Steady-as steady-state bosentan plasma concentrations and AUCs were similar at oral doses of 2 and 4 mg/kg(AUCτ: 3,577 ng·h/mL and 3,371 ng·h/mL for 2 mg/kg twice daily and 4 mg/kg twice daily, respectively). $0$0$0In study AC-052-373 [FUTURE 3], using dispersible tablets, the exposure to bosentan in the patients treated with 2 mg/kg twice daily was comparable to that in the FUTURE 1 study. In the overall population (n = 31), 2 mg/kg twice daily resulted in a daily exposure of 8,535 ng·h/mL; AUCτwas 4,268 ng·h/mL (CV: 61%). In patients between 3 months and 2 years, the daily exposure was 7,879 ng·h/mL; AUCτwas 3,939 ng·h/mL (CV: 72%). In patients between 3 months and 1 year (n=2), AUCτwas 5,914 ng·h/mL (CV: 85%) and in patients between 1 and 2 years (n=7), AUCτwas 3,507 ng·h/mL (CV: 70%). In the patients above 2 years (n = 22) the daily exposure was 8,820 ng·h/mL; AUCτwas 4,410 ng·h/mL (CV: 58%). Dosing bosentan 2 mg/kg three times daily did not increase exposure, daily exposure was 7,275 ng·h/mL (CV: 83%, n = 27).$0$0$0$0$0$0Based on the findings in studies BREATHE-3, FUTURE 1, and FUTURE 1-3, it appears that the exposure to bosentan reaches a plateau at lower doses in paediatric patients than in adults, and that doses higher than 2 mg/kg twice daily (4 mg/kg twice daily or 2 mg/kg three times daily) will not result in greater exposure to bosentan in paediatric patients.$0$0In study AC-052-391 [FUTURE 4] conducted in neonates, bosentan concentrations increased slowly and continuously over the first dosing interval, resulting in low exposure (AUC0-12 in whole blood: 164 ng·h/mL, n = 11). At steady-state, AUCτ was 6,165 ng·h/mL (CV: 133%, n = 7), which is similar to the exposure observed in adult PAH patients receiving 125 mg twice daily and taking into account ablood/plasma distribution ratio of 0.6.$0$0$0Development of testicular tubular atrophy and impaired fertility has been linked with chronic administration of endothelin receptor antagonists in rodents.$0$0$0$0$0In 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, at exposures that were 21 and 43 times the expected therapeutic level in humans, respectively; nor was there any adverse effect on the development of the pre-implantation embryo or on implantation.$0$0$0$0$0$0Slightly increased incidence of testicular tubular atrophy was observed in rats given bosentan orally at doses as low as 125 mg/kg/day (about 4 times the maximum recommended human dose [MRHD] and the lowest doses tested) for two years but not at doses as high as 1500 mg/kg/day (about 50 times the MRHD) for 6 months. In a juvenile rat toxicity study, where rats were treated from Day 4 post partum up to adulthood, decreased absolute weights of testes and epididymides, and reduced number of sperm in epididymides were observed after weaning. The NOAEL was 21 times (at Day 21 post partum) and 2.3 times (Day 69 post partum) the human therapeutic exposure, respectively.$0$0However, no effects on general development, growth, sensory, cognitive function and reproductive performance were detected at 7 (males) and 19 (females) times the human therapeutic exposure at Day 21 post partum. At adult age (Day 69 post partum) no effects of bosentan were detected at 1.3 (males) and 2.6 (females) times the therapeutic exposure in children with PAH.

Updated on 28 April 2015

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data

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Paediatric population$0$0In children, the optimal maintenance dose has not been defined in well-controlled studies. However, paediatric Paediatric pharmacokinetic data have shown that bosentan plasma concentrations in childrenwith PAH aged from 1 year to 15 years were on average lower than in adult patients and were not increased by increasing the dose of Tracleer above 2 mg/kg body weight or by increasing the dosing frequency from twice daily to three times daily (see section 5.2). Increasing the dose or the dosing frequency will likely not result in additional clinical benefit.$0$0Based on these pharmacokinetic results, higher doses are unlikely to be more effective, and greater adverse reaction rates cannot formally be excluded in young children if the dose is increased. Whenwhen used in children with PAH 21 years and older, the recommended starting and maintenance dose is therefore 2 mg/kg morning and evening. No clinical study has been conducted to compare the efficacy/safety ratio of 2mg/kg to 4 mg/kg body weight twice daily in children.$0$0There is only limited clinical experience in paediatric patients under 2 years of age.$0$0In neonates with persistent pulmonary hypertension of the newborn (PPHN), the benefit of bosentan has not been shown in the standard-of-care treatment. No recommendation on a posology can be made (see sections 5.1 and 5.2).$0$0$0$0$0$0$0Paediatric population$0$0Interaction studies have only been performed in adults.$0$0$0$0$0$0$0Fertility$0$0Fertility studies in rats showed no effects on sperm parameters or fertility (see section 5.3).$0$0Animal studies showed testicular effects (see section 5.3). In a study investigating the effects of bosentan on testicular function in male PAH patients, 8 out of 24 patients showed a decreased sperm concentration from baseline of at least 42% after 3 or 6 months of treatment with bosentan. Based on these findings and preclinical data, it cannot be excluded that bosentan may have a detrimental effect on spermatogenesis in men. In male children, a long-term impact on fertility after treatment with bosentan cannot be excluded.$0$0$0$0$0$0$0Paediatric population$0$0Uncontrolled studies in paediatric patients with PAH (AC-052-356 [BREATHE-3]; AC-052-365 [FUTURE 1])$0$0Uncontrolled clinical studies in paediatric patients:$0$0The safety profile in this population the first paediatric uncontrolled study performed with the film-coated tablet (BREATHE-3: n = 19, median age 10 years [range 3–15 years], open-label bosentan 2mg/kg twice daily; treatment duration 12 weeks; FUTURE 1: n = 36, bosentan 2 mg/kg twice daily for 4 weeks followed by 4 mg/kg twice daily; treatment duration 12 weeks) was similar to that observed in the pivotal trials in adult patients with PAH. In BREATHE-3, the most frequent adverse reactions were flushing (21%), headache, and abnormal liver function test (each 16%). In FUTURE 1, the most frequent adverse reactions were infections (33%) and abdominal pain/discomfort (19%). There were no cases of liver enzyme elevations in the FUTURE 1 study.$0$0A pooled analysis of uncontrolled paediatric studies conducted in PAH with the bosentan 32 mg dispersible tablet formulation (FUTURE 1/2, FUTURE 3/Extension) included a total of 100 children treated with bosentan 2 mg/kg twice daily (n = 33), 2 mg/kg three times daily (n = 31), or 4 mg/kg twice daily (n = 36). At enrolment, six patients were between 3 months and 1 year old, 15 children were between 1 and less than 2 years old, and 79 were between 2 and 12 years old. The median treatment duration was 71.8 weeks (range 0.4–258 weeks).$0$0The safety profile in this pooled analysis of uncontrolled paediatric studies was similar to that observed in the pivotal trials in adult patients with PAH except for infections, which were more frequently reported than in adults (69.0% vs 41.3%).This difference in infection frequency may in part be due to the longer median treatment exposure in the paediatric set (median 71.8 weeks) compared to the adult set (median 17.4 weeks). The most frequent adverse events were upper respiratory tract infections (25%), pulmonary (arterial) hypertension (20%), nasopharyngitis (17%), pyrexia (15%), vomiting (13%), bronchitis (10%), abdominal pain (10%), and diarrhoea (10%). There was no relevant difference in adverse event frequencies between patients above and below the age of 2 years, however this is based on only 21 children less than 2 years, including 6 patients between 3 months to 1 year of age. Adverse events of liver abnormalities and anaemia/haemoglobin decrease occurred in 9% and 5% of patients, respectively.$0$0In a randomised placebo-controlled study, conducted in PPHN patients (FUTURE-4), a total of 13 neonates were treated with the bosentan dispersible tablet formulation at a dose of 2 mg/kg twice daily (8 patients were on placebo). The median bosentan and placebo treatment duration was, respectively, 4.5 days (range 0.5–10.0 days) and 4.0 days (range 2.5-6.5 days). The most frequent adverse events in the bosentan- and the placebo-treated patients were, respectively, anaemia or haemoglobin decrease (7 and 2 patients), generalised oedema (3 and 0 patients), and vomiting (2 and 0 patients).$0$0Laboratory abnormalities$0$0$0$0In the pooled analysis of 100 PAH patients from uncontrolled paediatric studies FUTURE 1/2 and FUTURE 3/Extension, elevations in liver aminotransferases ≥ 3 × ULN were observed in 2% of patients.$0$0In the FUTURE-4 study including 13 neonates with PPHN treated with bosentan 2 mg/kg twice daily for less than 10 days (range 0.5–10.0 days) there were no cases of liver aminotransferases ≥ 3 × ULN during treatment, but one case of hepatitis occurred 3 days after the end of bosentan treatment.$0$0Haemoglobin$0$0A In the adult placebo-controlled studies, a decrease in haemoglobin concentration to below 10 g/dL from baseline was reported in 8.0% of bosentan-treated patients and 3.9% of placebo-treated patients (see section 4.4).$0$0$0$0$0$0$0In the pooled analysis of 100 PAH children from uncontrolled paediatric studies FUTURE 1/2 and FUTURE 3/Extension, a decrease in haemoglobin concentration from baseline to below 10 g/dL was reported in 10.0% of patients. There was no decrease to below 8 g/dL.$0$0In the FUTURE-4 study, 6 out of 13 bosentan-treated neonates with PPHN experienced a decrease in haemoglobin from within the reference range at baseline to below the lower limit of normal during the treatment.$0$0$0$0$0$0Efficacy$0$0$0$0$0$0Studiesy performed in children with pulmonary arterial hypertension$0$0One study has been conducted in children with pulmonary hypertension.$0$0BREATHE-3 (AC-052-356)$0$0Bosentan film-coated tablets were evaluated in an open-label non-controlled uncontrolled study in 19 paediatric patients with pulmonary arterial hypertension aged (AC-052-356 [BREATHE-3]:aged 3-–to 15 years. This study was primarily designed as a pharmacokinetic study (see section 5.2). Patients had primary pulmonary hypertension, (10 patients) , andor pulmonary arterial hypertension related to congenital heart diseases, (9 patients). This study was primarily designed as a pharmacokinetic study (see section 5.2) and were in WHO functional class II (n = 15 patients, 79%) or class III (n = 4 patients, 21%) at baseline. Patients were divided into and dosed according to three body-weight groups and dosed with bosentan at approximately 2 mg/kg twice daily for 12 weeks. Half of the patients in each group were already being treated with intravenous epoprostenol and the dose of epoprostenol remained constant for the duration of the study. The age range was 3–15 years. Patients were in WHO functional class II (n = 15 patients, 79%) or class III (n = 4 patients, 21%) at baseline.$0$0$0$0$0$0$0FUTURE 1/2 (AC-052-365/AC-052-367)$0$0FUTURE 1 was an open-label, uncontrolled study that was conducted with the dispersible tablet formulation of bosentan administered at a maintenance dose of 4 mg/kg twice daily to 36 patients from 2 to 11 years of age. It was primarily designed as a pharmacokinetic study (see section 5.2). At baseline, patients had idiopathic (31 patients [86%]) or familial (5 patients [14%]) PAH, and were in WHO functional class II (n = 23 patients, 64%) or class III (n = 13 patients, 36%). In the FUTURE 1 study, the median exposure to study treatment was 13.1 weeks (range: 8.4 to 21.1). 33 of these patients were provided with continued treatment with bosentan dispersible tablets at a dose of 4 mg/kg twice daily in the FUTURE 2 uncontrolled extension phase for a median overall treatment duration of 2.3 years (range: 0.2 to 5.0 years). At baseline in FUTURE 1, 9 patients were taking epoprostenol. 9 patients were newly initiated on PAH-specific medication during the study. The Kaplan-Meier event-free estimate for worsening of PAH (death, lung transplantation, or hospitalisation for PAH worsening) at 2 years was 78.9%. The Kaplan-Meier estimate of overall survival at 2 years was 91.2%.$0$0FUTURE 3 (AC-052-373)$0$0In this open-label randomised study with the bosentan 32 mg dispersible tablet formulation, 64 children with stable PAH from 3 months to 11 years of age were randomised to 24 weeks bosentan treatment 17$0$02 mg/kg twice daily (n = 33) or 2 mg/kg three times daily (n = 31). 43 (67.2%) were ≥ 2 years to 11 years old, 15 (23.4%) were between 1 and 2 years old, and 6 (9.4%) were between 3 months and 1 year old. The study was primarily designed as a pharmacokinetic study (see section 5.2) and efficacy endpoints were only exploratory. The aetiology of PAH, according to Dana Point classification, included idiopathic PAH (46%), heritable PAH (3%), associated PAH after corrective cardiac surgery (38%), and PAH-CHD associated with systemic-to-pulmonary shunts, including Eisenmenger syndrome (13%). Patients were in WHO functional class I (n = 19 patients, 29 %), class II (n = 27 patients, 42%) or class III (n = 18 patients, 28%) at start of study treatment. At study entry, patients were treated with PAH medications (most frequently PDE-5 inhibitor [sildenafil] alone [35.9%], bosentan alone [10.9%], and a combination of bosentan, iloprost, and sildenafil in 10.9% of patients) and continued their PAH treatment during the study.$0$0At study start, less than half of the patients included (45.3% = 29/64) had bosentan treatment alone not combined with other PAH-medication. 40.6% (26/64) remained on bosentan monotherapy during the 24 weeks of study treatment without experiencing PAH worsening. The analysis on the global population included (64 patients) showed that the majority had remained at least stable (i.e., without deterioration) based on non-paediatric-specific WHO functional class assessment (97% twice daily, 100% three times daily) and physicians’ global clinical impression (94% twice daily, 93% three times daily) during the treatment period. The Kaplan-Meier event-free estimate for worsening of PAH (death, lung transplantation, or hospitalisation for PAH worsening) at 24 weeks was 96.9% and 96.7% in the twice daily and three times daily groups, respectively.$0$0There was no evidence of any clinical benefit with 2 mg/kg three times daily as compared to 2 mg/kg twice daily dosing.$0$0$0$0Study performed in neonates with persistent pulmonary hypertension of the newborn (PPHN):$0$0FUTURE 4 (AC-052-391)$0$0This was a double-blind, placebo-controlled, randomised study in pre-term or term neonates (gestational age 36–42 weeks) with PPHN. Patients with suboptimal response to inhaled nitric oxide (iNO) despite at least 4 hours of continuous treatment were treated with bosentan dispersible tablets at 2 mg/kg twice daily (N = 13) or placebo (N = 8) via nasogastric tube as add-on therapy on top of iNO until complete weaning of iNO or until treatment failure (defined as need for extra-corporeal membrane oxygenation [ECMO] or initiation of alternative pulmonary vasodilator) and for a maximum of 14 days.$0$0The median exposure to study treatment was 4.5 (range: 0.5–10.0) days in the bosentan group and 4.0 (range: 2.5–6.5) days in the placebo group.$0$0The results did not indicate an additional benefit of bosentan in this population:$0$0• The median time to complete weaning from iNO was 3.7 days (95% CLs 1.17, 6.95) on bosentan and 2.9 days (95% CLs 1.26, 4.23) on placebo (p = 0.34).$0$0• The median time to complete weaning from mechanical ventilation was 10.8 days (95% CLs 3.21, 12.21 days) on bosentan and 8.6 days (95% CLs 3.71, 9.66 days) on placebo (p = 0.24).$0$0• One patient in the bosentan group had treatment failure (need for ECMO as per protocol definition), which was declared based on increasing Oxigenation Index values within 8 h after the first study drug dose. This patient recovered within the 60-day follow-up period. AC-052-356 was an open-label, non- uncontrolled study;$0$0$0$0$0$0$0Pharmacokinetics in special populations$0$0Based on the investigated range of each variable, it is not expected that the pharmacokinetics of bosentan will be influenced by gender, body weight, race, or age in the adult population to any relevant extent. No pharmacokinetic data are available in children under 2 years.$0$0Children$0$0Pharmacokinetics were studied in paediatric patients in 4 clinical studies (BREATHE-3, FUTURE 1, FUTURE-3 and FUTURE-4 see section 5.1). Due to limited data in children below 2 years of age, pharmacokinetics remain not well characterised in this age category.$0$0TheStudy AC-052-356 [BREATHE-3]) evaluated the pharmacokinetics of single and multiple oral doses of the film-coated tablet formulation of bosentan were studied in paediatric patients 19 children aged from 3 to 15 years with pulmonary arterial hypertension (PAH) who were dosed on the basis of body weight (see section 5.1, AC-052-356 [BREATHE-3]). Thewith 2 mg/kg twice daily. In this study, the exposure to bosentan decreased with time in a manner consistent with the known auto-induction properties of bosentan. The mean AUC (CV%) values of bosentan in paediatric patients treated with 31.25, 62.5 or 125 mg twice daily were 3,496 (49), 5,428 (79), and 6,124 (27) ng·h/mL, respectively, and were lower than the value of 8,149 (47) ng·h/mL observed in adult patients with pulmonary arterial hypertension PAH receiving 125 mg twice daily. At steady state, the systemic exposures in paediatric patients weighing 10–20 kg, 20–40 kg and > 40 kg were 43%, 67% and 75%, respectively, of the adult systemic exposure.$0$0In a second pharmacokinetic study (study AC-052-365 [FUTURE 1]), dispersible tablets were administered in 36 paediatric patients PAH children aged from 2– to 11 years. with PAH were treated at 2 and 4 mg/kg twice daily with the dispersible tablet. No dose proportionality was observed . Steady-as steady-state bosentan plasma concentrations and AUCs were similar at oral doses of 2 and 4 mg/kg(AUCτ: 3,577 ng·h/mL and 3,371 ng·h/mL for 2 mg/kg twice daily and 4 mg/kg twice daily, respectively). $0$0$0In study AC-052-373 [FUTURE 3], using dispersible tablets, the exposure to bosentan in the patients treated with 2 mg/kg twice daily was comparable to that in the FUTURE 1 study. In the overall population (n = 31), 2 mg/kg twice daily resulted in a daily exposure of 8,535 ng·h/mL; AUCτwas 4,268 ng·h/mL (CV: 61%). In patients between 3 months and 2 years, the daily exposure was 7,879 ng·h/mL; AUCτwas 3,939 ng·h/mL (CV: 72%). In patients between 3 months and 1 year (n=2), AUCτwas 5,914 ng·h/mL (CV: 85%) and in patients between 1 and 2 years (n=7), AUCτwas 3,507 ng·h/mL (CV: 70%). In the patients above 2 years (n = 22) the daily exposure was 8,820 ng·h/mL; AUCτwas 4,410 ng·h/mL (CV: 58%). Dosing bosentan 2 mg/kg three times daily did not increase exposure, daily exposure was 7,275 ng·h/mL (CV: 83%, n = 27).$0$0$0$0$0$0Based on the findings in studies BREATHE-3, FUTURE 1, and FUTURE 1-3, it appears that the exposure to bosentan reaches a plateau at lower doses in paediatric patients than in adults, and that doses higher than 2 mg/kg twice daily (4 mg/kg twice daily or 2 mg/kg three times daily) will not result in greater exposure to bosentan in paediatric patients.$0$0In study AC-052-391 [FUTURE 4] conducted in neonates, bosentan concentrations increased slowly and continuously over the first dosing interval, resulting in low exposure (AUC0-12 in whole blood: 164 ng·h/mL, n = 11). At steady-state, AUCτ was 6,165 ng·h/mL (CV: 133%, n = 7), which is similar to the exposure observed in adult PAH patients receiving 125 mg twice daily and taking into account ablood/plasma distribution ratio of 0.6.$0$0$0Development of testicular tubular atrophy and impaired fertility has been linked with chronic administration of endothelin receptor antagonists in rodents.$0$0$0$0$0In 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, at exposures that were 21 and 43 times the expected therapeutic level in humans, respectively; nor was there any adverse effect on the development of the pre-implantation embryo or on implantation.$0$0$0$0$0$0Slightly increased incidence of testicular tubular atrophy was observed in rats given bosentan orally at doses as low as 125 mg/kg/day (about 4 times the maximum recommended human dose [MRHD] and the lowest doses tested) for two years but not at doses as high as 1500 mg/kg/day (about 50 times the MRHD) for 6 months. In a juvenile rat toxicity study, where rats were treated from Day 4 post partum up to adulthood, decreased absolute weights of testes and epididymides, and reduced number of sperm in epididymides were observed after weaning. The NOAEL was 21 times (at Day 21 post partum) and 2.3 times (Day 69 post partum) the human therapeutic exposure, respectively.$0$0However, no effects on general development, growth, sensory, cognitive function and reproductive performance were detected at 7 (males) and 19 (females) times the human therapeutic exposure at Day 21 post partum. At adult age (Day 69 post partum) no effects of bosentan were detected at 1.3 (males) and 2.6 (females) times the therapeutic exposure in children with PAH.

Updated on 25 June 2014

Reasons for updating

  • Change to Section 4.8 – Undesirable effects - how to report a side effect

Legal category:Product subject to medical prescription which may not be renewed (A)

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$0Reportingof suspected adverse reactions$0$0Reportingsuspected adverse reactions after authorisation of the medicinal product isimportant. It allows continued monitoring of the benefit/risk balance of themedicinal product. Healthcare professionals are asked to report any suspectedadverse reactions via thenational reporting system listed below.$0$0 $0$0United Kingdom$0$0Yellow Card Scheme$0$0Website: www.mhra.gov.uk/yellowcard$0$0 $0$0Ireland$0$0Pharmacovigilance Section $0$0Irish Medicines Board $0$0Kevin O’Malley House $0$0Earlsfort Centre $0$0Earlsfort Terrace $0$0IRL - Dublin2$0$0Tel: +353 1 6764971$0$0Fax: +353 1 6762517$0$0Website: www.imb.ie$0$0e-mail: imbpharmacovigilance@imb.ie$0$0 $0$0Malta$0$0ADR Reporting$0$0The Medicines Authority $0$0Post-Licensing Directorate$0$0203 Level 3, Rue D'Argens$0$0GŻR-1368 Gżira$0$0Website: www.medicinesauthority.gov.mt$0$0e-mail: postlicensing.medicinesauthority@gov.mt$0

Updated on 25 June 2014

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  • Change to Section 4.8 – Undesirable effects - how to report a side effect

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$0Reportingof suspected adverse reactions$0$0Reportingsuspected adverse reactions after authorisation of the medicinal product isimportant. It allows continued monitoring of the benefit/risk balance of themedicinal product. Healthcare professionals are asked to report any suspectedadverse reactions via thenational reporting system listed below.$0$0 $0$0United Kingdom$0$0Yellow Card Scheme$0$0Website: www.mhra.gov.uk/yellowcard$0$0 $0$0Ireland$0$0Pharmacovigilance Section $0$0Irish Medicines Board $0$0Kevin O’Malley House $0$0Earlsfort Centre $0$0Earlsfort Terrace $0$0IRL - Dublin2$0$0Tel: +353 1 6764971$0$0Fax: +353 1 6762517$0$0Website: www.imb.ie$0$0e-mail: imbpharmacovigilance@imb.ie$0$0 $0$0Malta$0$0ADR Reporting$0$0The Medicines Authority $0$0Post-Licensing Directorate$0$0203 Level 3, Rue D'Argens$0$0GŻR-1368 Gżira$0$0Website: www.medicinesauthority.gov.mt$0$0e-mail: postlicensing.medicinesauthority@gov.mt$0

Updated on 08 February 2013

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  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

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Change of address of MAH from BSI Building, to Chiswick Tower

Updated on 08 February 2013

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  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

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Change of address of MAH from BSI Building, to Chiswick Tower

Updated on 11 May 2012

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  • Change to section 10 - Date of revision of the text

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Change to date of revision of text

Updated on 11 May 2012

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  • Change to section 10 - Date of revision of the text

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Change to date of revision of text

Updated on 12 January 2012

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  • Change to section 5.1 - Pharmacodynamic properties

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Section 5.1 (pharmacodynamic properties) has been updated to include EARLY and BREATHE-5 open-label extension data

Updated on 12 January 2012

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  • Change to section 5.1 - Pharmacodynamic properties

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Section 5.1 (pharmacodynamic properties) has been updated to include EARLY and BREATHE-5 open-label extension data

Updated on 15 March 2011

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  • Change to section 4.8 - Undesirable effects

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Section 4.8 had been updated to comply with the current SmPC guideline

Updated on 15 March 2011

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  • Change to section 4.8 - Undesirable effects

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Section 4.8 had been updated to comply with the current SmPC guideline

Updated on 12 May 2010

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  • Change to section 4.4 - Special warnings and precautions for use

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Safety and tolerability of bosentan in an exploratory, uncontrolled 12-week study in 11 patients with pulmonary hypertension secondary to severe COPD are included as new information

Updated on 12 May 2010

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  • Change to section 4.4 - Special warnings and precautions for use

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Safety and tolerability of bosentan in an exploratory, uncontrolled 12-week study in 11 patients with pulmonary hypertension secondary to severe COPD are included as new information

Updated on 04 February 2010

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  • Change to section 4.8 - Undesirable effects

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Rare undesirable events of neutropenia and leukopenia added

Updated on 04 February 2010

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  • Change to section 4.8 - Undesirable effects

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Rare undesirable events of neutropenia and leukopenia added

Updated on 03 August 2009

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  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

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The updated sections of the SmPC are:

4.4,

 

Pulmonary arterial hypertension associated with HIV infection

 

There is limited clinical study experience with the use of Tracleer in patients with PAH associated with HIV infection, treated with antiretroviral medicinal products (see section 5.1). An interaction study between bosentan and lopinavir+ritonavir in healthy subjects showed increased plasma concentrations of bosentan with the maximum level during the first 4 days of treatment (see section 4.5). When treatment with Tracleer is initiated in patients who require ritonavir-boosted protease inhibitors, the patient's tolerability of Tracleer should be closely monitored with special attention, at the beginning of the initiation phase, to the risk of hypotension and to liver function tests An increased long-term risk of hepatic toxicity and haematological adverse events cannot be excluded when bosentan is used in combination with antiretroviral medicinal products. Due to the potential for interactions related to the inducing effect of bosentan on CYP450 (see section 4.5), which could affect the efficacy of antiretroviral therapy, these patients should also be monitored carefully regarding their HIV infection.;

 

4.5,

 

Interaction with other medicinal products and other forms of interaction

 

Cyclosporine A, : co-administration of Tracleer and cyclosporine A (a calcineurin inhibitor) is contraindicated (see section 4.3). Indeed, when co-administered, initial trough concentrations of bosentan were approximately 30-fold higher than those measured after bosentan alone. At steady state, bosentan plasma concentrations were 3- to 4-fold higher than with bosentan alone. The mechanism of this interaction is

co-administration of Tracleer and cyclosporine A (a calcineurin inhibitor) is contraindicated (see section 4.3). Indeed, when co-administered, initial trough concentrations of bosentan were approximately 30-fold higher than those measured after bosentan alone. At steady state, bosentan plasma concentrations were 3- to 4-fold higher than with bosentan alone. The mechanism of this interaction is

 

 

most likely inhibition of transport protein-mediated uptake of bosentan into hepatocytes by cyclosporine.. The blood concentrations of cyclosporine A (a CYP3A4 substrate) decreased by approximately 50%. This is most likely due to induction of CYP3A4 by bosentan.

 

Antiretroviral agents,

Lopinavir+Ritonavir (and other boosted protease inhibitors): Co-administration of Tracleer 125 mg twice daily and lopinavir+ritonavir 400+100mg twice daily during 9.5 days in healthy volunteers, resulted in initial trough plasma concentrations of bosentan that were approximately 48-fold higher than those measured after Tracleer administered alone. On day 9, plasma concentrations of bosentan were approximately 5-fold higher than with Tracleer administered alone. Inhibition by ritonavir of transport protein mediated uptake into hepatocytes and of CYP3A4, thereby reducing the clearance of bosentan, most likely causes this interaction. When administered concomitantly with lopinavir+ritonavir or other ritonavir-boosted protease inhibitors, the patient’s tolerability of Tracleer should be monitored.

Co-administration of Tracleer 125 mg twice daily and lopinavir+ritonavir 400+100mg twice daily during 9.5 days in healthy volunteers, resulted in initial trough plasma concentrations of bosentan that were approximately 48-fold higher than those measured after Tracleer administered alone. On day 9, plasma concentrations of bosentan were approximately 5-fold higher than with Tracleer administered alone. Inhibition by ritonavir of transport protein mediated uptake into hepatocytes and of CYP3A4, thereby reducing the clearance of bosentan, most likely causes this interaction. When administered concomitantly with lopinavir+ritonavir or other ritonavir-boosted protease inhibitors, the patient’s tolerability of Tracleer should be monitored.

After co-administration of Tracleer for 9.5 days, the plasma exposures to lopinavir and ritonavir decreased to a clinically non significant extent (by approximately 14% and 17%, respectively). However, full induction by bosentan might not have been reached and further decrease of protease inhibitors cannot be excluded. Appropriate monitoring of the HIV therapy is recommended. Similar effects would be expected with other ritonavir-boosted protease inhibitors (see section 4.4.).

 

Other antiretroviral agents:

No specific recommendation can be made with regard to other available antiretroviral agents due to the lack of data. It is emphasized that due to a marked hepatotoxicity of nevirapine that could cumulate with bosentan liver toxicity, this combination is not recommended.

 

5.1.

 

Pharmacodynamic properties

 

 

An open label, non-comparative study (AC-052-362; BREATHE-4) was performed in 16 patients with WHO Class III PAH associated with HIV infection. Patients were treated with Tracleer 62.5 mg bid for 4 weeks followed by 125 mg bid for a further 12 weeks. After 16 weeks treatment, there were significant improvements from baseline in exercise capacity: mean increase in 6-minute walk test: +91.4 meters from 332.6 meters on average at baseline (p < 0.001). No formal conclusion can be drawn regarding the effects of bosentan on antiretroviral drug efficacy (see also Section 4.4).

Updated on 03 August 2009

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Free text change information supplied by the pharmaceutical company



The updated sections of the SmPC are:

4.4,

 

Pulmonary arterial hypertension associated with HIV infection

 

There is limited clinical study experience with the use of Tracleer in patients with PAH associated with HIV infection, treated with antiretroviral medicinal products (see section 5.1). An interaction study between bosentan and lopinavir+ritonavir in healthy subjects showed increased plasma concentrations of bosentan with the maximum level during the first 4 days of treatment (see section 4.5). When treatment with Tracleer is initiated in patients who require ritonavir-boosted protease inhibitors, the patient's tolerability of Tracleer should be closely monitored with special attention, at the beginning of the initiation phase, to the risk of hypotension and to liver function tests An increased long-term risk of hepatic toxicity and haematological adverse events cannot be excluded when bosentan is used in combination with antiretroviral medicinal products. Due to the potential for interactions related to the inducing effect of bosentan on CYP450 (see section 4.5), which could affect the efficacy of antiretroviral therapy, these patients should also be monitored carefully regarding their HIV infection.;

 

4.5,

 

Interaction with other medicinal products and other forms of interaction

 

Cyclosporine A, : co-administration of Tracleer and cyclosporine A (a calcineurin inhibitor) is contraindicated (see section 4.3). Indeed, when co-administered, initial trough concentrations of bosentan were approximately 30-fold higher than those measured after bosentan alone. At steady state, bosentan plasma concentrations were 3- to 4-fold higher than with bosentan alone. The mechanism of this interaction is

co-administration of Tracleer and cyclosporine A (a calcineurin inhibitor) is contraindicated (see section 4.3). Indeed, when co-administered, initial trough concentrations of bosentan were approximately 30-fold higher than those measured after bosentan alone. At steady state, bosentan plasma concentrations were 3- to 4-fold higher than with bosentan alone. The mechanism of this interaction is

 

 

most likely inhibition of transport protein-mediated uptake of bosentan into hepatocytes by cyclosporine.. The blood concentrations of cyclosporine A (a CYP3A4 substrate) decreased by approximately 50%. This is most likely due to induction of CYP3A4 by bosentan.

 

Antiretroviral agents,

Lopinavir+Ritonavir (and other boosted protease inhibitors): Co-administration of Tracleer 125 mg twice daily and lopinavir+ritonavir 400+100mg twice daily during 9.5 days in healthy volunteers, resulted in initial trough plasma concentrations of bosentan that were approximately 48-fold higher than those measured after Tracleer administered alone. On day 9, plasma concentrations of bosentan were approximately 5-fold higher than with Tracleer administered alone. Inhibition by ritonavir of transport protein mediated uptake into hepatocytes and of CYP3A4, thereby reducing the clearance of bosentan, most likely causes this interaction. When administered concomitantly with lopinavir+ritonavir or other ritonavir-boosted protease inhibitors, the patient’s tolerability of Tracleer should be monitored.

Co-administration of Tracleer 125 mg twice daily and lopinavir+ritonavir 400+100mg twice daily during 9.5 days in healthy volunteers, resulted in initial trough plasma concentrations of bosentan that were approximately 48-fold higher than those measured after Tracleer administered alone. On day 9, plasma concentrations of bosentan were approximately 5-fold higher than with Tracleer administered alone. Inhibition by ritonavir of transport protein mediated uptake into hepatocytes and of CYP3A4, thereby reducing the clearance of bosentan, most likely causes this interaction. When administered concomitantly with lopinavir+ritonavir or other ritonavir-boosted protease inhibitors, the patient’s tolerability of Tracleer should be monitored.

After co-administration of Tracleer for 9.5 days, the plasma exposures to lopinavir and ritonavir decreased to a clinically non significant extent (by approximately 14% and 17%, respectively). However, full induction by bosentan might not have been reached and further decrease of protease inhibitors cannot be excluded. Appropriate monitoring of the HIV therapy is recommended. Similar effects would be expected with other ritonavir-boosted protease inhibitors (see section 4.4.).

 

Other antiretroviral agents:

No specific recommendation can be made with regard to other available antiretroviral agents due to the lack of data. It is emphasized that due to a marked hepatotoxicity of nevirapine that could cumulate with bosentan liver toxicity, this combination is not recommended.

 

5.1.

 

Pharmacodynamic properties

 

 

An open label, non-comparative study (AC-052-362; BREATHE-4) was performed in 16 patients with WHO Class III PAH associated with HIV infection. Patients were treated with Tracleer 62.5 mg bid for 4 weeks followed by 125 mg bid for a further 12 weeks. After 16 weeks treatment, there were significant improvements from baseline in exercise capacity: mean increase in 6-minute walk test: +91.4 meters from 332.6 meters on average at baseline (p < 0.001). No formal conclusion can be drawn regarding the effects of bosentan on antiretroviral drug efficacy (see also Section 4.4).

Updated on 19 August 2008

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

The European licence for bosentan has been extended from PAH WHO FC III to also include FC II.  This has led to a change in Secton 4.1 Therapeutic indications 'Some improvements have also been shown in patients with PAH WHO functional class II (see section 5.1)."

 As a consequence, sections 4.4, 4.8 and 5.1 of SmPC have been updated. Additionally, AnnexII has been amended using the standard text to reflect the latest version of RMP as agreed by the CHMP.

Updated on 19 August 2008

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

Free text change information supplied by the pharmaceutical company

 

The European licence for bosentan has been extended from PAH WHO FC III to also include FC II.  This has led to a change in Secton 4.1 Therapeutic indications 'Some improvements have also been shown in patients with PAH WHO functional class II (see section 5.1)."

 As a consequence, sections 4.4, 4.8 and 5.1 of SmPC have been updated. Additionally, AnnexII has been amended using the standard text to reflect the latest version of RMP as agreed by the CHMP.

Updated on 14 May 2008

Reasons for updating

  • New SPC for medicines.ie

Legal category:Product subject to medical prescription which may not be renewed (A)

Updated on 14 May 2008

Reasons for updating

  • New SPC for medicines.ie

Janssen Sciences Ireland (a Johnson & Johnson Company)

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