Updated on 10/05/2012 and displayed until Current
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Change to section 10 date of revision of the text
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| Date of revision of text on the SPC: 20-Apr-2012 |
| Legal Category: POM |
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YES |
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| Change to date of revision of text
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Updated on 12/01/2012 and displayed until 10/05/2012
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Change to section 5.1 - Pharmacodynamic Properties
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| Date of revision of text on the SPC: 01-Dec-2011 |
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| In section 5.1 (Pharmacodynamic properties), the EARLY and BREATHE-5 open-label extension data has been included.
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Updated on 15/03/2011 and displayed until 12/01/2012
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Change to section 4.8 - Undesirable Effects
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| Date of revision of text on the SPC: 28-Feb-2011 |
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| Section 4.8 updated to comply with the current SmPC guidance
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Updated on 12/05/2010 and displayed until 15/03/2011
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Change to section 4.4 - Special warnings and precautions for Use
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| Date of revision of text on the SPC: 22-Apr-2010 |
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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
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Updated on 05/02/2010 and displayed until 12/05/2010
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Change to section 4.8 - Undesirable Effects
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| Date of revision of text on the SPC: 20-Jan-2010 |
| Legal Category: POM |
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Rare undesirable events of neutropenia and leukopenia added
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Updated on 04/08/2009 and displayed until 05/02/2010
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Change to section 4.4 - Special warnings and precautions for Use
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Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
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Change to section 5.1 - Pharmacodynamic Properties
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| Date of revision of text on the SPC: 01-Jul-2009 |
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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).
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Updated on 22/08/2008 and displayed until 04/08/2009
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Change to section 4.8 - Undesirable Effects
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Change to section 4.1 - Therapeutic indications
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Change to section 4.4 - Special warnings and precautions for Use
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Change to section 5.1 - Pharmacodynamic Properties
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| Date of revision of text on the SPC: 29-Jul-2008 |
| Legal Category: POM |
| Black Triangle (CHM):
YES |
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| 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.
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Updated on 09/01/2008 and displayed until 22/08/2008
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Change to section 4.4 - Special warnings and precautions for Use
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Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
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Change to section 4.6 - Pregnancy and Lactation
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| Date of revision of text on the SPC: 12/2007 |
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Section 4.4 (Special warnings and precautions for use): Use in women of child-bearing potential section has been updated to include
- Recommendation that, prior to bosentan initiation, the absence of pregnancy should be checked, advice on appropriate methods of contraception provided and adequate contraception initiated.
- Information that Tracleer may render hormonal contraceptives (including oral, injectable, transdermal and implantable forms) ineffective and therefore these should not be used as the sole method of contraception.
- Due to the risk of both Tracleer and PAH in pregnancy, monthly pregnancy tests are recommended to enable early detection of pregnancy.
Section 4.5 (Interaction with other medicinal products and other forms of interaction): Hormonal contraceptives section amended to reinforce that hormonal contraceptives of all types are not considered reliable methods of contraception.
Section 4.6 (Pregnancy and lactation) Update to section, including
- Removal of warning that women must not become pregnant for 3 months after stopping Tracleer.
- Recommendation that, prior to bosentan initiation, the absence of pregnancy should be checked, advice on appropriate methods of contraception provided and adequate contraception initiated.
- Addition of text explaining that due to the risk of both Tracleer and PAH in pregnancy, monthly pregnancy tests are recommended to enable early detection of pregnancy.
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Updated on 06/12/2007 and displayed until 09/01/2008
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Addition of separate SPCs covering individual presentations
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