Tracleer

HOS-093292 · has-adverse-reaction-information · PDF-Seite 34

In 20 placebo-controlled studies, conducted in a variety of therapeutic indications, a total of 2 486 patients were treated with bosentan at daily doses ranging from 100 mg to 2 000 mg and 1 838 patients were treated with placebo. The mean treatment duration was 45 weeks. Adverse reactions were defined as events occurring in at least 1% of patients on bosentan and at a frequency at least 0.5% more than on placebo. The most frequent adverse reactions are headache (11.5%), oedema / fluid retention (13.2%), abnormal liver function test (10.9%) and anaemia / haemoglobin decrease (9.9%). Treatment with bosentan has been associated with dose-dependent elevations in liver aminotransferases and decreases in haemoglobin concentration (see section 4.4). Adverse reactions observed in 20 placebo-controlled studies and post-marketing experience with bosentan are ranked according to frequency using the following convention: very common ( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1 000 to < 1/100); rare ( 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. No clinically relevant differences in adverse reactions were observed between the overall dataset and the approved indications. System organ class Frequency Adverse reaction Blood and lymphatic system Common Anaemia, haemoglobin decrease, disorders (see section 4.4) Not known Anaemia or haemoglobin decreases requiring red blood cell transfusion1 Uncommon Thrombocytopenia1 Uncommon Neutropenia, leukopenia1 Immune system disorders Common Hypersensitivity reactions (including dermatitis, pruritus and rash)2 Rare Anaphylaxis and/or angioedema1 Nervous system disorders

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HOS-093286 · has-adverse-reaction-information · PDF-Seite 11

In 20 placebo-controlled studies, conducted in a variety of therapeutic indications, a total of 2 486 patients were treated with bosentan at daily doses ranging from 100 mg to 2 000 mg and 1 838 patients were treated with placebo. The mean treatment duration was 45 weeks. Adverse reactions were defined as events occurring in at least 1% of patients on bosentan and at a frequency at least 0.5% more than on placebo. The most frequent adverse reactions are headache (11.5%), oedema / fluid retention (13.2%), abnormal liver function test (10.9%) and anaemia / haemoglobin decrease (9.9%). Treatment with bosentan has been associated with dose-dependent elevations in liver aminotransferases and decreases in haemoglobin concentration (see section 4.4). Adverse reactions observed in 20 placebo-controlled studies and post-marketing experience with bosentan are ranked according to frequency using the following convention: very common ( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1 000 to < 1/100); rare ( 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. No clinically relevant differences in adverse reactions were observed between the overall dataset and the approved indications. System organ class Frequency Adverse reaction Blood and lymphatic system Common Anaemia, haemoglobin decrease, disorders (see section 4.4) Not known Anaemia or haemoglobin decreases requiring red blood cell transfusion1 Uncommon Thrombocytopenia1 Uncommon Neutropenia, leukopenia1 Immune system disorders Common Hypersensitivity reactions (including dermatitis, pruritus and rash)2 Rare Anaphylaxis and/or angioedema1 Nervous system disorders

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HOS-093288 · has-contraindication-information · PDF-Seite 27

 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1  Moderate to severe hepatic impairment, i.e., Child-Pugh class B or C (see section 5.2) 27  Baseline values of liver aminotransferases, i.e., aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), greater than 3  the upper limit of normal (ULN; see section 4.4)  Concomitant use of cyclosporine A (see section 4.5)  Pregnancy (see sections 4.4 and 4.6)  Women of childbearing potential who are not using reliable methods of contraception (see sections 4.4, 4.5 and 4.6)

HOS-093282 · has-contraindication-information · PDF-Seite 4

 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1  Moderate to severe hepatic impairment, i.e., Child-Pugh class B or C (see section 5.2) 4  Baseline values of liver aminotransferases, i.e., aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), greater than 3  the upper limit of normal (ULN; see section 4.4)  Concomitant use of cyclosporine A (see section 4.5)  Pregnancy (see sections 4.4 and 4.6)  Women of childbearing potential who are not using reliable methods of contraception (see sections 4.4, 4.5 and 4.6)

HOS-093281 · has-indication-information · PDF-Seite 2

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). Tracleer is also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease (see section 5.1). 2

HOS-093287 · has-indication-information · PDF-Seite 25

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). Tracleer is also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease (see section 5.1).

HOS-093290 · has-interaction-information · PDF-Seite 31

Bosentan is an inducer of the cytochrome P450 (CYP) isoenzymes CYP2C9 and CYP3A4. In vitro data also suggest an induction of CYP2C19. Consequently, plasma concentrations of substances metabolised by these isoenzymes will be decreased when Tracleer is co-administered. The possibility of altered efficacy of medicinal products metabolised by these isoenzymes should be considered. The dosage of these products may need to be adjusted after initiation, dose change or discontinuation of concomitant Tracleer treatment. Bosentan is metabolised by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of bosentan (see ketoconazole). The influence of CYP2C9 inhibitors on bosentan concentration has not been studied. The combination should be used with caution. Fluconazole and other inhibitors of both CYP2C9 and CYP3A4: Co-administration with fluconazole, which inhibits mainly CYP2C9, but to some extent also CYP3A4, could lead to large increases in plasma concentrations of bosentan. The combination is not recommended. For the same reason, concomitant administration of both a potent CYP3A4 inhibitor (such as ketoconazole, itraconazole or ritonavir) and a CYP2C9 inhibitor (such as voriconazole) with Tracleer is not recommended. Cyclosporine A: Co-administration of Tracleer and cyclosporine A (a calcineurin inhibitor) is contraindicated (see section 4.3). 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. Tacrolimus, sirolimus: Co-administration of tacrolimus or sirolimus and Tracleer has not been studied in man but co-administration of tacrolimus or sirolimus and Tracleer may result in increased plasma concentrations of bosentan in analogy to co-administration with cyclosporine A. Concomitant Tracleer may reduce the plasma concentrations of tacrolimus and sirolimus. Therefore, concomitant use of Tracleer and tacrolimus or sirolimus is not advisable. Patients in need of the combination should be closely monitored for adverse events related to Tracleer and fo

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HOS-093284 · has-interaction-information · PDF-Seite 7

Bosentan is an inducer of the cytochrome P450 (CYP) isoenzymes CYP2C9 and CYP3A4. In vitro data also suggest an induction of CYP2C19. Consequently, plasma concentrations of substances metabolised by these isoenzymes will be decreased when Tracleer is co-administered. The possibility 7 of altered efficacy of medicinal products metabolised by these isoenzymes should be considered. The dosage of these products may need to be adjusted after initiation, dose change or discontinuation of concomitant Tracleer treatment. Bosentan is metabolised by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of bosentan (see ketoconazole). The influence of CYP2C9 inhibitors on bosentan concentration has not been studied. The combination should be used with caution. Fluconazole and other inhibitors of both CYP2C9 and CYP3A4: Co-administration with fluconazole, which inhibits mainly CYP2C9, but to some extent also CYP3A4, could lead to large increases in plasma concentrations of bosentan. The combination is not recommended. For the same reason, concomitant administration of both a potent CYP3A4 inhibitor (such as ketoconazole, itraconazole or ritonavir) and a CYP2C9 inhibitor (such as voriconazole) with Tracleer is not recommended. Cyclosporine A: Co-administration of Tracleer and cyclosporine A (a calcineurin inhibitor) is contraindicated (see section 4.3). 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. Tacrolimus, sirolimus: Co-administration of tacrolimus or sirolimus and Tracleer has not been studied in man but co-administration of tacrolimus or sirolimus and Tracleer may result in increased plasma concentrations of bosentan in analogy to co-administration with cyclosporine A. Concomitant Tracleer may reduce the plasma concentrations of tacrolimus and sirolimus. Therefore, concomitant use of Tracleer and tacrolimus or sirolimus is not advisable. Patients in need of the combination should be closel

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HOS-093285 · has-pregnancy-information · PDF-Seite 10

Pregnancy Studies in animals have shown reproductive toxicity (teratogenicity, embryotoxicity; see section 5.3). There are no reliable data on the use of Tracleer in pregnant women. The potential risk for humans is still unknown. Tracleer is contraindicated in pregnancy (see section 4.3). Women of childbearing potential Before the initiation of Tracleer treatment in women of childbearing potential, the absence of pregnancy should be checked, appropriate advice on reliable methods of contraception provided, and reliable contraception initiated. Patients and prescribers must be aware that due to potential pharmacokinetic interactions, Tracleer may render hormonal contraceptives ineffective (see section 4.5). Therefore, women of childbearing potential must not use hormonal contraceptives (including oral, injectable, transdermal or implantable forms) as the sole method of contraception but must use an additional or an alternative reliable method of contraception. If there is any doubt about what contraceptive advice should be given to the individual patient, consultation with a gynaecologist is recommended. Because of possible hormonal contraception failure during Tracleer treatment, and also bearing in mind the risk that pulmonary hypertension severely deteriorates with pregnancy, monthly pregnancy tests during treatment with Tracleer are recommended to allow early detection of pregnancy. Breast-feeding Data from a case report describe the presence of bosentan in human milk in a low concentration. There is insufficient information about the effects of bosentan on the breastfed infant. A risk to the breastfed infant cannot be excluded. Breast-feeding is not recommended during treatment with Tracleer. Fertility Animal studies showed testicular effects (see section 5.3). In a clinical study investigating the effects of bosentan on testicular function in male PAH patients, six of the 24 subjects (25%) had a decreased sperm concentration of at least 50% from baseline at 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. 10

HOS-093291 · has-pregnancy-information · PDF-Seite 33

Pregnancy Studies in animals have shown reproductive toxicity (teratogenicity, embryotoxicity; see section 5.3). There are no reliable data on the use of Tracleer in pregnant women. The potential risk for humans is still unknown. Tracleer is contraindicated in pregnancy (see section 4.3). Women of childbearing potential Before the initiation of Tracleer treatment in women of childbearing potential, the absence of pregnancy should be checked, appropriate advice on reliable methods of contraception provided, and reliable contraception initiated. Patients and prescribers must be aware that due to potential pharmacokinetic interactions, Tracleer may render hormonal contraceptives ineffective (see section 4.5). Therefore, women of childbearing potential must not use hormonal contraceptives (including oral, injectable, transdermal or implantable forms) as the sole method of contraception but must use an additional or an alternative reliable method of contraception. If there is any doubt about what contraceptive advice should be given to the individual patient, consultation with a gynaecologist is recommended. Because of possible hormonal contraception failure during Tracleer treatment, and also bearing in mind the risk that pulmonary hypertension severely deteriorates with pregnancy, monthly pregnancy tests during treatment with Tracleer are recommended to allow early detection of pregnancy. Breast-feeding Data from a case report describe the presence of bosentan in human milk in a low concentration. There is insufficient information about the effects of bosentan on the breastfed infant. A risk to the breastfed infant cannot be excluded. Breast-feeding is not recommended during treatment with Tracleer. Fertility Animal studies showed testicular effects (see section 5.3). In a clinical study investigating the effects of bosentan on testicular function in male PAH patients, six of the 24 subjects (25%) had a decreased 33 sperm concentration of at least 50% from baseline at 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.

HOS-093283 · has-warning-information · PDF-Seite 5

The efficacy of Tracleer has not been established in patients with severe PAH. Transfer to a therapy that is recommended at the severe stage of the disease (e.g., epoprostenol) should be considered if the clinical condition deteriorates (see section 4.2). The benefit/risk balance of bosentan has not been established in patients with WHO class I functional status of PAH. Tracleer should only be initiated if the systemic systolic blood pressure is higher than 85 mmHg. Tracleer has not been shown to have a beneficial effect on the healing of existing digital ulcers. Liver function Elevations in liver aminotransferases, i.e., aspartate and alanine aminotransferases (AST and/or ALT), associated with bosentan are dose dependent. Liver enzyme changes typically occur within the first 26 weeks of treatment but may also occur late in treatment (see section 4.8). These increases may be partly due to competitive inhibition of the elimination of bile salts from hepatocytes but other mechanisms, which have not been clearly established, are probably also involved in the occurrence of liver dysfunction. The accumulation of bosentan in hepatocytes leading to cytolysis with potentially severe damage of the liver, or an immunological mechanism, are not excluded. Liver dysfunction risk may also be increased when medicinal products that are inhibitors of the bile salt export pump, e.g., rifampicin, glibenclamide and cyclosporine A (see sections 4.3 and 4.5), are co-administered with bosentan, but limited data are available. Liver aminotransferase levels must be measured prior to initiation of treatment and subsequently at monthly intervals for the duration of treatment with Tracleer. In addition, liver aminotransferase levels must be measured 2 weeks after any dose increase. Recommendations in the event of ALT/AST elevations ALT/AST levels Treatment and monitoring recommendations > 3 and  5  ULN The result should be confirmed by a second liver test; if confirmed, a decision should be made on an individual basis to continue Tracleer, possibly at a reduced dose, or to stop Tracleer administration (see section 4.2). Monitoring of aminotransferase levels should be continued at least every 2 weeks. If the aminotransferase levels return to pre-treatment values continuing or re- introducing Tracleer according to the conditions describ

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HOS-093289 · has-warning-information · PDF-Seite 28

The efficacy of Tracleer has not been established in patients with severe PAH. Transfer to a therapy that is recommended at the severe stage of the disease (e.g., epoprostenol) should be considered if the clinical condition deteriorates (see section 4.2). The benefit/risk balance of bosentan has not been established in patients with WHO class I functional status of PAH. Tracleer should only be initiated if the systemic systolic blood pressure is higher than 85 mmHg. Tracleer has not been shown to have a beneficial effect on the healing of existing digital ulcers. Liver function Elevations in liver aminotransferases, i.e., aspartate and alanine aminotransferases (AST and/or ALT), associated with bosentan are dose dependent. Liver enzyme changes typically occur within the first 26 weeks of treatment but may also occur late in treatment (see section 4.8). These increases may be partly due to competitive inhibition of the elimination of bile salts from hepatocytes but other mechanisms, which have not been clearly established, are probably also involved in the occurrence of liver dysfunction. The accumulation of bosentan in hepatocytes leading to cytolysis with potentially severe damage of the liver, or an immunological mechanism, are not excluded. Liver dysfunction risk may also be increased when medicinal products that are inhibitors of the bile salt export pump, e.g., rifampicin, glibenclamide and cyclosporine A (see sections 4.3 and 4.5), are co-administered with bosentan, but limited data are available. Liver aminotransferase levels must be measured prior to initiation of treatment and subsequently at monthly intervals for the duration of treatment with Tracleer. In addition, liver aminotransferase levels must be measured 2 weeks after any dose increase. Recommendations in the event of ALT/AST elevations ALT/AST levels Treatment and monitoring recommendations > 3 and  5  ULN The result should be confirmed by a second liver test; if confirmed, a decision should be made on an individual basis to continue Tracleer, possibly at a reduced dose, or to stop Tracleer administration (see section 4.2). Monitoring of aminotransferase levels should be continued at least every 2 weeks. If the aminotransferase levels return to pre-treatment values continuing or re- introducing Tracleer according to the conditions describ

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