Tracleer

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Tracleer 62.5 mg film-coated tablets 
 
Tracleer 125 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Tracleer 62.5 mg film-coated tablets 
Each film-coated tablet contains 62.5 mg bosentan (as monohydrate). 
 
Tracleer 125 mg film-coated tablets 
Each film-coated tablet contains 125 mg bosentan (as monohydrate). 
 
Excipient with known effect 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablets): 
 
Tracleer 62.5 mg film-coated tablets 
Orange-white, round, biconvex, film-coated tablets, embossed with “62,5” on one side. 
 
Tracleer 125 mg film-coated tablets 
Orange-white, oval, biconvex, film-coated tablets, embossed with “125” on one side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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). 
 



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4.2 Posology and method of administration 
 
Method of administration 
 
Tablets are to be taken orally morning and evening, with or without food. The film-coated tablets are 
to be swallowed with water. 
 
Patients should be advised not to swallow the desiccant found in the white high-density polyethylene 
bottles. 
 
Posology 
 
Pulmonary arterial hypertension 
 
Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH. 
A Patient Alert Card providing important safety information that patients need to be aware of before 
and during treatment with Tracleer is included in the pack. 
 
Adults 
In adult patients, Tracleer treatment should be initiated at a dose of 62.5 mg twice daily for 4 weeks 
and then increased to the maintenance dose of 125 mg twice daily. The same recommendations apply 
to re-introduction of Tracleer after treatment interruption (see section 4.4). 
 
Paediatric population 
Paediatric pharmacokinetic data have shown that bosentan plasma concentrations in children with 
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. 
 
Based on these pharmacokinetic results, when used in children with PAH aged 1 year and older, the 
recommended starting and maintenance dose is 2 mg/kg morning and evening. 
 
In 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). 
 
Management in the event of clinical deterioration of PAH 
 
In the event of clinical deterioration (e.g., decrease in 6-minute walk test distance by at least 10% 
compared with pre-treatment measurement) despite Tracleer treatment for at least 8 weeks (target dose 
for at least 4 weeks), alternative therapies should be considered. However, some patients who show no 
response after 8 weeks of treatment with Tracleer may respond favourably after an additional 4 to 
8 weeks of treatment. 
 
In the event of late clinical deterioration despite treatment with Tracleer (i.e., after several months of 
treatment), the treatment should be re-assessed. Some patients not responding well to 125 mg twice 
daily of Tracleer may slightly improve their exercise capacity when the dose is increased to 250 mg 
twice daily. A careful benefit/risk assessment should be made, taking into consideration that the liver 
toxicity is dose dependent (see sections 4.4 and 5.1). 
 



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Discontinuation of treatment 
 
There is limited experience with abrupt discontinuation of Tracleer in patients with PAH. No evidence 
for acute rebound has been observed. However, to avoid the possible occurrence of harmful clinical 
deterioration due to potential rebound effect, gradual dose reduction (halving the dose for 3 to 7 days) 
should be considered. Intensified monitoring is recommended during the discontinuation period. 
If the decision to withdraw Tracleer is taken, it should be done gradually while an alternative therapy 
is introduced. 
 
Systemic sclerosis with ongoing digital ulcer disease 
 
Treatment should only be initiated and monitored by a physician experienced in the treatment of 
systemic sclerosis. 
A Patient Alert Card providing important safety information that patients need to be aware of before 
and during treatment with Tracleer is included in the pack. 
 
 
Adults 
Tracleer treatment should be initiated at a dose of 62.5 mg twice daily for 4 weeks and then increased 
to the maintenance dose of 125 mg twice daily. The same recommendations apply to re-introduction of 
Tracleer after treatment interruption (see section 4.4). 
 
Controlled clinical study experience in this indication is limited to 6 months (see section 5.1). 
 
The patient’s response to treatment and need for continued therapy should be re-evaluated on a regular 
basis. A careful benefit/risk assessment should be made, taking into consideration the liver toxicity of 
bosentan (see sections 4.4 and 4.8). 
 
Paediatric population 
There are no data on the safety and efficacy in patients under the age of 18 years. Pharmacokinetic 
data are not available for Tracleer in young children with this disease. 
 
Special populations 
 
Hepatic impairment 
 
Tracleer is contraindicated in patients with moderate to severe liver dysfunction (see sections 4.3, 4.4 
and 5.2). No dose adjustment is needed in patients with mild hepatic impairment (i.e., Child-Pugh 
class A) (see section 5.2). 
 
Renal impairment 
 
No dose adjustment is required in patients with renal impairment. No dose adjustment is required in 
patients undergoing dialysis (see section 5.2). 
 
Elderly 
 
No dose adjustment is required in patients over the age of 65 years. 
 
4.3 Contraindications 
 
• 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) 



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• 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) 
 
4.4 Special warnings and precautions for use 
 
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 described below should be 
considered. 

> 5 and ≤ 8 × ULN The result should be confirmed by a second liver test; if confirmed, treatment 
should be stopped and aminotransferase levels monitored at least every 
2 weeks. If the aminotransferase levels return to pre-treatment values re-
introducing Tracleer according to the conditions described below should be 
considered. 



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> 8 × ULN Treatment must be stopped and re-introduction of Tracleer is not to be 
considered. 

 
In the event of associated clinical symptoms of liver injury, i.e., nausea, vomiting, fever, abdominal 
pain, jaundice, unusual lethargy or fatigue, flu-like syndrome (arthralgia, myalgia, fever), treatment 
must be stopped and re-introduction of Tracleer is not to be considered. 
 
 
Re-introduction of treatment 
Re-introduction of treatment with Tracleer should only be considered if the potential benefits of 
treatment with Tracleer outweigh the potential risks and when liver aminotransferase levels are within 
pre-treatment values. The advice of a hepatologist is recommended. Re-introduction must follow the 
guidelines detailed in section 4.2. Aminotransferase levels must then be checked within 3 days 
after re-introduction, then again after a further 2 weeks, and thereafter according to the 
recommendations above. 
ULN = upper limit of normal 
 
Haemoglobin concentration 
 
Treatment with bosentan has been associated with dose-related decreases in haemoglobin 
concentration (see section 4.8). In placebo-controlled studies, bosentan-related decreases in 
haemoglobin concentration were not progressive, and stabilised after the first 4–12 weeks of 
treatment. It is recommended that haemoglobin concentrations be checked prior to initiation of 
treatment, every month during the first 4 months, and quarterly thereafter. If a clinically relevant 
decrease in haemoglobin concentration occurs, further evaluation and investigation should be 
undertaken to determine the cause and need for specific treatment. In the post-marketing period, cases 
of anaemia requiring red blood cell transfusion have been reported (see section 4.8). 
 
Women of childbearing potential 
 
As Tracleer may render hormonal contraceptives ineffective, and taking into account the risk that 
pulmonary hypertension deteriorates with pregnancy as well as the teratogenic effects observed in 
animals: 
 
• Tracleer treatment must not be initiated in women of childbearing potential unless they practise 

reliable contraception and the result of the pre-treatment pregnancy test is negative 
• Hormonal contraceptives cannot be the sole method of contraception during treatment with 

Tracleer 
• Monthly pregnancy tests are recommended during treatment to allow early detection of 

pregnancy 
 
For further information see sections 4.5 and 4.6. 
 
Pulmonary veno-occlusive disease 
 
Cases of pulmonary oedema have been reported with vasodilators (mainly prostacyclins) when used in 
patients with pulmonary veno-occlusive disease. Consequently, should signs of pulmonary oedema 
occur when Tracleer is administered in patients with PAH, the possibility of associated veno-occlusive 
disease should be considered. In the post-marketing period there have been rare reports of pulmonary 
oedema in patients treated with Tracleer who had a suspected diagnosis of pulmonary veno-occlusive 
disease. 
 



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Pulmonary arterial hypertension patients with concomitant left ventricular failure 
 
No specific study has been performed in patients with pulmonary hypertension and concomitant left 
ventricular dysfunction. However, 1,611 patients (804 bosentan- and 807 placebo-treated patients) 
with severe chronic heart failure (CHF) were treated for a mean duration of 1.5 years in a placebo-
controlled study (study AC-052-301/302 [ENABLE 1 & 2]). In this study there was an increased 
incidence of hospitalisation due to CHF during the first 4–8 weeks of treatment with bosentan, which 
could have been the result of fluid retention. In this study, fluid retention was manifested by early 
weight gain, decreased haemoglobin concentration and increased incidence of leg oedema. At the end 
of this study, there was no difference in overall hospitalisations for heart failure nor in mortality 
between bosentan- and placebo-treated patients. Consequently, it is recommended that patients be 
monitored for signs of fluid retention (e.g., weight gain), especially if they concomitantly suffer from 
severe systolic dysfunction. Should this occur, starting treatment with diuretics is recommended, or the 
dose of existing diuretics should be increased. Treatment with diuretics should be considered in 
patients with evidence of fluid retention before the start of treatment with Tracleer. 
 
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. 
 
Pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD) 
 
Safety and tolerability of bosentan was investigated in an exploratory, uncontrolled 12-week study in 
11 patients with pulmonary hypertension secondary to severe COPD (stage III of GOLD 
classification). An increase in minute ventilation and a decrease in oxygen saturation were observed, 
and the most frequent adverse event was dyspnoea, which resolved with discontinuation of bosentan. 
 
Concomitant use with other medicinal products 
 
Concomitant use of Tracleer and cyclosporine A is contraindicated (see sections 4.3 and 4.5). 
 
Concomitant use of Tracleer with glibenclamide, fluconazole and rifampicin is not recommended. For 
further details please refer to section 4.5. 
 
Concomitant administration of both a CYP3A4 inhibitor and a CYP2C9 inhibitor with Tracleer should 
be avoided (see section 4.5). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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 



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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 for tacrolimus and sirolimus blood 
concentrations. 
 
Glibenclamide: Co-administration of bosentan 125 mg twice daily for 5 days decreased the plasma 
concentrations of glibenclamide (a CYP3A4 substrate) by 40%, with potential significant decrease of 
the hypoglycaemic effect. The plasma concentrations of bosentan were also decreased by 29%. In 
addition, an increased incidence of elevated aminotransferases was observed in patients receiving 
concomitant therapy. Both glibenclamide and bosentan inhibit the bile salt export pump, which could 
explain the elevated aminotransferases. This combination should not be used. No drug-drug interaction 
data are available with the other sulfonylureas. 
 
Rifampicin: Co-administration in 9 healthy subjects for 7 days of bosentan 125 mg twice daily with 
rifampicin, a potent inducer of CYP2C9 and CYP3A4, decreased the plasma concentrations of 
bosentan by 58%, and this decrease could achieve almost 90% in an individual case. As a result, a 
significantly reduced effect of bosentan is expected when it is co-administered with rifampicin. 
Concomitant use of rifampicin and Tracleer is not recommended. Data on other CYP3A4 inducers, 
e.g., carbamazepine, phenobarbital, phenytoin and St. John’s wort are lacking, but their concomitant 
administration is expected to lead to reduced systemic exposure to bosentan. A clinically significant 
reduction of efficacy cannot be excluded. 
 
Lopinavir+ritonavir (and other ritonavir-boosted protease inhibitors): Co-administration of bosentan 
125 mg twice daily and lopinavir+ritonavir 400+100 mg twice daily for 9.5 days in healthy volunteers 
resulted in initial trough plasma concentrations of bosentan that were approximately 48-fold higher 
than those measured after bosentan administered alone. On day 9, plasma concentrations of bosentan 
were approximately 5-fold higher than with bosentan administered alone. Inhibition by ritonavir of 
transport protein-mediated uptake into hepatocytes and of CYP3A4, thereby reducing the clearance of 



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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 bosentan 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 a 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. Due to the marked hepatotoxicity of nevirapine, which 
could add to bosentan liver toxicity, this combination is not recommended. 
Hormonal contraceptives: Co-administration of bosentan 125 mg twice daily for 7 days with a single 
dose of oral contraceptive containing norethisterone 1 mg + ethinyl estradiol 35 mcg decreased the 
AUC of norethisterone and ethinyl estradiol by 14% and 31%, respectively. However, decreases in 
exposure were as much as 56% and 66%, respectively, in individual subjects. Therefore, hormone-
based contraceptives alone, regardless of the route of administration (i.e., oral, injectable, transdermal 
or implantable forms), are not considered as reliable methods of contraception (see sections 4.4 and 
4.6). 
 
Warfarin: Co-administration of bosentan 500 mg twice daily for 6 days decreased the plasma 
concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A4 substrate) by 
29% and 38%, respectively. Clinical experience with concomitant administration of bosentan with 
warfarin in patients with PAH did not result in clinically relevant changes in International Normalized 
Ratio (INR) or warfarin dose (baseline versus end of the clinical studies). In addition, the frequency of 
changes in warfarin dose during the studies due to changes in INR or due to adverse events was 
similar among bosentan- and placebo-treated patients. No dose adjustment is needed for warfarin and 
similar oral anticoagulant agents when bosentan is initiated, but intensified monitoring of INR is 
recommended, especially during bosentan initiation and the up-titration period. 
 
Simvastatin: Co-administration of bosentan 125 mg twice daily for 5 days decreased the plasma 
concentrations of simvastatin (a CYP3A4 substrate) and its active β-hydroxy acid metabolite by 34% 
and 46%, respectively. The plasma concentrations of bosentan were not affected by concomitant 
simvastatin. Monitoring of cholesterol levels and subsequent dosage adjustment should be considered. 
 
Ketoconazole: Co-administration for 6 days of bosentan 62.5 mg twice daily with ketoconazole, a 
potent CYP3A4 inhibitor, increased the plasma concentrations of bosentan approximately 2-fold. No 
dose adjustment of Tracleer is considered necessary. Although not demonstrated through in vivo 
studies, similar increases in bosentan plasma concentrations are expected with the other potent 
CYP3A4 inhibitors (such as itraconazole or ritonavir). However, when combined with a CYP3A4 
inhibitor, patients who are poor metabolisers of CYP2C9 are at risk of increases in bosentan plasma 
concentrations that may be of higher magnitude, thus leading to potential harmful adverse events. 
 
Epoprostenol: Limited data obtained from a study (AC-052-356 [BREATHE-3]) in which 
10 paediatric patients received the combination of bosentan and epoprostenol indicate that after both 
single- and multiple-dose administration, the Cmax and AUC values of bosentan were similar in 
patients with or without continuous infusion of epoprostenol (see section 5.1). 
 
Sildenafil: Co-administration of bosentan 125 mg twice daily (steady state) with sildenafil 80 mg three 
times a day (at steady state) concomitantly administered during 6 days in healthy volunteers resulted 
in a 63% decrease in the sildenafil AUC and a 50% increase in the bosentan AUC. Caution is 
recommended in the case of co-administration. 



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Tadalafil: Bosentan (125 mg twice daily) reduced tadalafil (40 mg once per day) systemic exposure by 
42% and Cmax by 27% following multiple dose co-administration. Tadalafil did not affect the exposure 
(AUC and Cmax) of bosentan or its metabolites. 
 
Digoxin: Co-administration for 7 days of bosentan 500 mg twice daily with digoxin decreased the 
AUC, Cmax and Cmin of digoxin by 12%, 9% and 23%, respectively. The mechanism for this interaction 
may be induction of P-glycoprotein. This interaction is unlikely to be of clinical relevance. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
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 
 
It is not known whether bosentan is excreted into human breast milk. Breast-feeding is not 
recommended during treatment with Tracleer. 
 
Fertility 
 
Animal 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. 
 
4.7 Effects on ability to drive and use machines 
 
No specific studies have been conducted to assess the direct effect of Tracleer on the ability to drive 



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and use machines. However, Tracleer may induce hypotension, with symptoms of dizziness, blurred 
vision or syncope that could affect the ability to drive or use machines. 
 
4.8 Undesirable effects 
 
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 2000 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 
disorders 

Common Anaemia, haemoglobin decrease, 
(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 Very common Headache3  
 Common Syncope1, 4 
Eye disorders Not known Blurred vision1 
Cardiac disorders Common Palpitations1, 4 
Vascular disorders Common Flushing  
 Common Hypotension1, 4 
Respiratory, thoracic and 
mediastinal disorders 

Common Nasal congestion1 

Gastrointestinal disorders Common Gastrooesophageal reflux disease 
Diarrhoea 

Hepatobiliary disorders Very common Abnormal liver function test (see 
section 4.4) 

 Uncommon Aminotransferase elevations 
associated with hepatitis 
(including possible exacerbation 
of underlying hepatitis) and/or 



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jaundice1 (see section 4.4) 
 Rare Liver cirrhosis, liver failure1 
Skin and subcutaneous disorders Common Erythema 
General disorders and 
administration site conditions  

Very common  
 

Oedema, fluid retention5 
 

1 Data derived from post-marketing experience, frequencies based on statistical modelling of placebo-controlled clinical 
trial data. 

2 Hypersensitivity reactions were reported in 9.9% of patients on bosentan and 9.1% of patients on placebo. 
3 Headache was reported in 11.5% of patients on bosentan and 9.8% of patients on placebo. 
4 These types of reactions can also be related to the underlying disease. 
5 Oedema or fluid retention was reported in 13.2% of patients on bosentan and 10.9% of patients on placebo. 
 
In the post-marketing period rare cases of unexplained hepatic cirrhosis were reported after prolonged 
therapy with Tracleer in patients with multiple co-morbidities and therapies with medicinal products. 
There have also been rare reports of liver failure. These cases reinforce the importance of strict 
adherence to the monthly schedule for monitoring of liver function for the duration of treatment with 
Tracleer (see section 4.4). 
 
Paediatric population 
 
Uncontrolled clinical studies in paediatric patients 
 
The safety profile in 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 2 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%). 
 
A 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). 
 
The 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 with 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. 
 
In 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 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). 
 



13 

Laboratory abnormalities 
 
Liver test abnormalities 
 
In the clinical programme, dose-dependent elevations in liver aminotransferases generally occurred 
within the first 26 weeks of treatment, usually developed gradually, and were mainly asymptomatic. In 
the post-marketing period rare cases of liver cirrhosis and liver failure have been reported. 
 
The mechanism of this adverse effect is unclear. These elevations in aminotransferases may reverse 
spontaneously while continuing treatment with the maintenance dose of Tracleer or after dose 
reduction, but interruption or cessation may be necessary (see section 4.4). 
In the 20 integrated placebo-controlled studies, elevations in liver aminotransferases ≥ 3 ×ULN were 
observed in 11.2% of the bosentan-treated patients as compared to 2.4% of the placebo-treated 
patients. Elevations to ≥ 8 × ULN were seen in 3.6% of the bosentan-treated patients and 0.4% of the 
placebo-treated patients. Elevations in aminotransferases were associated with elevated bilirubin 
(≥ 2 × ULN) without evidence of biliary obstruction in 0.2% (5 patients) on bosentan and 0.3% 
(6 patients) on placebo. 
 
In the pooled analysis of 100 PAH children from uncontrolled paediatric studies FUTURE 1/2 and 
FUTURE 3/Extension, elevations in liver aminotransferases ≥ 3 × ULN were observed in 2% of 
patients. 
 
In 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. 
 
Haemoglobin 
 
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). 
 
In 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. 
 
In 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. 
 
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 in Appendix V. 
 
4.9 Overdose 
 
Bosentan has been administered as a single dose of up to 2,400 mg to healthy subjects and up to 
2,000 mg/day for 2 months in patients with a disease other than pulmonary hypertension. The most 
common adverse reaction was headache of mild to moderate intensity. 
 



14 

Massive overdose may result in pronounced hypotension requiring active cardiovascular support. In 
the post-marketing period there was one reported overdose of 10,000 mg of Tracleer taken by an 
adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating and 
blurred vision. He recovered completely within 24 hours with blood pressure support. Note: bosentan 
is not removed through dialysis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: other antihypertensives, ATC code: C02KX01 
 
Mechanism of action 
 
Bosentan is a dual endothelin receptor antagonist (ERA) with affinity for both endothelin A and B 
(ETA and ETB) receptors. Bosentan decreases both pulmonary and systemic vascular resistance 
resulting in increased cardiac output without increasing heart rate. 
 
The neurohormone endothelin-1 (ET-1) is one of the most potent vasoconstrictors known and can also 
promote fibrosis, cell proliferation, cardiac hypertrophy and remodelling, and is pro-inflammatory. 
These effects are mediated by endothelin binding to ETA and ETB receptors located in the endothelium 
and vascular smooth muscle cells. ET-1 concentrations in tissues and plasma are increased in several 
cardiovascular disorders and connective tissue diseases, including PAH, scleroderma, acute and 
chronic heart failure, myocardial ischaemia, systemic hypertension and atherosclerosis, suggesting a 
pathogenic role of ET-1 in these diseases. In PAH and heart failure, in the absence of endothelin 
receptor antagonism, elevated ET-1 concentrations are strongly correlated with the severity and 
prognosis of these diseases. 
 
Bosentan competes with the binding of ET-1 and other ET peptides to both ETA and ETB receptors, 
with a slightly higher affinity for ETA receptors (Ki = 4.1–43 nanomolar) than for ETB receptors 
(Ki = 38–730 nanomolar). Bosentan specifically antagonises ET receptors and does not bind to other 
receptors. 
 
Efficacy 
 
Animal models 
In animal models of pulmonary hypertension, chronic oral administration of bosentan reduced 
pulmonary vascular resistance and reversed pulmonary vascular and right ventricular hypertrophy. In 
an animal model of pulmonary fibrosis, bosentan reduced collagen deposition in the lungs. 
 
Efficacy in adult patients with pulmonary arterial hypertension 
Two randomised, double-blind, multi-centre, placebo-controlled studies have been conducted in 32 
(study AC-052-351) and 213 (study AC-052-352 [BREATHE-1]) adult patients with WHO functional 
class III–IV PAH (primary pulmonary hypertension or pulmonary hypertension secondary mainly to 
scleroderma). After 4 weeks of bosentan 62.5 mg twice daily, the maintenance doses studied in these 
studies were 125 mg twice daily in AC-052-351, and 125 mg twice daily and 250 mg twice daily in 
AC-052-352. 
 
Bosentan was added to patients’ current therapy, which could include a combination of anticoagulants, 
vasodilators (e.g., calcium channel blockers), diuretics, oxygen and digoxin, but not epoprostenol. 
Control was placebo plus current therapy. 
 



15 

The primary endpoint for each study was change in 6-minute walk distance at 12 weeks for the first 
study and 16 weeks for the second study. In both studies, treatment with bosentan resulted in 
significant increases in exercise capacity. The placebo-corrected increases in walk distance compared 
with baseline were 76 metres (p = 0.02; t-test) and 44 metres (p = 0.0002; Mann-Whitney U test) at the 
primary endpoint of each study, respectively. The differences between the two groups, 125 mg twice 
daily and 250 mg twice daily, were not statistically significant but there was a trend towards improved 
exercise capacity in the group treated with 250 mg twice daily. 
 
The improvement in walk distance was apparent after 4 weeks of treatment, was clearly evident after 
8 weeks of treatment and was maintained for up to 28 weeks of double-blind treatment in a subset of 
the patient population. 
 
In a retrospective responder analysis based on change in walking distance, WHO functional class and 
dyspnoea of the 95 patients randomised to bosentan 125 mg twice daily in the placebo-controlled 
studies, it was found that at week 8, 66 patients had improved, 22 were stable and 7 had deteriorated. 
Of the 22 patients stable at week 8, 6 improved at week 12/16 and 4 deteriorated compared with 
baseline. Of the 7 patients who deteriorated at week 8, 3 improved at week 12/16 and 4 deteriorated 
compared with baseline. 
 
Invasive haemodynamic parameters were assessed in the first study only. Treatment with bosentan led 
to a significant increase in cardiac index associated with a significant reduction in pulmonary artery 
pressure, pulmonary vascular resistance and mean right atrial pressure. 
 
A reduction in symptoms of PAH was observed with bosentan treatment. Dyspnoea measurement 
during walk tests showed an improvement in bosentan-treated patients. In the AC-052-352 study, 92% 
of the 213 patients were classified at baseline as WHO functional class III and 8% as class IV. 
Treatment with bosentan led to a WHO functional class improvement in 42.4% of patients (placebo 
30.4%). The overall change in WHO functional class during both studies was significantly better 
among bosentan-treated patients as compared with placebo-treated patients. Treatment with bosentan 
was associated with a significant reduction in the rate of clinical worsening compared with placebo at 
28 weeks (10.7% vs 37.1%, respectively; p = 0.0015). 
 
In a randomised, double-blind, multi-centre, placebo-controlled study (AC-052-364 [EARLY]), 
185 PAH patients in WHO functional class II (mean baseline 6-minute walk distance of 435 metres) 
received bosentan 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily (n = 93), or 
placebo (n = 92) for 6 months. Enrolled patients were PAH-treatment-naïve (n = 156) or on a stable 
dose of sildenafil (n = 29). The co-primary endpoints were percentage change from baseline in 
pulmonary vascular resistance (PVR) and change from baseline in 6-minute walk distance to Month 6 
versus placebo. The table below illustrates the pre-specified protocol analyses. 
 
 PVR (dyn.sec/cm5) 6-Minute Walk Distance (m) 
 Placebo (n=88) Bosentan (n=80) Placebo (n=91) Bosentan (n=86) 
Baseline (BL); mean (SD) 802 (365) 851 (535) 431 (92) 443 (83) 
Change from BL; mean (SD) 128 (465) −69 (475) −8 (79) 11 (74) 
Treatment effects −22.6% 19 
95% CL −34, −10 −4, 42 
P-value < 0.0001 0.0758 
CL = confidence limit; PVR = pulmonary vascular resistance; SD = standard deviation. 
 
Treatment with bosentan was associated with a reduction in the rate of clinical worsening, defined as a 
composite of symptomatic progression, hospitalisation for PAH and death, compared with placebo 
(proportional risk reduction 77%, 95% confidence interval [CI] 20–94%, p = 0.0114). The treatment 
effect was driven by improvement in the component symptomatic progression. There was one 



16 

hospitalisation related to PAH worsening in the bosentan group and three hospitalisations in the 
placebo group. Only one death occurred in each treatment group during the 6-month double-blind 
study period, therefore no conclusion can be drawn on survival. 
 
Long-term data were generated from all 173 patients who were treated with bosentan in the controlled 
phase and/or were switched from placebo to bosentan in the open-label extension phase of the EARLY 
study. The mean duration of exposure to bosentan treatment was 3.6 ± 1.8 years (up to 6.1 years), with 
73% of patients treated for at least 3 years and 62% for at least 4 years. Patients could receive 
additional PAH treatment as required in the open-label extension. The majority of patients were 
diagnosed with idiopathic or heritable PAH (61%). Overall, 78% of patients remained in WHO 
functional class II. Kaplan-Meier estimates of survival were 90% and 85% at 3 and 4 years after the 
start of treatment, respectively. At the same timepoints, 88% and 79% of patients remained free from 
PAH worsening (defined as all-cause death, lung transplantation, atrial septostomy or start of 
intravenous or subcutaneous prostanoid treatment). The relative contributions of previous placebo 
treatment in the double-blind phase and of other medications started during the open-label extension 
period are unknown. 
 
In a prospective, multi-centre, randomised, double-blind, placebo-controlled study (AC-052-405 
[BREATHE-5]), patients with PAH WHO functional class III and Eisenmenger physiology associated 
with congenital heart disease received bosentan 62.5 mg twice daily for 4 weeks, then 125 mg twice 
daily for a further 12 weeks (n = 37, of whom 31 had a predominantly right to left, bidirectional 
shunt). The primary objective was to show that bosentan did not worsen hypoxaemia. After 16 weeks, 
the mean oxygen saturation was increased in the bosentan group by 1.0% (95% CI –0.7%–2.8%) as 
compared to the placebo group (n = 17), showing that bosentan did not worsen hypoxaemia. The mean 
pulmonary vascular resistance was significantly reduced in the bosentan group (with a predominant 
effect observed in the subgroup of patients with bidirectional intracardiac shunt). After 16 weeks, the 
mean placebo-corrected increase in 6-minute walk distance was 53 metres (p = 0.0079), reflecting 
improvement in exercise capacity. Twenty-six patients continued to receive bosentan in the 24-week 
open-label extension phase (AC-052-409) of the BREATHE-5 study (mean duration of treatment = 
24.4 ± 2.0 weeks) and, in general, efficacy was maintained. 
 
An open-label, non-comparative study (AC-052-362 [BREATHE-4]) was performed in 16 patients 
with WHO functional class III PAH associated with HIV infection. Patients were treated with 
bosentan 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily for a further 12 weeks. 
After 16 weeks’ treatment, there were significant improvements from baseline in exercise capacity: the 
mean increase in 6-minute walk distance was 91.4 metres from 332.6 metres 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). 
 
There are no studies to demonstrate beneficial effects of Tracleer treatment on survival. However, 
long-term vital status was recorded for all 235 patients who were treated with bosentan in the two 
pivotal placebo-controlled studies (AC-052-351 and AC-052-352) and/or their two uncontrolled, 
open-label extensions. The mean duration of exposure to bosentan was 1.9 years ± 0.7 years (min: 
0.1 years; max: 3.3 years) and patients were observed for a mean of 2.0 ± 0.6 years. The majority of 
patients were diagnosed as primary pulmonary hypertension (72%) and were in WHO functional class 
III (84%). In this total population, Kaplan-Meier estimates of survival were 93% and 84% 1 and 2 
years after the start of treatment with bosentan, respectively. Survival estimates were lower in the 
subgroup of patients with PAH secondary to systemic sclerosis. The estimates may have been 
influenced by the initiation of epoprostenol treatment in 43/235 patients. 
 



17 

Studies performed in children with pulmonary arterial hypertension 
 
BREATHE-3 (AC-052-356) 
Bosentan film-coated tablets were evaluated in an open-label uncontrolled study in 19 paediatric 
patients with PAH 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) or PAH related to 
congenital heart diseases (9 patients) and were in WHO functional class II (n = 15, 79%) or class III 
(n = 4, 21%) at baseline. Patients were divided into 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. 
 
Haemodynamics were measured in 17 patients. The mean increase from baseline in cardiac index was 
0.5 L/min/m2, the mean decrease in mean pulmonary arterial pressure was 8 mmHg, and the mean 
decrease in PVR was 389 dyn·sec·cm-5. These haemodynamic improvements from baseline were 
similar with or without co-administration of epoprostenol. Changes in exercise test parameters at week 
12 from baseline were highly variable and none were significant. 
 
FUTURE 1/2 (AC-052-365/AC-052-367) 
FUTURE 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, 64%) or class III (n = 13, 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%. 
 
FUTURE 3 (AC-052-373) 
In 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 2 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 related to congenital heart disease associated with systemic-to-
pulmonary shunts, including Eisenmenger syndrome (13%). Patients were in WHO functional class I 
(n = 19, 29 %), class II (n = 27, 42%) or class III (n = 18, 28%) at start of study treatment. At study 
entry, patients were treated with PAH medications (most frequently phosphodiesterase type-5 inhibitor 
[sildenafil] alone [35.9%], bosentan alone [10.9%], and a combination of bosentan, iloprost, and 
sildenafil [10.9%]) and continued their PAH treatment during the study. 
 
At 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 physician’s global clinical impression (94% twice daily, 93% three times 



18 

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. 
 
There was no evidence of any clinical benefit with 2 mg/kg three times daily as compared to 2 mg/kg 
twice daily dosing. 
 
Study performed in neonates with persistent pulmonary hypertension of the newborn (PPHN): 
 
FUTURE 4 (AC-052-391) 
This 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. 
 
The 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. 
 
The results did not indicate an additional benefit of bosentan in this population: 
• The median time to complete weaning from iNO was 3.7 days (95% confidence limits [CLs] 

1.17, 6.95) on bosentan and 2.9 days (95% CLs 1.26, 4.23) on placebo (p = 0.34).  
• 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). 
• One patient in the bosentan group had treatment failure (need for ECMO as per protocol 

definition), which was declared based on increasing Oxygenation Index values within 8 h after 
the first study drug dose. This patient recovered within the 60-day follow-up period. 

 
Combination with epoprostenol 
The combination of bosentan and epoprostenol has been investigated in two studies: AC-052-355 
(BREATHE-2) and AC-052-356 (BREATHE-3). AC-052-355 was a multi-centre, randomised, 
double-blind, parallel-group study of bosentan versus placebo in 33 patients with severe PAH who 
were receiving concomitant epoprostenol therapy. AC-052-356 was an open-label, uncontrolled study; 
10 of the 19 paediatric patients were on concomitant bosentan and epoprostenol therapy during the 12-
week study. The safety profile of the combination was not different from the one expected with each 
component and the combination therapy was well tolerated in children and adults. The clinical benefit 
of the combination has not been demonstrated. 
 
Systemic sclerosis with digital ulcer disease 
Two randomised, double-blind, multi-centre, placebo-controlled studies have been conducted in 122 
(study AC-052-401 [RAPIDS-1]) and 190 (study AC-052-331 [RAPIDS-2]) adult patients with 
systemic sclerosis and digital ulcer disease (either ongoing digital ulcers or a history of digital ulcers 
within the previous year). In study AC-052-331, patients had to have at least one digital ulcer of recent 
onset, and across the two studies 85% of patients had ongoing digital ulcer disease at baseline. After 
4 weeks of bosentan 62.5 mg twice daily, the maintenance dose studied in both these studies was 
125 mg twice daily. The duration of double-blind therapy was 16 weeks in study AC-052-401, and 
24 weeks in study AC-052-331. 
 
Background treatments for systemic sclerosis and digital ulcers were permitted if they remained 
constant for at least 1 month prior to the start of treatment and during the double-blind study period. 
 



19 

The number of new digital ulcers from baseline to study endpoint was a primary endpoint in both 
studies. Treatment with bosentan resulted in fewer new digital ulcers for the duration of therapy, 
compared with placebo. In study AC-052-401, during 16 weeks of double-blind therapy, patients in 
the bosentan group developed a mean of 1.4 new digital ulcers vs 2.7 new digital ulcers in the placebo 
group (p = 0.0042). In study AC-052-331, during 24 weeks of double-blind therapy, the corresponding 
figures were 1.9 vs 2.7 new digital ulcers, respectively (p = 0.0351). In both studies, patients on 
bosentan were less likely to develop multiple new digital ulcers during the study and took longer to 
develop each successive new digital ulcer than did those on placebo. The effect of bosentan on 
reduction of the number of new digital ulcers was more pronounced in patients with multiple digital 
ulcers. 
 
No effect of bosentan on time to healing of digital ulcers was observed in either study. 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of bosentan have mainly been documented in healthy subjects. Limited data in 
patients show that the exposure to bosentan in adult PAH patients is approximately 2-fold greater than 
in healthy adult subjects. 
 
In healthy subjects, bosentan displays dose- and time-dependent pharmacokinetics. Clearance and 
volume of distribution decrease with increased intravenous doses and increase with time. After oral 
administration, the systemic exposure is proportional to dose up to 500 mg. At higher oral doses, Cmax 
and AUC increase less than proportionally to the dose. 
 
Absorption 
 
In healthy subjects, the absolute bioavailability of bosentan is approximately 50% and is not affected 
by food. The maximum plasma concentrations are attained within 3–5 hours. 
 
Distribution 
 
Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. Bosentan does not penetrate 
into erythrocytes. 
 
A volume of distribution (Vss) of about 18 litres was determined after an intravenous dose of 250 mg. 
 
Biotransformation and elimination 
 
After a single intravenous dose of 250 mg, the clearance was 8.2 L/h. The terminal elimination half-
life (t1/2) is 5.4 hours. 
 
Upon multiple dosing, plasma concentrations of bosentan decrease gradually to 50–65% of those seen 
after single dose administration. This decrease is probably due to auto-induction of metabolising liver 
enzymes. Steady-state conditions are reached within 3–5 days. 
 
Bosentan is eliminated by biliary excretion following metabolism in the liver by the cytochrome P450 
isoenzymes, CYP2C9 and CYP3A4. Less than 3% of an administered oral dose is recovered in urine. 
 
Bosentan forms three metabolites and only one of these is pharmacologically active. This metabolite is 
mainly excreted unchanged via the bile. In adult patients, the exposure to the active metabolite is 
greater than in healthy subjects. In patients with evidence of the presence of cholestasis, the exposure 
to the active metabolite may be increased. 
 



20 

Bosentan is an inducer of CYP2C9 and CYP3A4 and possibly also of CYP2C19 and the 
P-glycoprotein. In vitro, bosentan inhibits the bile salt export pump in hepatocyte cultures. 
 
In vitro data demonstrated that bosentan had no relevant inhibitory effect on the CYP isoenzymes 
tested (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4). Consequently, bosentan is not expected to 
increase the plasma concentrations of medicinal products metabolised by these isoenzymes. 
 
Pharmacokinetics in special populations 
 
Based 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. 
 
Children 
Pharmacokinetics 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. 
 
Study AC-052-356 (BREATHE-3) evaluated the pharmacokinetics of single and multiple oral doses of 
the film-coated tablet formulation of bosentan in 19 children aged from 3 to 15 years with PAH who 
were dosed on the basis of body weight with 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 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. 
 
In study AC-052-365 (FUTURE 1), dispersible tablets were administered in 36 PAH children aged 
from 2 to 11 years. No dose proportionality was observed, 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). The average exposure 
to bosentan in these paediatric patients was about half the exposure in adult patients at the 125 mg 
twice daily maintenance dose but showed a large overlap with the exposures in adults. 
 
In 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; AUCτ was 
4,268 ng·h/mL (CV: 61%). In patients between 3 months and 2 years the daily exposure was 7,879 
ng·h/mL; AUCτ was 3,939 ng·h/mL (CV: 72%). In patients between 3 months and 1 year (n = 2) 
AUCτ was 5,914 ng·h/mL (CV: 85%), and in patients between 1 and 2 years (n = 7) AUCτ was 
3,507 ng·h/mL (CV: 70%). In the patients above 2 years (n = 22) the daily exposure was 8,820 
ng·h/mL; AUCτ was 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). 
 
Based on the findings in studies BREATHE-3, FUTURE 1, and FUTURE-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. 
 
In 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 



21 

to the exposure observed in adult PAH patients receiving 125 mg twice daily and taking into account a 
blood/plasma distribution ratio of 0.6. 
 
The consequences of these findings regarding hepatotoxicity are unknown. Gender and concomitant 
use of intravenous epoprostenol had no significant effect on the pharmacokinetics of bosentan. 
 
Hepatic impairment 
In patients with mildly impaired liver function (Child-Pugh class A) no relevant changes in the 
pharmacokinetics have been observed. The steady-state AUC of bosentan was 9% higher and the AUC 
of the active metabolite, Ro 48-5033, was 33% higher in patients with mild hepatic impairment than in 
healthy volunteers. 
 
The impact of moderately impaired liver function (Child-Pugh class B) on the pharmacokinetics of 
bosentan and its primary metabolite Ro 48-5033 was investigated in a study including 5 patients with 
pulmonary hypertension associated with portal hypertension and Child-Pugh class B hepatic 
impairment, and 3 patients with PAH from other causes and normal liver function. In the patients with 
Child-Pugh class B liver impairment, the mean (95% CI) steady-state AUC of bosentan was 360 (212–
613) ng⋅h/mL, i.e., 4.7 times higher, and the mean (95% CI) AUC of the active metabolite Ro 48-5033 
was 106 (58.4–192) ng⋅h/mL, i.e., 12.4 times higher than in the patients with normal liver function 
(bosentan: mean [95% CI] AUC: 76.1 [9.07–638] ng⋅h/mL; Ro 48-5033: mean [95% CI] AUC 8.57 
[1.28–57.2] ng⋅h/ml). Though the number of patients included was limited and with high variability, 
these data indicate a marked increase in the exposure to bosentan and its primary metabolite Ro 48-
5033 in patients with moderate liver function impairment (Child-Pugh class B). 
 
The pharmacokinetics of bosentan have not been studied in patients with Child-Pugh class C hepatic 
impairment. Tracleer is contraindicated in patients with moderate to severe hepatic impairment, i.e., 
Child-Pugh class B or C (see section 4.3). 
 
Renal impairment 
In patients with severe renal impairment (creatinine clearance 15–30 mL/min), plasma concentrations 
of bosentan decreased by approximately 10%. Plasma concentrations of bosentan metabolites 
increased about 2-fold in these patients as compared with subjects with normal renal function. No dose 
adjustment is required in patients with renal impairment. There is no specific clinical experience in 
patients undergoing dialysis. Based on physicochemical properties and the high degree of protein 
binding, bosentan is not expected to be removed from the circulation by dialysis to any significant 
extent (see section 4.2). 
 
5.3 Preclinical safety data 
 
A 2-year carcinogenicity study in mice showed an increased combined incidence of hepatocellular 
adenomas and carcinomas in males, but not in females, at plasma concentrations about 2 to 4 times the 
plasma concentrations achieved at the therapeutic dose in humans. In rats, oral administration of 
bosentan for 2 years produced a small, significant increase in the combined incidence of thyroid 
follicular cell adenomas and carcinomas in males, but not in females, at plasma concentrations about 9 
to 14 times the plasma concentrations achieved at the therapeutic dose in humans. Bosentan was 
negative in tests for genotoxicity. There was evidence of a mild thyroid hormonal imbalance induced 
by bosentan in rats. However, there was no evidence of bosentan affecting thyroid function (thyroxine, 
TSH) in humans. 
 
The effect of bosentan on mitochondrial function is unknown. 
 
Bosentan has been shown to be teratogenic in rats at plasma levels higher than 1.5 times the plasma 
concentrations achieved at the therapeutic dose in humans. Teratogenic effects, including 



22 

malformations of the head and face and of the major vessels, were dose dependent. The similarities of 
the pattern of malformations observed with other ET receptor antagonists and in ET knock-out mice 
indicate a class effect. Appropriate precautions must be taken for women of childbearing potential (see 
sections 4.3, 4.4 and 4.6). 
 
Development of testicular tubular atrophy and impaired fertility has been linked with chronic 
administration of endothelin receptor antagonists in rodents. 
 
In fertility studies in male and female rats, 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. 
 
Slightly 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 1,500 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. 
 
However, 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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Maize starch 
Pregelatinised starch 
Sodium starch glycolate (Type A) 
Povidone 
Glycerol dibehenate 
Magnesium stearate 
 
Film coat: 
Hypromellose 
Glycerol triacetate 
Talc 
Titanium dioxide (E171) 
Iron oxide yellow (E172) 
Iron oxide red (E172) 
Ethylcellulose 
 
6.2 Incompatibilities 
 
Not applicable. 
 



23 

6.3 Shelf life 
 
4 years 
For white high-density polyethylene bottles, use within 30 days after the first opening. 
 
6.4 Special precautions for storage 
 
For PVC/PE/PVDC/aluminium-blisters: 
Do not store above 30°C. 
 
For white high-density polyethylene bottles: 
This medicinal product does not require any special storage conditions. 
For storage conditions after first opening of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Tracleer 62.5 mg film-coated tablets 
PVC/PE/PVDC/aluminium-blisters containing 14 film-coated tablets. 
Cartons contain 14, 56 or 112 film-coated tablets. 
 
White high-density polyethylene bottles with a silica gel desiccant containing 56 film-coated tablets. 
Cartons contain 56 film-coated tablets. 
 
Tracleer 125 mg film-coated tablets 
PVC/PE/PVDC/aluminium-blisters containing 14 film-coated tablets. 
Cartons contain 56 or 112 film-coated tablets. 
 
White high-density polyethylene bottles with a silica gel desiccant containing 56 film-coated tablets. 
Cartons contain 56 film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
No special requirements for disposal. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Janssen-Cilag International NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
Tracleer 62.5 mg film-coated tablets 
EU/1/02/220/001 
EU/1/02/220/002 



24 

EU/1/02/220/003 
EU/1/02/220/007 
 
Tracleer 125 mg film-coated tablets 
EU/1/02/220/004 
EU/1/02/220/005 
EU/1/02/220/008 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 May 2002 
 
Date of latest renewal: 20 April 2012 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/. 



25 

 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tracleer 32 mg dispersible tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each dispersible tablet contains 32 mg bosentan (as monohydrate). 
 
Excipients with known effect 
Each dispersible tablet contains 3.7 mg of aspartame (E951). 
 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Dispersible tablet: 
 
Pale yellow to off-white, clover-shape tablets, quadrisected on one side and debossed with “32” on the 
other side. The dispersible tablet can be divided into four equal parts. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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). 
 
4.2 Posology and method of administration 
 
Method of administration 
 
Tablets are to be taken orally morning and evening, with or without food. 
 
The dispersible tablets should be added to a little water on a spoon, and the liquid stirred to aid 
dissolution, before swallowing. A little more water should be added to the spoon and swallowed by the 



26 

patient, to make sure all of the medicine has been administered. If possible, a glass of water should be 
taken to ensure that all the medicine has been ingested. If necessary, the dispersible tablet can be 
divided by breaking it along the lines cut into the surface (see section 6.6). 
 
The dispersible tablet has been studied only in paediatric patients. A bioavailability comparison 
between dispersible tablets and film-coated tablets performed in adult subjects indicated lower 
exposure to bosentan with the dispersible tablet (see section 5.2). Thus its use in adults should be 
reserved for patients who cannot take the film-coated tablet. 
 
Posology 
 
Pulmonary arterial hypertension 
 
Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH. 
A Patient Alert Card providing important safety information that patients need to be aware of before 
and during treatment with Tracleer is included in the pack. 
 
Adults 
In adult patients, Tracleer treatment should be initiated at a dose of 62.5 mg twice daily for 4 weeks 
and then increased to the maintenance dose of 125 mg twice daily. The same recommendations apply 
to re-introduction of Tracleer after treatment interruption (see section 4.4). 
 
Paediatric population 
Paediatric pharmacokinetic data have shown that bosentan plasma concentrations in children with 
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. 
 
Based on these pharmacokinetic results, when used in children with PAH aged 1 year and older, the 
recommended starting and maintenance dose is 2 mg/kg morning and evening. 
 
In 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). 
 
Management in the event of clinical deterioration of PAH 
 
In the event of clinical deterioration (e.g., decrease in 6-minute walk test distance by at least 10% 
compared with pre-treatment measurement) despite Tracleer treatment for at least 8 weeks (target dose 
for at least 4 weeks), alternative therapies should be considered. However, some patients who show no 
response after 8 weeks of treatment with Tracleer may respond favourably after an additional 4 to 
8 weeks of treatment. 
 
In the event of late clinical deterioration despite treatment with Tracleer (i.e., after several months of 
treatment), the treatment should be re-assessed. Some patients not responding well to 125 mg twice 
daily of Tracleer may slightly improve their exercise capacity when the dose is increased to 250 mg 
twice daily. A careful benefit/risk assessment should be made, taking into consideration that the liver 
toxicity is dose dependent (see sections 4.4 and 5.1). 
 



27 

Discontinuation of treatment 
 
There is limited experience with abrupt discontinuation of Tracleer in patients with PAH. No evidence 
for acute rebound has been observed. However, to avoid the possible occurrence of harmful clinical 
deterioration due to potential rebound effect, gradual dose reduction (halving the dose for 3 to 7 days) 
should be considered. Intensified monitoring is recommended during the discontinuation period. 
If the decision to withdraw Tracleer is taken, it should be done gradually while an alternative therapy 
is introduced. 
 
Systemic sclerosis with ongoing digital ulcer disease 
 
Treatment should only be initiated and monitored by a physician experienced in the treatment of 
systemic sclerosis. 
A Patient Alert Card providing important safety information that patients need to be aware of before 
and during treatment with Tracleer is included in the pack. 
 
Adults 
Tracleer treatment should be initiated at a dose of 62.5 mg twice daily for 4 weeks and then increased 
to the maintenance dose of 125 mg twice daily. The same recommendations apply to re-introduction of 
Tracleer after treatment interruption (see section 4.4). 
 
Controlled clinical study experience in this indication is limited to 6 months (see section 5.1). 
 
The patient’s response to treatment and need for continued therapy should be re-evaluated on a regular 
basis. A careful benefit/risk assessment should be made, taking into consideration the liver toxicity of 
bosentan (see sections 4.4 and 4.8). 
 
Paediatric population 
There are no data on the safety and efficacy in patients under the age of 18 years. Pharmacokinetic 
data are not available for Tracleer in young children with this disease. 
 
Special populations 
 
Hepatic impairment 
 
Tracleer is contraindicated in patients with moderate to severe liver dysfunction (see sections 4.3, 4.4 
and 5.2). No dose adjustment is needed in patients with mild hepatic impairment (i.e., Child-Pugh 
class A) (see section 5.2). 
 
Renal impairment 
 
No dose adjustment is required in patients with renal impairment. No dose adjustment is required in 
patients undergoing dialysis (see section 5.2). 
 
Elderly 
 
No dose adjustment is required in patients over the age of 65 years. 
 
4.3 Contraindications 
 
• 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) 



28 

• 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) 
 
4.4 Special warnings and precautions for use 
 
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 described below should be 
considered. 

> 5 and ≤ 8 × ULN The result should be confirmed by a second liver test; if confirmed, treatment 
should be stopped and aminotransferase levels monitored at least every 
2 weeks. If the aminotransferase levels return to pre-treatment values re-
introducing Tracleer according to the conditions described below should be 
considered. 

> 8 × ULN Treatment must be stopped and re-introduction of Tracleer is not to be 
considered. 

 



29 

In the event of associated clinical symptoms of liver injury, i.e., nausea, vomiting, fever, abdominal 
pain, jaundice, unusual lethargy or fatigue, flu-like syndrome (arthralgia, myalgia, fever), treatment 
must be stopped and re-introduction of Tracleer is not to be considered. 
 
Re-introduction of treatment 
Re-introduction of treatment with Tracleer should only be considered if the potential benefits of 
treatment with Tracleer outweigh the potential risks and when liver aminotransferase levels are within 
pre-treatment values. The advice of a hepatologist is recommended. Re-introduction must follow the 
guidelines detailed in section 4.2. Aminotransferase levels must then be checked within 3 days 
after re-introduction, then again after a further 2 weeks, and thereafter according to the 
recommendations above. 
ULN = upper limit of normal 
 
Haemoglobin concentration 
 
Treatment with bosentan has been associated with dose-related decreases in haemoglobin 
concentration (see section 4.8). In placebo-controlled studies, bosentan-related decreases in 
haemoglobin concentration were not progressive, and stabilised after the first 4–12 weeks of 
treatment. It is recommended that haemoglobin concentrations be checked prior to initiation of 
treatment, every month during the first 4 months, and quarterly thereafter. If a clinically relevant 
decrease in haemoglobin concentration occurs, further evaluation and investigation should be 
undertaken to determine the cause and need for specific treatment. In the post-marketing period, cases 
of anaemia requiring red blood cell transfusion have been reported (see section 4.8). 
 
Women of childbearing potential 
 
As Tracleer may render hormonal contraceptives ineffective, and taking into account the risk that 
pulmonary hypertension deteriorates with pregnancy as well as the teratogenic effects observed in 
animals: 
 
• Tracleer treatment must not be initiated in women of childbearing potential unless they practise 

reliable contraception and the result of the pre-treatment pregnancy test is negative 
• Hormonal contraceptives cannot be the sole method of contraception during treatment with 

Tracleer 
• Monthly pregnancy tests are recommended during treatment to allow early detection of 

pregnancy 
 
For further information see sections 4.5 and 4.6. 
 
Pulmonary veno-occlusive disease 
 
Cases of pulmonary oedema have been reported with vasodilators (mainly prostacyclins) when used in 
patients with pulmonary veno-occlusive disease. Consequently, should signs of pulmonary oedema 
occur when Tracleer is administered in patients with PAH, the possibility of associated veno-occlusive 
disease should be considered. In the post-marketing period there have been rare reports of pulmonary 
oedema in patients treated with Tracleer who had a suspected diagnosis of pulmonary veno-occlusive 
disease. 
 
Pulmonary arterial hypertension patients with concomitant left ventricular failure 
 
No specific study has been performed in patients with pulmonary hypertension and concomitant left 
ventricular dysfunction. However, 1,611 patients (804 bosentan- and 807 placebo-treated patients) 
with severe chronic heart failure (CHF) were treated for a mean duration of 1.5 years in a placebo-



30 

controlled study (study AC-052-301/302 [ENABLE 1 & 2]). In this study there was an increased 
incidence of hospitalisation due to CHF during the first 4–8 weeks of treatment with bosentan, which 
could have been the result of fluid retention. In this study, fluid retention was manifested by early 
weight gain, decreased haemoglobin concentration and increased incidence of leg oedema. At the end 
of this study, there was no difference in overall hospitalisations for heart failure nor in mortality 
between bosentan- and placebo-treated patients. Consequently, it is recommended that patients be 
monitored for signs of fluid retention (e.g., weight gain), especially if they concomitantly suffer from 
severe systolic dysfunction. Should this occur, starting treatment with diuretics is recommended, or the 
dose of existing diuretics should be increased. Treatment with diuretics should be considered in 
patients with evidence of fluid retention before the start of treatment with Tracleer. 
 
 
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. 
 
Pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD) 
 
Safety and tolerability of bosentan was investigated in an exploratory, uncontrolled 12-week study in 
11 patients with pulmonary hypertension secondary to severe COPD (stage III of GOLD 
classification). An increase in minute ventilation and a decrease in oxygen saturation were observed, 
and the most frequent adverse event was dyspnoea, which resolved with discontinuation of bosentan. 
 
Concomitant use with other medicinal products 
 
Concomitant use of Tracleer and cyclosporine A is contraindicated (see sections 4.3 and 4.5). 
 
Concomitant use of Tracleer with glibenclamide, fluconazole and rifampicin is not recommended. For 
further details please refer to section 4.5. 
 
Concomitant administration of both a CYP3A4 inhibitor and a CYP2C9 inhibitor with Tracleer should 
be avoided (see section 4.5). 
 
Excipient 
 
Tracleer 32 mg dispersible tablets contain a source of phenylalanine (Aspartame – E951). This may be 
harmful for people with phenylketonuria. Neither non-clinical nor clinical data are available to assess 
aspartame use in infants below 12 weeks of age. 
 



31 

4.5 Interaction with other medicinal products and other forms of interaction 
 
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 for tacrolimus and sirolimus blood 
concentrations. 
 
Glibenclamide: Co-administration of bosentan 125 mg twice daily for 5 days decreased the plasma 
concentrations of glibenclamide (a CYP3A4 substrate) by 40%, with potential significant decrease of 
the hypoglycaemic effect. The plasma concentrations of bosentan were also decreased by 29%. In 
addition, an increased incidence of elevated aminotransferases was observed in patients receiving 
concomitant therapy. Both glibenclamide and bosentan inhibit the bile salt export pump, which could 
explain the elevated aminotransferases. This combination should not be used. No drug-drug interaction 
data are available with the other sulfonylureas. 
 
Rifampicin: Co-administration in 9 healthy subjects for 7 days of bosentan 125 mg twice daily with 
rifampicin, a potent inducer of CYP2C9 and CYP3A4, decreased the plasma concentrations of 
bosentan by 58%, and this decrease could achieve almost 90% in an individual case. As a result, a 
significantly reduced effect of bosentan is expected when it is co-administered with rifampicin. 
Concomitant use of rifampicin and Tracleer is not recommended. Data on other CYP3A4 inducers, 
e.g., carbamazepine, phenobarbital, phenytoin and St. John’s wort are lacking, but their concomitant 
administration is expected to lead to reduced systemic exposure to bosentan. A clinically significant 
reduction of efficacy cannot be excluded. 
 



32 

Lopinavir+ritonavir (and other ritonavir-boosted protease inhibitors): Co-administration of bosentan 
125 mg twice daily and lopinavir+ritonavir 400+100 mg twice daily for 9.5 days in healthy volunteers 
resulted in initial trough plasma concentrations of bosentan that were approximately 48-fold higher 
than those measured after bosentan administered alone. On day 9, plasma concentrations of bosentan 
were approximately 5-fold higher than with bosentan 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 bosentan 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 a 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. Due to the marked hepatotoxicity of nevirapine, which 
could add to bosentan liver toxicity, this combination is not recommended. 
 
Hormonal contraceptives: Co-administration of bosentan 125 mg twice daily for 7 days with a single 
dose of oral contraceptive containing norethisterone 1 mg + ethinyl estradiol 35 mcg decreased the 
AUC of norethisterone and ethinyl estradiol by 14% and 31%, respectively. However, decreases in 
exposure were as much as 56% and 66%, respectively, in individual subjects. Therefore, hormone-
based contraceptives alone, regardless of the route of administration (i.e., oral, injectable, transdermal 
or implantable forms), are not considered as reliable methods of contraception (see sections 4.4 and 
4.6). 
 
Warfarin: Co-administration of bosentan 500 mg twice daily for 6 days decreased the plasma 
concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A4 substrate) by 
29% and 38%, respectively. Clinical experience with concomitant administration of bosentan with 
warfarin in patients with PAH did not result in clinically relevant changes in International Normalized 
Ratio (INR) or warfarin dose (baseline versus end of the clinical studies). In addition, the frequency of 
changes in warfarin dose during the studies due to changes in INR or due to adverse events was 
similar among bosentan- and placebo-treated patients. No dose adjustment is needed for warfarin and 
similar oral anticoagulant agents when bosentan is initiated, but intensified monitoring of INR is 
recommended, especially during bosentan initiation and the up-titration period. 
 
Simvastatin: Co-administration of bosentan 125 mg twice daily for 5 days decreased the plasma 
concentrations of simvastatin (a CYP3A4 substrate) and its active β-hydroxy acid metabolite by 34% 
and 46%, respectively. The plasma concentrations of bosentan were not affected by concomitant 
simvastatin. Monitoring of cholesterol levels and subsequent dosage adjustment should be considered. 
 
Ketoconazole: Co-administration for 6 days of bosentan 62.5 mg twice daily with ketoconazole, a 
potent CYP3A4 inhibitor, increased the plasma concentrations of bosentan approximately 2-fold. No 
dose adjustment of Tracleer is considered necessary. Although not demonstrated through in vivo 
studies, similar increases in bosentan plasma concentrations are expected with the other potent 
CYP3A4 inhibitors (such as itraconazole or ritonavir). However, when combined with a CYP3A4 
inhibitor, patients who are poor metabolisers of CYP2C9 are at risk of increases in bosentan plasma 
concentrations that may be of higher magnitude, thus leading to potential harmful adverse events. 
 
Epoprostenol: Limited data obtained from a study (AC-052-356 [BREATHE-3]) in which 
10 paediatric patients received the combination of bosentan and epoprostenol indicate that after both 



33 

single- and multiple-dose administration, the Cmax and AUC values of bosentan were similar in 
patients with or without continuous infusion of epoprostenol (see section 5.1). 
 
Sildenafil: Co-administration of bosentan 125 mg twice daily (steady state) with sildenafil 80 mg three 
times a day (at steady state) concomitantly administered during 6 days in healthy volunteers resulted 
in a 63% decrease in the sildenafil AUC and a 50% increase in the bosentan AUC. Caution is 
recommended in the case of co-administration. 
 
Tadalafil: Bosentan (125 mg twice daily) reduced tadalafil (40 mg once per day) systemic exposure by 
42% and Cmax by 27% following multiple dose co-administration. Tadalafil did not affect the exposure 
(AUC and Cmax) of bosentan or its metabolites. 
 
Digoxin: Co-administration for 7 days of bosentan 500 mg twice daily with digoxin decreased the 
AUC, Cmax and Cmin of digoxin by 12%, 9% and 23%, respectively. The mechanism for this interaction 
may be induction of P-glycoprotein. This interaction is unlikely to be of clinical relevance. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
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 
 
It is not known whether bosentan is excreted into human breast milk. Breast-feeding is not 
recommended during treatment with Tracleer. 
 
Fertility 
 
Animal 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 



34 

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. 
 
4.7 Effects on ability to drive and use machines 
 
No specific studies have been conducted to assess the direct effect of Tracleer on the ability to drive 
and use machines. However, Tracleer may induce hypotension, with symptoms of dizziness, blurred 
vision or syncope that could affect the ability to drive or use machines. 
 
4.8 Undesirable effects 
 
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 2000 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 
disorders 

Common Anaemia, haemoglobin decrease, 
(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 Very common Headache3 
 Common Syncope1, 4 
Eye disorders Not known Blurred vision1 
Cardiac disorders Common Palpitations1, 4 
Vascular disorders Common Flushing 
 Common Hypotension1, 4 
Respiratory, thoracic and 
mediastinal disorders 

Common Nasal congestion1 

Gastrointestinal disorders Common Gastrooesophageal reflux disease 



35 

Diarrhoea 
Hepatobiliary disorders Very common Abnormal liver function test (see 

section 4.4) 
 Uncommon Aminotransferase elevations 

associated with hepatitis 
(including possible exacerbation 
of underlying hepatitis) and/or 
jaundice1 (see section 4.4) 

 Rare Liver cirrhosis, liver failure1 
Skin and subcutaneous disorders Common Erythema 
General disorders and 
administration site conditions  

Very common 
 

Oedema, fluid retention5 
 

1 Data derived from post-marketing experience, frequencies based on statistical modelling of placebo-controlled clinical 
trial data. 

2 Hypersensitivity reactions were reported in 9.9% of patients on bosentan and 9.1% of patients on placebo. 
3 Headache was reported in 11.5% of patients on bosentan and 9.8% of patients on placebo. 
4 These types of reactions can also be related to the underlying disease. 
5 Oedema or fluid retention was reported in 13.2% of patients on bosentan and 10.9% of patients on placebo. 
 
In the post-marketing period rare cases of unexplained hepatic cirrhosis were reported after prolonged 
therapy with Tracleer in patients with multiple co-morbidities and therapies with medicinal products. 
There have also been rare reports of liver failure. These cases reinforce the importance of strict 
adherence to the monthly schedule for monitoring of liver function for the duration of treatment with 
Tracleer (see section 4.4). 
 
Paediatric population 
 
Uncontrolled clinical studies in paediatric patients 
 
The safety profile in 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 2 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%). 
 
A 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). 
 
The 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 
with 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. 
 



36 

In 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 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). 
 
Laboratory abnormalities 
 
Liver test abnormalities 
 
In the clinical programme, dose-dependent elevations in liver aminotransferases generally occurred 
within the first 26 weeks of treatment, usually developed gradually, and were mainly asymptomatic. In 
the post-marketing period rare cases of liver cirrhosis and liver failure have been reported. 
 
The mechanism of this adverse effect is unclear. These elevations in aminotransferases may reverse 
spontaneously while continuing treatment with the maintenance dose of Tracleer or after dose 
reduction, but interruption or cessation may be necessary (see section 4.4). 
 
In the 20 integrated placebo-controlled studies, elevations in liver aminotransferases ≥ 3 × ULN were 
observed in 11.2% of the bosentan-treated patients as compared to 2.4% of the placebo-treated 
patients. Elevations to ≥ 8 × ULN were seen in 3.6% of the bosentan-treated patients and 0.4% of the 
placebo-treated patients. Elevations in aminotransferases were associated with elevated bilirubin 
(≥ 2 × ULN) without evidence of biliary obstruction in 0.2% (5 patients) on bosentan and 0.3% 
(6 patients) on placebo. 
 
In the pooled analysis of 100 PAH children from uncontrolled paediatric studies FUTURE 1/2 and 
FUTURE 3/Extension, elevations in liver aminotransferases ≥ 3 × ULN were observed in 2% of 
patients. 
 
In 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. 
 
Haemoglobin 
 
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). 
 
In 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. 
 
In 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. 
 
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 in Appendix V. 



37 

 
4.9 Overdose 
 
Bosentan has been administered as a single dose of up to 2,400 mg to healthy subjects and up to 
2,000 mg/day for 2 months in patients with a disease other than pulmonary hypertension. The most 
common adverse reaction was headache of mild to moderate intensity. 
 
Massive overdose may result in pronounced hypotension requiring active cardiovascular support. In 
the post-marketing period there was one reported overdose of 10,000 mg of Tracleer taken by an 
adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating and 
blurred vision. He recovered completely within 24 hours with blood pressure support. Note: bosentan 
is not removed through dialysis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: other antihypertensives, ATC code: C02KX01 
 
Mechanism of action 
 
Bosentan is a dual endothelin receptor antagonist (ERA) with affinity for both endothelin A and B 
(ETA and ETB) receptors. Bosentan decreases both pulmonary and systemic vascular resistance 
resulting in increased cardiac output without increasing heart rate. 
 
The neurohormone endothelin-1 (ET-1) is one of the most potent vasoconstrictors known and can also 
promote fibrosis, cell proliferation, cardiac hypertrophy and remodelling, and is pro-inflammatory. 
These effects are mediated by endothelin binding to ETA and ETB receptors located in the endothelium 
and vascular smooth muscle cells. ET-1 concentrations in tissues and plasma are increased in several 
cardiovascular disorders and connective tissue diseases, including PAH, scleroderma, acute and 
chronic heart failure, myocardial ischaemia, systemic hypertension and atherosclerosis, suggesting a 
pathogenic role of ET-1 in these diseases. In PAH and heart failure, in the absence of endothelin 
receptor antagonism, elevated ET-1 concentrations are strongly correlated with the severity and 
prognosis of these diseases. 
 
Bosentan competes with the binding of ET-1 and other ET peptides to both ETA and ETB receptors, 
with a slightly higher affinity for ETA receptors (Ki = 4.1–43 nanomolar) than for ETB receptors 
(Ki = 38–730 nanomolar). Bosentan specifically antagonises ET receptors and does not bind to other 
receptors. 
 
Efficacy 
 
Animal models 
In animal models of pulmonary hypertension, chronic oral administration of bosentan reduced 
pulmonary vascular resistance and reversed pulmonary vascular and right ventricular hypertrophy. In 
an animal model of pulmonary fibrosis, bosentan reduced collagen deposition in the lungs. 
 
Efficacy in adult patients with pulmonary arterial hypertension 
Two randomised, double-blind, multi-centre, placebo-controlled studies have been conducted in 32 
(study AC-052-351) and 213 (study AC-052-352 [BREATHE-1]) adult patients with WHO functional 
class III–IV PAH (primary pulmonary hypertension or pulmonary hypertension secondary mainly to 
scleroderma). After 4 weeks of bosentan 62.5 mg twice daily, the maintenance doses studied in these 



38 

studies were 125 mg twice daily in AC-052-351, and 125 mg twice daily and 250 mg twice daily in 
AC-052-352. 
 
Bosentan was added to patients’ current therapy, which could include a combination of anticoagulants, 
vasodilators (e.g., calcium channel blockers), diuretics, oxygen and digoxin, but not epoprostenol. 
Control was placebo plus current therapy. 
 
The primary endpoint for each study was change in 6-minute walk distance at 12 weeks for the first 
study and 16 weeks for the second study. In both studies, treatment with bosentan resulted in 
significant increases in exercise capacity. The placebo-corrected increases in walk distance compared 
with baseline were 76 metres (p = 0.02; t-test) and 44 metres (p = 0.0002; Mann-Whitney U test) at the 
primary endpoint of each study, respectively. The differences between the two groups, 125 mg twice 
daily and 250 mg twice daily, were not statistically significant but there was a trend towards improved 
exercise capacity in the group treated with 250 mg twice daily. 
 
The improvement in walk distance was apparent after 4 weeks of treatment, was clearly evident after 
8 weeks of treatment and was maintained for up to 28 weeks of double-blind treatment in a subset of 
the patient population. 
 
In a retrospective responder analysis based on change in walking distance, WHO functional class and 
dyspnoea of the 95 patients randomised to bosentan 125 mg twice daily in the placebo-controlled 
studies, it was found that at week 8, 66 patients had improved, 22 were stable and 7 had deteriorated. 
Of the 22 patients stable at week 8, 6 improved at week 12/16 and 4 deteriorated compared with 
baseline. Of the 7 patients who deteriorated at week 8, 3 improved at week 12/16 and 4 deteriorated 
compared with baseline. 
 
Invasive haemodynamic parameters were assessed in the first study only. Treatment with bosentan led 
to a significant increase in cardiac index associated with a significant reduction in pulmonary artery 
pressure, pulmonary vascular resistance and mean right atrial pressure. 
 
A reduction in symptoms of PAH was observed with bosentan treatment. Dyspnoea measurement 
during walk tests showed an improvement in bosentan-treated patients. In the AC-052-352 study, 92% 
of the 213 patients were classified at baseline as WHO functional class III and 8% as class IV. 
Treatment with bosentan led to a WHO functional class improvement in 42.4% of patients (placebo 
30.4%). The overall change in WHO functional class during both studies was significantly better 
among bosentan-treated patients as compared with placebo-treated patients. Treatment with bosentan 
was associated with a significant reduction in the rate of clinical worsening compared with placebo at 
28 weeks (10.7% vs 37.1%, respectively; p = 0.0015). 
 
In a randomised, double-blind, multi-centre, placebo-controlled study (AC-052-364 [EARLY]), 
185 PAH patients in WHO functional class II (mean baseline 6-minute walk distance of 435 metres) 
received bosentan 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily (n = 93), or 
placebo (n = 92) for 6 months. Enrolled patients were PAH-treatment-naïve (n = 156) or on a stable 
dose of sildenafil (n = 29). The co-primary endpoints were percentage change from baseline in 
pulmonary vascular resistance (PVR) and change from baseline in 6-minute walk distance to Month 6 
versus placebo. The table below illustrates the pre-specified protocol analyses. 
 
 PVR (dyn.sec/cm5) 6-Minute Walk Distance (m) 
 Placebo (n=88) Bosentan (n=80) Placebo (n=91) Bosentan (n=86) 
Baseline (BL); mean (SD) 802 (365) 851 (535) 431 (92) 443 (83) 
Change from BL; mean (SD) 128 (465) −69 (475) −8 (79) 11 (74) 
Treatment effects −22.6% 19 
95% CL −34, −10 −4, 42 



39 

P-value < 0.0001 0.0758 
CL = confidence limit; PVR = pulmonary vascular resistance; SD = standard deviation.  
 
Treatment with bosentan was associated with a reduction in the rate of clinical worsening, defined as a 
composite of symptomatic progression, hospitalisation for PAH and death, compared with placebo 
(proportional risk reduction 77%, 95% confidence interval [CI] 20–94%, p = 0.0114). The treatment 
effect was driven by improvement in the component symptomatic progression. There was one 
hospitalisation related to PAH worsening in the bosentan group and three hospitalisations in the 
placebo group. Only one death occurred in each treatment group during the 6-month double-blind 
study period, therefore no conclusion can be drawn on survival. 
 
Long-term data were generated from all 173 patients who were treated with bosentan in the controlled 
phase and/or were switched from placebo to bosentan in the open-label extension phase of the EARLY 
study. The mean duration of exposure to bosentan treatment was 3.6 ± 1.8 years (up to 6.1 years), with 
73% of patients treated for at least 3 years and 62% for at least 4 years. Patients could receive 
additional PAH treatment as required in the open-label extension. The majority of patients were 
diagnosed with idiopathic or heritable PAH (61%). Overall, 78% of patients remained in WHO 
functional class II. Kaplan-Meier estimates of survival were 90% and 85% at 3 and 4 years after the 
start of treatment, respectively. At the same timepoints, 88% and 79% of patients remained free from 
PAH worsening (defined as all-cause death, lung transplantation, atrial septostomy or start of 
intravenous or subcutaneous prostanoid treatment). The relative contributions of previous placebo 
treatment in the double-blind phase and of other medications started during the open-label extension 
period are unknown. 
 
In a prospective, multi-centre, randomised, double-blind, placebo-controlled study (AC-052-405 
[BREATHE-5]), patients with PAH WHO functional class III and Eisenmenger physiology associated 
with congenital heart disease received bosentan 62.5 mg twice daily for 4 weeks, then 125 mg twice 
daily for a further 12 weeks (n = 37, of whom 31 had a predominantly right to left, bidirectional 
shunt). The primary objective was to show that bosentan did not worsen hypoxaemia. After 16 weeks, 
the mean oxygen saturation was increased in the bosentan group by 1.0% (95% CI –0.7%–2.8%) as 
compared to the placebo group (n = 17), showing that bosentan did not worsen hypoxaemia. The mean 
pulmonary vascular resistance was significantly reduced in the bosentan group (with a predominant 
effect observed in the subgroup of patients with bidirectional intracardiac shunt). After 16 weeks, the 
mean placebo-corrected increase in 6-minute walk distance was 53 metres (p = 0.0079), reflecting 
improvement in exercise capacity. Twenty-six patients continued to receive bosentan in the 24-week 
open-label extension phase (AC-052-409) of the BREATHE-5 study (mean duration of treatment = 
24.4 ± 2.0 weeks) and, in general, efficacy was maintained. 
 
An open-label, non-comparative study (AC-052-362 [BREATHE-4]) was performed in 16 patients 
with WHO functional class III PAH associated with HIV infection. Patients were treated with 
bosentan 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily for a further 12 weeks. 
After 16 weeks’ treatment, there were significant improvements from baseline in exercise capacity: the 
mean increase in 6-minute walk distance was 91.4 metres from 332.6 metres 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). 
 
There are no studies to demonstrate beneficial effects of Tracleer treatment on survival. However, 
long-term vital status was recorded for all 235 patients who were treated with bosentan in the two 
pivotal placebo-controlled studies (AC-052-351 and AC-052-352) and/or their two uncontrolled, 
open-label extensions. The mean duration of exposure to bosentan was 1.9 years ± 0.7 years (min: 
0.1 years; max: 3.3 years) and patients were observed for a mean of 2.0 ± 0.6 years. The majority of 
patients were diagnosed as primary pulmonary hypertension (72%) and were in WHO functional class 
III (84%). In this total population, Kaplan-Meier estimates of survival were 93% and 84% 1 and 2 



40 

years after the start of treatment with bosentan, respectively. Survival estimates were lower in the 
subgroup of patients with PAH secondary to systemic sclerosis. The estimates may have been 
influenced by the initiation of epoprostenol treatment in 43/235 patients. 
 
Studies performed in children with pulmonary arterial hypertension 
 
BREATHE-3 (AC-052-356) 
Bosentan film-coated tablets were evaluated in an open-label uncontrolled study in 19 paediatric 
patients with PAH 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) or PAH related to 
congenital heart diseases (9 patients) and were in WHO functional class II (n = 15, 79%) or class III 
(n = 4, 21%) at baseline. Patients were divided into 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. 
 
Haemodynamics were measured in 17 patients. The mean increase from baseline in cardiac index was 
0.5 L/min/m2, the mean decrease in mean pulmonary arterial pressure was 8 mmHg, and the mean 
decrease in PVR was 389 dyn·sec·cm-5. These haemodynamic improvements from baseline were 
similar with or without co-administration of epoprostenol. Changes in exercise test parameters at week 
12 from baseline were highly variable and none were significant. 
 
FUTURE 1/2 (AC-052-365/AC-052-367) 
FUTURE 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, 64%) or class III (n = 13, 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%. 
 
FUTURE 3 (AC-052-373) 
In 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 2 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 related to congenital heart disease associated with systemic-to-
pulmonary shunts, including Eisenmenger syndrome (13%). Patients were in WHO functional class I 
(n = 19, 29 %), class II (n = 27, 42%) or class III (n = 18, 28%) at start of study treatment. At study 
entry, patients were treated with PAH medications (most frequently phosphodiesterase type-5 inhibitor 
[sildenafil] alone [35.9%], bosentan alone [10.9%], and a combination of bosentan, iloprost, and 
sildenafil [10.9%]) and continued their PAH treatment during the study. 
 
At 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 



41 

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 physician’s 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. 
 
There was no evidence of any clinical benefit with 2 mg/kg three times daily as compared to 2 mg/kg 
twice daily dosing. 
 
Study performed in neonates with persistent pulmonary hypertension of the newborn (PPHN): 
 
FUTURE 4 (AC-052-391) 
This 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. 
 
The 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. 
 
The results did not indicate an additional benefit of bosentan in this population: 
• The median time to complete weaning from iNO was 3.7 days (95% confidence limits [CLs] 

1.17, 6.95) on bosentan and 2.9 days (95% CLs 1.26, 4.23) on placebo (p = 0.34). 
• 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). 
• One patient in the bosentan group had treatment failure (need for ECMO as per protocol 

definition), which was declared based on increasing Oxygenation Index values within 8 h after 
the first study drug dose. This patient recovered within the 60-day follow-up period. 

 
Combination with epoprostenol 
The combination of bosentan and epoprostenol has been investigated in two studies: AC-052-355 
(BREATHE-2) and AC-052-356 (BREATHE-3). AC-052-355 was a multi-centre, randomised, 
double-blind, parallel-group study of bosentan versus placebo in 33 patients with severe PAH who 
were receiving concomitant epoprostenol therapy. AC-052-356 was an open-label, uncontrolled study; 
10 of the 19 paediatric patients were on concomitant bosentan and epoprostenol therapy during the 12-
week study. The safety profile of the combination was not different from the one expected with each 
component and the combination therapy was well tolerated in children and adults. The clinical benefit 
of the combination has not been demonstrated. 
 
Systemic sclerosis with digital ulcer disease 
Two randomised, double-blind, multi-centre, placebo-controlled studies have been conducted in 122 
(study AC-052-401 [RAPIDS-1]) and 190 (study AC-052-331 [RAPIDS-2]) adult patients with 
systemic sclerosis and digital ulcer disease (either ongoing digital ulcers or a history of digital ulcers 
within the previous year). In study AC-052-331, patients had to have at least one digital ulcer of recent 
onset, and across the two studies 85% of patients had ongoing digital ulcer disease at baseline. After 
4 weeks of bosentan 62.5 mg twice daily, the maintenance dose studied in both these studies was 



42 

125 mg twice daily. The duration of double-blind therapy was 16 weeks in study AC-052-401, and 
24 weeks in study AC-052-331. 
 
Background treatments for systemic sclerosis and digital ulcers were permitted if they remained 
constant for at least 1 month prior to the start of treatment and during the double-blind study period. 
 
The number of new digital ulcers from baseline to study endpoint was a primary endpoint in both 
studies. Treatment with bosentan resulted in fewer new digital ulcers for the duration of therapy, 
compared with placebo. In study AC-052-401, during 16 weeks of double-blind therapy, patients in 
the bosentan group developed a mean of 1.4 new digital ulcers vs 2.7 new digital ulcers in the placebo 
group (p = 0.0042). In study AC-052-331, during 24 weeks of double-blind therapy, the corresponding 
figures were 1.9 vs 2.7 new digital ulcers, respectively (p = 0.0351). In both studies, patients on 
bosentan were less likely to develop multiple new digital ulcers during the study and took longer to 
develop each successive new digital ulcer than did those on placebo. The effect of bosentan on 
reduction of the number of new digital ulcers was more pronounced in patients with multiple digital 
ulcers. 
 
No effect of bosentan on time to healing of digital ulcers was observed in either study. 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of bosentan have mainly been documented in healthy subjects. Limited data in 
patients show that the exposure to bosentan in adult PAH patients is approximately 2-fold greater than 
in healthy adult subjects. 
 
In healthy subjects, bosentan displays dose- and time-dependent pharmacokinetics. Clearance and 
volume of distribution decrease with increased intravenous doses and increase with time. After oral 
administration, the systemic exposure is proportional to dose up to 500 mg. At higher oral doses, Cmax 
and AUC increase less than proportionally to the dose. 
 
Absorption 
 
In healthy subjects, the absolute bioavailability of bosentan is approximately 50% and is not affected 
by food. The maximum plasma concentrations are attained within 3–5 hours. 
 
Distribution 
 
Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. Bosentan does not penetrate 
into erythrocytes. 
 
A volume of distribution (Vss) of about 18 litres was determined after an intravenous dose of 250 mg. 
 
Biotransformation and elimination 
 
After a single intravenous dose of 250 mg, the clearance was 8.2 L/h. The terminal elimination half-
life (t1/2) is 5.4 hours. 
 
Upon multiple dosing, plasma concentrations of bosentan decrease gradually to 50–65% of those seen 
after single dose administration. This decrease is probably due to auto-induction of metabolising liver 
enzymes. Steady-state conditions are reached within 3–5 days. 
 
Bosentan is eliminated by biliary excretion following metabolism in the liver by the cytochrome P450 
isoenzymes, CYP2C9 and CYP3A4. Less than 3% of an administered oral dose is recovered in urine. 



43 

 
Bosentan forms three metabolites and only one of these is pharmacologically active. This metabolite is 
mainly excreted unchanged via the bile. In adult patients, the exposure to the active metabolite is 
greater than in healthy subjects. In patients with evidence of the presence of cholestasis, the exposure 
to the active metabolite may be increased. 
 
Bosentan is an inducer of CYP2C9 and CYP3A4 and possibly also of CYP2C19 and the 
P-glycoprotein. In vitro, bosentan inhibits the bile salt export pump in hepatocyte cultures. 
 
In vitro data demonstrated that bosentan had no relevant inhibitory effect on the CYP isoenzymes 
tested (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4). Consequently, bosentan is not expected to 
increase the plasma concentrations of medicinal products metabolised by these isoenzymes. 
 
Comparison between formulations 
 
In a pharmacokinetic crossover study (AC-052-116), 16 healthy adult subjects received 62.5 mg 
bosentan using the 62.5 mg film-coated tablet formulation or 64 mg bosentan using the 32 mg 
dispersible tablet formulation. Following treatment with the dispersible tablet, exposure to bosentan 
was lower than with the film-coated tablet (ratio of geometric means for AUC0-∞ 0.87 [90% CI: 0.78, 
0.97]). Tmax and t1/2 of bosentan were not significantly affected by the formulation. 
 
Pharmacokinetics in special populations 
 
Based 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. 
 
Children 
Pharmacokinetics 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. 
 
Study AC-052-356 (BREATHE-3) evaluated the pharmacokinetics of single and multiple oral doses of 
the film-coated tablet formulation of bosentan in 19 children aged from 3 to 15 years with PAH who 
were dosed on the basis of body weight with 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 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. 
 
In study AC-052-365 (FUTURE 1), dispersible tablets were administered in 36 PAH children aged 
from 2 to 11 years. No dose proportionality was observed, 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). The average exposure 
to bosentan in these paediatric patients was about half the exposure in adult patients at the 125 mg 
twice daily maintenance dose but showed a large overlap with the exposures in adults. 
 
In 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; AUCτ was 
4,268 ng·h/mL (CV: 61%). In patients between 3 months and 2 years the daily exposure was 7,879 



44 

ng·h/mL; AUCτ was 3,939 ng·h/mL (CV: 72%). In patients between 3 months and 1 year (n = 2) 
AUCτ was 5,914 ng·h/mL (CV: 85%), and in patients between 1 and 2 years (n = 7) AUCτ was 
3,507 ng·h/mL (CV: 70%). In the patients above 2 years (n = 22) the daily exposure was 8,820 
ng·h/mL; AUCτ was 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). 
 
Based on the findings in studies BREATHE-3, FUTURE 1, and FUTURE-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. 
 
In 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 a 
blood/plasma distribution ratio of 0.6. 
 
The consequences of these findings regarding hepatotoxicity are unknown. Gender and concomitant 
use of intravenous epoprostenol had no significant effect on the pharmacokinetics of bosentan. 
 
Hepatic impairment 
In patients with mildly impaired liver function (Child-Pugh class A) no relevant changes in the 
pharmacokinetics have been observed. The steady-state AUC of bosentan was 9% higher and the AUC 
of the active metabolite, Ro 48-5033, was 33% higher in patients with mild hepatic impairment than in 
healthy volunteers. 
 
The impact of moderately impaired liver function (Child-Pugh class B) on the pharmacokinetics of 
bosentan and its primary metabolite Ro 48-5033 was investigated in a study including 5 patients with 
pulmonary hypertension associated with portal hypertension and Child-Pugh class B hepatic 
impairment, and 3 patients with PAH from other causes and normal liver function. In the patients with 
Child-Pugh class B liver impairment, the mean (95% CI) steady-state AUC of bosentan was 360 (212-
613) ng⋅h/mL, i.e., 4.7 times higher, and the mean (95% CI) AUC of the active metabolite Ro 48-5033 
was 106 (58.4–192) ng⋅h/mL, i.e., 12.4 times higher than in the patients with normal liver function 
(bosentan: mean [95% CI] AUC: 76.1 [9.07–638] ng⋅h/mL; Ro 48-5033: mean [95% CI] AUC 8.57 
[1.28–57.2] ng⋅h/ml). Though the number of patients included was limited and with high variability, 
these data indicate a marked increase in the exposure to bosentan and its primary metabolite Ro 48-
5033 in patients with moderate liver function impairment (Child-Pugh class B). 
 
The pharmacokinetics of bosentan have not been studied in patients with Child-Pugh class C hepatic 
impairment. Tracleer is contraindicated in patients with moderate to severe hepatic impairment, i.e., 
Child-Pugh class B or C (see section 4.3). 
 
Renal impairment 
In patients with severe renal impairment (creatinine clearance 15–30 mL/min), plasma concentrations 
of bosentan decreased by approximately 10%. Plasma concentrations of bosentan metabolites 
increased about 2-fold in these patients as compared with subjects with normal renal function. No dose 
adjustment is required in patients with renal impairment. There is no specific clinical experience in 
patients undergoing dialysis. Based on physicochemical properties and the high degree of protein 
binding, bosentan is not expected to be removed from the circulation by dialysis to any significant 
extent (see section 4.2). 
 



45 

5.3 Preclinical safety data 
 
A 2-year carcinogenicity study in mice showed an increased combined incidence of hepatocellular 
adenomas and carcinomas in males, but not in females, at plasma concentrations about 2 to 4 times the 
plasma concentrations achieved at the therapeutic dose in humans. In rats, oral administration of 
bosentan for 2 years produced a small, significant increase in the combined incidence of thyroid 
follicular cell adenomas and carcinomas in males, but not in females, at plasma concentrations about 9 
to 14 times the plasma concentrations achieved at the therapeutic dose in humans. Bosentan was 
negative in tests for genotoxicity. There was evidence of a mild thyroid hormonal imbalance induced 
by bosentan in rats. However, there was no evidence of bosentan affecting thyroid function (thyroxine, 
TSH) in humans. 
 
The effect of bosentan on mitochondrial function is unknown. 
 
Bosentan has been shown to be teratogenic in rats at plasma levels higher than 1.5 times the plasma 
concentrations achieved at the therapeutic dose in humans. Teratogenic effects, including 
malformations of the head and face and of the major vessels, were dose dependent. The similarities of 
the pattern of malformations observed with other ET receptor antagonists and in ET knock-out mice 
indicate a class effect. Appropriate precautions must be taken for women of childbearing potential (see 
sections 4.3, 4.4 and 4.6). 
 
Development of testicular tubular atrophy and impaired fertility has been linked with chronic 
administration of endothelin receptor antagonists in rodents. 
 
In fertility studies in male and female rats, 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. 
 
Slightly 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 1,500 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. 
 
However, 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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Cellulose microcrystalline 
Calcium hydrogen phosphate anhydrous 
Croscarmellose sodium 
Silica colloidal anhydrous 
Tartaric acid 
Tutti frutti flavour 



46 

Aspartame (E951) 
Acesulfame potassium 
Magnesium stearate 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
5 years 
 
The remaining parts of a divided dispersible tablet can be stored at room temperature and should be 
used within 7 days. 
 
6.4 Special precautions for storage 
 
Do not store above 25°C. 
 
6.5 Nature and contents of container 
 
Aluminium/Aluminium peel-push blisters containing 14 dispersible tablets. 
Cartons contain 56 dispersible tablets. 
 
6.6 Special precautions for disposal and other handling 
 
The dispersible tablet is contained in a child-proof blister. 
 
Each dispersible tablet can be dissolved in water to make a liquid medicine, by adding the tablet to a 
little water on a spoon, using enough water to cover the whole tablet. When the tablet has fully 
dissolved, give the liquid to the patient. 
 
If necessary, the dispersible tablet can be divided by breaking along the lines cut into the surface. Hold 
the tablet between the thumb and index finger on either side of one of the lines, with the line facing 
upwards, and break the tablet along the line (see figure below). 
 

 
 
The remaining parts of a divided dispersible tablet can be stored at room temperature and should be 
used within 7 days. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Janssen-Cilag International NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 



47 

 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/02/220/006 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 May 2002 
 
Date of latest renewal: 20 April 2012 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/. 



48 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



49 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Actelion Manufacturing GmbH 
Emil-Barell-Strasse 7 
79639 Grenzach-Wyhlen 
Germany 
 
Janssen Pharmaceutica NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium  
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2) 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs including liver reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2. of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 



50 

 
• Additional risk minimisation measures 
 
The educational programme consists of a Patient Alert Card to be held by the patient. The overall goal 
of the Patient Alert Card is to educate patients on important safety information that they need to be 
aware of before and during treatment with Tracleer. 
 
The Patient Alert Card, provided as part of the product packaging, aims to: 
• facilitate patients’ awareness of the need for regular blood tests for liver function. 
• inform patients of the need to avoid pregnancy and to ensure effective contraceptive measures 

are used. 



51 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



52 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



53 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
CARTON WITH 14, 56 AND 112 TABLETS 
 
OUTER CARTON/BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tracleer 62.5 mg film-coated tablets 
 
bosentan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 62.5 mg bosentan (as monohydrate) 
 
 
3. LIST OF EXCIPIENTS 
 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 film-coated tablets 
56 film-coated tablets 
112 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP {MM/YYYY} 
 
 



54 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Janssen-Cilag International NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/02/220/001 
EU/1/02/220/002 
EU/1/02/220/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Tracleer 62.5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



55 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 



56 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
CARTON WITH 56 AND 112 TABLETS 
 
OUTER CARTON/BLISTERS 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tracleer 125 mg film-coated tablets 
 
bosentan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 125 mg bosentan (as monohydrate) 
 
 
3. LIST OF EXCIPIENTS 
 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 film-coated tablets 
112 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP {MM/YYYY} 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C 



57 

 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Janssen-Cilag International NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/02/220/004 
EU/1/02/220/005 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Tracleer 125 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



58 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
CARTON WITH 56 TABLETS 
 
OUTER CARTON/BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tracleer 32 mg dispersible tablets 
 
bosentan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each dispersible tablet contains 32 mg bosentan (as monohydrate) 
 
 
3. LIST OF EXCIPIENTS 
 
Aspartame (E951), see the package leaflet for further information 
Aspartame (E951) may be harmful for people with phenylketonuria 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 dispersible tablets (14 x 4) 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP {MM/YYYY} 
 
 



59 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Janssen-Cilag International NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/02/220/006 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Tracleer 32 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



60 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
CARTON WITH 56 TABLETS 
 
OUTER CARTON & BOTTLE LABEL/ BOTTLES 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tracleer 62.5 mg film-coated tablets 
 
bosentan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 62.5 mg bosentan (as monohydrate) 
 
 
3. LIST OF EXCIPIENTS 
 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Do not swallow the desiccant. 
 
 
8. EXPIRY DATE 
 
EXP {MM/YYYY} 
Use within 30 days after the first opening 
 
Open date: 
 



61 

 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Janssen-Cilag International NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/02/220/007 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Tracleer 62.5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



62 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
CARTON WITH 56 TABLETS 
 
OUTER CARTON & BOTTLE LABEL/ BOTTLES 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tracleer 125 mg film-coated tablets 
 
bosentan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 125 mg bosentan (as monohydrate) 
 
 
3. LIST OF EXCIPIENTS 
 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Do not swallow the desiccant. 
 
 
8. EXPIRY DATE 
 
EXP {MM/YYYY} 
Use within 30 days after the first opening 
 
Open date: 
 



63 

 
9. SPECIAL STORAGE CONDITIONS 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Janssen-Cilag International NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/02/220/008 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Tracleer 125 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



64 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tracleer 62.5 mg tablets 
 
bosentan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Janssen-Cilag Int 
 
 
3. EXPIRY DATE 
 
EXP {MM/YYYY} 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 



65 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS  
 
BLISTERS 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tracleer 125 mg tablets 
 
bosentan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Janssen-Cilag Int 
 
 
3. EXPIRY DATE 
 
EXP {MM/YYYY} 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



66 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS  
 
BLISTERS 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tracleer 32 mg dispersible tablets 
 
bosentan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Janssen-Cilag Int 
 
 
3. EXPIRY DATE 
 
EXP {MM/YYYY} 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 



67 

((Front cover)) 

Important Safety Alerts for Patients taking  

Tracleer (bosentan) 
This card contains important information about Tracleer. Please read this card 
carefully before starting your treatment with Tracleer. 

Your name: __________________________________________________ 

Prescribing doctor: ________________________________________ 
If you have questions about Tracleer ask your doctor. 

Janssen-Cilag International NV 
 

((Back cover)) 

Contraception 
Do you currently use or take contraceptives? 

� Yes    � No 

If Yes, write the names of these here: 

______________________________________ 
______________________________________ 

Take this card to your doctor or your gynaecologist at your next visit and 
he/she will be able to advise you on whether you need to use additional or 
alternative contraceptive methods. 

((Inside 1)) 
If you are a woman of childbearing age read this page carefully 

Pregnancy 
Tracleer may harm the development of the foetus. Therefore, you must not take 
Tracleer if you are pregnant and you must also not become pregnant while 
taking Tracleer. 

Moreover, if you are suffering from pulmonary hypertension disease, the 
occurrence of a pregnancy can severely deteriorate the symptoms of your 
disease. If you suspect you may be pregnant, tell your doctor or gynaecologist. 

Contraception 
Birth control based on hormones – such as oral contraceptives or birth control 
pills, hormone injections, implants, or birth control skin patches don’t reliably 
prevent pregnancy in women who are taking Tracleer. You need to use a 
barrier form of birth control – like a condom, diaphragm or vaginal sponge – in 
addition to any of these kinds of hormonal birth control. Be sure to discuss any 
questions you may have with your doctor or your gynaecologist – complete the 
details on the back of this card and take it to your doctor or gynaecologist at 
your next visit. 

You should have a pregnancy test before initiation of Tracleer and every month 
during the treatment even if you think that you are not pregnant. 

Date of first monthly test: _________________________________ 

((Inside 2)) 
Blood Test for Liver Function 
Some patients taking Tracleer were found to have abnormal liver function 
tests. During treatment with Tracleer, your doctor will arrange for regular 
blood tests to check for changes in your liver function. 

Remember to have your liver blood test every month. 
After an increase in dose, an additional test will be done after 2 weeks. 

Date of first monthly test: _________________________________ 

Your monthly liver blood test schedule: 

 

� Jan ______  � May ______  � Sep _____ 

� Feb ______  � Jun ______  � Oct _____ 

� Mar ______  � Jul ______  � Nov _____ 

� Apr ______  � Aug ______  � Dec _____ 

 

PATIENT ALERT CARD 



68 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



69 

Package leaflet: Information for the user 
 

Tracleer 62.5 mg film-coated tablets 
Bosentan 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, please ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. 
 
 
What is in this leaflet 
1. What Tracleer is and what it is used for 
2. What you need to know before you take Tracleer 
3. How to take Tracleer 
4. Possible side effects 
5. How to store Tracleer 
6. Contents of the pack and other information 
 
 
1. What Tracleer is and what it is used for 
 
Tracleer tablets contain bosentan, which blocks a naturally occurring hormone called endothelin-1 
(ET-1), which causes blood vessels to narrow. Tracleer therefore causes blood vessels to expand and 
belongs to the class of medicines called “endothelin receptor antagonists”. 
 
Tracleer is used to treat: 
• Pulmonary arterial hypertension (PAH): PAH is a disease of severe narrowing of the blood 

vessels in the lungs resulting in high blood pressure in the blood vessels (the pulmonary 
arteries) that carry blood from the heart to the lungs. This pressure reduces the amount of 
oxygen that can get into the blood in the lungs, making physical activity more difficult. Tracleer 
widens the pulmonary arteries, making it easier for the heart to pump blood through them. This 
lowers the blood pressure and relieves the symptoms. 

 
Tracleer is used to treat patients with class III PAH to improve exercise capacity (the ability to carry 
out physical activity) and symptoms. The ‘class’ reflects the seriousness of the disease: ‘class III’ 
involves marked limitation of physical activity. Some improvements have also been shown in patients 
with class II PAH. ‘Class II’ involves slight limitation of physical activity. The PAH for which 
Tracleer is indicated can be: 
• primary (with no identified cause or familial); 
• caused by scleroderma (also called systemic sclerosis, a disease where there is abnormal growth 

of the connective tissue that supports the skin and other organs); 
• caused by congenital (inborn) heart defects with shunts (abnormal passageways) causing 

abnormal flow of blood through the heart and lungs. 
 
• Digital ulcers: (sores on the fingers and toes) in adult patients with a condition called 

scleroderma. Tracleer reduces the number of new finger and toe ulcers that appear. 
 
 



70 

2. What you need to know before you take Tracleer 
 
Do not take Tracleer 
• if you are allergic to bosentan or any of the other ingredients of this medicine (listed in 

section 6) 
• if you have liver problems (ask your doctor) 
• if you are pregnant, or could get pregnant because you are not using reliable contraceptive 

methods. Please read the information under “Contraceptives” and “Other medicines and 
Tracleer” 

• if you are taking cyclosporine A (a medicine used after a transplant or to treat psoriasis) 
 
If any of these apply to you, tell your doctor. 
 
Warnings and precautions 
Tests your doctor will do before treatment 
• a blood test to check your liver function 
• a blood test to check for anaemia (low haemoglobin) 
• a pregnancy test if you are a woman of childbearing potential 
Some patients taking Tracleer have been found to have abnormal liver function tests and anaemia (low 
haemoglobin). 
 
Tests your doctor will do during treatment 
During treatment with Tracleer, your doctor will arrange for regular blood tests to check for changes in 
your liver function and haemoglobin level. 
 
For all these tests please refer also to the Patient Alert Card (inside your pack of Tracleer tablets). It is 
important that you have these regular blood tests as long as you are taking Tracleer. We suggest you 
write the date of your most recent test and also of your next test (ask your doctor for the date) on the 
Patient Alert Card, to help you remember when your next test is due. 
 
Blood tests for liver function 
These will be done every month for the duration of treatment with Tracleer. After an increase in dose 
an additional test will be done after 2 weeks. 
 
Blood tests for anaemia 
These will be done every month for the first 4 months of treatment, then every 3 months after that, as 
patients taking Tracleer may get anaemia. 
 
If these results are abnormal, your doctor may decide to reduce your dose or stop treatment with 
Tracleer and to perform further tests to investigate the cause. 
 
Children and adolescents 
Tracleer is not recommended in paediatric patients with systemic sclerosis and ongoing digital ulcer 
disease. Please see also section 3. How to take Tracleer. 
 
Other medicines and Tracleer 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. It is especially important to tell your doctor if 
you are taking: 
• cyclosporine A (a medicine used after transplants and to treat psoriasis), which must not be used 

together with Tracleer. 
• sirolimus or tacrolimus, which are medicines used after transplants, as these are not 

recommended to be used together with Tracleer. 



71 

• glibenclamide (a diabetes medicine), rifampicin (a tuberculosis medicine), fluconazole (a 
medicine against fungal infections), ketoconazole (a medicine used to treat Cushing’s 
syndrome), or nevirapine (an HIV medicine), as these medicines are not recommended to be 
used together with Tracleer. 

• other medicines for the treatment of HIV infection, which may require special monitoring if 
used together with Tracleer. 

• hormonal contraceptives, which are not effective as the sole method of contraception when you 
take Tracleer. Inside your pack of Tracleer tablets you will find a Patient Alert Card which you 
should read carefully. Your doctor and/or gynaecologist will establish the contraception which 
is appropriate for you. 

• other medications for the treatment of pulmonary hypertension: sildenafil and tadalafil; 
• warfarin (an anticoagulant agent); 
• simvastatin (used to treat hypercholesterolaemia). 
 
Driving and using machines 
Tracleer has no or negligible influence on the ability to drive and use machines. However, Tracleer 
can induce hypotension (decrease of your blood pressure) which can make you feel dizzy, affect your 
vision and affect your ability to drive and use machines. Therefore, if you feel dizzy or that your 
vision is blurred while taking Tracleer, do not drive or operate any tools or machines. 
 
Women of childbearing age 
Do NOT take Tracleer if you are pregnant or planning to become pregnant. 
 
Pregnancy tests 
Tracleer may harm unborn babies conceived before starting or during treatment. If you are a woman 
who could become pregnant, your doctor will ask you to take a pregnancy test before you start taking 
Tracleer, and regularly while you are taking Tracleer. 
 
Contraceptives 
If it is possible that you could become pregnant, use a reliable form of birth control (contraception) 
while you are taking Tracleer. Your doctor or gynaecologist will advise you about reliable 
contraceptive methods while taking Tracleer. Because Tracleer may make hormonal contraception 
(e.g., oral, injection, implant, or skin patches) ineffective, this method on its own is not reliable. 
Therefore, if you use hormonal contraceptives you must also use a barrier method (e.g., female 
condom, diaphragm, contraceptive sponge, or your partner must also use a condom). Inside your pack 
of Tracleer tablets you will find a Patient Alert Card. You should complete this card and take it to your 
doctor at your next visit so that your doctor or gynaecologist can assess whether you need additional 
or alternative reliable contraceptive methods. Monthly pregnancy tests are recommended while you 
are taking Tracleer and are of childbearing age. 
 
Tell your doctor immediately if you become pregnant while you are taking Tracleer, or plan to become 
pregnant in the near future. 
 
Breast-feeding 
Tell your doctor immediately if you are breast-feeding. You are advised to stop breast-feeding if 
Tracleer is prescribed for you, because it is not known whether this medicine passes into breast milk. 
 
Fertility 
If you are a man taking Tracleer, it is possible that this medicine may lower your sperm count. It 
cannot be excluded that this may affect your ability to father a child. Talk to your doctor if you have 
any questions or concerns about this. 
 



72 

Tracleer contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’. 
 
3. How to take Tracleer 
 
Treatment with Tracleer should only be started and monitored by a doctor who has experience in the 
treatment of PAH or systemic sclerosis. Always take this medicine exactly as your doctor has told you. 
Check with your doctor or pharmacist if you are not sure. 
 
Tracleer with food and drink 
Tracleer can be taken with or without food. 
 
Recommended dose 
 
Adult 
The treatment in adults is usually started for the first 4 weeks with 62.5 mg twice daily (morning and 
evening), from then your doctor will usually advise you to take a 125 mg tablet twice daily, depending 
on how you react to Tracleer. 
 
Children and adolescents 
The dose recommendation in children is only for PAH. For children aged 1 year and older, treatment 
with Tracleer is usually started with 2 mg per kg bodyweight twice daily (morning and evening). Your 
doctor will advise you on your dosing. 
 
Please note that Tracleer is also available as a dispersible 32 mg tablet formulation, which may make 
correct dosing easier for children and patients with low body weight or difficulties to swallow film-
coated tablets. 
 
If you have the impression that the effect of Tracleer is too strong or too weak, talk to your doctor in 
order to find out whether your dose needs to be changed. 
 
How to take Tracleer 
Tablets should be taken (morning and evening), swallowed with water. The tablets can be taken with 
or without food. 
 
If you take more Tracleer than you should 
If you take more tablets than you have been told to take, contact your doctor immediately. 
 
If you forget to take Tracleer 
If you forget to take Tracleer, take a dose as soon as you remember, then continue to take your tablets 
at the usual times. Do not take a double dose to make up for forgotten tablets. 
 
If you stop taking Tracleer 
Suddenly stopping your treatment with Tracleer may lead to your symptoms getting worse. Do not 
stop taking Tracleer unless your doctor tells you to. Your doctor may tell you to reduce the dose over a 
few days before stopping completely. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 



73 

 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
The most serious side effects with Tracleer are 
• Abnormal liver function which may affect more than 1 in 10 people 
• Anaemia (low blood value) which may affect up to 1 in 10 people. Anaemia may occasionally 

require blood transfusion 
 
Your liver and blood values will be monitored during treatment with Tracleer (see section 2). It is 
important that you have these tests as ordered by your doctor. 
 
Signs that your liver may not be working properly include: 
• nausea (urge to vomit) 
• vomiting 
• fever (high temperature) 
• pain in your stomach (abdomen) 
• jaundice (yellowing of your skin or the whites of your eyes) 
• dark-coloured urine 
• itching of your skin 
• lethargy or fatigue (unusual tiredness or exhaustion) 
• flu-like syndrome (joint and muscle pain with fever) 
 
If you notice any of these signs tell your doctor immediately. 
 
Other side effects 
 
Very common (may affect more than one in 10 people): 
 
• Headache 
• Oedema (swelling of the legs and ankles or other signs of fluid retention) 
 
Common (may affect up to one in 10 people): 
 
• Flushed appearance or redness of skin 
• Hypersensitivity reactions (including skin inflammation, itching and rash) 
• Gastrooesophageal reflux disease (acid reflux) 
• Diarrhoea 
• Syncope (fainting) 
• Palpitations (fast or irregular heart beats) 
• Low blood pressure 
• Nasal congestion 
 
Uncommon (may affect up to one in 100 people): 
 
• Thrombocytopenia (low number of blood platelets) 
• Neutropenia/leukopenia (low number of white blood cells) 
• Elevated liver function tests with hepatitis (inflammation of the liver) including possible 

exacerbation of underlying hepatitis and/or jaundice (yellowing of the skin or the whites of the 
eyes) 

 



74 

Rare (may affect up to one in 1000 people): 
 
• Anaphylaxis (general allergic reaction), angioedema (swelling, most commonly around the eyes, 

lips, tongue or throat) 
• Cirrhosis (scarring) of the liver, liver failure (serious disturbance of liver function) 
 
Blurred vision have also been reported at an unknown frequency (frequency cannot be estimated from 
the available data). 
 
Side effects in children and adolescents 
The side effects that have been reported in children treated with Tracleer are the same as those in 
adults. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Tracleer 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and on the blister after 
“EXP”. 
For white high-density polyethylene bottles, use within 30 days after the first opening. 
 
For PVC/PE/PVDC/aluminium-blisters: 
Do not store above 30°C. 
 
For white high-density polyethylene bottles: 
This medicinal product does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away any medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Tracleer contains 
 
- Tracleer 62.5 mg film-coated tablets: The active substance is bosentan as monohydrate. Each 

tablet contains 62.5 mg of bosentan (as monohydrate). 
- The other ingredients in the tablet core are maize starch, pregelatinised starch, sodium starch 

glycolate (Type A), povidone, glycerol dibehenate and magnesium stearate. The film-coat 
contains hypromellose, glycerol triacetate, talc, titanium dioxide (E171), iron oxide yellow 
(E172), iron oxide red (E172) and ethylcellulose. 

 
What Tracleer looks like and contents of the pack 
 
Tracleer 62.5 mg film-coated tablets are orange-white, round film-coated tablets with “62,5” on one 
side. 



75 

 
PVC/PE/PVDC/aluminium-blisters containing 14 film-coated tablets. Cartons contain 14, 56 or 
112 film-coated tablets (Tracleer 62.5 mg film-coated tablets). 
 
White high-density polyethylene bottles with a silica gel desiccant containing 56 film-coated 
tablets. Cartons contain 56 film-coated tablets (Tracleer 62.5 mg film-coated tablets). 
Do not swallow the desiccant. 
 
Not all pack sizes may be marketed. 
 
Marketing authorisation holder: 
Janssen-Cilag International NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 
 
Manufacturer: 
Actelion Manufacturing GmbH 
Emil-Barell-Strasse 7 
79639 Grenzach-Wyhlen 
Germany 
 
Janssen Pharmaceutica NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
Actelion, a division of Janssen-Cilag 
International NV 
Tél/Tel: +32 14 64 94 11 
janssen@jacbe.jnj.com 
 

Lietuva 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +370 5 278 68 88 
lt@its.jnj.com 
 

България 
Actelion, a division of Janssen-Cilag 
International NV 
Тел.: +359 2 489 94 00 
jjsafety@its.jnj.com 
 

Luxembourg/Luxemburg 
Actelion, a division of Janssen-Cilag 
International NV 
Tél/Tel: +32 14 64 94 11 
janssen@jacbe.jnj.com 
 

Česká republika 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +420 227 012 227 
 

Magyarország 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +36 1 884 2858 
janssenhu@its.jnj.com 
 

Danmark 
Actelion, a division of Janssen-Cilag 
International NV 
Tlf: +45 4594 8282 
jacdk@its.jnj.com 

Malta 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +356 2397 6000 
 



76 

 
Deutschland 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +49 2137 955 955 
jancil@its.jnj.com 
 

Nederland 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +31 76 711 1111 
janssen@jacnl.jnj.com 
 

Eesti 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +372 617 7410 
ee@its.jnj.com 
 

Norge 
Actelion, a division of Janssen-Cilag 
International NV 
Tlf: +47 24 12 65 00 
jacno@its.jnj.com 
 

Ελλάδα 
Actelion, a division of Janssen-Cilag 
International NV 
Τηλ: +30 210 675 25 00  
 

Österreich 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +43 1 505 4527 
 

España 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +34 91 722 81 00  
contacto@its.jnj.com 
 

Polska 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +48 22 237 60 00 
 

France 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +33 (0)1 55 00 26 66 
 

Portugal 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +351 214 368 600 
 

Hrvatska 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +385 1 6610 700 
jjsafety@JNJCR.JNJ.com 
 

România 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +40 21 207 1800 
 

Ireland 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +353 1 800 709 122 
 

Slovenija 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +386 1 401 18 00 
Janssen_safety_slo@its.jnj.com 
 

Ísland 
Actelion, a division of Janssen-Cilag 
International NV 
Sími: +354 535 7000 
janssen@vistor.is 
 

Slovenská republika 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +421 232 408 400 
 

Italia 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: 800.688.777 / +39 02 2510 1 
janssenita@its.jnj.com 
 

Suomi/Finland 
Actelion, a division of Janssen-Cilag 
International NV 
Puh/Tel: +358 207 531 300 
jacfi@its.jnj.com 
 



77 

 
Κύπρος 
Actelion, a division of Janssen-Cilag 
International 
NV Τηλ: +30 210 675 25 00  
 

Sverige 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +46 8 626 50 00 
jacse@its.jnj.com 
 

Latvija 
Actelion, a division of Janssen-Cilag 
International NV 
Tel: +371 678 93561 
lv@its.jnj.com 
 

United Kingdom 
Janssen-Cilag Ltd. 
Tel: +44 1 494 567 444 
 

 
This leaflet was last revised in 
 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/. 



78 

Package leaflet: Information for the user 
 

Tracleer 125 mg film-coated tablets 
Bosentan 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, please ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. 
 
 
What is in this leaflet 
1. What Tracleer is and what it is used for 
2. What you need to know before you take Tracleer 
3. How to take Tracleer 
4. Possible side effects 
5. How to store Tracleer 
6. Contents of the pack and other information 
 
 
1. What Tracleer is and what it is used for 
 
Tracleer tablets contain bosentan, which blocks a naturally occurring hormone called endothelin-1 
(ET-1), which causes blood vessels to narrow. Tracleer therefore causes blood vessels to expand and 
belongs to the class of medicines called “endothelin receptor antagonists”. 
 
Tracleer is used to treat: 
• Pulmonary arterial hypertension (PAH): PAH is a disease of severe narrowing of the blood 

vessels in the lungs resulting in high blood pressure in the blood vessels (the pulmonary 
arteries) that carry blood from the heart to the lungs. This pressure reduces the amount of 
oxygen that can get into the blood in the lungs, making physical activity more difficult. Tracleer 
widens the pulmonary arteries, making it easier for the heart to pump blood through them. This 
lowers the blood pressure and relieves the symptoms. 

 
Tracleer is used to treat patients with class III PAH to improve exercise capacity (the ability to carry 
out physical activity) and symptoms. The ‘class’ reflects the seriousness of the disease: ‘class III’ 
involves marked limitation of physical activity. Some improvements have also been shown in patients 
with class II PAH. ‘Class II’ involves slight limitation of physical activity. The PAH for which 
Tracleer is indicated can be: 
• primary (with no identified cause or familial); 
• caused by scleroderma (also called systemic sclerosis, a disease where there is abnormal growth 

of the connective tissue that supports the skin and other organs); 
• caused by congenital (inborn) heart defects with shunts (abnormal passageways) causing 

abnormal flow of blood through the heart and lungs. 
 
• Digital ulcers: (sores on the fingers and toes) in adult patients with a condition called 

scleroderma. Tracleer reduces the number of new finger and toe ulcers that appear. 
 
 



79 

2. What you need to know before you take Tracleer 
 
Do not take Tracleer 
• if you are allergic to bosentan or any of the other ingredients of this medicine (listed in 

section 6) 
• if you have liver problems (ask your doctor) 
• if you are pregnant, or could get pregnant because you are not using reliable contraceptive 

methods. Please read the information under “Contraceptives” and “Other medicines and 
Tracleer” 

• if you are taking cyclosporine A (a medicine used after a transplant or to treat psoriasis) 
 
If any of these apply to you, tell your doctor. 
 
Warnings and precautions 
Tests your doctor will do before treatment 
• a blood test to check your liver function 
• a blood test to check for anaemia (low haemoglobin) 
• a pregnancy test if you are a woman of childbearing potential 
Some patients taking Tracleer have been found to have abnormal liver function tests and anaemia (low 
haemoglobin). 
 
Tests your doctor will do during treatment 
During treatment with Tracleer, your doctor will arrange for regular blood tests to check for changes in 
your liver function and haemoglobin level. 
 
For all these tests please refer also to the Patient Alert Card (inside your pack of Tracleer tablets). It is 
important that you have these regular blood tests as long as you are taking Tracleer. We suggest you 
write the date of your most recent test and also of your next test (ask your doctor for the date) on the 
Patient Alert Card, to help you remember when your next test is due. 
 
Blood tests for liver function 
These will be done every month for the duration of treatment with Tracleer. After an increase in dose 
an additional test will be done after 2 weeks. 
 
Blood tests for anaemia 
These will be done every month for the first 4 months of treatment, then every 3 months after that, as 
patients taking Tracleer may get anaemia. 
 
If these results are abnormal, your doctor may decide to reduce your dose or stop treatment with 
Tracleer and to perform further tests to investigate the cause. 
 
Children and adolescents 
Tracleer is not recommended in paediatric patients with systemic sclerosis and ongoing digital ulcer 
disease. Please see also section 3. How to take Tracleer. 
 
Other medicines and Tracleer 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. It is especially important to tell your doctor if 
you are taking: 
• cyclosporine A (a medicine used after transplants and to treat psoriasis), which must not be used 

together with Tracleer. 
• sirolimus or tacrolimus, which are medicines used after transplants, as these are not 

recommended to be used together with Tracleer. 



80 

• glibenclamide (a diabetes medicine), rifampicin (a tuberculosis medicine), fluconazole (a 
medicine against fungal infections), ketoconazole (a medicine used to treat Cushing’s 
syndrome), or nevirapine (an HIV medicine), as these medicines are not recommended to be 
used together with Tracleer. 

• other medicines for the treatment of HIV infection, which may require special monitoring if 
used together with Tracleer. 

• hormonal contraceptives, which are not effective as the sole method of contraception when you 
take Tracleer. Inside your pack of Tracleer tablets you will find a Patient Alert Card which you 
should read carefully. Your doctor and/or gynaecologist will establish the contraception which 
is appropriate for you. 

• other medications for the treatment of pulmonary hypertension: sildenafil and tadalafil; 
• warfarin (an anticoagulant agent); 
• simvastatin (used to treat hypercholesterolaemia). 
 
Driving and using machines 
Tracleer has no or negligible influence on the ability to drive and use machines. However, Tracleer 
can induce hypotension (decrease of your blood pressure) which can make you feel dizzy, affect your 
vision and affect your ability to drive and use machines. Therefore, if you feel dizzy or that your 
vision is blurred while taking Tracleer, do not drive or operate any tools or machines. 
 
Women of childbearing age 
Do NOT take Tracleer if you are pregnant or planning to become pregnant. 
 
Pregnancy tests 
Tracleer may harm unborn babies conceived before starting or during treatment. If you are a woman 
who could become pregnant, your doctor will ask you to take a pregnancy test before you start taking 
Tracleer, and regularly while you are taking Tracleer. 
 
Contraceptives 
If it is possible that you could become pregnant, use a reliable form of birth control (contraception) 
while you are taking Tracleer. Your doctor or gynaecologist will advise you about reliable 
contraceptive methods while taking Tracleer. Because Tracleer may make hormonal contraception 
(e.g., oral, injection, implant, or skin patches) ineffective, this method on its own is not reliable. 
Therefore, if you use hormonal contraceptives you must also use a barrier method (e.g., female 
condom, diaphragm, contraceptive sponge, or your partner must also use a condom). Inside your pack 
of Tracleer tablets you will find a Patient Alert Card. You should complete this card and take it to your 
doctor at your next visit so that your doctor or gynaecologist can assess whether you need additional 
or alternative reliable contraceptive methods. Monthly pregnancy tests are recommended while you 
are taking Tracleer and are of childbearing age. 
 
Tell your doctor immediately if you become pregnant while you are taking Tracleer, or plan to become 
pregnant in the near future. 
 
Breast-feeding 
Tell your doctor immediately if you are breast-feeding. You are advised to stop breast-feeding if 
Tracleer is prescribed for you, because it is not known whether this medicine passes into breast milk. 
 
Fertility 
If you are a man taking Tracleer, it is possible that this medicine may lower your sperm count. It 
cannot be excluded that this may affect your ability to father a child. Talk to your doctor if you have 
any questions or concerns about this. 
 



81 

Tracleer contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’. 
 
3. How to take Tracleer 
 
Treatment with Tracleer should only be started and monitored by a doctor who has experience in the 
treatment of PAH or systemic sclerosis. Always take this medicine exactly as your doctor has told you. 
Check with your doctor or pharmacist if you are not sure. 
 
Tracleer with food and drink 
Tracleer can be taken with or without food. 
 
Recommended dose 
 
Adult 
The treatment in adults is usually started for the first 4 weeks with 62.5 mg twice daily (morning and 
evening), from then your doctor will usually advise you to take a 125 mg tablet twice daily, depending 
on how you react to Tracleer. 
 
Children and adolescents 
The dose recommendation in children is only for PAH. For children aged 1 year and older, treatment 
with Tracleer is usually started with 2 mg per kg bodyweight twice daily (morning and evening). Your 
doctor will advise you on your dosing. 
 
Please note that Tracleer is also available as a dispersible 32 mg tablet formulation, which may make 
correct dosing easier for children and patients with low body weight or difficulties to swallow film-
coated tablets. 
 
If you have the impression that the effect of Tracleer is too strong or too weak, talk to your doctor in 
order to find out whether your dose needs to be changed. 
 
How to take Tracleer 
Tablets should be taken (morning and evening), swallowed with water. The tablets can be taken with 
or without food. 
 
If you take more Tracleer than you should 
If you take more tablets than you have been told to take, contact your doctor immediately. 
 
If you forget to take Tracleer 
If you forget to take Tracleer, take a dose as soon as you remember, then continue to take your tablets 
at the usual times. Do not take a double dose to make up for forgotten tablets. 
 
If you stop taking Tracleer 
Suddenly stopping your treatment with Tracleer may lead to your symptoms getting worse. Do not 
stop taking Tracleer unless your doctor tells you to. Your doctor may tell you to reduce the dose over a 
few days before stopping completely. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 



82 

4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
The most serious side effects with Tracleer are 
• Abnormal liver function which may affect more than 1 in 10 people 
• Anaemia (low blood value) which may affect up to 1 in 10 people. Anaemia may occasionally 

require blood transfusion 
Your liver and blood values will be monitored during treatment with Tracleer (see section 2). It is 
important that you have these tests as ordered by your doctor. 
 
Signs that your liver may not be working properly include: 
• nausea (urge to vomit) 
• vomiting 
• fever (high temperature) 
• pain in your stomach (abdomen) 
• jaundice (yellowing of your skin or the whites of your eyes) 
• dark-coloured urine 
• itching of your skin 
• lethargy or fatigue (unusual tiredness or exhaustion) 
• flu-like syndrome (joint and muscle pain with fever) 
 
If you notice any of these signs tell your doctor immediately. 
 
Other side effects 
 
Very common (may affect more than one in 10 people): 
 
• Headache 
• Oedema (swelling of the legs and ankles or other signs of fluid retention) 
 
Common (may affect up to one in 10 people): 
 
• Flushed appearance or redness of skin 
• Hypersensitivity reactions (including skin inflammation, itching and rash) 
• Gastrooesophageal reflux disease (acid reflux) 
• Diarrhoea 
• Syncope (fainting) 
• Palpitations (fast or irregular heart beats) 
• Low blood pressure 
• Nasal congestion 
 
Uncommon (may affect up to one in 100 people): 
 
• Thrombocytopenia (low number of blood platelets) 
• Neutropenia/leukopenia (low number of white blood cells)  
• Elevated liver function tests with hepatitis (inflammation of the liver) including possible 

exacerbation of underlying hepatitis and/or jaundice (yellowing of the skin or the whites of the 
eyes) 

 



83 

Rare (may affect up to one in 1000 people): 
 
• Anaphylaxis (general allergic reaction), angioedema (swelling, most commonly around the eyes, 

lips, tongue or throat) 
• Cirrhosis (scarring) of the liver, liver failure (serious disturbance of liver function) 
 
Blurred vision have also been reported at an unknown frequency (frequency cannot be estimated from 
the available data). 
 
Side effects in children and adolescents 
The side effects that have been reported in children treated with Tracleer are the same as those in 
adults. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Tracleer 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and on the blister after 
“EXP”. 
For white high-density polyethylene bottles, use within 30 days after the first opening. 
 
For PVC/PE/PVDC/aluminium-blisters: 
Do not store above 30°C. 
 
For white high-density polyethylene bottles: 
This medicinal product does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away any medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Tracleer contains 
 
- Tracleer 125 mg film-coated tablets: The active substance is bosentan as monohydrate. Each 

tablet contains 125 mg of bosentan (as monohydrate). 
- The other ingredients in the tablet core are maize starch, pregelatinised starch, sodium starch 

glycolate (Type A), povidone, glycerol dibehenate and magnesium stearate. The film-coat 
contains hypromellose, glycerol triacetate, talc, titanium dioxide (E171), iron oxide yellow 
(E172), iron oxide red (E172) and ethylcellulose. 

 
What Tracleer looks like and contents of the pack 
 
Tracleer 125 mg film-coated tablets are orange-white, oval film-coated tablets with “125” on one side. 
 



84 

PVC/PE/PVDC/aluminium-blisters containing 14 film-coated tablets. Cartons contain 56 or 112 
film-coated tablets (Tracleer 125 mg film-coated tablets). 
 
White high-density polyethylene bottles with a silica gel desiccant containing 56 film-coated 
tablets. Cartons contain 56 film-coated tablets (Tracleer 125 mg film-coated tablets). 
Do not swallow the desiccant. 
 
Not all pack sizes may be marketed. 
 
Marketing authorisation holder: 
Janssen-Cilag International NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 
 
Manufacturer: 
Actelion Manufacturing GmbH 
Emil-Barell-Strasse 7 
79639 Grenzach-Wyhlen 
Germany 
 
Janssen Pharmaceutica NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
Actelion, a division of Janssen-Cilag International 
NV 
Tél/Tel: +32 14 64 94 11 
janssen@jacbe.jnj.com 
 

Lietuva 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +370 5 278 68 88 
lt@its.jnj.com 
 

България 
Actelion, a division of Janssen-Cilag International 
NV 
Тел.: +359 2 489 94 00 
jjsafety@its.jnj.com 
 

Luxembourg/Luxemburg 
Actelion, a division of Janssen-Cilag International 
NV 
Tél/Tel: +32 14 64 94 11 
janssen@jacbe.jnj.com 
 

Česká republika 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +420 227 012 227 
 

Magyarország 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +36 1 884 2858 
janssenhu@its.jnj.com 
 

Danmark 
Actelion, a division of Janssen-Cilag International 
NV 
Tlf: +45 4594 8282 
jacdk@its.jnj.com 
 

Malta 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +356 2397 6000 
 



85 

Deutschland 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +49 2137 955 955 
jancil@its.jnj.com 
 

Nederland 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +31 76 711 1111 
janssen@jacnl.jnj.com 
 

Eesti 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +372 617 7410 
ee@its.jnj.com 
 

Norge 
Actelion, a division of Janssen-Cilag International 
NV 
Tlf: +47 24 12 65 00 
jacno@its.jnj.com 
 

 
Ελλάδα 
Actelion, a division of Janssen-Cilag International 
NV 
Τηλ: +30 210 675 25 00 
 

 
Österreich 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +43 1 505 4527 
 

España 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +34 91 722 81 00 
contacto@its.jnj.com 
 

Polska 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +48 22 237 60 00 
 

France 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +33 (0)1 55 00 26 66 

Portugal 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +351 214 368 600 
 

Hrvatska 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +385 1 6610 700 
jjsafety@JNJCR.JNJ.com 
 

România 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +40 21 207 1800 
 

Ireland 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +353 1 800 709 122 
 

Slovenija 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +386 1 401 18 00 
Janssen_safety_slo@its.jnj.com 
 

Ísland 
Actelion, a division of Janssen-Cilag International 
NV 
Sími: +354 535 7000 
janssen@vistor.is 
 

Slovenská republika 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +421 232 408 400 
 

Italia 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: 800.688.777 / +39 02 2510 1 
janssenita@its.jnj.com 
 

Suomi/Finland 
Actelion, a division of Janssen-Cilag International 
NV 
Puh/Tel: +358 207 531 300 
jacfi@its.jnj.com 
 



86 

Κύπρος 
Actelion, a division of Janssen-Cilag International 
NV 
Τηλ: +30 210 675 25 00 
 

Sverige 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +46 8 626 50 00 
jacse@its.jnj.com 
 

Latvija 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +371 678 93561 
lv@its.jnj.com 
 

United Kingdom 
Janssen-Cilag Ltd. 
Tel: +44 1 494 567 444 
 

 
This leaflet was last revised in 
 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/. 



87 

Package leaflet: Information for the user 
 

Tracleer 32 mg dispersible tablets 
Bosentan 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, please ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. 
 
 
What is in this leaflet 
1. What Tracleer is and what it is used for 
2. What you need to know before you take Tracleer 
3. How to take Tracleer 
4. Possible side effects 
5. How to store Tracleer 
6. Contents of the pack and other information 
 
 
1. What Tracleer is and what it is used for 
 
Tracleer tablets contain bosentan, which blocks a naturally occurring hormone called endothelin-1 
(ET-1), which causes blood vessels to narrow. Tracleer therefore causes blood vessels to expand and 
belongs to the class of medicines called “endothelin receptor antagonists”. 
 
Tracleer is used to treat: 
• Pulmonary arterial hypertension (PAH): PAH is a disease of severe narrowing of the blood 

vessels in the lungs resulting in high blood pressure in the blood vessels (the pulmonary 
arteries) that carry blood from the heart to the lungs. This pressure reduces the amount of 
oxygen that can get into the blood in the lungs, making physical activity more difficult. Tracleer 
widens the pulmonary arteries, making it easier for the heart to pump blood through them. This 
lowers the blood pressure and relieves the symptoms. 
 

Tracleer is used to treat patients with class III PAH to improve exercise capacity (the ability to carry 
out physical activity) and symptoms. The ‘class’ reflects the seriousness of the disease: ‘class III’ 
involves marked limitation of physical activity. Some improvements have also been shown in patients 
with class II PAH. ‘Class II’ involves slight limitation of physical activity. The PAH for which 
Tracleer is indicated can be: 
• primary (with no identified cause or familial); 
• caused by scleroderma (also called systemic sclerosis, a disease where there is abnormal growth 

of the connective tissue that supports the skin and other organs); 
• caused by congenital (inborn) heart defects with shunts (abnormal passageways) causing 

abnormal flow of blood through the heart and lungs. 
 
• Digital ulcers: (sores on the fingers and toes) in adult patients with a condition called 

scleroderma. Tracleer reduces the number of new finger and toe ulcers that appear. 
 
 



88 

2. What you need to know before you take Tracleer 
 
Do not take Tracleer 
• if you are allergic to bosentan or any of the other ingredients of this medicine (listed in 

section 6) 
• if you have liver problems (ask your doctor) 
• if you are pregnant, or could get pregnant because you are not using reliable contraceptive 

methods. Please read the information under “Contraceptives” and “Other medicines and 
Tracleer” 

• if you are taking cyclosporine A (a medicine used after a transplant or to treat psoriasis) 
 
If any of these apply to you, tell your doctor. 
 
Warnings and precautions 
Tests your doctor will do before treatment 
• a blood test to check your liver function 
• a blood test to check for anaemia (low haemoglobin) 
• a pregnancy test if you are a woman of childbearing potential 
Some patients taking Tracleer have been found to have abnormal liver function tests and anaemia (low 
haemoglobin). 
 
Tests your doctor will do during treatment 
During treatment with Tracleer, your doctor will arrange for regular blood tests to check for changes in 
your liver function and haemoglobin level. 
 
For all these tests please refer also to the Patient Alert Card (inside your pack of Tracleer tablets). It is 
important that you have these regular blood tests as long as you are taking Tracleer. We suggest you 
write the date of your most recent test and also of your next test (ask your doctor for the date) on the 
Patient Alert Card, to help you remember when your next test is due. 
 
Blood tests for liver function 
These will be done every month for the duration of treatment with Tracleer. After an increase in dose 
an additional test will be done after 2 weeks. 
 
Blood tests for anaemia 
These will be done every month for the first 4 months of treatment, then every 3 months after that, as 
patients taking Tracleer may get anaemia. 
 
If these results are abnormal, your doctor may decide to reduce your dose or stop treatment with 
Tracleer and to perform further tests to investigate the cause. 
 
Children and adolescents 
Tracleer is not recommended in paediatric patients with systemic sclerosis and ongoing digital ulcer 
disease. Please see also section 3. How to take Tracleer. 
 
Other medicines and Tracleer 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. It is especially important to tell your doctor if 
you are taking: 
• cyclosporine A (a medicine used after transplants and to treat psoriasis), which must not be used 

together with Tracleer. 
• sirolimus or tacrolimus, which are medicines used after transplants, as these are not 

recommended to be used together with Tracleer. 



89 

• glibenclamide (a diabetes medicine), rifampicin (a tuberculosis medicine), fluconazole (a 
medicine against fungal infections), ketoconazole (a medicine used to treat Cushing’s 
syndrome), or nevirapine (an HIV medicine), as these medicines are not recommended to be 
used together with Tracleer. 

• other medicines for the treatment of HIV infection, which may require special monitoring if 
used together with Tracleer. 

• hormonal contraceptives, which are not effective as the sole method of contraception when you 
take Tracleer. Inside your pack of Tracleer tablets you will find a Patient Alert Card which you 
should read carefully. Your doctor and/or gynaecologist will establish the contraception which 
is appropriate for you. 

• other medications for the treatment of pulmonary hypertension: sildenafil and tadalafil; 
• warfarin (an anticoagulant agent); 
• simvastatin (used to treat hypercholesterolaemia). 
 
Driving and using machines 
Tracleer has no or negligible influence on the ability to drive and use machines. However, Tracleer 
can induce hypotension (decrease of your blood pressure) which can make you feel dizzy, affect your 
vision and affect your ability to drive and use machines. Therefore, if you feel dizzy or that your 
vision is blurred while taking Tracleer, do not drive or operate any tools or machines. 
 
Women of childbearing age 
Do NOT take Tracleer if you are pregnant or planning to become pregnant. 
 
Pregnancy tests 
Tracleer may harm unborn babies conceived before starting or during treatment. If you are a woman 
who could become pregnant, your doctor will ask you to take a pregnancy test before you start taking 
Tracleer, and regularly while you are taking Tracleer. 
 
Contraceptives 
If it is possible that you could become pregnant, use a reliable form of birth control (contraception) 
while you are taking Tracleer. Your doctor or gynaecologist will advise you about reliable 
contraceptive methods while taking Tracleer. Because Tracleer may make hormonal contraception 
(e.g., oral, injection, implant, or skin patches) ineffective, this method on its own is not reliable. 
Therefore, if you use hormonal contraceptives you must also use a barrier method (e.g., female 
condom, diaphragm, contraceptive sponge, or your partner must also use a condom). Inside your pack 
of Tracleer tablets you will find a Patient Alert Card. You should complete this card and take it to your 
doctor at your next visit so that your doctor or gynaecologist can assess whether you need additional 
or alternative reliable contraceptive methods. Monthly pregnancy tests are recommended while you 
are taking Tracleer and are of childbearing age. 
 
Tell your doctor immediately if you become pregnant while you are taking Tracleer, or plan to become 
pregnant in the near future. 
 
Breast-feeding 
Tell your doctor immediately if you are breast-feeding. You are advised to stop breast-feeding if 
Tracleer is prescribed for you, because it is not known whether this medicine passes into breast milk. 
 
Fertility 
If you are a man taking Tracleer, it is possible that this medicine may lower your sperm count. It 
cannot be excluded that this may affect your ability to father a child. Talk to your doctor if you have 
any questions or concerns about this. 
 
 



90 

Tracleer contains aspartame and sodium 
This medicine contains 3.7 mg of aspartame in each dispersible tablet. Aspartame is a source of 
phenylalanine. It may be harmful if you have phenylketonuria (PKU), a rare genetic disorder in which 
phenylalanine builds up because the body cannot remove it properly. 
 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’. 
 
3. How to take Tracleer 
 
Treatment with Tracleer should only be started and monitored by a doctor who has experience in the 
treatment of PAH or systemic sclerosis. Always take this medicine exactly as your doctor has told you. 
Check with your doctor or pharmacist if you are not sure. 
 
Tracleer with food and drink 
Tracleer can be taken with or without food. 
 
Recommended dose 
 
Adult 
The treatment in adults is usually started for the first 4 weeks with 62.5 mg twice daily (morning and 
evening), from then your doctor will usually advise you to take a 125 mg tablet twice daily, depending 
on how you react to Tracleer. 
 
Children and adolescents 
The dose recommendation in children is only for PAH. For children aged 1 year and older, treatment 
with Tracleer is usually started with 2 mg per kg bodyweight twice daily (morning and evening). Your 
doctor will advise you on your dosing. 
If necessary the dispersible tablet can be divided along the break-marks into four equal parts. 
 
If you have the impression that the effect of Tracleer is too strong or too weak, talk to your doctor in 
order to find out whether your dose needs to be changed. 
 
How to take Tracleer 
Tablets should be taken (morning and evening), swallowed with water. The tablets can be taken with 
or without food. 
 
The dispersible tablet is contained in a child-proof blister. 
 
To remove the dispersible tablet: 
 

 
 
1. Separate the individual blister cavity at the perforations. 
2. Peel off the top layer. 
3. Push the pharmaceutical product through the foil. 
 



91 

Each Tracleer dispersible tablet can be dissolved in water to make a liquid medicine. To make a liquid 
medicine, add the tablet to a little water on a spoon. Use enough water to cover the whole tablet. Leave 
for about one minute, until the tablet has fully dissolved, and then swallow all of the liquid. Add a 
little more water to the spoon and swallow all of the liquid to make sure all of the medicine has been 
taken. If possible, you should drink a glass of water to ensure that all the medicine has been taken. 
 
If necessary the dispersible tablet can be divided along the break-marks. Hold the tablet between the 
thumb and the index finger on either side of the score line, with the score line facing upwards. 
Separate into halves by breaking the tablet along the break-marks (see figure below). 

 
 
If you take more Tracleer than you should 
If you take more tablets than you have been told to take, contact your doctor immediately. 
 
If you forget to take Tracleer 
If you forget to take Tracleer, take a dose as soon as you remember, then continue to take your tablets 
at the usual times. Do not take a double dose to make up for forgotten tablets. 
 
If you stop taking Tracleer 
Suddenly stopping your treatment with Tracleer may lead to your symptoms getting worse. Do not 
stop taking Tracleer unless your doctor tells you to. Your doctor may tell you to reduce the dose over a 
few days before stopping completely. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
The most serious side effects with Tracleer are 
• Abnormal liver function which may affect more than 1 in 10 people 
• Anaemia (low blood value) which may affect up to 1 in 10 people. Anaemia may occasionally 

require blood transfusion 
Your liver and blood values will be monitored during treatment with Tracleer (see section 2). It is 
important that you have these tests as ordered by your doctor. 
 
Signs that your liver may not be working properly include: 
• nausea (urge to vomit) 
• vomiting 
• fever (high temperature) 
• pain in your stomach (abdomen) 
• jaundice (yellowing of your skin or the whites of your eyes) 
• dark-coloured urine 
• itching of your skin 
• lethargy or fatigue (unusual tiredness or exhaustion) 
• flu-like syndrome (joint and muscle pain with fever) 
 



92 

If you notice any of these signs tell your doctor immediately. 
 
 
Other side effects: 
 
Very common (may affect more than one in 10 people): 
 
• Headache 
• Oedema (swelling of the legs and ankles or other signs of fluid retention) 
 
Common (may affect up to one in 10 people): 
 
• Flushed appearance or redness of skin 
• Hypersensitivity reactions (including skin inflammation, itching and rash) 
• Gastrooesophageal reflux disease (acid reflux) 
• Diarrhoea 
• Syncope (fainting) 
• Palpitations (fast or irregular heart beats) 
• Low blood pressure 
• Nasal congestion 
 
Uncommon (may affect up to one in 100 people): 
 
• Thrombocytopenia (low number of blood platelets) 
• Neutropenia/leukopenia (low number of white blood cells) 
• Elevated liver function tests with hepatitis (inflammation of the liver) including possible 

exacerbation of underlying hepatitis and/or jaundice (yellowing of the skin or the whites of the 
eyes) 

 
Rare (may affect up to one in 1000 people): 
 
• Anaphylaxis (general allergic reaction), angioedema (swelling, most commonly around the eyes, 

lips, tongue or throat) 
• Cirrhosis (scarring) of the liver, liver failure (serious disturbance of liver function) 
 
Blurred vision have also been reported at an unknown frequency (frequency cannot be estimated from 
the available data). 
 
Side effects in children and adolescents 
The side effects that have been reported in children treated with Tracleer are the same as those in 
adults. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Tracleer 
 
Keep this medicine out of the sight and reach of children. 



93 

 
Do not use this medicine after the expiry date which is stated on the carton and on the blister after 
“EXP”. 
 
Do not store above 25°C. 
 
Remaining parts of a divided dispersible tablet can be stored at room temperature and should be used 
within 7 days. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away any medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Tracleer contains 
 
- The active substance is bosentan as monohydrate. Each dispersible tablet contains 32 mg of 

bosentan (as monohydrate). 
- The other ingredients are cellulose microcrystalline, calcium hydrogen phosphate anhydrous, 

croscarmellose sodium, silica colloidal anhydrous, tartaric acid, tutti frutti flavour, aspartame 
(E951, please read further information at the end of section 2), acesulfame potassium, 
magnesium stearate. 

 
What Tracleer looks like and contents of the pack 
 
Tracleer 32 mg dispersible tablets are pale yellow to off-white, clover-shape dispersible tablets, 
quadrisected on one side and debossed with “32” on the other side. 
 
Peel-push blisters containing 14 dispersible tablets; cartons contain 56 dispersible tablets. 
 
Marketing authorisation holder: 
Janssen-Cilag International NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 
 
Manufacturer: 
Actelion Manufacturing GmbH 
Emil-Barell-Strasse 7 
79639 Grenzach-Wyhlen 
Germany 
 
Janssen Pharmaceutica NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 
 
 



94 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
Actelion, a division of Janssen-Cilag International 
NV 
Tél/Tel: +32 14 64 94 11 
janssen@jacbe.jnj.com 
 
 

Lietuva 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +370 5 278 68 88 
lt@its.jnj.com 

България 
Actelion, a division of Janssen-Cilag International 
NV 
Тел.: +359 2 489 94 00 
jjsafety@its.jnj.com 
 

Luxembourg/Luxemburg 
Actelion, a division of Janssen-Cilag International 
NV 
Tél/Tel: +32 14 64 94 11 
janssen@jacbe.jnj.com 
 

Česká republika 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +420 227 012 227 
 

Magyarország 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +36 1 884 2858 
janssenhu@its.jnj.com 
 

Danmark 
Actelion, a division of Janssen-Cilag International 
NV 
Tlf: +45 4594 8282 
jacdk@its.jnj.com 
 

Malta 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +356 2397 6000 

Deutschland 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +49 2137 955 955 
jancil@its.jnj.com 
 

Nederland 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +31 76 711 1111 
janssen@jacnl.jnj.com 
 

Eesti 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +372 617 7410 
ee@its.jnj.com 
 

Norge 
Actelion, a division of Janssen-Cilag International 
NV 
Tlf: +47 24 12 65 00 
jacno@its.jnj.com 
 

Ελλάδα 
Actelion, a division of Janssen-Cilag International 
NV 
Τηλ: +30 210 675 25 00 
 

Österreich 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +43 1 505 4527 
 

España 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +34 91 722 81 00 
contacto@its.jnj.com 
 

Polska 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +48 22 237 60 00 
 

France 
Actelion, a division of Janssen-Cilag International 

Portugal 
Actelion, a division of Janssen-Cilag International 



95 

NV 
Tel: +33 (0)1 55 00 26 66 
 

NV 
Tel: +351 214 368 600 
 

Hrvatska 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +385 1 6610 700 
jjsafety@JNJCR.JNJ.com 
 

România 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +40 21 207 1800 

Ireland 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +353 1 800 709 122 
 

Slovenija 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +386 1 401 18 00 
Janssen_safety_slo@its.jnj.com 
 

Ísland 
Actelion, a division of Janssen-Cilag International 
NV 
Sími: +354 535 7000 
janssen@vistor.is 
 

Slovenská republika 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +421 232 408 400 
 

Italia 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: 800.688.777 / +39 02 2510 1 
janssenita@its.jnj.com 
 

Suomi/Finland 
Actelion, a division of Janssen-Cilag International 
NV 
Puh/Tel: +358 207 531 300 
jacfi@its.jnj.com 
 

Κύπρος 
Actelion, a division of Janssen-Cilag International 
NV 
Τηλ: +30 210 675 25 00 
 

Sverige 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +46 8 626 50 00 
jacse@its.jnj.com 
 

Latvija 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +371 678 93561 
lv@its.jnj.com 
 

United Kingdom 
Janssen-Cilag Ltd. 
Tel: +44 1 494 567 444 
 

 
This leaflet was last revised in 
 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET