TRACLEER 125mg tablets medication leaflet

Tracleer 62.5 mg film-coated tablets

Tracleer 125 mg film-coated tablets

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).

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.

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.

Treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms inpatients 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 interstitialpulmonary 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 WHOfunctional class II (see section 5.1).

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

Tablets are to be taken orally morning and evening, with or without food. The film-coated tablets areto be swallowed with water.

Patients should be advised not to swallow the desiccant found in the white high-density polyethylenebottles.

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 beforeand during treatment with Tracleer is included in the pack.

In adult patients, Tracleer treatment should be initiated at a dose of 62.5 mg twice daily for 4 weeksand then increased to the maintenance dose of 125 mg twice daily. The same recommendations applyto re-introduction of Tracleer after treatment interruption (see section 4.4).

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 increasedby increasing the dose of Tracleer above 2 mg/kg body weight or by increasing the dosing frequencyfrom twice daily to three times daily (see section 5.2). Increasing the dose or the dosing frequency willlikely not result in additional clinical benefit.

Based on these pharmacokinetic results, when used in children with PAH aged 1 year and older, therecommended starting and maintenance dose is 2 mg/kg morning and evening.

In neonates with persistent pulmonary hypertension of the newborn (PPHN), the benefit of bosentanhas 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 dosefor at least 4 weeks), alternative therapies should be considered. However, some patients who show noresponse after 8 weeks of treatment with Tracleer may respond favourably after an additional 4 to8 weeks of treatment.

In the event of late clinical deterioration despite treatment with Tracleer (i.e., after several months oftreatment), the treatment should be re-assessed. Some patients not responding well to 125 mg twicedaily of Tracleer may slightly improve their exercise capacity when the dose is increased to 250 mgtwice daily. A careful benefit/risk assessment should be made, taking into consideration that the livertoxicity is dose dependent (see sections 4.4 and 5.1).

There is limited experience with abrupt discontinuation of Tracleer in patients with PAH. No evidencefor acute rebound has been observed. However, to avoid the possible occurrence of harmful clinicaldeterioration 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 therapyis introduced.

Systemic sclerosis with ongoing digital ulcer disease

Treatment should only be initiated and monitored by a physician experienced in the treatment ofsystemic sclerosis.

A Patient Alert Card providing important safety information that patients need to be aware of beforeand during treatment with Tracleer is included in the pack.

Tracleer treatment should be initiated at a dose of 62.5 mg twice daily for 4 weeks and then increasedto 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 regularbasis. A careful benefit/risk assessment should be made, taking into consideration the liver toxicity ofbosentan (see sections 4.4 and 4.8).

There are no data on the safety and efficacy in patients under the age of 18 years. Pharmacokineticdata are not available for Tracleer in young children with this disease.

Tracleer is contraindicated in patients with moderate to severe liver dysfunction (see sections pct. 4.3, pct. 4.4and 5.2). No dose adjustment is needed in patients with mild hepatic impairment (i.e., Child-Pughclass A) (see section 5.2).

No dose adjustment is required in patients with renal impairment. No dose adjustment is required inpatients undergoing dialysis (see section 5.2).

No dose adjustment is required in patients over the age of 65 years.

- 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)

- Baseline values of liver aminotransferases, i.e., aspartate aminotransferase (AST) and/or alanineaminotransferase (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 (seesections 4.4, 4.5 and 4.6)

The efficacy of Tracleer has not been established in patients with severe PAH. Transfer to a therapythat is recommended at the severe stage of the disease (e.g., epoprostenol) should be considered if theclinical condition deteriorates (see section 4.2).

The benefit/risk balance of bosentan has not been established in patients with WHO class I functionalstatus 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.

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 first26 weeks of treatment but may also occur late in treatment (see section 4.8). These increases may bepartly due to competitive inhibition of the elimination of bile salts from hepatocytes but othermechanisms, which have not been clearly established, are probably also involved in the occurrence ofliver dysfunction. The accumulation of bosentan in hepatocytes leading to cytolysis with potentiallysevere damage of the liver, or an immunological mechanism, are not excluded. Liver dysfunction riskmay 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 withbosentan, but limited data are available.

Liver aminotransferase levels must be measured prior to initiation of treatment andsubsequently at monthly intervals for the duration of treatment with Tracleer. In addition, liveraminotransferase 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 decisionshould be made on an individual basis to continue Tracleer, possibly at areduced dose, or to stop Tracleer administration (see section 4.2). Monitoringof aminotransferase levels should be continued at least every 2 weeks. If theaminotransferase levels return to pre-treatment values continuing or re-introducing Tracleer according to the conditions described below should beconsidered.

> 5 and  8  ULN The result should be confirmed by a second liver test; if confirmed, treatmentshould be stopped and aminotransferase levels monitored at least every2 weeks. If the aminotransferase levels return to pre-treatment values re-introducing Tracleer according to the conditions described below should beconsidered.

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

In the event of associated clinical symptoms of liver injury, i.e., nausea, vomiting, fever, abdominalpain, jaundice, unusual lethargy or fatigue, flu-like syndrome (arthralgia, myalgia, fever), treatmentmust 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 oftreatment with Tracleer outweigh the potential risks and when liver aminotransferase levels are withinpre-treatment values. The advice of a hepatologist is recommended. Re-introduction must follow theguidelines detailed in section 4.2. Aminotransferase levels must then be checked within 3 daysafter re-introduction, then again after a further 2 weeks, and thereafter according to therecommendations above.

ULN = upper limit of normal

Treatment with bosentan has been associated with dose-related decreases in haemoglobinconcentration (see section 4.8). In placebo-controlled studies, bosentan-related decreases inhaemoglobin concentration were not progressive, and stabilised after the first 4-12 weeks oftreatment. It is recommended that haemoglobin concentrations be checked prior to initiation oftreatment, every month during the first 4 months, and quarterly thereafter. If a clinically relevantdecrease in haemoglobin concentration occurs, further evaluation and investigation should beundertaken to determine the cause and need for specific treatment. In the post-marketing period, casesof anaemia requiring red blood cell transfusion have been reported (see section 4.8).

As Tracleer may render hormonal contraceptives ineffective, and taking into account the risk thatpulmonary hypertension deteriorates with pregnancy as well as the teratogenic effects observed inanimals:

- Tracleer treatment must not be initiated in women of childbearing potential unless they practisereliable 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 ofpregnancy

For further information see sections 4.5 and 4.6.

Cases of pulmonary oedema have been reported with vasodilators (mainly prostacyclins) when used inpatients with pulmonary veno-occlusive disease. Consequently, should signs of pulmonary oedemaoccur when Tracleer is administered in patients with PAH, the possibility of associated veno-occlusivedisease should be considered. In the post-marketing period there have been rare reports of pulmonaryoedema in patients treated with Tracleer who had a suspected diagnosis of pulmonary veno-occlusivedisease.

Pulmonary arterial hypertension patients with concomitant left ventricular failure

No specific study has been performed in patients with pulmonary hypertension and concomitant leftventricular 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 increasedincidence of hospitalisation due to CHF during the first 4-8 weeks of treatment with bosentan, whichcould have been the result of fluid retention. In this study, fluid retention was manifested by earlyweight gain, decreased haemoglobin concentration and increased incidence of leg oedema. At the endof this study, there was no difference in overall hospitalisations for heart failure nor in mortalitybetween bosentan- and placebo-treated patients. Consequently, it is recommended that patients bemonitored for signs of fluid retention (e.g., weight gain), especially if they concomitantly suffer fromsevere systolic dysfunction. Should this occur, starting treatment with diuretics is recommended, or thedose of existing diuretics should be increased. Treatment with diuretics should be considered inpatients 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 associatedwith HIV infection, treated with antiretroviral medicinal products (see section 5.1). An interactionstudy between bosentan and lopinavir+ritonavir in healthy subjects showed increased plasmaconcentrations of bosentan, with the maximum level during the first 4 days of treatment (seesection 4.5). When treatment with Tracleer is initiated in patients who require ritonavir-boostedprotease inhibitors, the patient’s tolerability of Tracleer should be closely monitored with specialattention, 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 excludedwhen bosentan is used in combination with antiretroviral medicinal products. Due to the potential forinteractions related to the inducing effect of bosentan on CYP450 (see section 4.5), which could affectthe 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 in11 patients with pulmonary hypertension secondary to severe COPD (stage III of GOLDclassification). 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 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. Forfurther details please refer to section 4.5.

Concomitant administration of both a CYP3A4 inhibitor and a CYP2C9 inhibitor with Tracleer shouldbe avoided (see section 4.5).

Bosentan is an inducer of the cytochrome P450 (CYP) isoenzymes CYP2C9 and CYP3A4. In vitrodata also suggest an induction of CYP2C19. Consequently, plasma concentrations of substancesmetabolised by these isoenzymes will be decreased when Tracleer is co-administered. The possibilityof altered efficacy of medicinal products metabolised by these isoenzymes should be considered. Thedosage of these products may need to be adjusted after initiation, dose change or discontinuation ofconcomitant Tracleer treatment.

Bosentan is metabolised by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase theplasma concentration of bosentan (see ketoconazole). The influence of CYP2C9 inhibitors onbosentan 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 inplasma concentrations of bosentan. The combination is not recommended. For the same reason,concomitant administration of both a potent CYP3A4 inhibitor (such as ketoconazole, itraconazole orritonavir) and a CYP2C9 inhibitor (such as voriconazole) with Tracleer is not recommended.

Cyclosporine A: Co-administration of Tracleer and cyclosporine A (a calcineurin inhibitor) iscontraindicated (see section 4.3). When co-administered, initial trough concentrations of bosentanwere approximately 30-fold higher than those measured after bosentan alone. At steady state, bosentanplasma concentrations were 3- to 4-fold higher than with bosentan alone. The mechanism of thisinteraction is most likely inhibition of transport protein-mediated uptake of bosentan into hepatocytesby cyclosporine. The blood concentrations of cyclosporine A (a CYP3A4 substrate) decreased byapproximately 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 studiedin man but co-administration of tacrolimus or sirolimus and Tracleer may result in increased plasmaconcentrations of bosentan in analogy to co-administration with cyclosporine A. Concomitant Tracleermay 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 beclosely monitored for adverse events related to Tracleer and for tacrolimus and sirolimus bloodconcentrations.

Glibenclamide: Co-administration of bosentan 125 mg twice daily for 5 days decreased the plasmaconcentrations of glibenclamide (a CYP3A4 substrate) by 40%, with potential significant decrease ofthe hypoglycaemic effect. The plasma concentrations of bosentan were also decreased by 29%. Inaddition, an increased incidence of elevated aminotransferases was observed in patients receivingconcomitant therapy. Both glibenclamide and bosentan inhibit the bile salt export pump, which couldexplain the elevated aminotransferases. This combination should not be used. No drug-drug interactiondata are available with the other sulfonylureas.

Rifampicin: Co-administration in 9 healthy subjects for 7 days of bosentan 125 mg twice daily withrifampicin, a potent inducer of CYP2C9 and CYP3A4, decreased the plasma concentrations ofbosentan by 58%, and this decrease could achieve almost 90% in an individual case. As a result, asignificantly 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 concomitantadministration is expected to lead to reduced systemic exposure to bosentan. A clinically significantreduction of efficacy cannot be excluded.

Lopinavir+ritonavir (and other ritonavir-boosted protease inhibitors): Co-administration of bosentan125 mg twice daily and lopinavir+ritonavir 400+100 mg twice daily for 9.5 days in healthy volunteersresulted in initial trough plasma concentrations of bosentan that were approximately 48-fold higherthan those measured after bosentan administered alone. On day 9, plasma concentrations of bosentanwere approximately 5-fold higher than with bosentan administered alone. Inhibition by ritonavir oftransport protein-mediated uptake into hepatocytes and of CYP3A4, thereby reducing the clearance ofbosentan, most likely causes this interaction. When administered concomitantly withlopinavir+ritonavir, or other ritonavir-boosted protease inhibitors, the patient’s tolerability of Tracleershould be monitored.

After co-administration of bosentan for 9.5 days, the plasma exposures to lopinavir and ritonavirdecreased 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 proteaseinhibitors cannot be excluded. Appropriate monitoring of the HIV therapy is recommended. Similareffects 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 availableantiretroviral agents due to the lack of data. Due to the marked hepatotoxicity of nevirapine, whichcould 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 singledose 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 inexposure 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, transdermalor implantable forms), are not considered as reliable methods of contraception (see sections 4.4 and4.6).

Warfarin: Co-administration of bosentan 500 mg twice daily for 6 days decreased the plasmaconcentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A4 substrate) by29% and 38%, respectively. Clinical experience with concomitant administration of bosentan withwarfarin in patients with PAH did not result in clinically relevant changes in International Normalised

Ratio (INR) or warfarin dose (baseline versus end of the clinical studies). In addition, the frequency ofchanges in warfarin dose during the studies due to changes in INR or due to adverse events wassimilar among bosentan- and placebo-treated patients. No dose adjustment is needed for warfarin andsimilar oral anticoagulant agents when bosentan is initiated, but intensified monitoring of INR isrecommended, especially during bosentan initiation and the up-titration period.

Simvastatin: Co-administration of bosentan 125 mg twice daily for 5 days decreased the plasmaconcentrations of simvastatin (a CYP3A4 substrate) and its active -hydroxy acid metabolite by 34%and 46%, respectively. The plasma concentrations of bosentan were not affected by concomitantsimvastatin. 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, apotent CYP3A4 inhibitor, increased the plasma concentrations of bosentan approximately 2-fold. Nodose adjustment of Tracleer is considered necessary. Although not demonstrated through in vivostudies, similar increases in bosentan plasma concentrations are expected with the other potent

CYP3A4 inhibitors (such as itraconazole or ritonavir). However, when combined with a CYP3A4inhibitor, patients who are poor metabolisers of CYP2C9 are at risk of increases in bosentan plasmaconcentrations 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 which10 paediatric patients received the combination of bosentan and epoprostenol indicate that after bothsingle- and multiple-dose administration, the Cmax and AUC values of bosentan were similar inpatients 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 threetimes a day (at steady state) concomitantly administered during 6 days in healthy volunteers resultedin a 63% decrease in the sildenafil AUC and a 50% increase in the bosentan AUC. Caution isrecommended in the case of co-administration.

Tadalafil: Bosentan (125 mg twice daily) reduced tadalafil (40 mg once per day) systemic exposure by42% 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 interactionmay be induction of P-glycoprotein. This interaction is unlikely to be of clinical relevance.

Interaction studies have only been performed in adults.

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 isstill unknown. Tracleer is contraindicated in pregnancy (see section 4.3).

Before the initiation of Tracleer treatment in women of childbearing potential, the absence ofpregnancy should be checked, appropriate advice on reliable methods of contraception provided, andreliable contraception initiated. Patients and prescribers must be aware that due to potentialpharmacokinetic interactions, Tracleer may render hormonal contraceptives ineffective (seesection 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 butmust use an additional or an alternative reliable method of contraception. If there is any doubt aboutwhat contraceptive advice should be given to the individual patient, consultation with a gynaecologistis recommended. Because of possible hormonal contraception failure during Tracleer treatment, andalso 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 ofpregnancy.

It is not known whether bosentan is excreted into human breast milk. Breast-feeding is notrecommended during treatment with Tracleer.

Animal studies showed testicular effects (see section 5.3). In a clinical study investigating the effectsof bosentan on testicular function in male PAH patients, six of the 24 subjects (25%) had a decreasedsperm concentration of at least 50% from baseline at 6 months of treatment with bosentan. Based onthese findings and preclinical data, it cannot be excluded that bosentan may have a detrimental effecton spermatogenesis in men. In male children, a long-term impact on fertility after treatment withbosentan cannot be excluded.

No specific studies have been conducted to assess the direct effect of Tracleer on the ability to driveand use machines. However, Tracleer may induce hypotension, with symptoms of dizziness, blurredvision or syncope that could affect the ability to drive or use machines.

In 20 placebo-controlled studies, conducted in a variety of therapeutic indications, a total of2 486 patients were treated with bosentan at daily doses ranging from 100 mg to 2 000 mg and1 838 patients were treated with placebo. The mean treatment duration was 45 weeks. Adversereactions were defined as events occurring in at least 1% of patients on bosentan and at a frequency atleast 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 liveraminotransferases and decreases in haemoglobin concentration (see section 4.4).

Adverse reactions observed in 20 placebo-controlled studies and post-marketing experience withbosentan 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); veryrare (< 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 andthe approved indications.

System organ class Frequency Adverse reaction

Blood and lymphatic system Common Anaemia, haemoglobin decrease,disorders (see section 4.4)

Not known Anaemia or haemoglobindecreases requiring red blood celltransfusion1

Uncommon Thrombocytopenia1

Uncommon Neutropenia, leukopenia1

Immune system disorders Common Hypersensitivity reactions(including dermatitis, pruritus andrash)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 Common Nasal congestion1mediastinal disorders

Gastrointestinal disorders Common Gastrooesophageal reflux disease

Hepatobiliary disorders Very common Abnormal liver function test (seesection 4.4)

Uncommon Aminotransferase elevationsassociated with hepatitis(including possible exacerbationof underlying hepatitis) and/orjaundice1 (see section 4.4)

Rare Liver cirrhosis, liver failure1

Skin and subcutaneous disorders Common Erythema

General disorders and Very common Oedema, fluid retention5administration site conditions1 Data derived from post-marketing experience, frequencies based on statistical modelling of placebo-controlled clinicaltrial 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 prolongedtherapy 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 strictadherence to the monthly schedule for monitoring of liver function for the duration of treatment with

Tracleer (see section 4.4).

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 twicedaily; treatment duration 12 weeks) was similar to that observed in the pivotal trials in adult patientswith PAH. In BREATHE-3, the most frequent adverse reactions were flushing (21%), headache, andabnormal liver function test (each 16%).

A pooled analysis of uncontrolled paediatric studies conducted in PAH with the bosentan 32 mgdispersible tablet formulation (FUTURE 1/2, FUTURE 3/Extension) included a total of 100 childrentreated with bosentan 2 mg/kg twice daily (n = 33), 2 mg/kg three times daily (n = 31), or 4 mg/kgtwice daily (n = 36). At enrolment, six patients were between 3 months and 1 year old, 15 childrenwere between 1 and less than 2 years old, and 79 were between 2 and 12 years old. The mediantreatment duration was 71.8 weeks (range 0.4-258 weeks).

The safety profile in this pooled analysis of uncontrolled paediatric studies was similar to thatobserved in the pivotal trials in adult patients with PAH except for infections, which were morefrequently reported than in adults (69.0% vs 41.3%). This difference in infection frequency may inpart 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 upperrespiratory tract infections (25%), pulmonary (arterial) hypertension (20%), nasopharyngitis (17%),pyrexia (15%), vomiting (13%), bronchitis (10%), abdominal pain (10%), and diarrhoea (10%). Therewas no relevant difference in adverse event frequencies between patients above and below the age of2 years; however, this is based on only 21 children less than 2 years, including 6 patients between3 months to 1 year of age. Adverse events of liver abnormalities and anaemia/haemoglobin decreaseoccurred in 9% and 5% of patients, respectively.

In a randomised placebo-controlled study, conducted in PPHN patients (FUTURE-4), a total of13 neonates were treated with the bosentan dispersible tablet formulation at a dose of 2 mg/kg twicedaily (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 frequentadverse events in the bosentan- and placebo-treated patients were, respectively, anaemia orhaemoglobin decrease (7 and 2 patients), generalised oedema (3 and 0 patients), and vomiting (2 and0 patients).

Liver test abnormalities

In the clinical programme, dose-dependent elevations in liver aminotransferases generally occurredwithin the first 26 weeks of treatment, usually developed gradually, and were mainly asymptomatic. Inthe 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 reversespontaneously while continuing treatment with the maintenance dose of Tracleer or after dosereduction, but interruption or cessation may be necessary (see section 4.4).

In the 20 integrated placebo-controlled studies, elevations in liver aminotransferases  3 ULN wereobserved in 11.2% of the bosentan-treated patients as compared to 2.4% of the placebo-treatedpatients. Elevations to  8  ULN were seen in 3.6% of the bosentan-treated patients and 0.4% of theplacebo-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% ofpatients.

In the FUTURE-4 study including 13 neonates with PPHN treated with bosentan 2 mg/kg twice dailyfor less than 10 days (range 0.5-10.0 days), there were no cases of liver aminotransferases ≥ 3ULNduring treatment, but one case of hepatitis occurred 3 days after the end of bosentan treatment.

In the adult placebo-controlled studies, a decrease in haemoglobin concentration to below 10 g/dLfrom 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 wasreported 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 inhaemoglobin from within the reference range at baseline to below the lower limit of normal during thetreatment.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Bosentan has been administered as a single dose of up to 2 400 mg to healthy subjects and up to2 000 mg/day for 2 months in patients with a disease other than pulmonary hypertension. The mostcommon adverse reaction was headache of mild to moderate intensity.

Massive overdose may result in pronounced hypotension requiring active cardiovascular support. Inthe post-marketing period there was one reported overdose of 10 000 mg of Tracleer taken by anadolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating andblurred vision. He recovered completely within 24 hours with blood pressure support. Note: bosentanis not removed through dialysis.

Pharmacotherapeutic group: other antihypertensives, ATC code: C02KX01

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 resistanceresulting in increased cardiac output without increasing heart rate.

The neurohormone endothelin-1 (ET-1) is one of the most potent vasoconstrictors known and can alsopromote 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 endotheliumand vascular smooth muscle cells. ET-1 concentrations in tissues and plasma are increased in severalcardiovascular disorders and connective tissue diseases, including PAH, scleroderma, acute andchronic heart failure, myocardial ischaemia, systemic hypertension and atherosclerosis, suggesting apathogenic role of ET-1 in these diseases. In PAH and heart failure, in the absence of endothelinreceptor antagonism, elevated ET-1 concentrations are strongly correlated with the severity andprognosis 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 otherreceptors.

Animal models

In animal models of pulmonary hypertension, chronic oral administration of bosentan reducedpulmonary vascular resistance and reversed pulmonary vascular and right ventricular hypertrophy. Inan 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 in32 (study AC-052-351) and 213 (study AC-052-352 [BREATHE-1]) adult patients with WHOfunctional class III-IV PAH (primary pulmonary hypertension or pulmonary hypertension secondarymainly to scleroderma). After 4 weeks of bosentan 62.5 mg twice daily, the maintenance doses studiedin these studies were 125 mg twice daily in AC-052-351, and 125 mg twice daily and 250 mg twicedaily 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 firststudy and 16 weeks for the second study. In both studies, treatment with bosentan resulted insignificant increases in exercise capacity. The placebo-corrected increases in walk distance comparedwith baseline were 76 metres (p = 0.02; t-test) and 44 metres (p = 0.0002; Mann-Whitney U test) at theprimary endpoint of each study, respectively. The differences between the two groups, 125 mg twicedaily and 250 mg twice daily, were not statistically significant but there was a trend towards improvedexercise 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 after8 weeks of treatment and was maintained for up to 28 weeks of double-blind treatment in a subset ofthe patient population.

In a retrospective responder analysis based on change in walking distance, WHO functional class anddyspnoea of the 95 patients randomised to bosentan 125 mg twice daily in the placebo-controlledstudies, 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 withbaseline. Of the 7 patients who deteriorated at week 8, 3 improved at week 12/16 and 4 deterioratedcompared with baseline.

Invasive haemodynamic parameters were assessed in the first study only. Treatment with bosentan ledto a significant increase in cardiac index associated with a significant reduction in pulmonary arterypressure, pulmonary vascular resistance and mean right atrial pressure.

A reduction in symptoms of PAH was observed with bosentan treatment. Dyspnoea measurementduring 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 (placebo30.4%). The overall change in WHO functional class during both studies was significantly betteramong bosentan-treated patients as compared with placebo-treated patients. Treatment with bosentanwas associated with a significant reduction in the rate of clinical worsening compared with placebo at28 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), orplacebo (n = 92) for 6 months. Enrolled patients were PAH-treatment-naïve (n = 156) or on a stabledose of sildenafil (n = 29). The co-primary endpoints were percentage change from baseline inpulmonary vascular resistance (PVR) and change from baseline in 6-minute walk distance to Month6 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% 1995% 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 acomposite 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 treatmenteffect was driven by improvement in the component symptomatic progression. There was onehospitalisation related to PAH worsening in the bosentan group and three hospitalisations in theplacebo group. Only one death occurred in each treatment group during the 6-month double-blindstudy 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 controlledphase and/or were switched from placebo to bosentan in the open-label extension phase of the EARLYstudy. The mean duration of exposure to bosentan treatment was 3.6  1.8 years (up to 6.1 years), with73% of patients treated for at least 3 years and 62% for at least 4 years. Patients could receiveadditional PAH treatment as required in the open-label extension. The majority of patients werediagnosed with idiopathic or heritable PAH (61%). Overall, 78% of patients remained in WHOfunctional class II. Kaplan-Meier estimates of survival were 90% and 85% at 3 and 4 years after thestart 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 ofintravenous or subcutaneous prostanoid treatment). The relative contributions of previous placebotreatment in the double-blind phase and of other medications started during the open-label extensionperiod 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 associatedwith congenital heart disease received bosentan 62.5 mg twice daily for 4 weeks, then 125 mg twicedaily for a further 12 weeks (n = 37, of whom 31 had a predominantly right to left, bidirectionalshunt). 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%) ascompared to the placebo group (n = 17), showing that bosentan did not worsen hypoxaemia. The meanpulmonary vascular resistance was significantly reduced in the bosentan group (with a predominanteffect observed in the subgroup of patients with bidirectional intracardiac shunt). After 16 weeks, themean placebo-corrected increase in 6-minute walk distance was 53 metres (p = 0.0079), reflectingimprovement in exercise capacity. Twenty-six patients continued to receive bosentan in the 24-weekopen-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 patientswith WHO functional class III PAH associated with HIV infection. Patients were treated withbosentan 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: themean 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 drugefficacy (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 twopivotal 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 ofpatients 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 and2 years after the start of treatment with bosentan, respectively. Survival estimates were lower in thesubgroup of patients with PAH secondary to systemic sclerosis. The estimates may have beeninfluenced 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 paediatricpatients 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 tocongenital 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 bosentanat approximately 2 mg/kg twice daily for 12 weeks. Half of the patients in each group were alreadybeing treated with intravenous epoprostenol and the dose of epoprostenol remained constant for theduration of the study.

Haemodynamics were measured in 17 patients. The mean increase from baseline in cardiac index was0.5 L/min/m2, the mean decrease in mean pulmonary arterial pressure was 8 mmHg, and the meandecrease in PVR was 389 dyn·sec·cm-5. These haemodynamic improvements from baseline weresimilar with or without co-administration of epoprostenol. Changes in exercise test parameters atweek 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 tabletformulation of bosentan administered at a maintenance dose of 4 mg/kg twice daily to 36 patients from2 to 11 years of age. It was primarily designed as a pharmacokinetic study (see section 5.2). Atbaseline, 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 medianexposure to study treatment was 13.1 weeks (range: 8.4 to 21.1). 33 of these patients were providedwith 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 werenewly initiated on PAH-specific medication during the study. The Kaplan-Meier event-free estimatefor worsening of PAH (death, lung transplantation, or hospitalisation for PAH worsening) at 2 yearswas 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’ bosentantreatment 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 between3 months and 1 year old. The study was primarily designed as a pharmacokinetic study (seesection 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 aftercorrective cardiac surgery (38%), and PAH related to congenital heart disease associated withsystemic-to-pulmonary shunts, including Eisenmenger syndrome (13%). Patients were in WHOfunctional class I (n = 19, 29 %), class II (n = 27, 42%) or class III (n = 18, 28%) at start of studytreatment. At study entry, patients were treated with PAH medications (most frequentlyphosphodiesterase type-5 inhibitor [sildenafil] alone [35.9%], bosentan alone [10.9%], and acombination of bosentan, iloprost, and sildenafil [10.9%]) and continued their PAH treatment duringthe study.

At study start, less than half of the patients included (45.3% [29/64]) had bosentan treatment alone notcombined with other PAH medication. 40.6% (26/64) remained on bosentan monotherapy during the24 weeks of study treatment without experiencing PAH worsening. The analysis on the globalpopulation included (64 patients) showed that the majority had remained at least stable (i.e., withoutdeterioration) 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 timesdaily) 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/kgtwice 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 at2 mg/kg twice daily (N = 13) or placebo (N = 8) via nasogastric tube as add-on therapy on top of iNOuntil complete weaning of iNO or until treatment failure (defined as need for extra-corporealmembrane oxygenation [ECMO] or initiation of alternative pulmonary vasodilator), and for amaximum 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% CLs3.21, 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 protocoldefinition), which was declared based on increasing Oxygenation Index values within 8 h afterthe 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 whowere 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 eachcomponent and the combination therapy was well tolerated in children and adults. The clinical benefitof 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 withsystemic sclerosis and digital ulcer disease (either ongoing digital ulcers or a history of digital ulcerswithin the previous year). In study AC-052-331, patients had to have at least one digital ulcer of recentonset, and across the two studies 85% of patients had ongoing digital ulcer disease at baseline. After4 weeks of bosentan 62.5 mg twice daily, the maintenance dose studied in both these studies was125 mg twice daily. The duration of double-blind therapy was 16 weeks in study AC-052-401, and24 weeks in study AC-052-331.

Background treatments for systemic sclerosis and digital ulcers were permitted if they remainedconstant 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 bothstudies. 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 inthe bosentan group developed a mean of 1.4 new digital ulcers vs 2.7 new digital ulcers in the placebogroup (p = 0.0042). In study AC-052-331, during 24 weeks of double-blind therapy, the correspondingfigures were 1.9 vs 2.7 new digital ulcers, respectively (p = 0.0351). In both studies, patients onbosentan were less likely to develop multiple new digital ulcers during the study and took longer todevelop each successive new digital ulcer than did those on placebo. The effect of bosentan onreduction of the number of new digital ulcers was more pronounced in patients with multiple digitalulcers.

No effect of bosentan on time to healing of digital ulcers was observed in either study.

The pharmacokinetics of bosentan have mainly been documented in healthy subjects. Limited data inpatients show that the exposure to bosentan in adult PAH patients is approximately 2-fold greater thanin healthy adult subjects.

In healthy subjects, bosentan displays dose- and time-dependent pharmacokinetics. Clearance andvolume of distribution decrease with increased intravenous doses and increase with time. After oraladministration, the systemic exposure is proportional to dose up to 500 mg. At higher oral doses, Cmaxand AUC increase less than proportionally to the dose.

In healthy subjects, the absolute bioavailability of bosentan is approximately 50% and is not affectedby food. The maximum plasma concentrations are attained within 3-5 hours.

Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. Bosentan does not penetrateinto erythrocytes.

A volume of distribution (Vss) of about 18 litres was determined after an intravenous dose of 250 mg.

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 seenafter single dose administration. This decrease is probably due to auto-induction of metabolising liverenzymes. Steady-state conditions are reached within 3-5 days.

Bosentan is eliminated by biliary excretion following metabolism in the liver by the cytochrome P450isoenzymes, 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 ismainly excreted unchanged via the bile. In adult patients, the exposure to the active metabolite isgreater than in healthy subjects. In patients with evidence of the presence of cholestasis, the exposureto 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 isoenzymestested (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4). Consequently, bosentan is not expected toincrease the plasma concentrations of medicinal products metabolised by these isoenzymes.

Based on the investigated range of each variable, it is not expected that the pharmacokinetics ofbosentan will be influenced by gender, body weight, race, or age in the adult population to anyrelevant extent.

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 ofthe film-coated tablet formulation of bosentan in 19 children aged from 3 to 15 years with PAH whowere dosed on the basis of body weight with 2 mg/kg twice daily. In this study, the exposure tobosentan decreased with time in a manner consistent with the known auto-induction properties ofbosentan. The mean AUC (CV%) values of bosentan in paediatric patients treated with 31.25, 62.5 or125 mg twice daily were 3 496 (49), 5 428 (79), and 6 124 (27) ng h/mL, respectively, and were lowerthan the value of 8 149 (47) ng h/mL observed in adult patients with PAH receiving 125 mg twicedaily. 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 agedfrom 2 to 11 years. No dose proportionality was observed, as steady-state bosentan plasmaconcentrations and AUCs were similar at oral doses of 2 and 4 mg/kg (AUC: 3 577 ng h/mL and3 371 ng h/mL for 2 mg/kg twice daily and 4 mg/kg twice daily, respectively). The average exposureto bosentan in these paediatric patients was about half the exposure in adult patients at the 125 mgtwice 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 patientstreated with 2 mg/kg twice daily was comparable to that in the FUTURE 1 study. In the overallpopulation (n = 31), 2 mg/kg twice daily resulted in a daily exposure of 8 535 ng h/mL; AUCwas4 268 ng h/mL (CV: 61%). In patients between 3 months and 2 years the daily exposure was7 879 ng h/mL; AUCwas 3 939 ng h/mL (CV: 72%). In patients between 3 months and 1 year (n = 2)

AUCwas 5 914 ng h/mL (CV: 85%), and in patients between 1 and 2 years (n = 7) AUCwas3 507 ng h/mL (CV: 70%). In the patients above 2 years (n = 22) the daily exposure was8 820 ng h/mL; AUCwas 4 410 ng h/mL (CV: 58%). Dosing bosentan 2 mg/kg three times daily didnot 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 theexposure to bosentan reaches a plateau at lower doses in paediatric patients than in adults, and thatdoses higher than 2 mg/kg twice daily (4 mg/kg twice daily or 2 mg/kg three times daily) will notresult in greater exposure to bosentan in paediatric patients.

In study AC-052-391 (FUTURE 4) conducted in neonates, bosentan concentrations increased slowlyand continuously over the first dosing interval, resulting in low exposure (AUC0-12 in whole blood:164 ng h/mL, n = 11). At steady state, AUC was 6 165 ng h/mL (CV: 133%, n = 7), which is similarto the exposure observed in adult PAH patients receiving 125 mg twice daily and taking into account ablood/plasma distribution ratio of 0.6.

The consequences of these findings regarding hepatotoxicity are unknown. Gender and concomitantuse of intravenous epoprostenol had no significant effect on the pharmacokinetics of bosentan.

In patients with mildly impaired liver function (Child-Pugh class A) no relevant changes in thepharmacokinetics have been observed. The steady-state AUC of bosentan was 9% higher and the AUCof the active metabolite, Ro 48-5033, was 33% higher in patients with mild hepatic impairment than inhealthy volunteers.

The impact of moderately impaired liver function (Child-Pugh class B) on the pharmacokinetics ofbosentan and its primary metabolite Ro 48-5033 was investigated in a study including 5 patients withpulmonary hypertension associated with portal hypertension and Child-Pugh class B hepaticimpairment, 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 48-5033was 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 hepaticimpairment. Tracleer is contraindicated in patients with moderate to severe hepatic impairment, i.e.,

Child-Pugh class B or C (see section 4.3).

In patients with severe renal impairment (creatinine clearance 15-30 mL/min), plasma concentrationsof bosentan decreased by approximately 10%. Plasma concentrations of bosentan metabolitesincreased about 2-fold in these patients as compared with subjects with normal renal function. No doseadjustment is required in patients with renal impairment. There is no specific clinical experience inpatients undergoing dialysis. Based on physicochemical properties and the high degree of proteinbinding, bosentan is not expected to be removed from the circulation by dialysis to any significantextent (see section 4.2).

A 2-year carcinogenicity study in mice showed an increased combined incidence of hepatocellularadenomas and carcinomas in males, but not in females, at plasma concentrations about 2 to 4 times theplasma concentrations achieved at the therapeutic dose in humans. In rats, oral administration ofbosentan for 2 years produced a small, significant increase in the combined incidence of thyroidfollicular cell adenomas and carcinomas in males, but not in females, at plasma concentrations about 9to 14 times the plasma concentrations achieved at the therapeutic dose in humans. Bosentan wasnegative in tests for genotoxicity. There was evidence of a mild thyroid hormonal imbalance inducedby 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 plasmaconcentrations achieved at the therapeutic dose in humans. Teratogenic effects, includingmalformations of the head and face and of the major vessels, were dose dependent. The similarities ofthe pattern of malformations observed with other ET receptor antagonists and in ET knock-out miceindicate a class effect. Appropriate precautions must be taken for women of childbearing potential (seesections pct. 4.3, pct. 4.4 and 4.6).

Development of testicular tubular atrophy and impaired fertility has been linked with chronicadministration of endothelin receptor antagonists in rodents.

In fertility studies in male and female rats, no effects on sperm count, motility and viability, or onmating performance or fertility were observed at exposures that were 21 and 43 times the expectedtherapeutic level in humans, respectively; nor was there any adverse effect on the development of thepre-implantation embryo or on implantation.

Slightly increased incidence of testicular tubular atrophy was observed in rats given bosentan orally atdoses as low as 125 mg/kg/day (about 4 times the maximum recommended human dose [MRHD] andthe 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 partumup to adulthood, decreased absolute weights of testes and epididymides, and reduced number of spermin epididymides were observed after weaning. The NOAEL was 21 times (at Day 21 post partum) and2.3 times (Day 69 post partum) the human therapeutic exposure, respectively.

However, no effects on general development, growth, sensory, cognitive function and reproductiveperformance 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 at1.3 (males) and 2.6 (females) times the therapeutic exposure in children with PAH.

Maize starch

Pregelatinised starch

Sodium starch glycolate (Type A)

Povidone

Glycerol dibehenate

Magnesium stearate

Hypromellose

Glycerol triacetate

Talc

Titanium dioxide (E171)

Iron oxide yellow (E172)

Iron oxide red (E172)

Ethylcellulose

Not applicable.

4 years

For white high-density polyethylene bottles, use within 30 days after the first opening.

For PVC/PE/PVDC/aluminium-blisters:

Do not store above 25°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.

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.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

Tracleer 62.5 mg film-coated tablets

EU/1/02/220/001

EU/1/02/220/002

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

Date of first authorisation: 15 May 2002

Date of latest renewal: 20 April 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/.