ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Tracleer 62.5 mg film-coated tablets
2.
Each film-coated tablet contains 62.5 mg bosentan (as monohydrate).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablets):
Orange-white, round, biconvex, film-coated tablets, embossed with “62,5” on one side.
4.
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) PAH
•
PAH secondary to scleroderma without significant interstitial pulmonary disease
•
PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger’s physiology
Some improvements have also been shown in patients with PAH 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).
Tablets are to be taken orally morning and evening, with or without food. The film-coated tablets are
to be swallowed with water.
Pulmonary arterial hypertension
Treatment should only be initiated and monitored by a physician experienced in the treatment of
pulmonary arterial hypertension.
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.
For paediatric patients aged 2 years or older, the optimal maintenance dose has not been defined in
well-controlled studies. However, paediatric pharmacokinetic data have shown that bosentan plasma
concentrations in children were on average lower than in adult patients and were not increased by
increasing the dose of Tracleer above 2 mg/kg body weight twice daily (see section 5.2). Based on
these pharmacokinetic results, higher doses are unlikely to be more effective, and greater adverse
event rates cannot formally be excluded in young children if the dose is increased. No clinical study
has been conducted to compare the efficacy/safety ratio of 2 mg/kg to 4 mg/kg body weight twice
daily in children.
2
There is only limited clinical experience in paediatric patients under 2
years of age.
In the case 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 case 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).
Discontinuation of treatment
There is limited experience with abrupt discontinuation of Tracleer. 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.
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.
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).
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
Dosage in hepatic impairment
No dose adjustment is needed in patients with mild hepatic impairment (i.e., Child-Pugh class A) (see
section 5.2). Tracleer is contraindicated in patients with moderate to severe liver dysfunction (see
sections 4.3, 4.4 and 5.2).
Dosage in 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).
Dosage in elderly patients
No dose adjustment is required in patients over the age of 65 years.
3
•
Hypersensitivity to the active substance or to any of the excipients
•
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 aminotransferases (AST) and/or
alanine aminotransferases (ALT), greater than 3 times the upper limit of normal (see
section 4.4)
•
Concomitant use of cyclosporine A (see section 4.5)
•
Pregnancy (see sections 4.4 and 4.6)
•
Women of child-bearing potential who are not using reliable methods of contraception (see
sections 4.4, 4.5 and 4.6)
The efficacy of Tracleer has not been established in patients with severe pulmonary arterial
hypertension. 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 pulmonary arterial hypertension.
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 case of ALT/AST elevations
ALT/AST levels
Treatment and monitoring recommendations
> 3 and ≤ 5 × ULN
Confirm by another 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). Continue to monitor
aminotransferase levels at least every 2 weeks. If the aminotransferase levels
return to pre-treatment values consider continuing or re-introducing Tracleer
according to the conditions described below.
> 5 and ≤ 8 × ULN
Confirm by another liver test; if confirmed, stop treatment and monitor
aminotransferase levels at least every 2 weeks. If the aminotransferase levels
4
return to pre-treatment values consider re-introducing Tracleer according to
the conditions described below.
> 8 × ULN
Treatment must be stopped and re-introduction of Tracleer is not to be
considered.
In the case 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 child-bearing potential
Tracleer treatment must not be initiated in women of child-bearing potential unless they practise
reliable contraception (see section 4.5) and the result of the pre-treatment pregnancy test is negative
(see section 4.6).
Before the initiation of Tracleer treatment in women of child-bearing 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 child-bearing potential must not use hormonal contraceptives (including
oral, injectable, transdermal and implantable forms) as the sole method of contraception but should
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.
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
5
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-
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
Glibenclamide:
Tracleer should not be used concomitantly with glibenclamide, due to an increased
risk of elevated liver aminotransferases (see section 4.5). An alternative antidiabetic medicinal
product should be used in patients in whom an antidiabetic treatment is indicated.
Fluconazole:
concomitant use of Tracleer with fluconazole is not recommended (see section 4.5).
Although not studied, this combination may lead to large increases in plasma concentrations of
bosentan.
Rifampicin:
co-administration of Tracleer with rifampicin is not recommended (see section 4.5).
Concomitant administration of both a CYP3A4 inhibitor and a CYP2C9 inhibitor with Tracleer
should be avoided (see section 4.5).
6
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.
Concomitant 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). Indeed, when co-administered, initial trough concentrations of
bosentan were approximately 30-fold higher than those measured after bosentan alone. At steady
state, bosentan plasma concentrations were 3- to 4-fold higher than with bosentan alone. The
mechanism of this interaction is most likely inhibition of transport protein-mediated uptake of
bosentan into hepatocytes by cyclosporine. The blood concentrations of cyclosporine A (a CYP3A4
substrate) decreased by approximately 50%. This is most likely due to induction of CYP3A4 by
bosentan.
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. In this context, this combination should not be used (see
section 4.4). No drug-drug interaction data are available with the other sulfonylureas.
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 pulmonary arterial hypertension did not result in clinically relevant changes
in International Normalized Ratio (INR) or warfarin dose (baseline versus end of the clinical studies).
7
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.
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. 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.
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 C
max
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.
Digoxin:
co-administration for 7 days of bosentan 500 mg twice daily with digoxin decreased the
AUC, C
max
and C
min
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.
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 of 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).
8
Other antiretroviral agents:
no specific recommendation can be made with regard to other available
antiretroviral agents due to the lack of data. It is emphasised that due to the marked hepatotoxicity of
nevirapine, which could accumulate with bosentan liver toxicity, this combination is not
recommended.
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).
Use in women of child-bearing potential
Before the initiation of Tracleer treatment in women of child-bearing 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 child-bearing 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.
Use during lactation
It is not known whether bosentan is excreted into human breast milk. Breast-feeding is not
recommended during treatment with Tracleer.
No studies on the effect of Tracleer on the ability to drive and use machines have been performed.
Tracleer may cause dizziness, which could affect the ability to drive or use machines.
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. The most commonly reported
adverse drug reactions (as occurring in at least 1% of patients on bosentan and at a frequency at least
0.5% more than on placebo) are headache (11.5% vs 9.8%), oedema/fluid retention (13.2% vs 10.9%),
abnormal liver function test (10.9% vs 4.6%) and anaemia/haemoglobin decrease (9.9% vs 4.9%).
Treatment with bosentan has been associated with dose-dependent elevations in liver
aminotransferases and decreases in haemoglobin concentration (see section 4.4, Special warnings and
precautions for use).
Adverse reactions/undesirable effects in 20 placebo-controlled studies 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).
9
Reports from post-marketing experience are included in
Italics
, with frequency categories based on
adverse event reporting rates on bosentan in the 20 placebo-controlled studies.
Frequency categories do not account for other factors, including varying study duration, pre-existing
conditions, and baseline patient characteristics. Within each frequency grouping, undesirable effects
are presented in order of decreasing seriousness. No clinically relevant differences in undesirable
effects 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
1
Anaemia or haemoglobin
decreases requiring red blood
cell transfusion
Uncommon
Thrombocytopenia
Uncommon
Neutropenia, leukopenia
Immune system disorders
Common
Hypersensitivity reactions
(including dermatitis, pruritus
and rash)
2
Rare
Anaphylaxis and/or
angioedema
Nervous system disorders
Very common
Headache
3
,
Common
Syncope
4
Cardiac disorders
Common
Palpitations
4
Vascular disorders
Common
Flushing
Common
Hypotension
4
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
and/or jaundice
(see
section 4.4)
Rare
Liver cirrhosis, liver failure
Skin and subcutaneous
disorders
Common
Erythema
General disorders and
administration site conditions
Very common
Oedema, fluid retention
5
1
Frequency cannot be estimated from the available 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).
Uncontrolled studies in paediatric patients with PAH (AC-052-356 [BREATHE-3]; AC-052-365
[FUTURE 1])
The safety profile in this population (BREATHE-3: n = 19, bosentan 2 mg/kg twice daily; treatment
duration 12 weeks; FUTURE 1: n = 36, bosentan 2 mg/kg twice daily for 4 weeks followed by
10
4 mg/kg twice daily; treatment duration 12 weeks) was similar to that observed in the pivotal trials in
adult patients with PAH. In BREATHE-3, the most frequent adverse events were flushing (21%),
headache, and abnormal liver function test (each 16%). In FUTURE 1, the most frequent adverse
events were infections (33%) and abdominal pain/discomfort (19%). There were no cases of liver
enzyme elevations in the FUTURE 1 study.
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 times the
upper limit of normal (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.
Haemoglobin
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).
Bosentan has been administered as a single dose of up to 2400 mg to healthy subjects and up to
2000 mg/day for 2 months in patients with a disease other than pulmonary hypertension. The most
common adverse event 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.
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
(ET
A
and ET
B
) receptors. Bosentan decreases both pulmonary and systemic vascular resistance
resulting in increased cardiac output without increasing heart rate.
11
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 ET
A
and ET
B
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 pulmonary
arterial hypertension, scleroderma, acute and chronic heart failure, myocardial ischaemia, systemic
hypertension and atherosclerosis, suggesting a pathogenic role of ET-1 in these diseases. In
pulmonary arterial hypertension 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 ET
A
and ET
B
receptors,
with a slightly higher affinity for ET
A
receptors (K
i
= 4.1–43 nanomolar) than for ET
B
receptors
(K
i
= 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 pulmonary arterial hypertension (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.
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
to 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.
12
A reduction in symptoms of pulmonary arterial hypertension 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/cm
5
)
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 effect
−22.6%
19
95% CL
−34, −10
−4, 42
P-value
< 0.0001
0.0758
PV R = pul monar y v ascul ar r esi st ance
Treatment wi th bosentan was associ ated wi th a reducti on i n the rate of cl i ni cal worseni ng, def i ned as
a composi te of symptomati c progressi on, hospi tal i sati on f or PA H and death, compared wi th pl acebo
(proporti onal ri sk reducti on 77%, 95% 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.
In a prospective, multi-centre, randomised, double-blind, placebo-controlled study (AC-052-409
[BREATHE-5]), patients with pulmonary arterial hypertension 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), or placebo (n = 17). 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, 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.
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).
13
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.
Study performed in children with pulmonary arterial hypertension
One study has been conducted in children with pulmonary hypertension. Bosentan has been evaluated
in an open-label non-controlled study in 19 paediatric patients with pulmonary arterial hypertension
(AC-052-356 [BREATHE-3]: primary pulmonary hypertension, 10 patients, and pulmonary arterial
hypertension related to congenital heart diseases, 9 patients). This study was primarily designed as a
pharmacokinetic study (see section 5.2). Patients were divided into and dosed according to three
body-weight groups for 12 weeks. Half of the patients in each group were already being treated with
intravenous epoprostenol and the dose of epoprostenol remained constant for the duration of the
study. The age range was 3–15 years. Patients were in WHO functional class II (n = 15 patients, 79%)
or class III (n = 4 patients, 21%) at baseline.
Haemodynamics were measured in 17 patients. The mean increase from baseline in cardiac index was
0.5 L/min/m
2
, 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.
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 pulmonary
arterial hypertension who were receiving concomitant epoprostenol therapy. AC-052-356 was an
open-label, non-controlled 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.
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
14
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 pulmonary arterial hypertension 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, C
max
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 (V
ss
) 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 (t
1/2
) 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.
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
15
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. No pharmacokinetic data are available in children under 2 years.
Children
The pharmacokinetics of single and multiple oral doses were studied in paediatric patients with
pulmonary arterial hypertension who were dosed on the basis of body weight (see section 5.1, AC-
052-356 [BREATHE-3]). The exposure to bosentan decreased with time in a manner consistent with
the known auto-induction properties of bosentan. The mean AUC (CV%) values of bosentan in
paediatric patients treated with 31.25, 62.5 or 125 mg twice daily were 3,496 (49), 5,428 (79), and
6,124 (27) ng·h/mL, respectively, and were lower than the value of 8,149 (47) ng·h/mL observed in
adult patients with pulmonary arterial hypertension 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 a second pharmacokinetic study (AC-052-365 [FUTURE 1]), 36 paediatric patients aged 2–11
years with PAH were treated at 2 and 4 mg/kg twice daily with the dispersible tablet. No dose
proportionality was observed. Steady-state bosentan plasma concentrations were similar at oral doses
of 2 and 4 mg/kg. The AUC
τ
was 3,577 ng·h/mL for 2 mg/kg twice daily and 3,371 ng·h/mL for
4 mg/kg twice daily.The average exposure to bosentan in 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. Based on the findings in studies BREATHE-3 and FUTURE 1, 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 will not result in greater exposure to bosentan
in paediatric patients.
The consequences of these findings regarding hepatotoxicity are unknown.
Gender and the
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 pharmacokinetics of bosentan have not been studied in patients with
Child-Pugh class B or C hepatic impairment and Tracleer is contra-indicated in this patient population
(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 to 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
16
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
Actelion Registration Ltd
BSI Building 13
th
Floor
389 Chiswick High Road
London W4 4AL
United Kingdom
8.
EU/1/02/220/001
EU/1/02/220/002
EU/1/02/220/003
9.
Date of first authorisation: 15 May 2002
Date of renewal: 15 May 2007
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
.
18
1.
Tracleer 125 mg film-coated tablets
2.
Each film-coated tablet contains 125 mg bosentan (as monohydrate).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablets):
Orange-white, oval, biconvex, film-coated tablets, embossed with “125” on one side.
4.
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) PAH
•
PAH secondary to scleroderma without significant interstitial pulmonary disease
•
PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger’s physiology
Some improvements have also been shown in patients with PAH 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).
Tablets are to be taken orally morning and evening, with or without food. The film-coated tablets are
to be swallowed with water.
Pulmonary arterial hypertension
Treatment should only be initiated and monitored by a physician experienced in the treatment of
pulmonary arterial hypertension.
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.
For paediatric patients aged 2 years or older, the optimal maintenance dose has not been defined in
well-controlled studies. However, paediatric pharmacokinetic data have shown that bosentan plasma
concentrations in children were on average lower than in adult patients and were not increased by
increasing the dose of Tracleer above 2 mg/kg body weight twice daily (see section 5.2). Based on
these pharmacokinetic results, higher doses are unlikely to be more effective, and greater adverse
event rates cannot formally be excluded in young children if the dose is increased. No clinical study
has been conducted to compare the efficacy/safety ratio of 2 mg/kg to 4 mg/kg body weight twice
daily in children.
19
There is only limited clinical experience in paediatric patients under 2
years of age.
In the case 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 case 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).
Discontinuation of treatment
There is limited experience with abrupt discontinuation of Tracleer. 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.
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.
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).
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
Dosage in hepatic impairment
No dose adjustment is needed in patients with mild hepatic impairment (i.e., Child-Pugh class A) (see
section 5.2). Tracleer is contraindicated in patients with moderate to severe liver dysfunction (see
sections 4.3, 4.4 and 5.2).
Dosage in 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).
Dosage in elderly patients
No dose adjustment is required in patients over the age of 65 years.
20
•
Hypersensitivity to the active substance or to any of the excipients
•
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 aminotransferases (AST) and/or
alanine aminotransferases (ALT), greater than 3 times the upper limit of normal (see
section 4.4)
•
Concomitant use of cyclosporine A (see section 4.5)
•
Pregnancy (see sections 4.4 and 4.6)
•
Women of child-bearing potential who are not using reliable methods of contraception (see
sections 4.4, 4.5 and 4.6)
The efficacy of Tracleer has not been established in patients with severe pulmonary arterial
hypertension. 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 pulmonary arterial hypertension.
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 case of ALT/AST elevations
ALT/AST levels
Treatment and monitoring recommendations
> 3 and ≤ 5 × ULN
Confirm by another 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). Continue to monitor
aminotransferase levels at least every 2 weeks. If the aminotransferase levels
return to pre-treatment values consider continuing or re-introducing Tracleer
according to the conditions described below.
> 5 and ≤ 8 × ULN
Confirm by another liver test; if confirmed, stop treatment and monitor
aminotransferase levels at least every 2 weeks. If the aminotransferase levels
21
return to pre-treatment values consider re-introducing Tracleer according to
the conditions described below.
> 8 × ULN
Treatment must be stopped and re-introduction of Tracleer is not to be
considered.
In the case 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 child-bearing potential
Tracleer treatment must not be initiated in women of child-bearing potential unless they practise
reliable contraception (see section 4.5) and the result of the pre-treatment pregnancy test is negative
(see section 4.6).
Before the initiation of Tracleer treatment in women of child-bearing 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 child-bearing potential must not use hormonal contraceptives (including
oral, injectable, transdermal and implantable forms) as the sole method of contraception but should
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.
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
22
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-
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
Glibenclamide:
Tracleer should not be used concomitantly with glibenclamide, due to an increased
risk of elevated liver aminotransferases (see section 4.5). An alternative antidiabetic medicinal
product should be used in patients in whom an antidiabetic treatment is indicated.
Fluconazole:
concomitant use of Tracleer with fluconazole is not recommended (see section 4.5).
Although not studied, this combination may lead to large increases in plasma concentrations of
bosentan.
Rifampicin:
co-administration of Tracleer with rifampicin is not recommended (see section 4.5).
Concomitant administration of both a CYP3A4 inhibitor and a CYP2C9 inhibitor with Tracleer
should be avoided (see section 4.5).
23
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.
Concomitant 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). Indeed, when co-administered, initial trough concentrations of
bosentan were approximately 30-fold higher than those measured after bosentan alone. At steady
state, bosentan plasma concentrations were 3- to 4-fold higher than with bosentan alone. The
mechanism of this interaction is most likely inhibition of transport protein-mediated uptake of
bosentan into hepatocytes by cyclosporine. The blood concentrations of cyclosporine A (a CYP3A4
substrate) decreased by approximately 50%. This is most likely due to induction of CYP3A4 by
bosentan.
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. In this context, this combination should not be used (see
section 4.4). No drug-drug interaction data are available with the other sulfonylureas.
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 pulmonary arterial hypertension did not result in clinically relevant changes
in International Normalized Ratio (INR) or warfarin dose (baseline versus end of the clinical studies).
24
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.
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. 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.
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 C
max
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.
Digoxin:
co-administration for 7 days of bosentan 500 mg twice daily with digoxin decreased the
AUC, C
max
and C
min
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.
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 of 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).
25
Other antiretroviral agents:
no specific recommendation can be made with regard to other available
antiretroviral agents due to the lack of data. It is emphasised that due to the marked hepatotoxicity of
nevirapine, which could accumulate with bosentan liver toxicity, this combination is not
recommended.
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).
Use in women of child-bearing potential
Before the initiation of Tracleer treatment in women of child-bearing 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 child-bearing 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.
Use during lactation
It is not known whether bosentan is excreted into human breast milk. Breast-feeding is not
recommended during treatment with Tracleer.
No studies on the effect of Tracleer on the ability to drive and use machines have been performed.
Tracleer may cause dizziness, which could affect the ability to drive or use machines.
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. The most commonly reported
adverse drug reactions (as occurring in at least 1% of patients on bosentan and at a frequency at least
0.5% more than on placebo) are headache (11.5% vs 9.8%), oedema/fluid retention (13.2% vs 10.9%),
abnormal liver function test (10.9% vs 4.6%) and anaemia/haemoglobin decrease (9.9% vs 4.9%).
Treatment with bosentan has been associated with dose-dependent elevations in liver
aminotransferases and decreases in haemoglobin concentration (see section 4.4, Special warnings and
precautions for use).
Adverse reactions/undesirable effects in 20 placebo-controlled studies 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).
Reports from post-marketing experience are included in
Italics
, with frequency categories based on
adverse event reporting rates on bosentan in the 20 placebo-controlled studies.
26
Frequency categories do not account for other factors, including varying study duration, pre-existing
conditions, and baseline patient characteristics. Within each frequency grouping, undesirable effects
are presented in order of decreasing seriousness. No clinically relevant differences in undesirable
effects 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
1
Anaemia or haemoglobin
decreases requiring red blood
cell transfusion
Uncommon
Thrombocytopenia
Uncommon
Neutropenia, leukopenia
Immune system disorders
Common
Hypersensitivity reactions
(including dermatitis, pruritus
and rash)
2
Rare
Anaphylaxis and/or
angioedema
Nervous system disorders
Very common
Headache
3
Common
Syncope
4
Cardiac disorders
Common
Palpitations
4
Vascular disorders
Common
Flushing
Common
Hypotension
4
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
and/or jaundice,
(see
section 4.4)
Rare
Liver cirrhosis, liver failure
Skin and subcutaneous
disorders
Common
Erythema
General disorders and
administration site conditions
Very common
Oedema, fluid retention
5
1
Frequency cannot be estimated from the available 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).
Uncontrolled studies in paediatric patients with PAH (AC-052-356 [BREATHE-3]; AC-052-365
[FUTURE 1])
The safety profile in this population (BREATHE-3: n = 19, bosentan 2 mg/kg twice daily; treatment
duration 12 weeks; FUTURE 1: n = 36, bosentan 2 mg/kg twice daily for 4 weeks followed by
4 mg/kg twice daily; treatment duration 12 weeks) was similar to that observed in the pivotal trials in
adult patients with PAH. In BREATHE-3, the most frequent adverse events were flushing (21%),
27
headache, and abnormal liver function test (each 16%). In FUTURE 1, the most frequent adverse
events were infections (33%) and abdominal pain/discomfort (19%). There were no cases of liver
enzyme elevations in the FUTURE 1 study.
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 times the
upper limit of normal (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.
Haemoglobin
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).
Bosentan has been administered as a single dose of up to 2400 mg to healthy subjects and up to
2000 mg/day for 2 months in patients with a disease other than pulmonary hypertension. The most
common adverse event 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.
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
(ET
A
and ET
B
) 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 ET
A
and ET
B
receptors located in the
28
endothelium and vascular smooth muscle cells. ET-1 concentrations in tissues and plasma are
increased in several cardiovascular disorders and connective tissue diseases, including pulmonary
arterial hypertension, scleroderma, acute and chronic heart failure, myocardial ischaemia, systemic
hypertension and atherosclerosis, suggesting a pathogenic role of ET-1 in these diseases. In
pulmonary arterial hypertension 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 ET
A
and ET
B
receptors,
with a slightly higher affinity for ET
A
receptors (K
i
= 4.1–43 nanomolar) than for ET
B
receptors
(K
i
= 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 pulmonary arterial hypertension (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.
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
to 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 pulmonary arterial hypertension was observed with bosentan treatment.
Dyspnoea measurement during walk tests showed an improvement in bosentan-treated patients. In the
29
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/cm
5
)
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 effect
−22.6%
19
95% CL
−34, −10
−4, 42
P-value
< 0.0001
0.0758
PVR = pulmonary vascular resistance
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% 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.
In a prospective, multi-centre, randomised, double-blind, placebo-controlled study (AC-052-409
[BREATHE-5]), patients with pulmonary arterial hypertension 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), or placebo (n = 17). 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, 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.
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,
30
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.
Study performed in children with pulmonary arterial hypertension
One study has been conducted in children with pulmonary hypertension. Bosentan has been evaluated
in an open-label non-controlled study in 19 paediatric patients with pulmonary arterial hypertension
(AC-052-356 [BREATHE-3]: primary pulmonary hypertension, 10 patients, and pulmonary arterial
hypertension related to congenital heart diseases, 9 patients). This study was primarily designed as a
pharmacokinetic study (see section 5.2). Patients were divided into and dosed according to three
body-weight groups for 12 weeks. Half of the patients in each group were already being treated with
intravenous epoprostenol and the dose of epoprostenol remained constant for the duration of the
study. The age range was 3–15 years. Patients were in WHO functional class II (n = 15 patients, 79%)
or class III (n = 4 patients, 21%) at baseline.
Haemodynamics were measured in 17 patients. The mean increase from baseline in cardiac index was
0.5 L/min/m
2
, 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.
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 pulmonary
arterial hypertension who were receiving concomitant epoprostenol therapy. AC-052-356 was an
open-label, non-controlled 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.
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
31
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 pulmonary arterial hypertension 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, C
max
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 (V
ss
) 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 (t
1/2
) 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.
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
32
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 child-bearing potential
(see sections 4.3, 4.4 and 4.6).
In fertility studies in male and female rats at plasma concentrations 21 and 43 times, respectively, the
expected therapeutic level in humans, no effects on sperm count, motility and viability, or on mating
performance or fertility were observed, nor was there any adverse effect on the development of the
pre-implantation embryo or on implantation.
6.
6.1 List of excipients
Tablet core:
Maize starch
Pregelatinised starch
Sodium starch glycollate
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.
6.3 Shelf life
4 years
6.4 Special precautions for storage
Do not store above 30°C.
6.5 Nature and contents of container
PVC/PE/PVDC/aluminium-blisters containing 14 film-coated tablets.
Cartons contain 56 or 112 film-coated tablets.
34
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
Actelion Registration Ltd
BSI Building 13
th
Floor
389 Chiswick High Road
London W4 4AL
United Kingdom
8.
EU/1/02/220/004
EU/1/02/220/005
9.
Date of first authorisation: 15 May 2002
Date of renewal: 15 May 2007
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
.
35
1.
Tracleer 32 mg dispersible tablets
2.
Each dispersible tablet contains 32 mg bosentan (as monohydrate).
Excipient: 3.7 mg of Aspartame (E951) are present in each dispersible tablet.
For a full list of excipients, see section 6.1.
3.
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.
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) PAH
•
PAH secondary to scleroderma without significant interstitial pulmonary disease
•
PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger’s physiology
Some improvements have also been shown in patients with PAH 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).
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 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. Direct bioavailability comparison
has not been performed between dispersible tablets and film coated tablets. Thus its use should be
reserved for patients who cannot take the film-coated tablet.
Pulmonary arterial hypertension
Treatment should only be initiated and monitored by a physician experienced in the treatment of
pulmonary arterial hypertension.
36
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.
For paediatric patients aged 2 years or older, the optimal maintenance dose has not been defined in
well-controlled studies. However, paediatric pharmacokinetic data have shown that bosentan plasma
concentrations in children were on average lower than in adult patients and were not increased by
increasing the dose of Tracleer above 2 mg/kg body weight twice daily (see section 5.2). Based on
these pharmacokinetic results, higher doses are unlikely to be more effective, and greater adverse
event rates cannot formally be excluded in young children if the dose is increased. No clinical study
has been conducted to compare the efficacy/safety ratio of 2 mg/kg to 4 mg/kg body weight twice
daily in children.
There is only limited clinical experience in paediatric patients under 2
years of age
In the case 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 case 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).
Discontinuation of treatment
There is limited experience with abrupt discontinuation of Tracleer. 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.
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.
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).
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
Dosage in hepatic impairment
37
No dose adjustment is needed in patients with mild hepatic impairment (i.e., Child-Pugh class A) (see
section 5.2). Tracleer is contraindicated in patients with moderate to severe liver dysfunction (see
sections 4.3, 4.4 and 5.2).
Dosage in 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).
Dosage in elderly patients
No dose adjustment is required in patients over the age of 65 years.
•
Hypersensitivity to the active substance or to any of the excipients
•
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 aminotransferases (AST) and/or
alanine aminotransferases (ALT), greater than 3 times the upper limit of normal (see
section 4.4)
•
Concomitant use of cyclosporine A (see section 4.5)
•
Pregnancy (see sections 4.4 and 4.6)
•
Women of child-bearing potential who are not using reliable methods of contraception (see
sections 4.4, 4.5 and 4.6)
The efficacy of Tracleer has not been established in patients with severe pulmonary arterial
hypertension. 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 pulmonary arterial hypertension.
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.
38
Recommendations in case of ALT/AST elevations
ALT/AST levels
Treatment and monitoring recommendations
> 3 and ≤ 5 × ULN
Confirm by another 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). Continue to monitor
aminotransferase levels at least every 2 weeks. If the aminotransferase levels
return to pre-treatment values consider continuing or re-introducing Tracleer
according to the conditions described below.
> 5 and ≤ 8 × ULN
Confirm by another liver test; if confirmed, stop treatment and monitor
aminotransferase levels at least every 2 weeks. If the aminotransferase levels
return to pre-treatment values consider re-introducing Tracleer according to
the conditions described below.
> 8 × ULN
Treatment must be stopped and re-introduction of Tracleer is not to be
considered.
In the case 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 child-bearing potential
Tracleer treatment must not be initiated in women of child-bearing potential unless they practise
reliable contraception (see section 4.5) and the result of the pre-treatment pregnancy test is negative
(see section 4.6).
Before the initiation of Tracleer treatment in women of child-bearing 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 child-bearing potential must not use hormonal contraceptives (including
oral, injectable, transdermal and implantable forms) as the sole method of contraception but should
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.
39
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.
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-
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
40
Glibenclamide:
Tracleer should not be used concomitantly with glibenclamide, due to an increased
risk of elevated liver aminotransferases (see section 4.5). An alternative antidiabetic medicinal
product should be used in patients in whom an antidiabetic treatment is indicated.
Fluconazole:
concomitant use of Tracleer with fluconazole is not recommended (see section 4.5).
Although not studied, this combination may lead to large increases in plasma concentrations of
bosentan.
Rifampicin:
co-administration of Tracleer with rifampicin is not recommended (see section 4.5).
Concomitant administration of both a CYP3A4 inhibitor and a CYP2C9 inhibitor with Tracleer
should be avoided (see section 4.5).
Tracleer 32 mg dispersible tablets contain a source of phenylalanine (Aspartame – E951). This may
be harmful for people with phenylketonuria.
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.
Concomitant 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). Indeed, when co-administered, initial trough concentrations of
bosentan were approximately 30-fold higher than those measured after bosentan alone. At steady
state, bosentan plasma concentrations were 3- to 4-fold higher than with bosentan alone. The
mechanism of this interaction is most likely inhibition of transport protein-mediated uptake of
bosentan into hepatocytes by cyclosporine. The blood concentrations of cyclosporine A (a CYP3A4
substrate) decreased by approximately 50%. This is most likely due to induction of CYP3A4 by
bosentan.
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
41
explain the elevated aminotransferases. In this context, this combination should not be used (see
section 4.4). No drug-drug interaction data are available with the other sulfonylureas.
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 pulmonary arterial hypertension 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.
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. 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.
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 C
max
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.
Digoxin:
co-administration for 7 days of bosentan 500 mg twice daily with digoxin decreased the
AUC, C
max
and C
min
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.
42
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 of 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. It is emphasised that due to the marked hepatotoxicity of
nevirapine, which could accumulate with bosentan liver toxicity, this combination is not
recommended.
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).
Use in women of child-bearing potential
Before the initiation of Tracleer treatment in women of child-bearing 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 child-bearing 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.
Use during lactation
It is not known whether bosentan is excreted into human breast milk. Breast-feeding is not
recommended during treatment with Tracleer.
No studies on the effect of Tracleer on the ability to drive and use machines have been performed.
Tracleer may cause dizziness, which could affect the ability to drive or use machines.
43
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. The most commonly reported
adverse drug reactions (as occurring in at least 1% of patients on bosentan and at a frequency at least
0.5% more than on placebo) are headache (11.5% vs 9.8%), oedema/fluid retention (13.2% vs 10.9%),
abnormal liver function test (10.9% vs 4.6%) and anaemia/haemoglobin decrease (9.9% vs 4.9%).
Treatment with bosentan has been associated with dose-dependent elevations in liver
aminotransferases and decreases in haemoglobin concentration (see section 4.4, Special warnings and
precautions for use).
Adverse reactions/undesirable effects in 20 placebo-controlled studies 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).
Reports from post-marketing experience are included in
Italics
, with frequency categories based on
adverse event reporting rates on bosentan in the 20 placebo-controlled studies.
Frequency categories do not account for other factors, including varying study duration, pre-existing
conditions, and baseline patient characteristics. Within each frequency grouping, undesirable effects
are presented in order of decreasing seriousness. No clinically relevant differences in undesirable
effects 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
1
Anaemia or haemoglobin
decreases requiring red blood
cell transfusion
Uncommon
Thrombocytopenia
Uncommon
Neutropenia, leukopenia
Immune system disorders
Common
Hypersensitivity reactions
(including dermatitis, pruritus
and rash)
2
Rare
Anaphylaxis and/or
angioedema
Nervous system disorders
Very common
Headache
3
Common
Syncope
4
Cardiac disorders
Common
Palpitations
4
Vascular disorders
Common
Flushing
Common
Hypotension
4
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
and/or jaundice,
(see
section 4.4)
Rare
Liver cirrhosis, liver failure
Skin and subcutaneous
disorders
Common
Erythema
General disorders and
administration site conditions
Very common
Oedema, fluid retention
5
1
Frequency cannot be estimated from the available data.
44
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).
Uncontrolled studies in paediatric patients with PAH (AC-052-356 [BREATHE-3]; AC-052-365
[FUTURE 1])
The safety profile in this population (BREATHE-3: n = 19, bosentan 2 mg/kg twice daily; treatment
duration 12 weeks; FUTURE 1: n = 36, bosentan 2 mg/kg twice daily for 4 weeks followed by
4 mg/kg twice daily; treatment duration 12 weeks) was similar to that observed in the pivotal trials in
adult patients with PAH. In BREATHE-3, the most frequent adverse events were flushing (21%),
headache, and abnormal liver function test (each 16%). In FUTURE 1, the most frequent adverse
events were infections (33%) and abdominal pain/discomfort (19%). There were no cases of liver
enzyme elevations in the FUTURE 1 study.
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 times the
upper limit of normal (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.
Haemoglobin
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).
Bosentan has been administered as a single dose of up to 2400 mg to healthy subjects and up to
2000 mg/day for 2 months in patients with a disease other than pulmonary hypertension. The most
common adverse event 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
45
blurred vision. He recovered completely within 24 hours with blood pressure support. Note: bosentan
is not removed through dialysis.
5.
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
(ET
A
and ET
B
) 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 ET
A
and ET
B
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 pulmonary
arterial hypertension, scleroderma, acute and chronic heart failure, myocardial ischaemia, systemic
hypertension and atherosclerosis, suggesting a pathogenic role of ET-1 in these diseases. In
pulmonary arterial hypertension 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 ET
A
and ET
B
receptors,
with a slightly higher affinity for ET
A
receptors (K
i
= 4.1–43 nanomolar) than for ET
B
receptors
(K
i
= 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 pulmonary arterial hypertension (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.
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
to 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
46
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 pulmonary arterial hypertension 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/cm
5
)
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 effect
−22.6%
19
95% CL
−34, −10
−4, 42
P-value
< 0.0001
0.0758
PVR = pulmonary vascular resistance
Treatment wi th bosentan was associ ated wi th a reducti on i n the rate of cl i ni cal worseni ng, def i ned as
a composi te of symptomati c progressi on, hospi tal i sati on f or PA H and death, compared wi th pl acebo
(proporti onal ri sk reducti on 77%, 95% 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.
In a prospective, multi-centre, randomised, double-blind, placebo-controlled study (AC-052-409
[BREATHE-5]), patients with pulmonary arterial hypertension WHO functional class III and
Eisenmenger physiology associated with congenital heart disease received bosentan 62.5 mg twice
47
daily for 4 weeks, then 125 mg twice daily for a further 12 weeks (n = 37), or placebo (n = 17). 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, 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.
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.
Study performed in children with pulmonary arterial hypertension
One study has been conducted in children with pulmonary hypertension. Bosentan has been evaluated
in an open-label non-controlled study in 19 paediatric patients with pulmonary arterial hypertension
(AC-052-356 [BREATHE-3]: primary pulmonary hypertension, 10 patients, and pulmonary arterial
hypertension related to congenital heart diseases, 9 patients). This study was primarily designed as a
pharmacokinetic study (see section 5.2). Patients were divided into and dosed according to three
body-weight groups for 12 weeks. Half of the patients in each group were already being treated with
intravenous epoprostenol and the dose of epoprostenol remained constant for the duration of the
study. The age range was 3–15 years. Patients were in WHO functional class II (n = 15 patients, 79%)
or class III (n = 4 patients, 21%) at baseline.
Haemodynamics were measured in 17 patients. The mean increase from baseline in cardiac index was
0.5 L/min/m
2
, 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.
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 pulmonary
arterial hypertension who were receiving concomitant epoprostenol therapy. AC-052-356 was an
open-label, non-controlled 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.
48
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.
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 pulmonary arterial hypertension 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, C
max
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 (V
ss
) 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 (t
1/2
) is 5.4 hours.
49
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.
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. No pharmacokinetic data are available in children under 2 years.
Children
The pharmacokinetics of single and multiple oral doses were studied in paediatric patients with
pulmonary arterial hypertension who were dosed on the basis of body weight (see section 5.1, AC-
052-356 [BREATHE-3]). The exposure to bosentan decreased with time in a manner consistent with
the known auto-induction properties of bosentan. The mean AUC (CV%) values of bosentan in
paediatric patients treated with 31.25, 62.5 or 125 mg twice daily were 3,496 (49), 5,428 (79), and
6,124 (27) ng·h/mL, respectively, and were lower than the value of 8,149 (47) ng·h/mL observed in
adult patients with pulmonary arterial hypertension 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 a second pharmacokinetic study (AC-052-365 [FUTURE 1]), 36 paediatric patients aged 2–11
years with PAH were treated at 2 and 4 mg/kg twice daily with the dispersible tablet. No dose
proportionality was observed. Steady-state bosentan plasma concentrations were similar at oral doses
of 2 and 4 mg/kg. The AUC
τ
was 3,577 ng·h/mL for 2 mg/kg twice daily and 3,371 ng·h/mL for
4 mg/kg twice daily. The average exposure to bosentan in 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. Based on the findings in studies BREATHE-3 and FUTURE 1, 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 will not result in greater exposure to bosentan
in paediatric patients.
The consequences of these findings regarding hepatotoxicity are unknown.
Gender and the
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 pharmacokinetics of bosentan have not been studied in patients with
50
6.3 Shelf life
3 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.
Actelion Registration Ltd
BSI Building 13
th
Floor
389 Chiswick High Road
London W4 4AL
United Kingdom
8.
EU/1/02/220/006
9.
Date of first authorisation: 15 May 2002
52
Date of renewal: 15 May 2007
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
.
53
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
54
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Actelion Pharmaceuticals Deutschland GmbH
Basler Strasse 63-65
79100 Freiburg
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2)
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The MAH shall agree the details of a controlled distribution system with the National Competent
Authorities and must implement such programme nationally to ensure that prior to prescribing all
health care professionals who intend to prescribe and/or dispense Tracleer are provided with a
Prescriber Kit containing the following:
•
Information about Tracleer
•
Patient Information Booklet/Patient Reminder Card
The MAH shall set up a surveillance programme/registry to collect information on the demographics,
safety and outcome data from patients prescribed Tracleer to reduce the number of new digital ulcers
in patients with systemic sclerosis and ongoing digital ulcer disease. The data to be collected shall be
agreed with the CHMP. Details of the operation of the surveillance programme/registry shall be
agreed with the National Competent Authorities in each Member State.
The information provided about Tracleer shall contain the following key elements:
•
That Tracleer is teratogenic in animals
o
Use in pregnant women is contraindicated
o
The need for effective contraception
o
That there is an interaction with hormonal contraceptives
o
Monthly pregnancy tests in women of child bearing potential are recommended.
•
That Tracleer is hepatotoxic
o
Tracleer should not be used in Child Pugh Class B or C, ie moderate to severe
hepatic impairment.
o
Need for liver function tests to be measured:
Prior to initiation of treatment
At monthly intervals during complete course of the treatment
Two weeks after any dose increase.
o
Need for close monitoring and dosage adjustment if levels rise above 3 x upper
limit normal (ULN):
>3 and ≤ 5 x ULN: Confirm levels and if confirmed, reduce the daily dose
or stop treatment and monitor liver function at least every 2 weeks.
>5 and ≤ 8 x ULN: Confirm levels and if confirmed stop treatment and
monitor liver function at least every 2 weeks.
In the above circumstances, if the levels return to pre-treatment values,
continuing or re-introducing Tracleer may be considered.
55
> 8 x ULN or any of the above with associated clinical symptoms of liver
injury: Treatment must be stopped and re-introduction of Tracleer is not to
be considered.
•
That treatment with Tracleer is associated with a decrease in haemoglobin.
o
Need for blood monitoring
Prior to initiation of treatment
Monthly during the first 4 months
Quarterly thereafter.
•
That co-administration of Tracleer with cyclosporine is contraindicated.
•
That the safety database of Tracleer in the indication to reduce the number of new digital
ulcers in patients with systemic sclerosis and ongoing digital ulcer disease is limited and
physicians are encouraged to enrol patients in the surveillance programme/registry to
further increase knowledge about the product. The surveillance programme/registry
should prompt doctors to report adverse reactions.
The patient information shall contain the following information:
•
That Tracleer is teratogenic in animals
•
That pregnant women must not take Tracleer
•
That women of child bearing potential must use effective contraception
•
That hormonal contraceptives on their own are not effective
•
The need for regular pregnancy tests
•
That Tracleer causes a decrease in haemoglobin and the need for regular blood tests
•
That Tracleer is hepatotoxic and the need for regular monitoring of liver function
The MAH shall agree with each National Competent Authority the content of a "Reminder Letter" to
all known prescribers of Tracleer, reminding them of the safety concerns with Tracleer in relation to
pregnancy.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH ensures that the system of pharmacovigilance, as described in version 6 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 11 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
56
PSURs
The MAH will submit 6-monthly PSURs including liver reports, unless otherwise specified by the
CHMP.
57
ANNEX III
LABELLING AND PACKAGE LEAFLET
58
A. LABELLING
59
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON WITH 14, 56 AND 112 TABLETS
1.
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.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight 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.
60
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Actelion Registration Ltd
BSI Building 13
th
Floor
389 Chiswick High Road
London W4 4AL
United Kingdom
EU/1/02/220/001
EU/1/02/220/002
EU/1/02/220/003
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Tracleer 62.5 mg
61
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON WITH 56 AND 112 TABLETS
1.
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.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight 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.
62
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Actelion Registration Ltd
BSI Building 13
th
Floor
389 Chiswick High Road
London W4 4AL
United Kingdom
EU/1/02/220/004
EU/1/02/220/005
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Tracleer 125 mg
63
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON WITH 56 TABLETS
1.
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.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25 °C.
64
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Actelion Registration Ltd
BSI Building 13
th
Floor
389 Chiswick High Road
London W4 4AL
United Kingdom
EU/1/02/220/006
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Tracleer 32 mg
65
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
Tracleer 62.5 mg tablets
bosentan
2.
Actelion
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Lot
5.
OTHER
66
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
Tracleer 125 mg tablets
bosentan
2.
Actelion
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Lot
5.
OTHER
67
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
Tracleer 32 mg dispersible tablets
bosentan
2.
Actelion
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Lot
5.
OTHER
68
PATIENT REMINDER CARD
((Front cover))
((Back cover))
Important Safety Reminders for Patients taking
Tracleer (bosentan)
This card contains important information about Tracleer. Please read this card
carefully before starting your treatment with Tracleer.
Contraception
Do you currently use or take contraceptives?
Yes
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.
Your name: __________________________________________________
Prescribing doctor: ________________________________________
If you have questions about Tracleer ask your doctor.
Actelion Registration Ltd
((Inside 1))
If you are a female patient of child bearing age read this page
carefully
((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: _________________________________
Pregnancy
Tracleer may harm the development of the foetus. Therefore, you should not
take Tracleer if you are pregnant and you should 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.
Your monthly liver blood test schedule:
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.
Jan ______
May ______
Sep _____
Feb ______
Jun ______
Oct _____
Mar ______
Jul ______
Nov _____
Apr ______
Aug ______
Dec _____
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:
69
No
B. PACKAGE LEAFLET
70
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.
-
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. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Tracleer is and what it is used for
2.
Before you take Tracleer
3.
How to take Tracleer
4.
Possible side effects
5.
How to store Tracleer
6.
Further information
1.
WHAT TRACLEER IS AND WHAT IT IS USED FOR
Tracleer tablets contain bosentan and belong to the class of medicines called “endothelin receptor
antagonists”.
Tracleer is used to treat
pulmonary arterial hypertension
(PAH). PAH is high blood pressure in the
blood vessels (the pulmonary arteries) that carry blood from the heart to the lungs. 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 also used to treat
digital ulcers
(ulcers of the fingers) in people with a condition called
scleroderma. Tracleer reduces the number of new finger ulcers that appear.
2.
BEFORE YOU TAKE TRACLEER
Do not take Tracleer…
•
if you are allergic
(hypersensitive)
to bosentan
or any of the other ingredients of the tablet
•
if you have
liver problems
(ask your doctor)
•
if you are pregnant, or could get pregnant
because you are not using reliable contraceptive
methods (hormonal contraceptives alone are not effective when you take 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.
Take special care with Tracleer
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 child-bearing potential
71
Some patients taking Tracleer have been found to have abnormal liver function tests and anaemia
(low haemoglobin). 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 Reminder 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 reminder 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.
Tracleer may affect your liver. 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
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.
Pregnancy tests for women of child-bearing age:
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.
•
Don’t take Tracleer if you are pregnant or planning to become pregnant.
•
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 Reminder 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
child-bearing age.
•
Tell your doctor immediately if you become pregnant while you are taking Tracleer, or plan to
become pregnant in the near future.
72
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.
Taking other medicines
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:
•
hormonal contraceptives (as these are not effective as the sole method of contraception when
you take Tracleer). Inside your pack of Tracleer tablets you will find a patient reminder card
which you should read carefully. Your doctor and/or gynaecologist will establish the
contraception which is appropriate for you.
•
glibenclamide (for diabetes) (as this combination may increase the risk of side effects)
•
cyclosporine A (a medicine used after transplants and to treat psoriasis), or any other drugs
used to prevent rejection of transplanted organs (as these drugs may increase the concentrations
of Tracleer in your blood)
•
fluconazole (to treat fungal infections) (as this drug may increase the concentrations of Tracleer
in your blood)
•
rifampicin (to treat tuberculosis) (as this drug may reduce the efficacy of Tracleer)
•
medicines for the treatment of HIV infection
Taking Tracleer with food and drink
Tracleer can be taken with or without food.
Driving and using machines
If you feel dizzy
while taking Tracleer, do not drive or operate any tools or machines.
3.
HOW TO TAKE TRACLEER
Always take Tracleer exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
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.
Usual 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 patients with low body weight
For children and patients with low body weight, 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.
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 at once.
If you forget to take Tracleer
73
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 product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Tracleer can cause side effects, although not everybody gets them.
These side effects may occur with certain frequencies, which are defined as follows:
•
very common: affects more than 1 user in 10
•
common: affects 1 to 10 users in 100
•
uncommon: affects 1 to 10 users in 1,000
•
rare: affects 1 to 10 users in 10,000
•
very rare: affects less than 1 user in 10,000
When Tracleer was taken in clinical studies, the following side effects occurred:
Very common side effects
•
Headache
•
Abnormal liver function test
•
Oedema (swelling of the legs and ankles or other signs of fluid retention)
Common side effects
•
Anaemia (low number of red blood cells) or haemoglobin decreases
•
Flushed appearance
•
Hypersensitivity reactions (including skin inflammation, itching and rash)
•
Gastrooesophageal reflux disease (acid reflux)
•
Diarrhoea
•
Skin redness
The following side effects have occurred during the marketed use of Tracleer:
Common
•
Syncope (fainting)
•
Palpitations (fast or irregular heart beats)
•
Low blood pressure
Uncommon
•
Thrombocytopenia (low number of blood platelets)
•
Neutropenia/leukopenia (low number of white blood cells)
•
Elevated liver function tests with hepatitis (inflammation of the liver) and/or jaundice
(yellowing of the skin or the whites of the eyes)
Rare
•
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)
74
Not known
(cannot be estimated from the available data)
•
Anaemia (low number of red blood cells) or haemoglobin decreases requiring
blood transfusion
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet or signs
of allergic reaction (e.g., swelling of the face or tongue, rash, itch) while you are taking Tracleer, or if
any of the side effects mentioned above worry you, please tell your doctor or pharmacist.
5.
HOW TO STORE TRACLEER
Keep out of the reach and sight of children.
Do not use Tracleer after the expiry date which is stated on the carton and on the blister after “EXP”.
Do not store above 30 °C.
6.
FURTHER 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
glycollate, 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.
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).
Not all pack sizes may be marketed.
Marketing authorisation holder:
Actelion Registration Ltd
BSI Building 13
th
Floor
389 Chiswick High Road
London W4 4AL
United Kingdom
Manufacturer:
Actelion Pharmaceuticals Deutschland GmbH
Basler Strasse 63-65
79100 Freiburg
Germany
75
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
Actelion Pharmaceuticals Belgium N.V.
Tél/Tel: +32-(0)15 284 777
Luxembourg/Luxemburg
Actelion Pharmaceuticals Belgium N.V.
Tél/Tel: +32-(0)15 284 777
България
Аквахим ЕООД
Te
л.
: +
359 2 807 50 00
Magyarország
Actelion Pharmaceuticals Ltd
Tel: +48 (0) 500 145 920
Česká republika
Actelion Pharmaceuticals CZ, s.r.o.
Tel: +420 221 968 006
Malta
Actelion Pharmaceuticals Ltd
Tel: +48 (0) 500 145 920
Danmark
Actelion Danmark,
Filial af Actelion Pharmaceuticals Sverige AB,
Sverige
Tlf: +45 3694 45 95
Nederland
Actelion Pharmaceuticals Nederland B.V.
Tel: +31 (0)348 435950
Deutschland
Actelion Pharmaceuticals Deutschland GmbH
Tel: +49 761 45 64 0
Norge
Actelion Pharmaceuticals Sverige AB,
Filial Norge
Tlf: +47 22480370
Eesti
Nycomed SEFA AS
Tel: +372 6112 569
Österreich
Actelion Pharmaceuticals Austria GmbH
Tel: +43 1 505 4527
Ελλάδα
Actelion Pharmaceuticals Eλλάς Α.Ε.
Τηλ: +30 210 675 25 00
Polska
Actelion Pharma Polska Sp. z o.o.
Tel: +48 (0) 500 145 920
España
Actelion Pharmaceuticals España S.L.
Tel: +34 93 253 10 64
Portugal
Actelion Pharmaceuticals Portugal Lda.
Tel: +351 21 358 6120
France
Actelion Pharmaceuticals France SAS
Tél: +33 1 58 62 32 32
România
Geneva Romfarm Internacional
Tel: + 40 (021) 231 3561
Ireland
Actelion Pharmaceuticals UK Ltd
Tel: +353 1890 771 648
Slovenija
Medis d.o.o.
Tel: +386-(0)1 589 69 00
Ísland
Actelion Pharmaceuticals Sverige AB
Sími: +46 (0)8 544 982 50
Slovenská republika
Actelion Pharmaceuticals SK, s.r.o.
Tel: +420 221 968 006
Italia
Actelion Pharmaceuticals Italia S.r.l.
Tel: +39 0542 64 87 40
Suomi/Finland
Actelion Pharmaceuticals Sverige AB,
Filial Finland
Puh/Tel: +358 9 2510 7720
76
Κύπρος
Actelion Pharmaceuticals Eλλάς Α.Ε.
Τηλ: +30 210 675 25 00
Sverige
Actelion Pharmaceuticals Sverige AB
Tel: +46 8 544 982 50
Latvija
Nycomed Latvija
Tel: +371 784 0082
United Kingdom
Actelion Pharmaceuticals UK Ltd
Tel: +44 845 075 0555
Lietuva
Nycomed atstovybė
Tel: +370 5210 9070
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
77
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.
-
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. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Tracleer is and what it is used for
2.
Before you take Tracleer
3.
How to take Tracleer
4.
Possible side effects
5.
How to store Tracleer
6.
Further information
1.
WHAT TRACLEER IS AND WHAT IT IS USED FOR
Tracleer tablets contain bosentan and belong to the class of medicines called “endothelin receptor
antagonists”.
Tracleer is used to treat
pulmonary arterial hypertension
(PAH). PAH is high blood pressure in the
blood vessels (the pulmonary arteries) that carry blood form the heart to the lungs. 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 also used to treat
digital ulcers
(ulcers of the fingers) in people with a condition called
scleroderma. Tracleer reduces the number of new finger ulcers that appear.
2.
BEFORE YOU TAKE TRACLEER
Do not take Tracleer…
•
if you are allergic
(hypersensitive)
to bosentan
or any of the other ingredients of the tablet
•
if you have
liver problems
(ask your doctor)
•
if you are pregnant, or could get pregnant
because you are not using reliable contraceptive
methods (hormonal contraceptives alone are not effective when you take 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.
Take special care with Tracleer
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 child-bearing potential
78
Some patients taking Tracleer have been found to have abnormal liver function tests and anaemia
(low haemoglobin). 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 Reminder 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 reminder 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.
Tracleer may affect your liver. 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
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.
Pregnancy tests for women of child-bearing age:
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.
•
Don’t take Tracleer if you are pregnant or planning to become pregnant.
•
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 Reminder 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
child-bearing age.
•
Tell your doctor immediately if you become pregnant while you are taking Tracleer, or plan to
become pregnant in the near future.
79
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.
Taking other medicines
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:
•
hormonal contraceptives (as these are not effective as the sole method of contraception when
you take Tracleer). Inside your pack of Tracleer tablets you will find a patient reminder card
which you should read carefully. Your doctor and/or gynaecologist will establish the
contraception which is appropriate for you.
•
glibenclamide (for diabetes) (as this combination may increase the risk of side effects)
•
cyclosporine A (a medicine used after transplants and to treat psoriasis), or any other drugs
used to prevent rejection of transplanted organs (as these drugs may increase the concentrations
of Tracleer in your blood)
•
fluconazole (to treat fungal infections) (as this drug may increase the concentrations of Tracleer
in your blood)
•
rifampicin (to treat tuberculosis) (as this drug may reduce the efficacy of Tracleer)
•
medicines for the treatment of HIV infection
Taking Tracleer with food and drink
Tracleer can be taken with or without food.
Driving and using machines
If you feel dizzy
while taking Tracleer, do not drive or operate any tools or machines.
3.
HOW TO TAKE TRACLEER
Always take Tracleer exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
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.
Usual 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 patients with low body weight
For children and patients with low body weight, 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.
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 at once.
80
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 product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Tracleer can cause side effects, although not everybody gets them.
These side effects may occur with certain frequencies, which are defined as follows:
•
very common: affects more than 1 user in 10
•
common: affects 1 to 10 users in 100
•
uncommon: affects 1 to 10 users in 1,000
•
rare: affects 1 to 10 users in 10,000
•
very rare: affects less than 1 user in 10,000
When Tracleer was taken in clinical studies, the following side effects occurred:
Very common side effects
•
Headache
•
Abnormal liver function test
•
Oedema (swelling of the legs and ankles or other signs of fluid retention)
Common side effects
•
Anaemia (low number of red blood cells) or haemoglobin decreases
•
Flushed appearance
•
Hypersensitivity reactions (including skin inflammation, itching and rash)
•
Gastrooesophageal reflux disease (acid reflux)
•
Diarrhoea
•
Skin redness
The following side effects have occurred during the marketed use of Tracleer:
Common
•
Syncope (fainting)
•
Palpitations (fast or irregular heart beats)
•
Low blood pressure
Uncommon
•
Thrombocytopenia (low number of blood platelets)
•
Neutropenia/leukopenia (low number of white blood cells)
•
Elevated liver function tests with hepatitis (inflammation of the liver) and/or jaundice
(yellowing of the skin or the whites of the eyes)
Rare
•
Anaphylaxis (general allergic reaction), angioedema (swelling, most commonly around the
eyes, lips, tongue or throat)
81
•
Cirrhosis (scarring) of the liver, liver failure (serious disturbance of liver function)
Not known
(cannot be estimated from the available data)
•
Anaemia (low number of red blood cells) or haemoglobin decreases requiring
blood transfusion
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet or signs
of allergic reaction (e.g., swelling of the face or tongue, rash, itch) while you are taking Tracleer, or if
any of the side effects mentioned above worry you, please tell your doctor or pharmacist.
5.
HOW TO STORE TRACLEER
Keep out of the reach and sight of children.
Do not use Tracleer after the expiry date which is stated on the carton and on the blister after “EXP”.
Do not store above 30°C.
6.
FURTHER 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
glycollate, 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.
PVC/PE/PVDC/aluminium-blisters
containing
14 film-coated tablets.
Cartons contain 56 or 112
film-coated tablets (Tracleer 125 mg film-coated tablets).
Not all pack sizes may be marketed.
Marketing authorisation holder:
Actelion Registration Ltd
BSI Building 13
th
Floor
389 Chiswick High Road
London W4 4AL
United Kingdom
Manufacturer:
Actelion Pharmaceuticals Deutschland GmbH
Basler Strasse 63-65
79100 Freiburg
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
82
België/Belgique/Belgien
Actelion Pharmaceuticals Belgium N.V.
Tél/Tel: +32-(0)15 284 777
Luxembourg/Luxemburg
Actelion Pharmaceuticals Belgium N.V.
Tél/Tel: +32-(0) 15 284 777
България
Аквахим ЕООД
Te
л.
: +
359 2 807 50 00
Magyarország
Actelion Pharmaceuticals Ltd
Tel: +48 (0) 500 145 920
Česká republika
Actelion Pharmaceuticals CZ, s.r.o.
Tel: +420 221 968 006
Malta
Actelion Pharmaceuticals Ltd
Tel: +48 (0) 500 145 920
Danmark
Actelion Danmark,
Filial af Actelion Pharmaceuticals Sverige AB,
Sverige
Tlf: +45 3694 45 95
Nederland
Actelion Pharmaceuticals Nederland B.V.
Tel: +31 (0)348 435950
Deutschland
Actelion Pharmaceuticals Deutschland GmbH
Tel: +49 761 45 64 0
Norge
Actelion Pharmaceuticals Sverige AB,
Filial Norge
Tlf: +47 22480370
Eesti
Nycomed SEFA AS
Tel: +372 6112 569
Österreich
Actelion Pharmaceuticals Austria GmbH
Tel: +43 1 505 4527
Ελλάδα
Actelion Pharmaceuticals Eλλάς Α.Ε.
Τηλ: +30 210 675 25 00
Polska
Actelion Pharma Polska Sp. z o.o.
Tel: +48 (0) 500 145 920
España
Actelion Pharmaceuticals España S.L.
Tel: +34 93 253 10 64
Portugal
Actelion Pharmaceuticals Portugal Lda.
Tel: +351 21 358 6120
France
Actelion Pharmaceuticals France SAS
Tél: +33 1 58 62 32 32
România
Geneva Romfarm Internacional
Tel: + 40 (021) 231 3561
Ireland
Actelion Pharmaceuticals UK Ltd
Tel: +353 1890 771 648
Slovenija
Medis d.o.o.
Tel: +386-(0)1 589 69 00
Ísland
Actelion Pharmaceuticals Sverige AB
Sími: +46 (0)8 544 982 50
Slovenská republika
Actelion Pharmaceuticals SK, s.r.o.
Tel: +420 221 968 006
Italia
Actelion Pharmaceuticals Italia S.r.l.
Tel: +39 0542 64 87 40
Suomi/Finland
Actelion Pharmaceuticals Sverige AB,
Filial Finland
Puh/Tel: +358 9 2510 7720
Κύπρος
Actelion Pharmaceuticals Eλλάς Α.Ε.
Τηλ: +30 210 675 25 00
Sverige
Actelion Pharmaceuticals Sverige AB
Tel: +46 8 544 982 50
83
Latvija
Nycomed Latvija
Tel: +371 784 0082
United Kingdom
Actelion Pharmaceuticals UK Ltd
Tel: +44 845 075 0555
Lietuva
Nycomed atstovybė
Tel: +370 5210 9070
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
84
PACKAGE LEAFLET: INFORMATION FOR THE USER
Tracleer 32 mg dispersible tablets
Bosentan
Read all of this leaflet carefully before you start taking this medicine.
-
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. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Tracleer is and what it is used for
2.
Before you take Tracleer
3.
How to take Tracleer
4.
Possible side effects
5.
How to store Tracleer
6.
Further information
1.
WHAT TRACLEER IS AND WHAT IT IS USED FOR
Tracleer tablets contain bosentan and belong to the class of medicines called “endothelin receptor
antagonists”.
Tracleer is used to treat
pulmonary arterial hypertension
(PAH). PAH is high blood pressure in the
blood vessels (the pulmonary arteries) that carry blood from the heart t the lungs. 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 also used to treat
digital ulcers
(ulcers of the fingers) in people with a condition called
scleroderma. Tracleer reduces the number of new finger ulcers that appear.
2.
BEFORE YOU TAKE TRACLEER
Do not take Tracleer…
•
if you are allergic
(hypersensitive)
to bosentan
or any of the other ingredients of the tablet
•
if you have
liver problems
(ask your doctor)
•
if you are pregnant, or could get pregnant
because you are not using reliable contraceptive
methods (hormonal contraceptives alone are not effective when you take 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.
Take special care with Tracleer
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 child-bearing potential
85
Some patients taking Tracleer have been found to have abnormal liver function tests and anaemia
(low haemoglobin). 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 Reminder 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 reminder 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.
Tracleer may affect your liver. 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
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.
Pregnancy tests for women of child-bearing age:
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.
•
Don’t take Tracleer if you are pregnant or planning to become pregnant.
•
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 Reminder 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
child-bearing age.
•
Tell your doctor immediately if you become pregnant while you are taking Tracleer, or plan to
become pregnant in the near future.
86
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.
Taking other medicines
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:
•
hormonal contraceptives (as these are not effective as the sole method of contraception when
you take Tracleer). Inside your pack of Tracleer tablets you will find a patient reminder card
which you should read carefully. Your doctor and/or gynaecologist will establish the
contraception which is appropriate for you.
•
glibenclamide (for diabetes) (as this combination may increase the risk of side effects)
•
cyclosporine A (a medicine used after transplants and to treat psoriasis), or any other drugs
used to prevent rejection of transplanted organs (as these drugs may increase the concentrations
of Tracleer in your blood)
•
fluconazole (to treat fungal infections) (as this drug may increase the concentrations of Tracleer
in your blood)
•
rifampicin (to treat tuberculosis) (as this drug may reduce the efficacy of Tracleer)
•
medicines for the treatment of HIV infection
Taking Tracleer with food and drink
Tracleer can be taken with or without food.
Driving and using machines
If you feel dizzy
while taking Tracleer, do not drive or operate any tools or machines.
Important information about some of the ingredients of Tracleer
Each Tracleer 32 mg dispersible tablets contains 3.7 mg of Aspartame (E951) which is a source of
phenylalanine. Aspartame may be harmful for people with phenylketonuria.
3.
HOW TO TAKE TRACLEER
Always take Tracleer exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
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.
Usual 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 patients with low body weight
For children and patients with low body weight, 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.
Tablets should be taken (morning and evening), swallowed with water. The tablets can be taken with
or without food.
87
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 layers.
3.
Push the pharmaceutical product through the foil.
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 at once.
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 product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Tracleer can cause side effects, although not everybody gets them.
These side effects may occur with certain frequencies, which are defined as follows:
•
very common: affects more than 1 user in 10
•
common: affects 1 to 10 users in 100
88
•
uncommon: affects 1 to 10 users in 1,000
•
rare: affects 1 to 10 users in 10,000
•
very rare: affects less than 1 user in 10,000
When Tracleer was taken in clinical studies, the following side effects occurred:
Very common side effects
•
Headache
•
Abnormal liver function test
•
Oedema (swelling of the legs and ankles or other signs of fluid retention)
Common side effects
•
Anaemia (low number of red blood cells) or haemoglobin decreases
•
Flushed appearance
•
Hypersensitivity reactions (including skin inflammation, itching and rash)
•
Gastrooesophageal reflux disease (acid reflux)
•
Diarrhoea
•
Skin redness
The following side effects have occurred during the marketed use of Tracleer:
Common
•
Syncope (fainting)
•
Palpitations (fast or irregular heart beats)
•
Low blood pressure
Uncommon
•
Thrombocytopenia (low number of blood platelets)
•
Neutropenia/leukopenia (low number of white blood cells)
•
Elevated liver function tests with hepatitis (inflammation of the liver) and/or jaundice
(yellowing of the skin or the whites of the eyes)
Rare
•
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)
Not known
(cannot be estimated from the available data)
•
Anaemia (low number of red blood cells) or haemoglobin decreases requiring
blood transfusion
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet or signs
of allergic reaction (e.g., swelling of the face or tongue, rash, itch) while you are taking Tracleer, or if
any of the side effects mentioned above worry you, please tell your doctor or pharmacist.
5.
HOW TO STORE TRACLEER
Keep out of the reach and sight of children.
Do not use Tracleer after the expiry date which is stated on the carton and on the blister after “EXP”.
Do not store above 25 °C.
89
Remaining parts of a divided dispersible tablet can be stored at room temperature and should be used
within 7 days.
6.
FURTHER 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), 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:
Actelion Registration Ltd
BSI Building 13
th
Floor
389 Chiswick High Road
London W4 4AL
United Kingdom
Manufacturer:
Actelion Pharmaceuticals Deutschland GmbH
Basler Strasse 63-65
79100 Freiburg
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
Actelion Pharmaceuticals Belgium N.V.
Tél/Tel: +32-(0)15 284 777
Luxembourg/Luxemburg
Actelion Pharmaceuticals Belgium N.V.
Tél/Tel: +32-(0)15 284 777
България
Аквахим ЕООД
Te
л.
: +
359 2 807 50 00
Magyarország
Actelion Pharmaceuticals Ltd
Tel: +48 (0) 500 145 920
Česká republika
Actelion Pharmaceuticals CZ, s.r.o.
Tel: +420 221 968 006
Malta
Actelion Pharmaceuticals Ltd
Tel: +48 (0) 500 145 920
Danmark
Actelion Danmark,
Filial af Actelion Pharmaceuticals Sverige AB,
Sverige
Tlf: +45 3694 45 95
Nederland
Actelion Pharmaceuticals Nederland B.V.
Tel: +31 (0)348 435950
90
Deutschland
Actelion Pharmaceuticals Deutschland GmbH
Tel: +49 761 45 64 0
Norge
Actelion Pharmaceuticals Sverige AB,
Filial Norge
Tlf: +47 22480370
Eesti
Nycomed SEFA AS
Tel: +372 6112 569
Österreich
Actelion Pharmaceuticals Austria GmbH
Tel: +43 1 505 4527
Ελλάδα
Actelion Pharmaceuticals Eλλάς Α.Ε.
Τηλ: +30 210 675 25 00
Polska
Actelion Pharma Polska Sp. z o.o.
Tel: +48 (0) 500 145 920
España
Actelion Pharmaceuticals España S.L.
Tel: +34 93 253 10 64
Portugal
Actelion Pharmaceuticals Portugal Lda.
Tel: +351 21 358 6120
France
Actelion Pharmaceuticals France SAS
Tél: +33 1 58 62 32 32
România
Geneva Romfarm Internacional
Tel: + 40 (021) 231 3561
Ireland
Actelion Pharmaceuticals UK Ltd
Tel: +353 1890 771 648
Slovenija
Medis d.o.o.
Tel: +386-(0)1 589 69 00
Ísland
Actelion Pharmaceuticals Sverige AB
Sími: +46 (0)8 544 982 50
Slovenská republika
Actelion Pharmaceuticals SK, s.r.o.
Tel: +420 221 968 006
Italia
Actelion Pharmaceuticals Italia S.r.l.
Tel: +39 0542 64 87 40
Suomi/Finland
Actelion Pharmaceuticals Sverige AB,
Filial Finland
Puh/Tel: +358 9 2510 7720
Κύπρος
Actelion Pharmaceuticals Eλλάς Α.Ε.
Τηλ: +30 210 675 25 00
Sverige
Actelion Pharmaceuticals Sverige AB
Tel: +46 8 544 982 50
Latvija
Nycomed Latvija
Tel: +371 784 0082
United Kingdom
Actelion Pharmaceuticals UK Ltd
Tel: +44 845 075 0555
Lietuva
Nycomed atstovybė
Tel: +370 5210 9070
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
91
Source: European Medicines Agency
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