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BOSENTAN CIPLA 62.5 MG FILM-COATED TABLETS

Active substance(s): BOSENTAN MONOHYDRATE / BOSENTAN MONOHYDRATE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Bosentan Cipla 62.5 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablets contains 62.5 mg bosentan (as monohydrate)
For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Film-coated tablet.
Bosentan Cipla are cream to pale yellow coloured, circular biconvex film coated
tablet, debossed with ‘62.5’ on one side and plain on the other side. Diameter – 6.10
mm ± 0.20 mm.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Bosentan Cipla is indicated for the treatment of pulmonary arterial hypertension
(PAH) to improve exercise capacity and symptoms in patients with WHO functional
class III. Efficacy has been shown in:




Primary (idiopathic and heritable) pulmonary arterial hypertension
Pulmonary arterial hypertension secondary to scleroderma without significant
interstitial pulmonary disease
Pulmonary arterial hypertension associated with congenital systemic-topulmonary shunts and Eisenmenger's physiology

Some improvements have also been shown in patients with pulmonary arterial
hypertension WHO functional class II (see section 5.1).
Bosentan Cipla is also indicated to reduce the number of new digital ulcers in patients
with systemic sclerosis and ongoing digital ulcer disease (see section 5.1).

4.2

Posology and method of administration
Posology
Pulmonary arterial hypertension
Treatment should only be initiated and monitored by a physician experienced in the
treatment of pulmonary arterial hypertension.
Adults
In adult patients, Bosentan Cipla treatment should be initiated at a dose of 62.5 mg
twice daily for 4 weeks and then increased to the maintenance dose of 125 mg twice
daily. The same recommendations apply to re-introduction of Bosentan Cipla after
treatment interruption (see section 4.4).
Paediatric population
Paediatric pharmacokinetic data have shown that bosentan plasma concentrations in
children with PAH aged from 1 year to 15 years were on average lower than in adult
patients and were not increased by increasing the dose of bosentan above 2 mg/kg
body weight or by increasing the dosing frequency from twice daily to three times
daily (see section 5.2). Increasing the dose or the dosing frequency will likely not
result in additional clinical benefit.
Based on these pharmacokinetic results, when used in children with PAH 1 year and
older, the recommended starting and maintenance dose is 2 mg/kg morning and
evening.
In neonates with persistent pulmonary hypertension of the newborn (PPHN), the
benefit of bosentan has not been shown in the standard-of-care treatment. No
recommendation on a posology can be made (see sections 5.1 and 5.2).

Dose of bosentan 2 mg/kg are not possible with these medicinal products in children
with a body weight below 31 kg. For such patients a bosentan tablet with lower
strength is needed.
Management in case of clinical deterioration of PAH
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 bosentan 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 bosentan may respond favourably after an additional 4 to 8 weeks of
treatment.
In the case of late clinical deterioration despite treatment with bosentan (i.e., after
several months of treatment), the treatment should be re-assessed. Some patients not
responding well to 125 mg twice daily of bosentan 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 bosentan in patients with
pulmonary arterial hypertension. 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 bosentan 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.
Adults
Bosentan Cipla treatment should be initiated at a dose of 62.5 mg twice daily for 4
weeks and then increased to the maintenance dose of 125 mg twice daily. The same
recommendations apply to re-introduction of Bosentan Cipla after treatment
interruption (see section 4.4).
Controlled clinical study experience in this indication is limited to 6 months (see
section 5.1).
The patient's response to treatment and need for continued therapy should be reevaluated on a regular basis. A careful benefit/risk assessment should be made, taking
into consideration the liver toxicity of bosentan (see sections 4.4 and 4.8).
Paediatric population
There are no data on the safety and efficacy in patients under the age of 18 years.
Pharmacokinetic data are not available for bosentan in young children with this
disease.
Special populations
Hepatic impairment
Bosentan is contraindicated in patients with moderate to severe liver dysfunction (see
sections 4.3, 4.4 and 5.2). No dose adjustment is needed in patients with mild hepatic
impairment (i.e., Child-Pugh class A) (see section 5.2).
Renal impairment
No dose adjustment is required in patients with renal impairment. No dose adjustment
is required in patients undergoing dialysis (see section 5.2).
Elderly
No dose adjustment is required in patients over the age of 65 years.
Method of administration

Deleted:

population

Tablets are to be taken orally morning and evening, with or without food. The filmcoated tablets are to be swallowed with water.

4.3

Contraindications







4.4

Hypersensitivity to the active substance or to any of the excipients listed in
section 6.1
Moderate to severe hepatic impairment , i.e., Child-Pugh class B or C (see
section 5.2)
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)

Special warnings and precautions for use
The efficacy of bosentan 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.
Bosentan should only be initiated if the systemic systolic blood pressure is higher
than 85 mmHg.
Bosentan 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
bosentan. 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

The result should be confirmed by a second liver test; if
confirmed, a decision should be made on an individual
basis to continue bosentan, possibly at a reduced dose, or to
stop Bosentan Cipla administration (see section 4.2).
Monitoring of aminotransferase levels should be continued
at least every 2 weeks. If the aminotransferase levels return
to pre-treatment values continuing or re-introducing
Bosentan Cipla according to the conditions described
below should be considered.

> 5 and ≤ 8 × ULN

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

> 8 × ULN

Treatment must be stopped and re-introduction of Bosentan
Cipla 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
Bosentan Cipla is not to be considered.
Re-introduction of treatment
Re-introduction of treatment with Bosentan Cipla should only be considered if the
potential benefits of treatment with Bosentan Cipla 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 reintroduction, 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, bosentanrelated 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
As Bosentan Cipla may render hormonal contraceptives ineffective, and taking into
account the risk that pulmonary hypertension deteriorates with pregnancy as well as
the teratogenic effects observed in animals:




Bosentan Cipla treatment must not be initiated in women of child-bearing
potential unless they practise reliable contraception and the result of the pretreatment pregnancy test is negative
Hormonal contraceptives cannot be the sole method of contraception during
treatment with Bosentan Cipla.
Monthly pregnancy tests are recommended during treatment to allow early
detection of pregnancy

For further information see sections 4.5 and 4.6.
Pulmonary veno-occlusive disease
Cases of pulmonary oedema have been reported with vasodilators (mainly
prostacyclins) when used in patients with pulmonary veno-occlusive disease.
Consequently, should signs of pulmonary oedema occur when Bosentan Cipla 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 Bosentan Cipla 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 bosentan.
Pulmonary arterial hypertension associated with HIV infection
There is limited clinical study experience with the use of bosentan 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 Bosentan Cipla is initiated in patients who require ritonavir-boosted protease
inhibitors, the patient's tolerability of Bosentan Cipla should be closely monitored
with special attention, at the beginning of the initiation phase, to the risk of
hypotension and to liver function tests. An increased long-term risk of hepatic
toxicity and haematological adverse events cannot be excluded when bosentan is used
in combination with antiretroviral medicinal products. Due to the potential for
interactions related to the inducing effect of bosentan on CYP450 (see section 4.5),
which could affect the efficacy of antiretroviral therapy, these patients should also be
monitored carefully regarding their HIV infection.
Pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD)
Safety and tolerability of bosentan was investigated in an exploratory, uncontrolled
12-week study in 11 patients with pulmonary hypertension secondary to severe
COPD (stage III of GOLD classification). An increase in minute ventilation and a
decrease in oxygen saturation were observed, and the most frequent adverse event
was dyspnoea, which resolved with discontinuation of bosentan.
Concomitant use with other medicinal products
Concomitant use of Bosentan Cipla and cyclosporine A is contraindicated (see
sections 4.3 and 4.5).
Concomitant use of Bosentan Cipla with glibenclamide, fluconazole and rifampicin is
not recommended. For further details please refer to section 4.5.
Concomitant administration of both a CYP3A4 inhibitor and a CYP2C9 inhibitor
with Bosentan Cipla should be avoided (see section 4.5).

4.5

Interaction with other medicinal products and other forms of interaction
Bosentan is an inducer of the cytochrome P450 (CYP) isoenzymes CYP2C9 and
CYP3A4. In vitro data also suggest an induction of CYP2C19. Consequently, plasma
concentrations of substances metabolised by these isoenzymes will be decreased
when Bosentan Cipla 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 Bosentan Cipla treatment.

Bosentan is metabolised by CYP2C9 and CYP3A4. Inhibition of these isoenzymes
may increase the plasma concentration of bosentan (see ketoconazole). The influence
of CYP2C9 inhibitors on bosentan concentration has not been studied. The
combination should be used with caution.
Fluconazole and other inhibitors of both CYP2C9 and CYP3A4
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 Bosentan Cipla is
not recommended.
Cyclosporine A
Co-administration of Bosentan Cipla and cyclosporine A (a calcineurin inhibitor) is
contraindicated (see section 4.3). When co-administered, initial trough concentrations
of bosentan were approximately 30-fold higher than those measured after bosentan
alone. At steady state, bosentan plasma concentrations were 3- to 4-fold higher than
with bosentan alone. The mechanism of this interaction is most likely inhibition of
transport protein-mediated uptake of bosentan into hepatocytes by cyclosporine. The
blood concentrations of cyclosporine A (a CYP3A4 substrate) decreased by
approximately 50%. This is most likely due to induction of CYP3A4 by bosentan.
Tacrolimus, sirolimus
Co-administration of tacrolimus or sirolimus and bosentan has not been studied in
man but co-administration of tacrolimus or sirolimus and bosentan may result in
increased plasma concentrations of bosentan in analogy to co-administration with
cyclosporine A. Concomitant bosentan may reduce the plasma concentrations of
tacrolimus and sirolimus. Therefore, concomitant use of bosentan and tacrolimus or
sirolimus is not advisable. Patients in need of the combination should be closely
monitored for adverse events related to bosentan and for tacrolimus and sirolimus
blood concentrations.
Glibenclamide
Co-administration of bosentan 125 mg twice daily for 5 days decreased the plasma
concentrations of glibenclamide (a CYP3A4 substrate) by 40%, with potential
significant decrease of the hypoglycaemic effect. The plasma concentrations of
bosentan were also decreased by 29%. In addition, an increased incidence of elevated
aminotransferases was observed in patients receiving concomitant therapy. Both
glibenclamide and bosentan inhibit the bile salt export pump, which could explain the
elevated aminotransferases. This combination should not be used. No drug-drug
interaction data are available with the other sulfonylureas.
Rifampicin

Co-administration in 9 healthy subjects for 7 days of bosentan 125 mg twice daily
with rifampicin, a potent inducer of CYP2C9 and CYP3A4, decreased the plasma
concentrations of bosentan by 58%, and this decrease could achieve almost 90% in an
individual case. As a result, a significantly reduced effect of bosentan is expected
when it is co-administered with rifampicin. Concomitant use of rifampicin and
bosentan is not recommended. Data on other CYP3A4 inducers, e.g., carbamazepine,
phenobarbital, phenytoin and St. John's Wort are lacking, but their concomitant
administration is expected to lead to reduced systemic exposure to bosentan. A
clinically significant reduction of efficacy cannot be excluded.
Lopinavir + ritonavir (and other ritonavir-boosted protease inhibitors)
Co-administration of bosentan 125 mg twice daily and lopinavir + ritonavir 400+100
mg twice daily for 9.5 days in healthy volunteers resulted in initial trough plasma
concentrations of bosentan that were approximately 48-fold higher than those
measured after bosentan administered alone. On day 9, plasma concentrations of
bosentan were approximately 5-fold higher than with bosentan administered alone.
Inhibition by ritonavir of transport protein-mediated uptake into hepatocytes and of
CYP3A4, thereby reducing the clearance of bosentan, most likely causes this
interaction. When administered concomitantly with lopinavir + ritonavir, or other
ritonavir-boosted protease inhibitors, the patient's tolerability of bosentan should be
monitored.
After co-administration of bosentan for 9.5 days, the plasma exposures to lopinavir
and ritonavir decreased to a clinically non-significant extent (by approximately 14%
and 17%, respectively). However, full induction by bosentan might not have been
reached and a further decrease of protease inhibitors cannot be excluded. Appropriate
monitoring of the HIV therapy is recommended. Similar effects would be expected
with other ritonavir-boosted protease inhibitors (see section 4.4).
Other antiretroviral agents
No specific recommendation can be made with regard to other available antiretroviral
agents due to the lack of data. Due to the marked hepatotoxicity of nevirapine, which
could add to bosentan liver toxicity, this combination is not recommended.
Hormonal contraceptives
Co-administration of bosentan 125 mg twice daily for 7 days with a single dose of
oral contraceptive containing norethisterone 1 mg + ethinyl estradiol 35 mcg
decreased the AUC of norethisterone and ethinyl estradiol by 14% and 31%,
respectively. However, decreases in exposure were as much as 56% and 66%,
respectively, in individual subjects. Therefore, hormone-based contraceptives alone,
regardless of the route of administration (i.e., oral, injectable, transdermal or
implantable forms), are not considered as reliable methods of contraception (see
sections 4.4 and 4.6).
Warfarin

Co-administration of bosentan 500 mg twice daily for 6 days decreased the plasma
concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A4
substrate) by 29% and 38%, respectively. Clinical experience with concomitant
administration of bosentan with warfarin in patients with 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 bosentan is considered necessary.
Although not demonstrated through in vivo studies, similar increases in bosentan
plasma concentrations are expected with the other potent CYP3A4 inhibitors (such as
itraconazole or ritonavir). However, when combined with a CYP3A4 inhibitor,
patients who are poor metabolisers of CYP2C9 are at risk of increases in bosentan
plasma concentrations that may be of higher magnitude, thus leading to potential
harmful adverse events.
Epoprostenol
Limited data obtained from a study (AC-052-356 [BREATHE-3]) in which 10
paediatric patients received the combination of bosentan and epoprostenol indicate
that after both single- and multiple-dose administration, the Cmax and AUC values of
bosentan were similar in patients with or without continuous infusion of epoprostenol
(see section 5.1).
Sildenafil
Co-administration of bosentan 125 mg twice daily (steady state) with sildenafil 80 mg
three times a day (at steady state) concomitantly administered during 6 days in
healthy volunteers resulted in a 63% decrease in the sildenafil AUC and a 50%
increase in the bosentan AUC. Caution is recommended in the case of coadministration.
Digoxin

Co-administration for 7 days of bosentan 500 mg twice daily with digoxin decreased
the AUC, Cmax and Cmin of digoxin by 12%, 9% and 23%, respectively. The
mechanism for this interaction may be induction of P-glycoprotein. This interaction is
unlikely to be of clinical relevance.
Paediatric population
Interaction studies have only been performed in adults.

4.6

Fertility, pregnancy and lactation
Pregnancy
Studies in animals have shown reproductive toxicity (teratogenicity, embryotoxicity,
see section 5.3). There are no reliable data on the use of bosentan in pregnant women.
The potential risk for humans is still unknown. Bosentan is contraindicated in
pregnancy (see section 4.3).
Use in women of child-bearing potential
Before the initiation of bosentan 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, bosentan 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 bosentan treatment, and also bearing in mind the risk that
pulmonary hypertension severely deteriorates with pregnancy, monthly pregnancy
tests during treatment with bosentan are recommended to allow early detection of
pregnancy
Breast-feeding
It is not known whether bosentan is excreted into human breast milk. Breast-feeding
is not recommended during treatment with bosentan.
Fertility
Animal studies showed testicular effects (see section 5.3). In a study investigating the
effects of bosentan on testicular function in male PAH patients, 8 out of 24 patients
showed a decreased sperm concentration from baseline of at least 42% after 3 or 6
months of treatment with bosentan. Based on these findings and preclinical data, it
cannot be excluded that bosentan may have a detrimental effect on spermatogenesis
in men. In male children, a long-term impact on fertility after treatment with bosentan
cannot be excluded.

4.7

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

4.8

Undesirable effects
In 20 placebo-controlled studies, conducted in a variety of therapeutic indications, a
total of 2,486 patients were treated with bosentan at daily doses ranging from 100 mg
to 2000 mg and 1,838 patients were treated with placebo. The mean treatment
duration was 45 weeks. Adverse reactions were defined as events occurring in at least
1% of patients on bosentan and at a frequency at least 0.5% more than on placebo.
The most frequent adverse reactions are headache (11.5%), oedema/fluid retention
(13.2%), abnormal liver function test (10.9%) and anaemia/haemoglobin decrease
(9.9%).
Treatment with bosentan has been associated with dose-dependent elevations in liver
aminotransferases and decreases in haemoglobin concentration (see section 4.4).
Adverse reactions observed in 20 placebo-controlled studies and post-marketing
experience with bosentan are ranked according to frequency using the following
convention: very common (≥ 1/10); common (≥1/100 to < 1/10); uncommon (≥
1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known
(cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of
decreasing seriousness. No clinically relevant differences in adverse reactions were
observed between the overall dataset and the approved indications.
System organ class
Blood and lymphatic system
disorders

Frequency
Common

Adverse reaction
Anaemia, haemoglobin decrease, (see
section 4.4)

Eye disorders

Thrombocytopenia1
Neutropenia, leukopenia1
Anaemia or haemoglobin decreases
requiring red blood cell transfusion1
Common
Hypersensitivity reactions (including
dermatitis, pruritus and rash)2
Rare
Anaphylaxis and/or angioedema1
Very common Headache3
Common
Syncope1, 4
Not known
Blurred vision

Cardiac disorders

Common

Uncommon
Uncommon
Not known
Immune system disorders

Nervous system disorders

Palpitations1, 4

Vascular disorders

Respiratory, thoracic and
mediastinal disorders
Gastrointestinal disorders
Hepatobiliary disorders

Common
Common
Common

Flushing
Hypotension1, 4
Nasal congestion1

Common

Gastrooesophageal reflux disease
Diarrhoea
Very common Abnormal liver function test , (see
section 4.4)
Uncommon
Aminotransferase elevations associated
with hepatitis (including possible
exacerbation of underlying hepatitis)
and/or jaundice1, (see section 4.4)
Rare
Liver cirrhosis, liver failure1
Common
Erythema

Skin and subcutaneous
disorders
General disorders and
Very common Oedema, fluid retention5
administration site conditions
1
Data derived from post-marketing experience, frequencies based on statistical
modelling of placebo-controlled clinical trial data.
2
Hypersensitivity reactions were reported in 9.9% of patients on bosentan and 9.1% of
patients on placebo.
3
Headache was reported in 11.5% of patients on bosentan and 9.8% of patients on
placebo.
4
These types of reactions can also be related to the underlying disease.
5
Oedema or fluid retention was reported in 13.2% of patients on bosentan and 10.9%
of patients on placebo.

In the post-marketing period rare cases of unexplained hepatic cirrhosis were reported
after prolonged therapy with bosentan 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 bosentan (see section
4.4).
Paediatric population
Uncontrolled clinical studies in paediatric patients
The safety profile in the first paediatric uncontrolled study performed with the filmcoated tablet (BREATHE-3: n = 19, median age 10 years [range 3-15 years], openlabel bosentan 2 mg/kg twice daily; treatment duration 12 weeks) was similar to that
observed in the pivotal trials in adult patients with PAH. In BREATHE-3, the most
frequent adverse reactions were flushing (21%), headache, and abnormal liver
function test (each 16%).
A pooled analysis of uncontrolled paediatric studies conducted in PAH with the
bosentan 32 mg dispersible tablet formulation (FUTURE 1/2, FUTURE 3/Extension)
included a total of 100 children treated with bosentan 2 mg/kg twice daily (n = 33), 2
mg/kg three times daily (n = 31), or 4 mg/kg twice daily (n = 36). At enrolment, six
patients were between 3 months and 1 year old, 15 children were between 1 and less

than 2 years old, and 79 were between 2 and 12 years old. The median treatment
duration was 71.8 weeks (range 0.4–258 weeks).
The safety profile in this pooled analysis of uncontrolled paediatric studies was
similar to that observed in the pivotal trials in adult patients with PAH except for
infections, which were more frequently reported than in adults (69.0% vs 41.3%).
This difference in infection frequency may in part be due to the longer median
treatment exposure in the paediatric set (median 71.8 weeks) compared to the adult
set (median 17.4 weeks). The most frequent adverse events were upper respiratory
tract infections (25%), pulmonary (arterial) hypertension (20%), nasopharyngitis
(17%), pyrexia (15%), vomiting (13%), bronchitis (10%), abdominal pain (10%), and
diarrhoea (10%). There was no relevant difference in adverse event frequencies
between patients above and below the age of 2 years, however this is based on only
21 children less than 2 years including 6 patients between 3 months to 1 year of age.
Adverse events of liver abnormalities and anaemia/haemoglobin decrease occurred in
9% and 5% of patients, respectively.
In a randomised placebo-controlled study, conducted in PPHN patients (FUTURE-4),
a total of 13 neonates were treated with the bosentan dispersible tablet formulation at
a dose of 2 mg/kg twice daily (8 patients were on placebo). The median bosentan and
placebo treatment duration was, respectively, 4.5 days (range 0.5–10.0 days) and 4.0
days (range 2.5–6.5 days). The most frequent adverse events in the bosentan and the
placebo-treated patients were, respectively, anaemia or haemoglobin decrease (7 and
2 patients), generalised oedema (3 and 0 patients), and vomiting (2 and 0 patients).
Laboratory abnormalities
Liver test abnormalities
In the clinical programme, dose-dependent elevations in liver aminotransferases
generally occurred within the first 26 weeks of treatment, usually developed
gradually, and were mainly asymptomatic. In the post-marketing period rare cases of
liver cirrhosis and liver failure have been reported.
The mechanism of this adverse effect is unclear. These elevations in
aminotransferases may reverse spontaneously while continuing treatment with the
maintenance dose of bosentan 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 bosentantreated 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 placebotreated patients. Elevations in aminotransferases were associated with elevated
bilirubin (≥ 2 × ULN) without evidence of biliary obstruction in 0.2% (5 patients) on
bosentan and 0.3% (6 patients) on placebo.
In the pooled analysis of 100 PAH patients from uncontrolled paediatric studies
FUTURE 1/2 and FUTURE 3/Extension, elevations in liver aminotransferases ≥ 3 ×
ULN were observed in 2% of patients.

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

Haemoglobin
In the adult placebo-controlled studies, a decrease in haemoglobin concentration to
below 10 g/dL from baseline was reported in 8.0% of bosentan-treated patients and
3.9% of placebo-treated patients (see section 4.4).
In the pooled analysis of 100 PAH children from uncontrolled paediatric studies
FUTURE 1/2 and FUTURE 3/Extension, a decrease in haemoglobin concentration
from baseline to below 10 g/dL was reported in 10.0% of patients. There was no
decrease to below 8 g/dL.

In the FUTURE-4 study, 6 out of 13 bosentan-treated neonates with PPHN
experienced a decrease in haemoglobin from within the reference range at baseline to
below the lower limit of normal during the treatment.
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9

Overdose
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 reaction was headache of mild to moderate
intensity.
Massive overdose may result in pronounced hypotension requiring active
cardiovascular support. In the post-marketing period there was one reported overdose
of 10,000 mg of bosentan taken by an adolescent male patient. He had symptoms of
nausea, vomiting, hypotension, dizziness, sweating and blurred vision. He recovered
completely within 24 hours with blood pressure support. Note: bosentan is not
removed through dialysis.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: other antihypertensives, ATC code: C02KX01

Mechanism of action
Bosentan is a dual endothelin receptor antagonist (ERA) with affinity for both
endothelin A and B (ETA and ETB) receptors. Bosentan decreases both pulmonary
and systemic vascular resistance resulting in increased cardiac output without
increasing heart rate.
The neurohormone endothelin-1 (ET-1) is one of the most potent vasoconstrictors
known and can also promote fibrosis, cell proliferation, cardiac hypertrophy and
remodelling, and is pro-inflammatory. These effects are mediated by endothelin
binding to ETA and ETB receptors located in the endothelium and vascular smooth
muscle cells. ET-1 concentrations in tissues and plasma are increased in several
cardiovascular disorders and connective tissue diseases, including 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 ETA and
ETB receptors, with a slightly higher affinity for ETA receptors (Ki = 4.1–43
nanomolar) than for ETB receptors (Ki = 38-730 nanomolar). Bosentan specifically
antagonises ET receptors and does not bind to other receptors.
Clinical efficacy and safety
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 placebocorrected 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 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.secl/cm5)

6-Minute Walk Distance (m)

Placebo
(n=88)
802 (365)

Bosentan
(n=80)
851 (535)

Placebo (n=91) Bosentan
(n=86)
431 (92)
443 (83)

−69 (475)

−8 (79)

Baseline (BL); mean
(SD)
Change from BL; mean 128 (465)
(SD)
Treatment effect
−22.6%
95% CL
−34, −10
P-value
< 0.0001
PVR = pulmonary vascular resistance

19
−4, 42
0.0758

11 (74)

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.
Long-term data were generated from all 173 patients who were treated with bosentan
in the controlled phase and/or were switched from placebo to bosentan in the openlabel extension phase of the EARLY study. The mean duration of exposure to
bosentan treatment was 3.6 ± 1.8 years (up to 6.1 years), with 73% of patients treated
for at least 3 years and 62% for at least 4 years. Patients could receive additional
PAH treatment as required in the open-label extension. The majority of patients were
diagnosed with idiopathic or heritable pulmonary arterial hypertension (61%).
Overall, 78% of patients remained in WHO functional class II. Kaplan-Meier
estimates of survival were 90% and 85% at 3 and 4 years after the start of treatment,
respectively. At the same time points, 88% and 79% of patients remained free from
PAH worsening (defined as all-cause death, lung transplantation, atrial septostomy or
start of intravenous or subcutaneous prostanoid treatment). The relative contributions
of previous placebo treatment in the double-blind phase and of other medications
started during the open-label extension period are unknown.
In a prospective, multi-centre, randomised, double-blind, placebo-controlled study
(AC-052-405 [BREATHE-5]), patients with 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, of whom 31 had a predominantly right to left,
bidirectional shunt). The primary objective was to show that bosentan did not worsen
hypoxaemia. After 16 weeks, the mean oxygen saturation was increased in the
bosentan group by 1.0% (95% CI –0.7%–2.8%) as compared to the placebo group (n
= 17 patients), showing that bosentan did not worsen hypoxaemia. The mean
pulmonary vascular resistance was significantly reduced in the bosentan group (with
a predominant effect observed in the subgroup of patients with bidirectional
intracardiac shunt). After 16 weeks, the mean placebo-corrected increase in 6-minute
walk distance was 53 metres (p = 0.0079), reflecting improvement in exercise
capacity. Twenty-six patients continued to receive bosentan in the 24-week openlabel extension phase (AC-052-409) of the BREATHE-5 study (mean duration of
treatment = 24.4 ± 2.0 weeks) and, in general, efficacy was maintained.
An open-label, non-comparative study (AC-052-362[BREATHE-4]) was performed
in 16 patients with WHO functional class III PAH associated with HIV infection.
Patients were treated with bosentan 62.5 mg twice daily for 4 weeks followed by 125
mg twice daily for a further 12 weeks. After 16 weeks' treatment, there were
significant improvements from baseline in exercise capacity: the mean increase in 6minute 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 bosentan 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
BREATHE-3 (AC-052-356)

Bosentan film-coated tablets were evaluated in an open-label uncontrolled study in 19
paediatric patients with pulmonary arterial hypertension aged 3 to 15 years. This
study was primarily designed as a pharmacokinetic study (see section 5.2). Patients
had primary pulmonary hypertension (10 patients) or pulmonary arterial hypertension
related to congenital heart disease (9 patients) and were in WHO functional class II (n
= 15 patients, 79%) or class III (n = 4 patients, 21%) at baseline. Patients were
divided into three body-weight groups and dosed with bosentan at approximately 2
mg/kg twice daily for 12 weeks. Half of the patients in each group were already being
treated with intravenous epoprostenol and the dose of epoprostenol remained constant
for the duration of the study.
Haemodynamics were measured in 17 patients. The mean increase from baseline in
cardiac index was 0.5 L/min/m2, the mean decrease in mean pulmonary arterial
pressure was 8 mmHg, and the mean decrease in PVR was 389 dyn·sec·cm-5. These
haemodynamic improvements from baseline were similar with or without coadministration of epoprostenol. Changes in exercise test parameters at week 12 from
baseline were highly variable and none were significant.
FUTURE 1/2 (AC-052-365/ AC-052-367)

FUTURE 1 was an open-label, uncontrolled study that was conducted with the
dispersible tablet formulation of bosentan administered at a maintenance dose of 4
mg/kg twice daily to 36 patients from 2 to 11 years of age. It was primarily designed
as a pharmacokinetic study (see section 5.2). At baseline, patients had idiopathic (31
patients [86%]) or familial (5 patients [14%]) PAH, and were in WHO functional
class II (n = 23 patients, 64%) or class III (n = 13 patients, 36%). In the FUTURE 1
study, the median exposure to study treatment was 13.1 weeks (range: 8.4 to 21.1). 33
of these patients were provided with continued treatment with bosentan dispersible
tablets at a dose of 4 mg/kg twice daily in the FUTURE 2 uncontrolled extension
phase for a median overall treatment duration of 2.3 years (range: 0.2 to 5.0 years).
At baseline in FUTURE 1, 9 patients were taking epoprostenol. 9 patients were newly
initiated on PAH-specific medication during the study. The Kaplan-Meier event-free
estimate for worsening of PAH (death, lung transplantation, or hospitalisation for
PAH worsening) at 2 years was 78.9%. The Kaplan-Meier estimate of overall
survival at 2 years was 91.2%.
FUTURE 3 (AC-052-373)
In this open-label randomised study with the bosentan 32 mg dispersible tablet
formulation, 64 children with stable PAH from 3 months to 11 years of age were

randomised to 24 weeks bosentan treatment 2 mg/kg twice daily (n = 33) or 2 mg/kg
three times daily (n = 31). 43 (67.2%) were ≥ 2 years to 11 years old, 15 (23.4%)
were between 1 and 2 years old, and 6 (9.4%) were between 3 months and 1 year old.
The study was primarily designed as a pharmacokinetic study (see section 5.2) and
efficacy endpoints were only exploratory. The aetiology of PAH, according to Dana
Point classification, included idiopathic PAH (46%), heritable PAH (3%), associated
PAH after corrective cardiac surgery (38%), and PAH-CHD associated with
systemic-to-pulmonary shunts, including Eisenmenger syndrome (13%). Patients
were in WHO functional class I (n = 19 patients, 29 %), class II (n = 27 patients,
42%) or class III (n = 18 patients, 28%) at start of study treatment. At study entry,
patients were treated with PAH-medications (most frequently PDE-5 inhibitor
[sildenafil] alone [35.9%], bosentan alone [10.9%], and a combination of bosentan,
iloprost, and sildenafil in 10.9% of patients) and continued their PAH treatment
during the study.
At study start, less than half of the patients included (45.3% = 29/64) had bosentan
treatment alone not combined with other PAH-medication. 40.6% (26/64) remained
on bosentan monotherapy during the 24 weeks of study treatment without
experiencing PAH worsening. The analysis on the global population included (64
patients) showed that the majority had remained at least stable (i.e., without
deterioration) based on non paediatric specific WHO functional class assessment
(97% twice daily, 100% three times daily) and physicians' global clinical impression
(94% twice daily, 93% three times daily) during the treatment period. The KaplanMeier event-free estimate for worsening of PAH (death, lung transplantation, or
hospitalisation for PAH worsening) at 24 weeks was 96.9% and 96.7% in the twice
daily and three times daily groups, respectively.
There was no evidence of any clinical benefit with 2 mg/kg three times daily as
compared to 2 mg/kg twice daily dosing.
Study performed in neonates with persistent pulmonary hypertension of the newborn
(PPHN):
FUTURE 4 (AC052391)
This was a double-blind, placebo-controlled, randomised study in pre-term or term
neonates (gestational age 36–42 weeks) with PPHN. Patients with suboptimal
response to inhaled nitric oxide (iNO) despite at least 4 hours of continuous treatment
were treated with bosentan dispersible tablets at 2 mg/kg twice daily (N = 13) or
placebo (N = 8) via nasogastric tube as add-on therapy on top of iNO until complete
weaning of iNO or until treatment failure (defined as need for extra-corporeal
membrane oxygenation [ECMO] or initiation of alternative pulmonary vasodilator)
and for a maximum of 14 days.
The median exposure to study treatment was 4.5 (range: 0.5–10.0) days in the
bosentan group and 4.0 (range: 2.5–6.5) days in the placebo group.
The results did not indicate an additional benefit of bosentan in this population:
• The median time to complete weaning from iNO was 3.7 days (95% CLs 1.17,
6.95) on bosentan and 2.9 days (95% CLs 1.26, 4.23) on placebo (p = 0.34).
• The median time to complete weaning from mechanical ventilation was 10.8
days (95% CLs 3.21, 12.21 days) on bosentan and 8.6 days (95% CLs 3.71,
9.66 days) on placebo (p = 0.24).

• One patient in the bosentan group had treatment failure (need for ECMO as per
protocol definition), which was declared based on increasing Oxigenation
Index values within 8 h after the first study drug dose. This patient recovered
within the 60-day follow-up period.
Combination with epoprostenol
The combination of bosentan and epoprostenol has been investigated in two studies:
AC-052-355 (BREATHE-2) and AC-052-356 (BREATHE-3). AC-052-355 was a
multi-centre, randomised, double-blind, parallel-group study of bosentan versus
placebo in 33 patients with severe pulmonary arterial hypertension who were
receiving concomitant epoprostenol therapy. AC-052-356 was an open-label,
uncontrolled study; 10 of the 19 paediatric patients were on concomitant bosentan
and epoprostenol therapy during the 12-week study. The safety profile of the
combination was not different from the one expected with each component and the
combination therapy was well tolerated in children and adults. The clinical benefit of
the combination has not been demonstrated.
Systemic sclerosis with digital ulcer disease
Two randomised, double-blind, multi-centre, placebo-controlled studies have been
conducted in 122 (study AC-052-401 [RAPIDS-1]) and 190 (study AC-052-331
[RAPIDS-2]) adult patients with systemic sclerosis and digital ulcer disease (either
ongoing digital ulcers or a history of digital ulcers within the previous year). In study
AC-052-331, patients had to have at least one digital ulcer of recent onset, and across
the two studies 85% of patients had ongoing digital ulcer disease at baseline. After 4
weeks of bosentan 62.5 mg twice daily, the maintenance dose studied in both these
studies was 125 mg twice daily. The duration of double-blind therapy was 16 weeks
in study AC-052-401, and 24 weeks in study AC-052-331.
Background treatments for systemic sclerosis and digital ulcers were permitted if they
remained constant for at least 1 month prior to the start of treatment and during the
double-blind study period.
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, Cmax and AUC increase less than
proportionally to the dose.
Absorption
In healthy subjects, the absolute bioavailability of bosentan is approximately 50% and
is not affected by food. The maximum plasma concentrations are attained within 3–5
hours.
Distribution
Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. Bosentan does
not penetrate into erythrocytes.
A volume of distribution (Vss) of about 18 litres was determined after an intravenous
dose of 250 mg.
Biotransformation and elimination
After a single intravenous dose of 250 mg, the clearance was 8.2 L/h. The terminal
elimination half-life (t1/2) is 5.4 hours.
Upon multiple dosing, plasma concentrations of bosentan decrease gradually to 50%–
65% of those seen after single dose administration. This decrease is probably due to
auto-induction of metabolising liver enzymes. Steady-state conditions are reached
within 3–5 days.
Bosentan is eliminated by biliary excretion following metabolism in the liver by the
cytochrome P450 isoenzymes, CYP2C9 and CYP3A4. Less than 3% of an
administered oral dose is recovered in urine.
Bosentan forms three metabolites and only one of these is pharmacologically active.
This metabolite is mainly excreted unchanged via the bile. In adult patients, the
exposure to the active metabolite is greater than in healthy subjects. In patients with
evidence of the presence of cholestasis, the exposure to the active metabolite may be
increased.
Bosentan is an inducer of CYP2C9 and CYP3A4 and possibly also of CYP2C19 and
the P-glycoprotein. In vitro, bosentan inhibits the bile salt export pump in hepatocyte
cultures.
In vitro data demonstrated that bosentan had no relevant inhibitory effect on the CYP
isoenzymes tested (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4). Consequently,
bosentan is not expected to increase the plasma concentrations of medicinal products
metabolised by these isoenzymes.

Pharmacokinetics in special populations
Based on the investigated range of each variable, it is not expected that the
pharmacokinetics of bosentan will be influenced by gender, body weight, race, or age
in the adult population to any relevant extent.
Children
Pharmacokinetics were studied in paediatric patients in 4 clinical studies
(BREATHE-3, FUTURE-1, FUTURE-3 and FUTURE-4 see section 5.1). Due to
limited data in children below 2 years of age, pharmacokinetics remain not well
characterised in this age category.
Study AC-052-356 [BREATHE-3]) evaluated the pharmacokinetics of single and
multiple oral doses of the film-coated tablet formulation of bosentan in 19 children
aged from 3 to 15 years with pulmonary arterial hypertension (PAH) who were dosed
on the basis of body weight with 2 mg/kg twice daily. In this study, the exposure to
bosentan decreased with time in a manner consistent with the known auto-induction
properties of bosentan. The mean AUC (CV%) values of bosentan in paediatric
patients treated with 31.25, 62.5 or 125 mg twice daily were 3,496 (49), 5,428 (79),
and 6,124 (27) ng·h/mL, respectively, and were lower than the value of 8,149 (47)
ng·h/mL observed in adult patients with PAH receiving 125 mg twice daily. At steady
state, the systemic exposures in paediatric patients weighing 10–20 kg, 20–40 kg and
> 40 kg were 43%, 67% and 75%, respectively, of the adult systemic exposure.
In study AC-052-365 [FUTURE 1], dispersible tablets were administered in 36 PAH
children aged from 2 to 11 years. No dose proportionality was observed as steadystate bosentan plasma concentrations and AUCs were similar at oral doses of 2 and 4
mg/kg (AUC : 3,577 ng·h/mL and 3.371 ng.h.mL for 2 mg/kg twice daily and 4
mg/kg twice daily respectively). The average exposure to bosentan in these paediatric
patients was about half the exposure in adult patients at the 125 mg twice daily
maintenance dose but showed a large overlap with the exposures in adults.
In study AC-052-373 [FUTURE 3], using dispersible tablets, the exposure to
bosentan in the patients treated with 2 mg/kg twice daily was comparable to that in
the FUTURE 1 study. In the overall population (n = 31), 2 mg/kg twice daily resulted
in a daily exposure of 8,535 ng·h/mL; AUC was 4,268 ng·h/mL (CV: 61%). In
patients between 3 months and 2 years, the daily exposure was 7,879 ng·h/mL; AUC
was 3,939 ng·h/mL (CV: 72%). In patients between 3 months and 1 year (n=2),
AUC was 5,914 ng·h/mL (CV: 85%) and in patients between 1 and 2 years (n=7),
AUC was 3,507 ng·h/mL (CV: 70%). In the patients above 2 years (n = 22) the daily
exposure was 8,820 ng·h/mL; AUC was 4,410 ng·h/mL (CV: 58%). Dosing
bosentan 2 mg/kg three times daily did not increase exposure, daily exposure was
7,275 ng·h/mL (CV: 83%, n = 27).
Based on the findings in studies BREATHE-3, FUTURE 1 and FUTURE-3, it
appears that the exposure to bosentan reaches a plateau at lower doses in paediatric
patients than in adults, and that doses higher than 2 mg/kg twice daily (4 mg/kg twice
daily or 2 mg/kg three times daily) will not result in greater exposure to bosentan in
paediatric patients.

In study AC-052-391 [FUTURE 4] conducted in neonates, bosentan concentrations
increased slowly and continuously over the first dosing interval, resulting in low
exposure (AUC0-12 in whole blood: 164 ng·h/mL, n = 11). At steady-state, AUC was
6,165 ng·h/mL (CV: 133%, n = 7), which is similar to the exposure observed in adult
PAH patients receiving 125 mg twice daily and taking into account a blood/plasma
distribution ratio of 0.6.
The consequences of these findings regarding hepatotoxicity are unknown. Gender
and 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 impact of moderately impaired liver function (Child-Pugh class B) on the
pharmacokinetics of bosentan and its primary metabolite Ro 48-5033 was
investigated in a study including 5 patients with pulmonary hypertension associated
with portal hypertension and Child-Pugh class B hepatic impairment, and 3 patients
with pulmonary arterial hypertension from other causes and normal liver function. In
the patients with Child-Pugh class B liver impairment, the mean (95% CI) steadystate AUC of bosentan was 360 (212-613) ng.h/mL, i.e., 4.7 times higher, and the
mean (95% CI) AUC of the active metabolite Ro 48-5033 was 106 (58.4-192)
ng.h/mL, i.e., 12.4 times higher than in the patients with normal liver function
(bosentan: mean [95% CI] AUC : 76.1 [9.07-638] ng.h/mL; Ro 48-5033: mean [95%
CI] AUC 8.57 [1.28-57.2] ng.h/ml). Though the number of patients included was
limited and with high variability, these data indicate a marked increase in the
exposure to bosentan and its primary metabolite Ro 48-5033 in patients with
moderate liver function impairment (Child-Pugh class B).
The pharmacokinetics of bosentan have not been studied in patients with Child-Pugh
class C hepatic impairment. Bosentan is contra-indicated in patients with moderate to
severe hepatic impairment, i.e., Child-Pugh class B or C (see section 4.3).
Renal impairment
In patients with severe renal impairment (creatinine clearance 15–30 mL/min),
plasma concentrations of bosentan decreased by approximately 10%. Plasma
concentrations of bosentan metabolites increased about 2-fold in these patients as
compared 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 negative in tests for genotoxicity. There was evidence of a
mild thyroid hormonal imbalance induced by bosentan in rats. However, there was no
evidence of bosentan affecting thyroid function (thyroxine, TSH) in humans.
The effect of bosentan on mitochondrial function is unknown.
Bosentan has been shown to be teratogenic in rats at plasma levels higher than 1.5
times the plasma concentrations achieved at the therapeutic dose in humans.
Teratogenic effects, including malformations of the head and face and of the major
vessels, were dose dependent. The similarities of the pattern of malformations
observed with other ET receptor antagonists and in ET knock-out mice indicate a
class effect. Appropriate precautions must be taken for women of child-bearing
potential (see sections 4.3, 4.4 and 4.6).
Development of testicular tubular atrophy and impaired fertility has been linked with
chronic administration of endothelin receptor antagonists in rodents.
In fertility studies in male and female rats, no effects on sperm count, motility and
viability, or on mating performance or fertility were observed at exposures that were
21 and 43 times the expected therapeutic level in humans, respectively; nor was there
any adverse effect on the development of the pre-implantation embryo or on
implantation.
Slightly increased incidence of testicular tubular atrophy was observed in rats given
bosentan orally at doses as low as 125 mg/kg/day (about 4 times the maximum
recommended human dose [MRHD] and the lowest doses tested) for two years but
not at doses as high as 1500 mg/kg/day (about 50 times the MRHD) for 6 months. In
a juvenile rat toxicity study, where rats were treated from Day 4 post partum up to
adulthood, decreased absolute weights of testes and epididymides, and reduced
number of sperm in epididymides were observed after weaning. The NOAEL was 21
times (at Day 21 post partum) and 2.3 times (Day 69 post partum) the human
therapeutic exposure, respectively.
However, no effects on general development, growth, sensory, cognitive function and
reproductive performance were detected at 7 (males) and 19 (females) times the
human therapeutic exposure at Day 21 post partum. At adult age (Day 69 post
partum) no effects of bosentan were detected at 1.3 (males) and 2.6 (females) times
the therapeutic exposure in children with PAH.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core
Maize starch,
Sodium starch glycolate (Type B),
Povidone (PVP K-30)
Pregelatinised starch maize,
Glycerol dibehenate,
Magnesium stearate,
Film coat
Hypromellose,
Titanium dioxide (E171),
Triacetin,
Talc,
Iron oxide yellow (E172),
Iron oxide red (E172),
Ethylcellulose,
Cetyl alcohol,
Sodium laurilsulfate.

6.2

Incompatibilities
Not Applicable

6.3

Shelf life
2 years

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
PVC/PE/PVDC, aluminium blister. Blister pack of 14’s, 56’s and 112 film-coated
tablets
Perforated unit dose blister: PVC/PE/PVDC, aluminium. Pack size 14 x 1, 56 x 1, 112
x 1 film coated tablets
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements

7

MARKETING AUTHORISATION HOLDER
Cipla Europe NV,
Uitbreidingstraat 80,
2600 Antwerp,
Belgium.

8

MARKETING AUTHORISATION NUMBER(S)
PL 43362/0013

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
02/06/2016

10

DATE OF REVISION OF THE TEXT
15/12/2016

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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