Tracleer

Package leaflet: Information for the user

Tracleer 62.5 mg film-coated tablets, 125 mg film-coated tablets

bosentan
Please read this leaflet carefully before taking this medicine because it contains
important information for you:

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist.

Contents of this leaflet:

1. What Tracleer is and what it is used for
2. What you need to know before taking Tracleer
3. How to take Tracleer
4. Possible side effects
5. How to store Tracleer
6. Contents of the pack and other information

1. What Tracleer is and what it is used for

Tracleer tablets contain bosentan, which blocks a naturally occurring hormone called endothelin-1 (ET-1) that causes narrowing of blood vessels. Tracleer therefore causes blood vessels to widen and belongs to a class of medicines known as “endothelin receptor antagonists”.

Tracleer is used to treat:

• Pulmonary arterial hypertension (PAH): PAH is a disease characterized by severe narrowing of the blood vessels in the lungs, resulting in increased pressure in the blood vessels carrying blood from the heart to the lungs (pulmonary arteries). This pressure reduces the amount of oxygen that can pass into the blood through the lungs, making physical activity more difficult. Tracleer widens the pulmonary arteries, making it easier for the heart to pump blood through them. This results in reduced blood pressure and alleviation of symptoms.

Tracleer is used to treat PAH patients in WHO functional class III to improve exercise capacity (ability to perform physical activity) and symptoms. The “class” reflects the severity of the disease: “class III” means marked limitation in physical activity. Some benefits have also been shown in PAH patients in class II. “Class II” means slight limitation in physical activity. The PAH for which Tracleer is indicated may be:

• primary (without an identifiable cause or familial);

• caused by scleroderma (also known as systemic sclerosis, a disease characterized by abnormal growth of connective tissue supporting the skin and other organs);

• caused by congenital (inborn) heart defects with shunts (abnormal passages) leading to abnormal blood flow through the heart and lungs.

• Digital ulcers: (sores on the fingers and toes) in adult patients with a condition called scleroderma. Tracleer reduces the number of new digital ulcers in fingers and toes.

2. What you should know before taking Tracleer

Do not take Tracleer:

• if you are allergic to bosentan or to any of the other ingredients of this medicine (listed in section 6)
• if you have liver problems (consult your doctor)
• if you are pregnant or could become pregnant and you are not using reliable contraceptive methods. Please read the information provided under “Contraceptives” and “Other medicines and Tracleer”
• if you are being treated with cyclosporine A (a medicine used after organ transplant or for the treatment of psoriasis)

In any of these cases, inform your doctor.
Warnings and precautions
Tests required by your doctor before starting Tracleer treatment

• a blood test to check your liver function
• a blood test to check for anaemia (low haemoglobin)
• a pregnancy test if you are a woman of childbearing age

Abnormal liver function tests and anaemia (low haemoglobin) have been observed in some patients treated with Tracleer.

Tests your doctor will prescribe during treatment
During treatment with Tracleer, your doctor will regularly request blood tests to monitor any changes in liver function and haemoglobin levels.
For all these tests, please also refer to the Patient Alert Card (included in your Tracleer tablet pack). It is important that you undergo these blood tests at regular intervals throughout the entire period of Tracleer treatment. It is advisable to record on the Patient Alert Card the date of your most recent test and the date of your next scheduled test (ask your doctor for this date), so that you do not forget when your next test is due.

Liver function blood tests
These will be performed every month for the entire duration of Tracleer treatment. After a dose increase, an additional test will be performed 2 weeks later.

Blood tests for anaemia
These will be performed every month for the first 4 months of treatment and then every 3 months thereafter, as patients taking Tracleer may develop anaemia.
If these test results are abnormal, your doctor may decide to reduce the dose or discontinue Tracleer treatment and carry out further investigations to determine the cause.

Children and adolescents
Tracleer is not recommended in paediatric patients with systemic sclerosis and active digital ulcers. Please also see section 3. How to take Tracleer.

Other medicines and Tracleer
Please inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription. It is especially important to inform your doctor if you are taking:

• cyclosporine A (a medicine used after organ transplants and for the treatment of psoriasis), which must not be used together with Tracleer.
• sirolimus or tacrolimus, which are medicines used after transplants; their use together with Tracleer is not recommended.
• glibenclamide (a medicine for diabetes), rifampicin (a medicine for tuberculosis), fluconazole (a medicine for fungal infections), ketoconazole (a medicine used for the treatment of Cushing's syndrome), or nevirapine (a medicine for HIV), as the use of these medicines together with Tracleer is not recommended.
• other medicines for the treatment of HIV infection, which may require special monitoring when used together with Tracleer.
• hormonal contraceptives, which are not effective as the sole method of contraception when you are taking Tracleer. Inside the Tracleer tablet pack, you will find a Patient Alert Card that you must read carefully. Your doctor and/or gynaecologist will advise you on the appropriate contraceptive method for you.
• other medicines for the treatment of pulmonary hypertension: sildenafil and tadalafil;
• warfarin (an anticoagulant);
• simvastatin (used to treat hypercholesterolaemia).

Driving and using machines
Tracleer does not affect, or affects negligibly, the ability to drive and use machines.
However, Tracleer may cause hypotension (lowering of your blood pressure), which may make you feel unstable and may affect your vision and your ability to drive or operate machinery.
Therefore, if you experience dizziness or blurred vision during treatment with Tracleer, do not drive or operate any tools or machinery.

Women of childbearing potential
DO NOT take Tracleer if you are pregnant or planning to become pregnant.
Pregnancy testing
Tracleer may harm the unborn child conceived before or during treatment. If you are a woman of childbearing age, your doctor will ask you to take a pregnancy test before starting Tracleer and regularly during treatment with Tracleer.
Contraception
If you are a woman of childbearing age, you must use a reliable method of birth control (contraception) while taking Tracleer. Your doctor or gynaecologist will advise you on reliable contraceptive methods while taking Tracleer. Since Tracleer may render hormonal contraception ineffective (e.g. oral, injectable, implantable contraceptives or contraceptive patches), this method alone 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 use a condom).
Inside your Tracleer tablet pack, you will find a Patient Alert Card. You must complete this card and bring 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. It is recommended to perform a pregnancy test every month during Tracleer treatment if you are of childbearing age.
Inform your doctor immediately if you become pregnant during treatment with Tracleer or if you plan to become pregnant in the near future.
Breast-feeding
Tracleer passes into breast milk. Breast-feeding should be discontinued if Tracleer is prescribed, as it may harm your baby. Talk to your doctor if you have any questions about this.
Fertility
If you are a man taking Tracleer, this medicine may reduce sperm count. It cannot be excluded that this may impair your ability to father a child. Talk to your doctor if you have any questions about this.
Tracleer contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per tablet, i.e. it is considered essentially 'sodium-free'.

3. How to take Tracleer

Treatment with Tracleer should be initiated and monitored only by a physician experienced in the
treatment of PAH or systemic sclerosis. Take this medicine exactly as prescribed by your doctor. If you
have any doubts, consult your doctor or pharmacist.
Tracleer with food and drink
Tracleer may be taken on an empty stomach or with food.
Recommended dose
Adults
In adults, treatment usually begins with one 62.5 mg tablet taken twice daily (morning and evening)
for the first 4 weeks. Afterwards, your doctor will usually recommend increasing to one 125 mg tablet
twice daily, depending on your response to Tracleer.
Children and adolescents
The recommended dose in children is indicated only for PAH. For children aged 1 year and older,
treatment with Tracleer usually starts at 2 mg per kg body weight twice daily (morning and evening).
Your doctor will advise on subsequent dosing.
Please note that Tracleer is also available in a 32 mg dispersible tablet formulation, which allows for
more accurate dosing in children and in patients with low body weight or difficulty swallowing coated
tablets.
If you feel that the effects of Tracleer are too strong or too weak, talk to your doctor to determine
whether your dose needs adjustment.
How to take Tracleer
Take the tablets (morning and evening) with water. Tablets may be taken with or without food.
If you take more Tracleer than you should
If you have taken more tablets than prescribed, contact your doctor immediately.
If you forget to take Tracleer
If you forget to take Tracleer, take a tablet as soon as you remember, then continue taking your tablets
at the usual times. Do not take a double dose to make up for a missed dose.
If you stop taking Tracleer
Stopping Tracleer treatment suddenly may lead to worsening of symptoms. Do not discontinue this
treatment unless instructed by your doctor. Your doctor may advise you to gradually reduce the dose
over several days before completely stopping Tracleer.
If you have further questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The most serious side effects associated with Tracleer are:

• Abnormal liver function, which may occur in more than 1 out of 10 users
• Anaemia (low blood test values), which may occur in 1 out of 10 users. Anaemia may occasionally require blood transfusion. Blood and liver function tests must be monitored during treatment with Tracleer (see section 2). It is important that you undergo these tests as prescribed by your doctor.

Signs of improper liver function include:

• nausea (feeling sick)
• vomiting
• fever (high temperature)
• stomach (abdominal) pain
• jaundice (yellowing of the skin or sclera, i.e. the white part of the eye)
• dark-coloured urine
• skin itching
• lethargy or fatigue (unusual tiredness or exhaustion)
• flu-like syndrome (joint and muscle pain with fever)

If you notice any of these signs, tell your doctor immediately.
Other side effects:
Very common (may occur in more than 1 out of 10 people ):

• headache
• oedema (swelling of the legs and ankles or other signs of fluid retention)

Common (may occur in up to 1 out of 10 people ):

• flushed appearance or skin redness
• hypersensitivity reactions (including skin inflammation, itching, and skin rash)
• gastroesophageal reflux disease (acid reflux)
• diarrhoea
• syncope (fainting)
• palpitations (fast or irregular heartbeat)
• low blood pressure
• nasal congestion

Uncommon (may occur in up to 1 out of 100 people ):

• thrombocytopenia (low number of platelets in the blood)
• neutropenia/leucopenia (low number of white blood cells)
• Elevated liver function values associated with hepatitis (liver inflammation), including possible worsening of underlying hepatitis and/or jaundice (yellowing of the skin or the white part of the eye)

Rare (may occur in up to 1 out of 1,000 people ):

• anaphylaxis (general allergic reaction), angioedema (swelling, most commonly around the eyes, lips, tongue or throat)
• liver cirrhosis (scarring), severe liver failure (serious impairment of liver function), autoimmune hepatitis (liver inflammation caused by the body's immune system attacking liver cells), which may also occur several months or years after starting treatment.

Blurred vision has also been reported, with a frequency not known (the frequency cannot be determined from the available data).
Additional side effects in children and adolescents
The side effects reported in children treated with Tracleer are the same as those in adults.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly through the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Tracleer

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and blister after "Exp".
For white high-density polyethylene bottles, use within 30 days of first opening.
For PVC/PE/PVDC/aluminium blisters:
Do not store above 25 °C.
For white high-density polyethylene bottles:
This medicine does not require any special storage conditions.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Tracleer contains

• Tracleer 62.5 mg film-coated tablets: The active substance is bosentan monohydrate. Each tablet contains 62.5 mg of bosentan (monohydrate).
• Tracleer 125 mg film-coated tablets: The active substance is bosentan monohydrate. Each tablet contains 125 mg of bosentan (monohydrate).
• The other components in the tablet are: maize starch, pregelatinized starch, sodium starch glycolate (Type A), povidone, glycerol dibehenate and magnesium stearate. The film coating contains hypromellose, glycerol triacetate, talc, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172) and ethylcellulose.

Description of the appearance of Tracleer and contents of the pack
Tracleer 62.5 mg film-coated tablets:
Tracleer 62.5 mg film-coated tablets are film-coated, round, orange-white tablets with the marking “62.5” printed on one side.
PVC/PE/PVDC/aluminum blisters containing 14 film-coated tablets. Cartons contain 14, 56 or 112 film-coated tablets (Tracleer 62.5 mg film-coated tablets).
White high-density polyethylene bottles with silica gel as desiccant, containing 56 film-coated tablets. Cardboard boxes contain 56 film-coated tablets (Tracleer 62.5 mg film-coated tablets).
Do not swallow the desiccant.

Tracleer 125 mg film-coated tablets:
Tracleer 125 mg film-coated tablets are film-coated, oval, orange-white tablets with the marking “125” printed on one side.
PVC/PE/PVDC/aluminum blisters containing 14 film-coated tablets. Cartons contain 56 or 112 film-coated tablets (Tracleer 125 mg film-coated tablets).
White high-density polyethylene bottles with silica gel as desiccant, containing 56 film-coated tablets. Cardboard boxes contain 56 film-coated tablets (Tracleer 125 mg film-coated tablets).
Do not swallow the desiccant.

Not all pack sizes may be marketed.

Marketing Authorization Holder
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

Manufacturer
Janssen Pharmaceutica NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

For further information about this medicine, please contact the local representative of the Marketing Authorization Holder.

België/Belgique/Belgien Lietuva
Janssen-Cilag NV UAB “JOHNSON & JOHNSON”
Tel/Tél: +32 14 64 94 11 Tel: +370 5 278 68 88
[email protected] [email protected]

България Luxembourg/Luxemburg
„Джонсън & Джонсън България” ЕООД Janssen-Cilag NV
Тел.: +359 2 489 94 00 Tél/Tel: +32 14 64 94 11
[email protected] [email protected]

Česká republika Magyarország
Janssen-Cilag s.r.o. Janssen-Cilag Kft.
Tel: +420 227 012 227 Tel.: +36 1 884 2858
[email protected]

Danmark Malta
Janssen-Cilag A/S AM MANGION LTD
Tlf: +45 4594 8282 Tel: +356 2397 6000
[email protected]

Deutschland Nederland
Janssen-Cilag GmbH Janssen-Cilag B.V.
Tel: 0800 086 9247 / +49 2137 955 6955 Tel: +31 76 711 1111
[email protected] [email protected]

Eesti Norge
UAB "JOHNSON & JOHNSON" Eesti filiaal Janssen-Cilag AS
Tel: +372 617 7410 Tlf: +47 24 12 65 00
[email protected] [email protected]

Ελλάδα Österreich
Janssen-Cilag Φαρμακευτική Μονοπρόσωπη Janssen-Cilag Pharma GmbH
Α.Ε.Β.Ε. Tel: +43 1 610 300
Tηλ: +30 210 80 90 000

España Polska
Janssen-Cilag, S.A. Janssen-Cilag Polska Sp. z o.o.
Tel: +34 91 722 81 00 Tel.: +48 22 237 60 00
[email protected]

France Portugal
Janssen-Cilag Janssen-Cilag Farmacêutica, Lda.
Tél: 0 800 25 50 75 / +33 1 55 00 40 03 Tel: +351 214 368 600
[email protected]

Hrvatska România
Johnson & Johnson S.E. d.o.o. Johnson & Johnson România SRL
Tel: +385 1 6610 700 Tel: +40 21 207 1800
[email protected]

Ireland Slovenija
Janssen Sciences Ireland UC Johnson & Johnson o.o.
Tel: 1 800 709 122 Tel: +386 1 401 18 00
[email protected] [email protected]

Ísland Slovenská republika
Janssen-Cilag AB Johnson & Johnson, s.r.o.
c/o Vistor ehf. Tel: +421 232 408 400
Sími: +354 535 7000
[email protected]

Italia Suomi/Finland
Janssen-Cilag SpA Janssen-Cilag Oy
Tel: 800.688.777 / +39 02 2510 1 Puh/Tel: +358 207 531 300
[email protected] [email protected]

Κύπρος Sverige
Βαρνάβας Χατζηπαναγής Λτδ Janssen-Cilag AB
Τηλ: +357 22 207 700 Tfn: +46 8 626 50 00
[email protected]

Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Tel: +371 678 93561
[email protected]

More detailed information on this medicine is available on the website of the European Medicines Agency: https://www.ema.europa.eu.

Package leaflet: Information for the user

Tracleer 32 mg dispersible tablets

bosentan
Please read this entire leaflet carefully before taking this medicine, as it contains
important information for you:

• Keep this leaflet. You may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any adverse reaction, including those not listed in this leaflet, contact your doctor or pharmacist.

Contents of this leaflet:

1. What Tracleer is and what it is used for
2. What you need to know before taking Tracleer
3. How to take Tracleer
4. Possible side effects
5. How to store Tracleer
6. Contents of the pack and other information

1. What Tracleer is and what it is used for

Tracleer tablets contain bosentan, which blocks a naturally occurring hormone called endothelin-1 (ET-1) that causes narrowing of blood vessels. Tracleer therefore causes blood vessels to widen and belongs to a class of medicines known as "endothelin receptor antagonists".

Tracleer is used to treat:

• Pulmonary arterial hypertension (PAH): PAH is a disease characterized by severe narrowing of the blood vessels in the lungs, resulting in increased blood pressure in the vessels carrying blood from the heart to the lungs (pulmonary arteries). This elevated pressure reduces the amount of oxygen that can pass into the blood through the lungs, making physical activity more difficult. Tracleer widens the pulmonary arteries, making it easier for the heart to pump blood through them. This results in reduced blood pressure and alleviation of symptoms.

Tracleer is used to treat PAH patients in WHO functional class III to improve exercise capacity (ability to perform physical activity) and symptoms. The "class" reflects the severity of the disease: "class III" indicates marked limitation in physical activity. Some benefits have also been observed in PAH patients in class II, where there is less limitation in physical activity. The PAH for which Tracleer is indicated may be:

• primary (without an identifiable cause or familial);

• caused by scleroderma (also known as systemic sclerosis, a disease characterized by abnormal growth of connective tissue supporting the skin and other organs);

• caused by congenital (inborn) heart defects with shunts (abnormal pathways) leading to abnormal blood flow through the heart and lungs.

• Digital ulcers: (sores on the fingers and toes) in adult patients with a condition called scleroderma. Tracleer reduces the number of new ulcers developing on the fingers and toes.

2. What you should know before taking Tracleer

Do not take Tracleer:

• if you are allergic to bosentan or to any of the other ingredients of this medicine (listed in section 6)
• if you have liver problems (consult your doctor)
• if you are pregnant or could become pregnant and you are not using reliable contraceptive methods. Please read the information provided under “Contraceptives” and “Other medicines and Tracleer”
• if you are being treated with cyclosporine A (a medicine used after organ transplantation or for the treatment of psoriasis)

In any of these cases, inform your doctor.
Warnings and precautions
Tests required by your doctor before starting Tracleer treatment

• a blood test to check your liver function
• a blood test to check for anemia (low hemoglobin)
• a pregnancy test if you are a woman of childbearing age

Abnormalities in liver function tests and anemia (low hemoglobin) have been observed in some patients treated with Tracleer.

Tests your doctor will prescribe during treatment
During treatment with Tracleer, your doctor will regularly request blood tests to monitor any changes in liver function and hemoglobin levels.
For all these tests, please also refer to the Patient Alert Card (included in your package of Tracleer tablets). It is important that you undergo these blood tests at regular intervals throughout the entire period of Tracleer administration. We recommend that you record on the Patient Alert Card the date of your most recent test and the date of your next scheduled test (ask your doctor for this date) so you do not forget when your next test is due.
Liver function blood tests
These will be performed every month for the entire duration of Tracleer treatment. An additional test will be performed 2 weeks after any dose increase.
Blood tests for anemia
These will be performed every month for the first 4 months of treatment and then every 3 months thereafter, as patients taking Tracleer may develop anemia.
If these test results are abnormal, your doctor may decide to reduce the dose or discontinue treatment with Tracleer and perform further tests to determine the cause.
Children and adolescents
Tracleer is not recommended in pediatric patients with systemic sclerosis and active digital ulcers. Please also see section 3. How to take Tracleer.
Other medicines and Tracleer
You should inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription. It is especially important to inform your doctor if you are taking:

• cyclosporine A (a medicine used after organ transplants and for the treatment of psoriasis), which must not be used together with Tracleer.
• sirolimus or tacrolimus, which are medicines used after transplants; their use together with Tracleer is not recommended.
• glibenclamide (a medicine for diabetes), rifampicin (a medicine for tuberculosis), fluconazole (a medicine for fungal infections), ketoconazole (a medicine used for the treatment of Cushing's syndrome), or nevirapine (an HIV medicine); the use of these medicines together with Tracleer is not recommended.
• other medicines for the treatment of HIV infection, which may require special monitoring when used together with Tracleer.
• hormonal contraceptives, which are not effective as the sole method of contraception when you are taking Tracleer. Inside the package of Tracleer tablets, you will find a Patient Alert Card that you must read carefully. Your treating doctor and/or gynecologist will determine the appropriate contraceptive method for you.
• other medicines for the treatment of pulmonary hypertension: sildenafil and tadalafil;
• warfarin (an anticoagulant);
• simvastatin (used to treat hypercholesterolemia).

Driving and using machines
Tracleer does not affect or affects negligibly the ability to drive and use machines.
However, Tracleer may cause hypotension (lowering of your blood pressure), which may make you feel unsteady and may affect your vision and your ability to drive or operate machinery.
Therefore, if you experience dizziness or blurred vision during treatment with Tracleer, do not drive or operate any tools or machinery.
Women of childbearing potential
DO NOT take Tracleer if you are pregnant or planning to become pregnant.
Pregnancy test
Tracleer may harm the unborn child conceived before or during treatment. If you are a woman of childbearing age, your doctor will require you to take a pregnancy test before starting Tracleer and regularly during treatment with Tracleer.
Contraceptives
If you are a woman of childbearing age, you must use a reliable method of birth control (contraception) while taking Tracleer. Your doctor or gynecologist will advise you on reliable contraceptive methods while taking Tracleer. Since Tracleer may make hormonal contraception ineffective (e.g. oral, injectable, implantable contraceptives, or contraceptive patches), this method alone 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 use a condom).
Inside your package of Tracleer tablets, you will find a Patient Alert Card. You must complete this card and bring it to your next medical visit, so that your doctor or gynecologist can assess whether you need additional or alternative reliable contraceptive methods. It is recommended to perform a pregnancy test every month during treatment with Tracleer if you are of childbearing age.
Inform your doctor immediately if you become pregnant during treatment with Tracleer or if you plan to become pregnant in the near future.
Breast-feeding
Tracleer passes into breast milk. Breast-feeding should be discontinued if Tracleer is prescribed, as it may harm your baby. Talk to your doctor if you have any questions about this.
Fertility
If you are a man taking Tracleer, this medicine may reduce sperm count. This could potentially impair your ability to father a child. Talk to your doctor if you have any questions about this.
Tracleer contains aspartame and sodium
This medicine contains 3.7 mg of aspartame per dispersible tablet. Aspartame is a source of phenylalanine. It may be harmful if you have phenylketonuria, a rare genetic disorder that causes phenylalanine to accumulate because the body cannot properly eliminate it.
This medicine contains less than 1 mmol (23 mg) of sodium per tablet, i.e. it is essentially ‘sodium-free’.

3. How to take Tracleer

Treatment with Tracleer should only be initiated and monitored by a physician experienced in the
treatment of PAH or systemic sclerosis. Always take this medicine exactly as instructed by your
doctor. If you have any doubts, consult your doctor or pharmacist.
Tracleer with food and drink
Tracleer may be taken on an empty stomach or with food.
Recommended dose
Adults
In adults, treatment usually begins with one 62.5 mg tablet twice daily (morning and evening) for the
first 4 weeks; thereafter, your doctor will usually recommend increasing to one 125 mg tablet twice
daily, depending on your response to Tracleer.
Children and adolescents
The recommended dose in children is only for PAH. For children aged 1 year and older, treatment
with Tracleer usually begins at 2 mg per kg of body weight twice daily (morning and evening); your
doctor will advise on subsequent dosing.
If necessary, the dispersible tablet may be divided along the scored lines into four equal parts.
If you feel that the effects of Tracleer are too strong or too weak, speak with your doctor to evaluate
whether a dose adjustment is needed.
How to take Tracleer
Take the tablets (morning and evening) with water. Tablets may be taken with or without food.
The dispersible tablet is contained in a child-resistant blister pack.
To remove the dispersible tablet:

1. Separate the individual blister cavity along the perforations.
2. Remove the top layers.
3. Push the tablet through the foil.

Each Tracleer dispersible tablet can be dissolved in water to form a liquid medicine. To do this, place
the tablet in a spoon with a small amount of water, using enough water to cover the entire tablet.
Wait about one minute until the tablet has completely dissolved, then swallow all the liquid. To
ensure complete intake of the medicine, add a little more water to the spoon and drink it. If possible,
drink a glass of water afterwards to ensure you have taken the full dose.
If necessary, the dispersible tablet may be divided by breaking it along the scored lines on the
surface. Hold the tablet between 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).

If you take more Tracleer than you should
If you have taken more tablets than prescribed, contact your doctor immediately.
If you forget to take Tracleer
If you forget to take Tracleer, take a tablet as soon as you remember, then continue taking the tablets
at your usual times. Do not take a double dose to make up for a missed dose.
If you stop taking Tracleer
Stopping Tracleer treatment suddenly may lead to worsening of symptoms. Do not discontinue this
treatment unless instructed by your doctor. Your doctor may advise you to gradually reduce the dose
over several days before completely stopping Tracleer.
If you have further questions about the use of this medicine, consult your doctor or pharmacist.

4 Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
The most serious side effects associated with Tracleer are:

• Abnormal liver function, which may occur in more than 1 in 10 users
• Anaemia (low blood test values), which may occur in 1 in 10 users. Anaemia may occasionally require blood transfusion. Liver and blood test values must be monitored during treatment with Tracleer (see section 2). It is important that you have these tests performed as prescribed by your doctor.

Signs of impaired liver function include:

• nausea (feeling sick)
• vomiting
• fever (high temperature)
• stomach (abdominal) pain
• jaundice (yellowing of the skin or whites of the eyes)
• dark-coloured urine
• skin itching
• lethargy or fatigue (unusual tiredness or weakness)
• flu-like syndrome (joint and muscle pain with fever)

If you notice any of these signs, tell your doctor immediately.
Other side effects:
Very common (may affect more than 1 in 10 people):

• headache
• oedema (swelling of the legs and ankles or other signs of fluid retention)

Common (may affect up to 1 in 10 people):

• flushed appearance or skin flushing
• hypersensitivity reactions (including skin inflammation, itching, and rash)
• gastroesophageal reflux disease (acid reflux)
• diarrhoea
• syncope (fainting)
• palpitations (fast or irregular heartbeat)
• low blood pressure
• nasal congestion

Uncommon (may affect up to 1 in 100 people):

• thrombocytopenia (low platelet count in the blood)
• neutropenia/leucopenia (low white blood cell count)
• Elevated liver function tests associated with hepatitis (liver inflammation), including possible worsening of underlying hepatitis and/or jaundice (yellowing of the skin or whites of the eyes)

Rare (may affect up to 1 in 1,000 people):

• anaphylaxis (generalized allergic reaction), angioedema (swelling, most commonly around the eyes, lips, tongue, or throat)
• liver cirrhosis (scarring), liver failure (severe impairment of liver function), autoimmune hepatitis (liver inflammation caused by the body's immune system attacking liver cells), which may occur several months or even years after starting treatment.

Blurred vision has also been reported, with a frequency not known (the frequency cannot be estimated from the available data).

Additional side effects in children and adolescents
The side effects reported in children treated with Tracleer are the same as those in adults.

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Tracleer

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and blister after "Exp".
Do not store above 25 °C.
Remaining parts of a divided dispersible tablet may be stored at room temperature and must be used within 7 days.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Tracleer contains

• The active substance is bosentan in the form of monohydrate. Each dispersible tablet contains 32 mg of bosentan (monohydrate).
• The other components are: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, anhydrous colloidal silicon dioxide, tartaric acid, tutti frutti flavouring, aspartame (E951, please read further information at the end of section 2), acesulfame potassium, magnesium stearate.

Description of the appearance of Tracleer and contents of the pack
Tracleer 32 mg dispersible tablets. Yellowish-white to off-white, clover-shaped tablets, divided into four parts on one side and marked with "32" on the other side.
Peel-push blisters containing 14 dispersible tablets. Carton packs containing 56 dispersible tablets.

Marketing Authorization Holder
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

Manufacturer
Janssen Pharmaceutica NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

For further information about this medicinal product, please contact the local representative of the Marketing Authorization Holder.

België/Belgique/Belgien Lietuva
Janssen-Cilag NV UAB “JOHNSON & JOHNSON”
Tel/Tél: +32 14 64 94 11 Tel: +370 5 278 68 88
[email protected] [email protected]

България Luxembourg/Luxemburg
„Джонсън & Джонсън България” ЕООД Janssen-Cilag NV
Тел.: +359 2 489 94 00 Tél/Tel: +32 14 64 94 11
[email protected] [email protected]

Česká republika Magyarország
Janssen-Cilag s.r.o. Janssen-Cilag Kft.
Tel: +420 227 012 227 Tel.: +36 1 884 2858
[email protected]

Danmark Malta
Janssen-Cilag A/S AM MANGION LTD
Tlf: +45 4594 8282 Tel: +356 2397 6000
[email protected]

Deutschland Nederland
Janssen-Cilag GmbH Janssen-Cilag B.V.
Tel: 0800 086 9247 / +49 2137 955 6955 Tel: +31 76 711 1111
[email protected] [email protected]

Eesti Norge
UAB "JOHNSON & JOHNSON" Eesti filiaal Janssen-Cilag AS
Tel: +372 617 7410 Tlf: +47 24 12 65 00
[email protected] [email protected]

Ελλάδα Österreich
Janssen-Cilag Φαρμακευτική Μονοπρόσωπη Janssen-Cilag Pharma GmbH
Α.Ε.Β.Ε. Tel: +43 1 610 300
Tηλ: +30 210 80 90 000

España Polska
Janssen-Cilag, S.A. Janssen-Cilag Polska Sp. z o.o.
Tel: +34 91 722 81 00 Tel.: +48 22 237 60 00
[email protected]

France Portugal
Janssen-Cilag Janssen-Cilag Farmacêutica, Lda.
Tél: 0 800 25 50 75 / +33 1 55 00 40 03 Tel: +351 214 368 600
[email protected]

Hrvatska România
Johnson & Johnson S.E. d.o.o. Johnson & Johnson România SRL
Tel: +385 1 6610 700 Tel: +40 21 207 1800
[email protected]

Ireland Slovenija

[email protected]
Iceland Slovakia

Janssen-Cilag AB
c/o Vistor ehf.
Tel: +354 535 7000
[email protected]
Italy Finland
Janssen-Cilag SpA Janssen-Cilag Oy
Tel: 800.688.777 / +39 02 2510 1 Puh/Tel: +358 207 531 300
[email protected] [email protected]
Cyprus Sverige
Varnavas Hadjipanagis Ltd Janssen-Cilag AB
Tel: +357 22 207 700 Tfn: +46 8 626 50 00
[email protected]
Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Tel: +371 678 93561
[email protected]
More detailed information on this medicine is available on the European Medicines Agency website:
https://www.ema.europa.eu.
ANNEX IV
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE
MARKETING AUTHORISATIONS
Scientific conclusions
Taking into account the evaluation by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Reports (PSURs) for bosentan, the scientific conclusions are as follows:
Based on available data regarding autoimmune hepatitis from clinical studies, literature, and spontaneous reports, including in some cases a close temporal relationship, improvement after discontinuation and/or recurrence upon re-administration of the drug (positive de-challenge and/or re-challenge), the PRAC Rapporteur considers that there is at least a reasonable possibility of a causal relationship between bosentan and autoimmune hepatitis.
The PRAC Rapporteur concluded that the product information for medicinal products containing bosentan should therefore be amended.
Having reviewed the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the general conclusions and the grounds for the recommendation.
Grounds for the variation to the terms of the marketing authorisations
Based on the scientific conclusions on bosentan, the CHMP considers that the benefit-risk balance of medicinal products containing bosentan remains favourable, subject to the proposed changes to the product information.
The CHMP recommends the variation to the terms of the marketing authorisations.