Consumer medicine information

Bosentan RBX

Bosentan

BRAND INFORMATION

Brand name

Bosentan RBX

Active ingredient

Bosentan

Schedule

SUMMARY CMI

BOSENTAN RBX

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using BOSENTAN RBX?

BOSENTAN RBX contains the active ingredient bosentan (as monohydrate). BOSENTAN RBX is used to for the treatment of high blood pressure in the blood vessels between the heart and the lungs. This condition is called pulmonary arterial hypertension. This medicine acts to reduce abnormally high blood pressure by widening these blood vessels.

For more information, see Section 1. Why am I using BOSENTAN RBX? in the full CMI.

2. What should I know before I use BOSENTAN RBX?

Do not use if you have ever had an allergic reaction to BOSENTAN RBX or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use BOSENTAN RBX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with BOSENTAN RBX and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use BOSENTAN RBX?

BOSENTAN RBX is taken by mouth, in the morning and evening, and can be taken with or without food.

More instructions can be found in Section 4. How do I use BOSENTAN RBX? in the full CMI.

5. What should I know while using BOSENTAN RBX?

Things you should do	It is very important that you have a liver function blood test before you start treatment and every month after that. You need to have pregnancy tests monthly if you are a female of childbearing age.
Things you should not do	Do not give the tablets to anyone else even if they have the same symptoms as you.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how BOSENTAN RBX affects you.
Looking after your medicine	Store below 25°C.

For more information, see Section 5. What should I know while using BOSENTAN RBX? in the full CMI.

6. Are there any side effects?

Common side effects include shortness of breath or difficulty in breathing; anaphylaxis and/ or swelling, most commonly around the eyes, lips, tongue or throat; nausea; vomiting; fever; unusual tiredness; stomach pain; yellowing of your skin or the whites of your eyes (jaundice); dark-coloured urine; chest pain. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNING: Bosentan may cause birth defects and is contraindicated in pregnancy. See Section 4.3 CONTRAINDICATIONS and Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE.
Rare cases of hepatic cirrhosis and hepatic failure have been reported in patients using bosentan. See Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE.

FULL CMI

BOSENTAN RBX

Active ingredient(s): Bosentan (as monohydrate)

Consumer Medicine Information (CMI)

This leaflet provides important information about using Bosentan RBX. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using BOSENTAN RBX.

Where to find information in this leaflet:

1. Why am I using BOSENTAN RBX?
2. What should I know before I use BOSENTAN RBX?
3. What if I am taking other medicines?
4. How do I use BOSENTAN RBX?
5. What should I know while using BOSENTAN RBX?
6. Are there any side effects?
7. Product details

1. Why am I using BOSENTAN RBX?

BOSENTAN RBX contains the active ingredient bosentan (as monohydrate). BOSENTAN RBX belongs to the class of medicines known as endothelin receptor antagonists.

BOSENTAN RBX is used to for the treatment of high blood pressure in the blood vessels between the heart and the lungs. This condition is called pulmonary arterial hypertension. This medicine acts to reduce abnormally high blood pressure by widening these blood vessels.

This medicine is only available with a doctor's prescription.

2. What should I know before I use BOSENTAN RBX?

Warnings

Do not use BOSENTAN RBX if:

you are allergic to bosentan, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
Being treated with ciclosporine A (a medicine used after a transplant or to treat psoriasis).
Being treated with glibenclamide (a medicine used for diabetes).
You have moderate to severe liver disorder.
After the expiry date (EXP) printed on the pack.
If you take it after the expiry date has passed, it may not work as well.
The packaging is torn or shows signs of tampering.

Check with your doctor if you:

have any other medical conditions:
- pulmonary arterial hypertension
- anaemia
- hypotension
- liver or renal disorders
- heart failure
- HIV infection
You are a woman of childbearing potential and not using reliable contraceptive methods. You must have a negative pregnancy test before beginning treatment. The test should be performed on the second day of a normal menstrual period or 11 days after the last unprotected sexual intercourse, whichever is later. Your doctor will advise you about using reliable contraception before taking or whilst taking this medicine.
Hormonal contraception on its own is not a reliable option because this medicine may make this method ineffective in preventing pregnancy. Hormonal contraceptives include ones you take orally (the pill), patches you put on your skin, ones that are injected and implants. You should always use additional methods of contraception such as condoms and IUDs and not rely just on hormonal contraception. You should have a pregnancy test every month while you are taking this medicine. You must stop taking this medicine for at least 3 months prior to becoming pregnant.
You are breastfeeding or planning to breastfeed.
It is not known whether BOSENTAN RBX passes into breast milk.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Do not take BOSENTAN RBX if you are:

Pregnant or intend to become pregnant
You must stop taking the medicine at least 3 months before trying to become pregnant.
It is known that this medicine causes harm to the developing baby if you take it during pregnancy and in the three months before becoming pregnant.
You are breastfeeding
Tell your doctor immediately if you are breastfeeding. You are advised to stop breastfeeding if this medicine is prescribed for you because it is not known if this drug passes into the milk in women who are taking this medicine.

Before you start to take BOSENTAN RBX

BOSENTAN RBX may harm sperm. All men should use effective birth control while taking this medicine and for 3 months after they stop taking it.

If sexually active, you must use a hormonal and barrier method of contraception.

This medicine may reduce the effectiveness of hormone contraceptives such as the pill and hormone patches, implants or injection. It is important to use other contraceptives, like condoms or an intrauterine device. Your doctor will advise you about using reliable contraceptives before taking this medicine.

You must have a negative pregnancy test at the time of starting treatment if you are sexually active.

Your doctor will need evidence that you are not pregnant.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with BOSENTAN RBX. These include:

hormonal contraceptives (oral, injectable, transdermal and implantable)
simvastatin, medicines for lowering blood fats
medicines for diabetes such as glibenclamide
medicines for fungal infections such as ketaconazole, itraconazole, fluconazole and voriconazole
medicines for bacterial infections such as rifampicin
medicine to prevent organ transplantation rejection such as Ciclosporine A, tacrolimus and sirolimus
medicines for rheumatoid arthritis or psoriasis/dermatitis
lopinavir+ritonavir or other ritonavir-boosted protease inhibitors (used to treat HIV);
warfarin (used as anti-coagulant medicine)
digoxin (used to treat heart rhythm disorders)
sildenafil or tadalafil (used to treat erectile dysfunction and/or also pulmonary hypertension
phenytoin, carbamazepine or phenobarbital (medicines for seizures)
nimodipine
nevirapine (an HIV medicine)
St John Wort

These medicines may be affected by BOSENTAN RBX or may affect how well it works. You may need to use different amounts of your medicines, or take different medicines. Your doctor will advise you.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect BOSENTAN RBX.

4. How do I use BOSENTAN RBX?

How much to take / use

The usual dose is one tablet, twice daily. For the first 4 weeks you will take a 62.5 mg tablet twice daily.
Depending on how you respond to the medicine, your doctor may increase the dosage after four weeks to a 125 mg tablet twice daily.
If you do not think the medicine is working or you think it is working too well, talk to your doctor. Your doctor may need to change the dose you are taking.
Follow the instructions provided and use BOSENTAN RBX exactly as your doctor has instructed you.
You should check with your doctor or pharmacist if you are unsure.

When to take BOSENTAN RBX

BOSENTAN RBX should be taken in the morning and evening.

How to take/use BOSENTAN RBX

BOSENTAN RBX is taken by mouth, in the morning and evening, and can be taken with or without food.

How long to take it

Do not stop taking this medicine unless your doctor tells you to.

Stopping your treatment may lead to a worsening of your symptoms. Your doctor may tell you to reduce the dose over a few days before stopping completely.

If you forget to use BOSENTAN RBX

BOSENTAN RBX should be used regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember and then go back to taking it as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

This may increase the chance of getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for hints.

If you use too much BOSENTAN RBX

If you think that you have used too much BOSENTAN RBX, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using BOSENTAN RBX?

Things you should do

It is very important that you have a liver function blood test before you start treatment and every month after that.

BOSENTAN RBX can cause liver damage if it is not found early. Because this side effect may not cause symptoms at first, only a blood test can show that you have early liver damage. Regular blood tests let your doctor change or stop your therapy before there is permanent damage.

You should have a blood test for anaemia after 1 and 3 months, and then every 3 months for the rest of your treatment.

You need to have pregnancy tests monthly if you are a female of childbearing age.

Things you should not do

Do not give the tablets to anyone else even if they have the same symptoms as you.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how BOSENTAN RBX affects you.

If you feel dizzy or your vision is blurred whilst taking this medicine, do not drive or operate any tools or machinery.

Looking after your medicine

Store below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects	What to do
shortness of breath or difficulty in breathing anaphylaxis and/ or swelling, most commonly around the eyes, lips, tongue or throat nausea vomiting fever unusual tiredness stomach pain yellowing of your skin or the whites of your eyes (jaundice) dark-coloured urine chest pain	Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

headache
respiratory tract infection
dizziness or fainting
anaemia
abnormal liver function test or liver disorders
inflamed throat and irritated nose passages
flushing (hot flashes)
ankle, leg swelling and joint or other signs of fluid retention
joint pain
low blood pressure
blood disorders
fast heart beat
tiredness
hypersensitivity reactions including itching, rash, skin inflammation,
skin redness
blocked or runny nose
heartburn or acid reflux
diarrhoea
blurred vision
nosebleed
body ache and pain
worsening of existing lung disease

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What BOSENTAN RBX contains

Active ingredient (main ingredient)	BOSENTAN RBX 62.5 mg: contains 62.5 mg bosentan (as monohydrate) per tablet. BOSENTAN RBX 12.5 mg: contains 12.5 mg bosentan (as monohydrate) per tablet.
Other ingredients (inactive ingredients)	maize starch, pregelatinised maize starch, sodium starch glycollate type A, povidone, glycerol dibehenate, magnesium stearate, hypromellose, glycerol triacetate, purified talc, titanium dioxide, iron oxide yellow, iron oxide red and ethylcellulose.
Potential allergens	-

Do not take this medicine if you are allergic to any of these ingredients.

What BOSENTAN RBX looks like

BOSENTAN RBX 62.5 mg (AUST R 257757) is film-coated tablets are light peach to peach coloured, round shaped, biconvex and debossed with ‘62.5’ on one side and plain on the other side.

BOSENTAN RBX 12.5 mg (AUST R 257753) is film-coated tablets are light peach to peach coloured, oval shaped, biconvex and debossed with ‘125’ on one side and plain on the other side.

Supplied in PVC/PE/PVdC/Al blister packs containing 56 and 60 tablets.

Not all pack sizes are marketed in Australia.

Who distributes BOSENTAN RBX

Sun Pharma ANZ Pty Ltd
Macquarie Park NSW 2113 Australia
[email protected]
Tel: 1800 726 229

This leaflet was prepared in May 2024.

Published by MIMS August 2024

BRAND INFORMATION

Brand name

Bosentan RBX

Active ingredient

Bosentan

Schedule

1 Name of Medicine

Bosentan (as monohydrate).

2 Qualitative and Quantitative Composition

Each tablet contains 62.5 mg bosentan (as monohydrate).
Each tablet contains 125 mg bosentan (as monohydrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Bosentan RBX (bosentan) 62.5 mg film-coated tablets are light peach to peach coloured, round shaped, biconvex and debossed with '62.5' on one side and plain on the other side.
Bosentan RBX (bosentan) 125 mg film-coated tablets are light peach to peach coloured, oval shaped, biconvex and debossed with '125' on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Bosentan is indicated for the treatment of:
idiopathic pulmonary arterial hypertension;
familial pulmonary arterial hypertension;
pulmonary arterial hypertension associated with scleroderma; or
pulmonary arterial hypertension associated with congenital systemic to pulmonary shunts including Eisenmenger's physiology, in patients with WHO functional Class II, III or IV symptoms.

4.2 Dose and Method of Administration

General.

Bosentan RBX should be administered under the supervision of a physician experienced in the management of pulmonary arterial hypertension.
Bosentan RBX treatment should be initiated at a dose of 62.5 mg twice daily for 4 weeks. Efficacy was demonstrated in clinical trial subjects who increased to a maintenance dose of 125 mg twice daily. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of liver injury.
Tablets should be administered morning and evening with or without food.
Serum liver aminotransferase (AST and ALT) levels must be measured prior to initiation of treatment with Bosentan RBX and monthly thereafter for the duration of treatment (see Section 4.4 Special Warnings and Precautions for Use, Potential liver injury). If elevated aminotransferase levels are seen, changes in monitoring and treatment must be initiated, as detailed below.

Dosage in patients with hepatic impairment.

Patients with hepatic abnormalities before starting bosentan treatment. Bosentan RBX must not be initiated in patients with moderate to severe hepatic impairment (Child-Pugh Class B and C) (see Section 4.3 Contraindications).
Bosentan RBX may be initiated at the usual starting dose in patients with mild hepatic impairment (Child-Pugh Class A, hepatic aminotransferases less than 3 x ULN). However, the use of Bosentan RBX in these patients may be associated with an increased risk of hepatotoxicity (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients who develop hepatic abnormalities during treatment. In patients who develop hepatic abnormalities during treatment with Bosentan RBX, the following actions should be taken.

Aminotransferase abnormalities.

ALT/AST levels: treatment and monitoring recommendations.
> 3 and ≤ 5 x ULN. Confirm by another aminotransferase test; if confirmed, reduce the daily dose or interrupt treatment, and monitor aminotransferase levels at least every 2 weeks. If the aminotransferase levels return to pre-treatment values, continue or re-introduce the treatment as appropriate (see below).
> 5 and ≤ 8 x ULN. Confirm by another aminotransferase test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 weeks. Once the aminotransferase levels return to pre-treatment values, consider re-introduction of the treatment (see below).
> 8 x ULN. Treatment should be stopped and re-introduction of Bosentan RBX should not be considered. There is no experience with the re-introduction of Bosentan RBX in these circumstances.
If Bosentan RBX is re-introduced it should be at the starting dose; aminotransferase levels should be checked within 3 days and thereafter according to the recommendations above.

Bilirubin abnormalities.

If liver aminotransferase elevations are accompanied by increases in bilirubin ≥ 2 x ULN, treatment should be stopped. There is no experience with the re-introduction of bosentan in these circumstances.

Clinical symptoms or signs of liver injury.

If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue), treatment must be stopped. There is no experience with the reintroduction of bosentan in these circumstances.

Use in women of childbearing potential.

Bosentan RBX treatment should only be initiated in women of childbearing potential following a negative pregnancy test and only in those who practice reliable contraception that does not depend solely upon hormonal contraceptives including oral, injectable, transdermal or implantable contraceptives. Double barrier contraception is recommended. Repeated monthly pregnancy tests during treatment with Bosentan RBX are recommended (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Hormonal contraceptives, including oral, injectable, transdermal and implantable contraceptives). Women must not become pregnant for at least three months after stopping treatment with Bosentan RBX.

Dosage in renally impaired patients.

The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment. In patients with severe renal impairment (creatinine clearance 15-30 mL/min), plasma concentrations of bosentan were essentially unchanged and plasma concentrations of the three metabolites were increased about 2-fold compared to people with normal renal function. These differences do not appear to be clinically important (see Section 5.2 Pharmacokinetic Properties, Special populations, Renal impairment).

Dosage in geriatric patients.

Clinical studies of bosentan were not adequate to determine whether subjects aged 65 and older respond differently than younger subjects; greater sensitivity to bosentan cannot be ruled out. Conditions more common in the elderly, such as hepatic impairment, renal impairment and decreased cardiac function, as well as concomitant diseases and other drug therapy, can have a clinically significant effect on bosentan pharmacokinetics (see Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use). Caution should be exercised in dose selection for elderly patients, and close clinical monitoring is required. The lowest effective dose should be used to prevent the occurrence of side effects (see Section 4.2 Dose and Method of Administration).

Dosage adjustment in children.

There is limited experience with the use of bosentan in children based on a pharmacokinetic study conducted in 19 children with PAH (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties). The pharmacokinetic findings showed that systemic exposure in children with PAH was lower than in adults with PAH. Although the number of patients studied in each dose group was generally insufficient to establish the optimal dosing regimen, the following doses are recommended in children aged 3 years and over (see Table 1).

Dosage adjustment in patients with low body weight.

In patients with a body weight below 40 kg but who are over 12 years of age the recommended initial and maintenance dose is 62.5 mg twice daily.

Discontinuation of treatment.

There is limited experience with abrupt discontinuation of bosentan. No evidence for acute rebound has been observed. Nevertheless, to avoid the potential for clinical deterioration, gradual dose reduction (62.5 mg twice daily for 3 to 7 days) should be considered. Intensified monitoring is recommended during the discontinuation period.

4.3 Contraindications

Pregnancy: pregnancy category X.

Women who are pregnant or who are likely to become pregnant.

Bosentan is expected to cause foetal harm if administered to pregnant women (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy). Pregnancy must be excluded before the start of treatment with bosentan and prevented thereafter by use of reliable contraception such as double-barrier contraception. It has been demonstrated that hormonal contraceptives, including oral, injectable, transdermal and implantable contraceptives may not be reliable in the presence of bosentan and should not be used as the sole contraceptive method in patients receiving bosentan. Double barrier contraception is recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Hormonal contraceptives, including oral, injectable, transdermal and implantable contraceptives). Input from a gynaecologist or similar expert on adequate contraception should be sought as needed.
Bosentan should be started only in patients known not to be pregnant. Women must not become pregnant for at least three months after stopping treatment with bosentan. For female patients of childbearing potential, a prescription for bosentan should not be issued by the prescriber unless the patient assures the prescriber that she is not sexually active or provides negative results from a urine or serum pregnancy test performed on the second day of the last normal menstrual period or 11 days after the last unprotected act of sexual intercourse, whichever is later. Follow-up urine or serum pregnancy tests should be obtained monthly in women of childbearing potential taking bosentan.
The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, she must notify the physician immediately for pregnancy testing. If the pregnancy test is positive, the physician and patient must discuss the risk to the pregnancy and the foetus.

Moderate or severe hepatic impairment.

Bosentan is contraindicated in patients with moderate or severe hepatic function impairment (Child Pugh Class B or C and/or baseline elevated aminotransferases > 3 x ULN). The risk of hepatotoxicity is increased in these patients and monitoring liver injury may be more difficult. Elimination of bosentan and its metabolites would also be markedly impaired in such patients (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Potential liver injury, Use in hepatic impairment; Section 5.1 Pharmacodynamic Properties).

Ciclosporin.

Co-administration of ciclosporin and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of bosentan and ciclosporin is contraindicated.

Glibenclamide.

An increased risk of liver enzyme elevations was observed in patients receiving glibenclamide concomitantly with bosentan. Therefore co-administration of glibenclamide and bosentan is contraindicated.

Hypersensitivity.

Bosentan is also contraindicated in patients who are hypersensitive to bosentan or any component of the medication. Observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash and angioedema.

4.4 Special Warnings and Precautions for Use

Potential liver injury.

Elevations in ALT or AST by more than 3 x ULN were observed in 11% of 658 bosentan-treated patients compared to 2% of 280 placebo-treated patients. Three-fold increases were seen in 12% of 188 PAH patients on 125 mg twice daily and 14% of 70 PAH patients on 250 mg twice daily. Eight-fold increases were seen in 4% of PAH patients on 125 mg twice daily and 7% of PAH patients on 250 mg twice daily. Bilirubin increases to ≥ 3 x ULN were associated with aminotransferase increases in 2 of 658 (0.3%) patients treated with bosentan. The combination of hepatocellular injury (increases in aminotransferases) and increases in total bilirubin has in many cases indicated potential for serious liver injury.
Bosentan has been associated with dose-related and treatment duration-related elevations in liver aminotransferases, i.e. aspartate and alanine aminotransferase (AST and ALT). 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. In the clinical programme, liver enzyme changes generally occurred within the first 26 weeks of treatment but may also occur late in treatment. These increases usually developed gradually, and were mainly asymptomatic, but some patients also reported abdominal pain, fever, fatigue or flu-like syndrome. The liver enzyme elevations returned, in 97% of cases during the clinical programme, to pre-treatment levels, without sequelae, within a few days to 9 weeks either spontaneously or after dose reduction or discontinuation. In the post-marketing period rare cases of liver cirrhosis and liver failure have been reported.
The increases in liver aminotransferases may partly be 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 (BSEP), e.g. rifampicin, glibenclamide and ciclosporin, are co-administered with bosentan, but limited data are available.
Elevations in gamma GT were observed in 11% of bosentan-treated patients.
Elevations in bilirubin or alkaline phosphatase were less common (bilirubin: bosentan 0.4% vs placebo 2.4%; alkaline phosphatase: bosentan 1.9% vs placebo 1.9%). Few patients developed jaundice.
Liver aminotransferase levels must be measured prior to initiation of treatment and monthly thereafter. If elevated aminotransferase levels are seen, changes in monitoring and treatment must be initiated (see Section 4.2 Dose and Method of Administration). If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, lethargy, fatigue, abdominal pain or jaundice) or increases in bilirubin ≥ 2 x ULN, treatment must be stopped. There is no experience with the reintroduction of bosentan in these circumstances.
In the post-marketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (> 12 months) therapy with bosentan in patients with multiple co-morbidities and drug therapies. 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 4.2 Dose and Method of Administration for information about patients who develop hepatic abnormalities during treatment). The contribution of bosentan in these cases could not be excluded.

Use in hepatic impairment.

Bosentan is contraindicated in patients with moderate or severe hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 5.1 Pharmacodynamic Properties). In addition, bosentan should generally be avoided in patients with elevated aminotransferases (> 3 x ULN) because these patients are at a greater risk and monitoring liver injury may be more difficult. Patients with mild hepatic impairment (hepatic aminotransferases 1 to 3 x ULN) may be commenced on bosentan, but have an increased risk of hepatotoxicity (see Section 4.8 Adverse Effects (Undesirable Effects)).

Haematological changes.

Treatment with bosentan caused a dose-related decrease in haemoglobin and haematocrit. 10% of 693 bosentan patients had clinically significant reductions in haematocrit or haemoglobin, with decreases in erythrocytes, and 5% had anaemia. Haemoglobin levels should be monitored periodically. It is recommended that haemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in haemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment.
A decrease in haemoglobin concentration by at least 1 g/dL was observed in 57% of bosentan-treated patients as compared to 29% of placebo-treated patients. In 80% of those patients whose haemoglobin decreased by at least 1 g/dL, the decrease occurred during the first 6 weeks of bosentan treatment.
Most of this decrease of haemoglobin concentration was detected during the first few weeks of bosentan treatment and haemoglobin levels stabilized by 4-12 weeks of bosentan treatment.
In placebo-controlled studies of all uses of bosentan, marked decreases in haemoglobin (> 15% decrease from baseline resulting in values < 1 g/dL) were observed in 6% of bosentan-treated patients and 3% of placebo-treated patients. 3% of bosentan patients had serious anaemia requiring withdrawal from the studies and/or blood transfusion. In patients with pulmonary arterial hypertension treated with doses of 125 mg and 250 mg twice daily, marked decreases in haemoglobin occurred in 3% compared to 1% in placebo-treated patients. Stopping bosentan generally resulted in patients' haemoglobin or haematocrit returning to baseline levels quickly.
During the course of treatment the haemoglobin concentration remained within normal limits in 68% of bosentan treated patients compared to 76% of placebo patients.
The explanation for the change in haemoglobin is not known, but it does not appear to be haemorrhage or haemolysis.
In the post-marketing period, cases of anaemia requiring red blood cell transfusion have been reported.

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 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 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, 1611 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. 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 hospitalisation 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.

Use in patients with pre-existing anaemia.

Particular caution should be exercised when initiating bosentan in patients with haemoglobin or haematocrit more than 30% below the lower limit of normal. Such patients were excluded from clinical trials of bosentan. The cause of anaemia should be determined and managed as appropriate, and haematological parameters should be checked more frequently than usual.

Use in patients with pre-existing hypotension.

Particular caution should be exercised when initiating bosentan in patients with pre-existing hypotension, and blood pressure in such patients should be monitored closely. Patients with systolic blood pressure < 85 mmHg were excluded from clinical trials of bosentan.

Use in patients receiving epoprostenol.

In a randomised, double blind trial (BREATHE-2), 32 patients were commenced on epoprostenol, to which bosentan (n=22) or placebo (n=11) was added two days later. The treatments were then carried out for 16 weeks. The trial failed to show any significant clinical benefit (6 minute walk, dyspnoea score, WHO functional class) or pharmacodynamic effect. The co-administration of bosentan with epoprostenol is, therefore, not recommended.

Use in CHD patients.

In the BREATHE-5 trial, oxygen saturation did not deteriorate in patients treated with bosentan compared with placebo. However, it is recommended as standard medical care that CHD patients have their oxygen saturation monitored as clinically indicated.

Use in patients with HIV infection.

If treatment with bosentan is initiated in patients who require ritonavir-boosted protease inhibitors, the patient's tolerability of bosentan 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 Interactions with Other Medicines and Other Forms of Interactions), which could affect the efficacy of antiretroviral therapy, these patients should also be monitored carefully regarding their HIV infection.

Use in the elderly.

Clinical studies of bosentan were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects; greater sensitivity to bosentan cannot be ruled out. Conditions more common in the elderly, such as hepatic impairment, renal impairment and decreased cardiac function, as well as concomitant diseases and other drug therapy, can have clinically significant effects on bosentan pharmacokinetics (see Section 5.2 Pharmacokinetic Properties). Caution should be exercised in treating elderly patients, and close clinical monitoring is required. The lowest effective dose should be used to prevent the occurrence of side effects (see Section 4.2 Dose and Method of Administration).

Paediatric use.

Various doses of bosentan have been assessed in a clinical study in paediatric patients with PPH or PAH related to congenital systemic to pulmonary communications, either as monotherapy or combined with epoprostenol (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The results indicate that the doses used were effective and appropriate in terms of safety and pharmacokinetics (see Section 4.2 Dose and Method of Administration, Dosage adjustment in children).

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Laboratory abnormalities.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Other drugs that affect bosentan.

(a) Demonstrated interactions. Co-administration of bosentan 125 mg twice daily for 6 days and ketoconazole, a potent CYP3A4 inhibitor, increased the exposure to bosentan 83%. No dose adjustment of bosentan is considered necessary, however, due to the possibility of increased exposure to bosentan, more frequent liver function monitoring is recommended during concomitant ketoconazole use.
Co-administration of bosentan and ciclosporin is contraindicated. 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.
Co-administration of bosentan and glibenclamide is contraindicated. Concomitant, steady state administration of bosentan 125 mg twice daily and glibenclamide decreased bosentan concentrations 30%. Concomitant glibenclamide administration predisposed patients to an increased risk of elevated liver aminotransferases.

Rifampicin.

Co-administration of bosentan and rifampicin in normal volunteers resulted in a mean 6-fold increase in bosentan trough levels after the first concomitant dose. Co-administration in 9 healthy subjects of bosentan 125 mg twice daily for 7 days and 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. The effect of bosentan on rifampicin levels has not been assessed. A subsequent significantly reduced effect of bosentan is expected when it is co-administered with rifampicin. When consideration of the potential benefits and known and unknown risks leads to concomitant use, measure LFTs weekly for the first 4 weeks before reverting to normal monitoring. 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.
Co-administration of bosentan 125 mg twice daily and lopinavir + ritonavir 400 + 100 mg twice daily during 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. If administered concomitantly with lopinavir + ritonavir or other ritonavir-boosted protease inhibitors, the patient's tolerability of bosentan should be monitored. In particular, markers of liver dysfunction such as LFTs and vascular (hypotension) adverse events should be monitored. After co-administration of bosentan for 9.5 days, the plasma exposures of lopinavir and ritonavir decreased to a clinically non significant extent (by approximately 14% and 17%, respectively). However, full induction by bosentan might not have been reached and a further decrease of protease inhibitors cannot be excluded. Appropriate monitoring of HIV therapy and indices of HIV infection progression are also recommended. Similar effects would be expected with other ritonavir-boosted protease inhibitors (see Section 4.4 Special Warnings and Precautions for Use).

Other antiretroviral agents.

No specific recommendation can be made with regard to other available antiretroviral agents due to the lack of data. It is emphasised that due to the marked hepatotoxicity of nevirapine, which could accumulate with bosentan liver toxicity, this combination is not recommended.
Losartan, digoxin and simvastatin did not affect bosentan plasma levels.
(b) Theoretical interactions. Concomitant administration of both a potent CYP3A4 inhibitor (such as ketoconazole, itraconazole and ritonavir) and a CYP2C9 inhibitor (such as voriconazole) in combination with bosentan may result in increased plasma levels of bosentan.
Caution should be exercised when bosentan is co-administered with known hepatotoxic drugs.
Concomitant use of bosentan with fluconazole is not recommended. Although not studied, this combination may lead to large increases in plasma concentrations of bosentan.
(c) Other interactions investigated. Digoxin, phenytoin and tolbutamide may cause a slight increase in free bosentan, but this slight increase is unlikely to be of clinical importance. There was no indication of a serum protein binding interaction between warfarin and bosentan.
Concomitant administration of bosentan and epoprostenol has shown to be safe and efficacious in a clinical study with paediatric PPH/PAH patients. The pharmacokinetics were similar to those in adult patients and healthy subjects in other studies.
Co-administration of tacrolimus or sirolimus with bosentan has not been studied in humans but may result in markedly increased plasma concentrations of bosentan in analogy to co-administration with ciclosporin. 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.

Effects of bosentan on other drugs.

(a) Demonstrated interactions. Co-administration of bosentan and glibenclamide is contraindicated. Concomitant, steady state administration of bosentan 125 mg twice daily and glibenclamide decreased glibenclamide concentrations 40%. Concomitant glibenclamide administration predisposed patients to an increased risk of elevated liver aminotransferases.
Co-administration of bosentan 500 mg twice daily for 6 days decreased the plasma concentrations of S- and R-warfarin by 29% and 38%, respectively. Clinical experience of 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 trials 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 the bosentan initiation and the up-titration period.
Co-administration of bosentan 500 mg twice daily for 7 days decreased the AUC, C_max and C_min of digoxin by 12%, 9% and 23%, respectively. Higher doses of digoxin may be required.
Co-administration of bosentan 125 mg twice daily for 5 days decreased the plasma concentrations of simvastatin, and its active b-hydroxy acid metabolite by 49% and 60%, respectively. Monitoring of cholesterol levels and subsequent dosage adjustment should be considered.
Co-administration of bosentan and ciclosporin is contraindicated. Concomitant, steady state administration of bosentan 500 mg twice daily and ciclosporin decreased cyclosporine A concentrations 50%.
Single dose bosentan did not affect nimodipine plasma levels.
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 of the sildenafil AUC and a 50% increase of the bosentan AUC. Caution is recommended in case of co-administration. The reduction in sildenafil plasma concentration with co-administration of bosentan has also been reported in a study of patients with primary arterial hypertension.

Tadalafil.

Bosentan reduced tadalafil systemic exposure following multiple dose co-administration. Tadalafil did not affect the exposure of bosentan or its metabolites.

Hormonal contraceptives, including oral, injectable, transdermal and implantable contraceptives.

An interaction study demonstrated that co-administration of bosentan and the oral hormonal contraceptive Ortho-Novum produced average decreases of norethindrone and ethinyl estradiol levels of 14% and 31% respectively. However, decreases in exposure were as much as 56% and 66% respectively in individual subjects. Therefore, hormonal contraceptives, including oral, injectable transdermal and implantable forms may not be reliable when bosentan is co-administered. Women should practise additional methods of contraception and not rely on hormonal contraception alone when taking bosentan.
(b) Theoretical interactions. 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 drugs metabolized by these isoenzymes will be decreased when bosentan is co-administered. The possibility of altered efficacy of medicinal products metabolized 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 treatment. Specifically, bosentan is expected to reduce the exposure to statins and oral hypoglycaemic agents that are predominantly metabolized by CYP3A4 or CYP2C9.
Bosentan is metabolised by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of bosentan (see ketoconazole). The influence of CYP2C9 inhibitors on bosentan concentration has not been studied. The combination should be used with caution. Concomitant administration with fluconazole, which inhibits mainly CYP2C9, but to some extent also CYP3A4, could lead to large increases in plasma concentrations of bosentan. The combination is not recommended. For the same reason, concomitant administration of both a potent CYP3A4 inhibitor (such as ketoconazole, itraconazole and ritonavir) and a CYP2C9 inhibitor (such as voriconazole) with bosentan is not recommended.
Nimodipine concentrations could decrease after multiple-dose administration of bosentan.
(c) Other interactions investigated. Bosentan did not lead to any significant changes in the serum protein binding of digoxin, glibenclamide, phenytoin, or warfarin. However, bosentan slightly increased the free serum concentrations of tolbutamide, but this slight increase is unlikely to be of clinical importance.
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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Male fertility: impairment of fertility/testicular function.

Many endothelin receptor antagonists have profound effects on the histology and function of the testes in animals. These drugs have been shown to induce atrophy of the seminiferous tubules of the testes and to reduce sperm counts and male fertility in rats when administered for longer than 10 weeks. Where studied, testicular tubular atrophy and decreases in male fertility observed with endothelin receptor antagonists appear irreversible.
In fertility studies in which male and female rats were treated with bosentan at oral doses of up to 1,500 mg/kg/day (50 times the MRHD on a mg/m² basis) or intravenous doses of up to 40 mg/kg/day, no effects on sperm count, sperm motility, mating performance or fertility were observed. An 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 MRHD and the lowest dose tested) for two years but not at doses as high as 1,500 mg/kg/day (about 50 times the MRHD) for 6 months. An increased incidence of tubular atrophy was not observed in mice treated for 2 years at doses up to 4,500 mg/kg/day (about 75 times the MRHD), or in dogs treated up to 12 months at doses up to 500 mg/kg/day (about 30 times the MRHD).
Twenty-five male patients with WHO functional class III and IV PAH and normal baseline sperm count were treated with bosentan 62.5 mg bid for 4 weeks followed by 125 mg bid for 5 months to assess any effects on testicular function. Twenty three completed the study and 2 discontinued due to adverse events not related to testicular function. Sperm count remained within the normal range in all 22 patients with data after 6 months and no changes in sperm morphology, sperm motility, or hormone levels were observed. One patient developed marked oligospermia at 3 months and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. Bosentan was discontinued and after two months the sperm count had returned to baseline levels. The relevance of this observation is uncertain considering the large natural intrasubject variability of sperm counts. Although, based on this finding, it cannot be excluded that endothelin receptor antagonists such as bosentan may have an effect on spermatogenesis, the absence of a systematic effect of chronic bosentan treatment on testicular function in humans observed in this study is in line with the toxicology data for bosentan.
In male children, long-term impact on fertility after treatment with bosentan cannot be excluded.
(Category X)
Bosentan was teratogenic in rats given oral doses ≥ 60 mg/kg/day (twice the maximum recommended human oral therapeutic dose of 125 mg twice daily, on a mg/m² basis). In an embryo-foetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses of 60 mg and 300 mg/kg/day (2 and 10 times, respectively, the maximum recommended human dose on a mg/mg² basis). Although birth defects were not observed in rabbits given oral doses of up to 1,500 mg/kg/day, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that teratogenicity is a class effect of these drugs.
There are minimal data on the use of bosentan in pregnant women from very few cases received in the post-marketing period. The potential risk for humans is still unknown, but bosentan must be considered a human teratogen and must not be used during pregnancy. Women must not become pregnant for at least 3 months after stopping treatment with bosentan. Bosentan is contraindicated in pregnancy (see Section 4.3 Contraindications).
Data from a case report describe the presence of bosentan in human milk. There is insufficient information about the effects of bosentan on the breastfed infant. Breastfeeding is not recommended.

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 can induce hypotension with symptoms of dizziness, blurred vision or syncope that could affect the ability to drive or use machines. See Section 4.8 Adverse Effects (Undesirable Effects).

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.
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. In 5 controlled clinical studies in patients with PAH 317 patients were treated with bosentan at daily doses ranging from 125 to 500 mg and 200 patients were treated with placebo. The mean treatment duration was 21 weeks.
The most commonly reported adverse events (occurring in at least 1% of patients on bosentan and more frequently than on placebo) were headache (11.1% vs 9.4%), upper respiratory tract infection (10.6% vs 9.0%), oedema peripheral (9.7% vs 8.3%), anaemia (6.2% vs 3.0%), haemoglobin decreased (3.7% vs 1.6%), alanine aminotransferase increased (3.3% vs 0.9%), flushing (3.2% vs 1.3%) and liver function test abnormal (3.1% vs 1.0%), see Table 2.

Additional adverse events occurring in the subset of patients treated for PAH, in at least 3% of patients on bosentan and more frequently than on placebo are presented in Table 3.

Treatment with bosentan has been associated with dose-dependent elevations in liver aminotransferases and decreases in haemoglobin concentration (see Section 4.4 Special Warnings and Precautions for Use).

Laboratory abnormalities.

Liver test abnormalities.

In the clinical programme, dose-dependent elevations in liver aminotransferases generally occurred within the first 26 weeks of treatment, usually developed gradually, and were mainly asymptomatic. In the post-marketing period rare cases of liver cirrhosis and liver failure have been reported.
The mechanism of this adverse effect is unclear. These elevations in aminotransferases may reverse spontaneously while continuing treatment with the maintenance dose of Tracleer or after dose reduction, but interruption or cessation may be necessary (see Section 4.4 Special Warnings and Precautions for Use).
In the 20 integrated placebo-controlled studies, elevations in liver aminotransferases ≥ 3 times the upper limit of normal (ULN) were observed in 11.2% of the bosentan-treated patients as compared to 2.4% of the placebo-treated patients. Elevations to ≥ 8 x ULN were seen in 3.6% of the bosentan-treated patients and 0.4% of the placebo-treated patients. Elevations in aminotransferases were associated with elevated bilirubin (≥ 2 x ULN) without evidence of biliary obstruction in 0.2% (5 patients) on bosentan and 0.3% (6 patients) on placebo.

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 Special Warnings and Precautions for Use).

Post-marketing experience.

Based on an exposure of about 121,000 patients to bosentan in the post-marketing period, the majority of adverse events have been similar to those reported in clinical trials.
ADR from clinical trial and post-marketing experience are listed below by system organ class with frequency classifications based on clinical trial experience. Adverse reaction frequency categories for events reported from post marketing experience may not reflect the frequency of adverse events occurring during normal clinical practice.
The following additional adverse reactions in Table 4 have been reported in the post marketing use. The reactions are ranked under headings of frequency using the following convention: very common (greater than or equal to 1/10), common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000), very rare (less than 1/10,000), and not known (cannot be estimated from available data).

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 drug therapies. 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.
In the post-marketing experience, very rare cases of DRESS have been reported (see Section 4.3 Contraindications).

4.9 Overdose

Bosentan has been given as a single dose of up to 2,400 mg in normal volunteers, or up to 2,000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the ciclosporin interaction study, in which doses of 500 mg and 1,000 mg twice daily of bosentan were given concomitantly with ciclosporin, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but not serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed.
Massive overdosage 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.
For information on the management of overdose, contact the Poisons Information Centre (Australia call 13 11 26).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The neurohormone endothelin-1 (ET-1) is a potent vasoconstrictor. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease.
Bosentan is a specific and competitive antagonist at endothelin receptor types ETA and ETB. Bosentan has a slightly higher affinity for ETA receptors than for ETB receptors.

Clinical trials.

Adult patients with pulmonary arterial hypertension.

WHO grade functional class III and IV. Two randomised, double-blind, multicentre, placebo-controlled trials were conducted in 32 and 213 patients. The larger study (BREATHE-1, Study 352) compared the two bosentan doses pooled (125 mg twice daily and 250 mg twice daily) of bosentan with placebo. The smaller study (Study 351) compared bosentan 125 mg twice daily with placebo.
Patients had severe (WHO Functional Class III-IV) pulmonary arterial hypertension: primary pulmonary hypertension (72%) or pulmonary hypertension secondary to scleroderma or other connective tissue diseases (21%), or to autoimmune disease (7%). There were no patients with pulmonary hypertension secondary to HIV, or pulmonary embolus.
In both studies, bosentan or placebo was added to patients' current therapy, which could have included a combination of digoxin, anticoagulants, diuretics, and vasodilators (e.g. calcium channel blockers, ACE inhibitors), but not epoprostenol. Bosentan was given at a dose of 62.5 mg twice daily for 4 weeks and then at 125 mg twice daily or 250 mg twice daily for either 12 (BREATHE-1) or 8 (Study 351) additional weeks. The primary study endpoint was 6-minute walking distance. In addition, symptoms and functional status were assessed. Haemodynamic measurements were made at 12 weeks in Study 351. The exploratory analysis of these prospectively defined secondary parameters showed results that are consistent with the results for the primary parameter.
The mean age was about 49 years. About 80% of patients were female, and about 80% were Caucasian. Patients had been diagnosed with pulmonary hypertension for a mean of 2.4 years.

Submaximal exercise capacity.

Results of the 6-minute walk distance at 3 months (Study 351) or 4 months (BREATHE-1) are shown in Table 5.

In both trials, treatment with bosentan resulted in a significant increase in exercise capacity. The improvement in walk distance was apparent after 1 month of treatment (with 62.5 mg twice daily) and fully developed by about 2 months of treatment (see Figure 1). It was maintained for up to 7 months of double-blind treatment. The placebo-subtracted mean increase in walking distance was somewhat greater with 250 mg twice daily (54 m) than with 125 mg twice daily (35 m). However, the higher dose is not recommended because of the potential for increased liver injury (see Section 4.2 Dose and Method of Administration).

Change from baseline in 6-minute walking distance from start of therapy to week 16 in the placebo and combined bosentan (125 mg and 250 mg twice daily) groups. Values are expressed as mean ± standard error of the mean.
There were no apparent differences in treatment effects on walk distance among subgroups analysed by demographic factors, baseline disease severity, or disease aetiology, but the studies had little power to detect such differences.

Haemodynamic changes.

Invasive haemodynamic parameters were assessed in Study 351. Treatment with bosentan led to a significant increase in cardiac index (CI) associated with a clinically relevant reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP) (see Table 6).

Symptoms and functional status.

Symptoms of pulmonary arterial hypertension were assessed by Borg Dyspnoea score, WHO functional class, and rate of "clinical worsening". In Study 351, clinical worsening was defined as death from all causes, lung transplantation or discontinuation of therapy due to clinical deterioration. In the BREATHE-1 study, clinical worsening was assessed as death from all causes, transplantation, hospitalisations or discontinuation of therapy due to worsening of PAH, need for prostacyclin or septostomy. There was a clinically relevant reduction in dyspnoea during walk tests (Borg Dyspnoea score), and clinically relevant improvement in WHO functional class in bosentan-treated patients. There was a clinically relevant reduction in the rate of clinical worsening (see Table 7).

There are limited data available on the minimum effective dose, dose response, and the clinically useful dose-range for bosentan.
There are no studies to demonstrate beneficial effects on survival of treatment with bosentan. However, long-term vital status was recorded for all 235 patients who were treated with bosentan in the two pivotal placebo-controlled trials (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; max: 3.3 years] and patients were observed for a mean of 2.0 ± 0.6 years. The majority of patients were diagnosed as PPH (72%) and were in WHO functional class III (84%). In this total population, Kaplan-Meier estimates of survival were 93% and 84% after 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.
WHO grade functional class II. In a randomised, double-blind, multi-centre, placebo-controlled trial (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 b.i.d. for 4 weeks followed by 125 mg b.i.d. (n=93), or placebo (n=92) for 6 months. Patients were diagnosed with idiopathic/familial PAH (n=112), PAH associated with connective tissue disease (n=34), congenital heart disease (n=32) or other (n=7). Enrolled patients were PAH-treatment naive (n=156) or on a stable dose of sildenafil (n=29). EARLY was designed as a superiority study with co-primary endpoints of percentage change from baseline in PVR, and change from baseline in 6-minute walk distance to 6 months versus placebo. Secondary endpoints included time to clinical worsening, Borg dyspnoea score, WHO functional class, and quality of life. With 85 patients per treatment group, a ≥ 20% reduction in the geometric mean PVR and a ≥ 35-meter increase in the mean 6-minute walk distance in the active vs. placebo group could be detected with > 99% and 91% power, respectively. The two primary endpoints were evaluated hierarchically, with the endpoint on walk distance tested only if the endpoint regarding PVR was significant, with both tested at a two-sided type-I error of 0.05. The main analysis was on the all-randomized analysis set.
Table 8 illustrates the outcomes in the main analysis of the two primary endpoints.

Patients with WHO functional class II PAH, on average, have only moderately impaired 6MWT and may therefore have a limited response range for improvement in this parameter. This could partly explain the lack of statistical significance for the 6MWT endpoint. However, there was a clear association between an absence of deterioration from baseline in 6MWT and stable WHO functional class in the EARLY population. No patient in the bosentan group who at least maintained baseline 6MWT had deterioration in functional class.
Treatment with bosentan was associated with a reduction in the rate of clinical worsening (see Figure 2), 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 (defined as appearance or worsening of right heart failure, ≥ 10% decrease from baseline in two 6-minute walk tests performed ≥ 2 weeks apart, or ≥ 5% decrease from baseline in two 6-minute walk tests performed ≥ 2 weeks apart associated with a ≥ 2-point increase in Borg dyspnoea index). There was one hospitalisation related to PAH worsening in the bosentan group and 3 hospitalisations in the placebo group. There was one death in each treatment group during the 6 month double-blind study period.

The EARLY study was designed and powered to evaluate the efficacy of bosentan in the patient population as a whole and was not powered to show statistical significance for each aetiological sub-group. No criteria to determine aetiological subgroup numbers or specific claims of a beneficial effect by subgroup were pre-specified. Subgroup analyses of treatment effects according to PAH aetiology were performed in the EARLY trial with the objective being to support absence of heterogeneity in treatment response between subgroups. For both co-primary endpoints the confidence intervals for treatment effects were overlapping between the major aetiological subgroups. The inclusion criteria for EARLY permitted recruitment of any patient with PAH determined to be idiopathic/familial or secondary to congenital heart defect, or connective tissue disease and other predefined aetiologies. For patients with congenital heart disease the defect had to be isolated and restrictive with no reverse shunt (atrial septum defect (ASD) < 2 cm, ventricular septum defect (VSD) < 1 cm or patent ductus arteriosus (PDA)). The population eventually enrolled reasonably reflected the relative incidences of PAH aetiologies seen in the real world setting. Consequently there was more data available for analysis in the most prevalent aetiological subgroups of idiopathic/familial PAH compared with the other subgroups.
Long-term data were generated from all 173 patients who were treated with bosentan in the controlled phase and/or were switched from placebo to bosentan in the open-label extension phase of the EARLY study. The mean duration of exposure to bosentan treatment was 3.6 ± 1.8 years (up to 6.1 years), with 73% of patients treated for at least 3 years and 62% for at least 4 years. Patients could receive additional PAH treatment as required in the open-label extension. The majority of patients were diagnosed with idiopathic or heritable pulmonary arterial hypertension (61%). Exercise capacity (6 minute walk distance) was maintained over the duration of bosentan treatment (mean change from baseline to end of treatment -3.7 m).
Overall, 78% of patients remained in WHO functional class I or II. Kaplan-Meier estimates of survival were 90% and 85% at 3 and 4 years after the start of treatment, respectively. At the same timepoints, 88% and 79% of patients remained free from PAH worsening (defined as all-cause death, lung transplantation, atrial septostomy or start of intravenous or subcutaneous prostanoid treatment). The relative contributions of previous placebo treatment in the double-blind phase and of other medications started during the open-label extension period are unknown.

Study performed in children with PAH.

One study has been conducted in children with pulmonary hypertension. Bosentan has been evaluated in an open-label non-controlled study in 19 paediatric patients with pulmonary arterial hypertension (AC-052-356, BREATHE-3: primary pulmonary hypertension 10 patients and pulmonary arterial hypertension related to congenital heart diseases 9 patients). This study was primarily designed as a pharmacokinetic study. Patients were divided into and dosed according to three body-weight groups for 12 weeks. Half of the patients in each group were already being treated with intravenous epoprostenol and the dose of epoprostenol remained constant for the duration of the trial. The age range was 3-15 years. Patients were in WHO functional class II (n=12 patients, 79%) or class III (n=4 patients, 21%) at baseline.
Haemodynamics were measured in 17 patients. The mean increase from baseline in cardiac index was 0.51/min/m², the mean decrease in mean pulmonary arterial pressure was 8 mmHg, and the mean decrease in pulmonary vascular resistance was 389 dyn.sec.cm^-5. These haemodynamic improvements from baseline were similar with or without co-administration of epoprostenol. Changes in exercise test parameters at Week 12 from baseline were highly variable and none were significant. The mean distance travelled in a 6 minute walk test decreased in the sub-group of children with CHD.

PAH associated with Eisenmenger's physiology.

In a prospective, multi-centre, randomised, double-blind, placebo-controlled study (BREATHE-5), patients with pulmonary arterial hypertension WHO Class III and Eisenmenger physiology associated with congenital heart disease received bosentan 62.5 mg bid for 4 weeks, then 125 mg bid for a further 12 weeks (n=37, of whom 31 had a predominantly right to left, bidirectional shunt). Patients with ductus arteriosus were excluded. 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 of exercise capacity (see Section 4.4 Special Warnings and Precautions for Use).
In the OL extension study (AC-052-409) of AC-052-405 (BREATHE-5) in patients with PAH WHO functional class III and Eisenmenger physiology associated with congenital heart disease, 26 patients continued to receive bosentan during a 24-week treatment period (mean 24.4 ± 2.0 weeks). The effects of bosentan demonstrated in the double-blind treatment period were generally maintained during longer term treatment (a total treatment period of 40 weeks).

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 trial of bosentan versus placebo in 33 patients with severe pulmonary arterial hypertension who were receiving concomitant epoprostenol therapy. AC-052-356 was an open-label, non-controlled trial; 10 of the 19 paediatric patients were on concomitant bosentan and epoprostenol therapy during the 12-week trial. 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.

5.2 Pharmacokinetic Properties

General.

After oral administration, maximum plasma concentrations of bosentan found in a study of the 125 mg tablets taken as a single dose, were attained within 3.7 ± 1.7 hours and the apparent elimination half-life (t_1/2) was 5.6 ± 1.6 hours in 16 fasted subjects. The pharmacokinetics of oral bosentan have not been studied in patients with pulmonary arterial hypertension. The clearance of intravenous bosentan was significantly lower in patients with primary pulmonary hypertension (3.8 L/h) than in healthy volunteers (9 L/h). Exposure is also expected to be greater in patients with pulmonary arterial hypertension since increased (30-40%) bosentan exposure has been observed in patients with severe chronic heart failure.

Absorption and distribution.

In healthy volunteers at a dose of 600 mg, the absolute bioavailability of bosentan from an oral suspension was 41%. At a dose of 125 mg, administration of bosentan with food did not have a significant effect on the extent of absorption but did increase the rate, leading to a 20% increase in peak plasma concentrations of bosentan. This is not expected to be clinically significant. The volume of distribution and clearance of bosentan are non-linear and decrease as the dose increases. The mean volume of distribution of 17.8 ± 3.6 L/h and the mean clearance of 8.8 ± 1.9 L were determined after a mean IV dose of 250 mg was administered to 18 healthy male volunteers. Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes.

Metabolism and excretion.

Bosentan is metabolised in the liver by the cytochrome P450 enzymes, CYP 2C9 and CYP 3A4, and eliminated by biliary excretion. 94% of a radioactive oral dose was recovered in faeces (30% was unchanged). Bosentan has three metabolites, one of which is pharmacologically active and may contribute 20% of the effect of bosentan. Bosentan is an inducer of CYP2C9 and CYP3A4 and possibly also of CYP 2C19. Total clearance after a single intravenous dose is about 8 L/hr. Upon multiple dosing, plasma concentrations decrease gradually to 50-65% of those seen after single dose administration, probably the effect of auto-induction of the metabolising liver enzymes. Steady state is reached within 3-5 days. Less than 3% of an administered oral dose is recovered in urine.

Special populations.

It is not known whether bosentan pharmacokinetics are influenced by gender, body weight, race, or age.

Hepatic function impairment.

The steady-state pharmacokinetics of bosentan and metabolites were studied in 8 patients with mild hepatic impairment (Child-Pugh Class A) without pulmonary hypertension. Compared to healthy controls, bosentan C_max, AUC and half-life were not significantly altered; AUC of the active metabolite Ro 48-5033 was increased by 33%; trough concentrations of Ro 48-5033 and Ro 64-1056 were increased by 75% and 20%, respectively. Based on these findings, no dosage adjustment is required in patients with mild hepatic impairment (see Section 4.2 Dose and Method of Administration).
The pharmacokinetics of bosentan have not been studied in patients with moderate to severe hepatic impairment. Bosentan is contraindicated in patients with moderate to severe hepatic abnormalities and/or baseline elevated aminotransferases > 3 x Upper Limit of Normal (ULN) (see Section 4.3 Contraindications).

Renal impairment.

In patients with severe renal impairment (creatinine clearance 15-30 mL/min), plasma concentrations of bosentan were essentially unchanged and plasma concentrations of the three metabolites were increased about 2-fold compared to people with normal renal function. These differences do not appear to be clinically important (see Section 4.2 Dose and Method of Administration).

Children.

The pharmacokinetics of bosentan at steady-state were studied in 19 children aged 3 to 15 years with PPH or PAH secondary to congenital systemic to pulmonary communications (AC-052-356 BREATHE-3). The number of patients studied in each dose group was insufficient to establish the optimal dosing regimen. In children weighing over 20 kg, administration of the recommended dose regimen (see Section 4.2 Dose and Method of Administration) led to bosentan plasma concentrations which were higher than those in healthy adults taking the recommended adult dose, but similar to those expected in adults with pulmonary hypertension. In children weighing 10-20 kg, bosentan plasma concentrations during administration of the recommended dose were lower than in healthy adults, and thus lower than those expected in adults with pulmonary hypertension. However, the recommended dose was associated with haemodynamic improvement and should not be exceeded on safety grounds. The steady-state half life of bosentan in children averaged 5 to 6 hours.

5.3 Preclinical Safety Data

Genotoxicity.

See Section 4.6 Fertility, Pregnancy and Lactation. There was no evidence for mutagenic or clastogenic activity of bosentan in a standard battery of in vitro tests (the microbial mutagenesis assay, the unscheduled DNA synthesis assay, the V-79 mammalian cell mutagenesis assay, and human lymphocyte assay) and an in vivo mouse miconucleus assay.

Carcinogenicity.

Two years of dietary administration of bosentan to mice produced an increased incidence of hepatocellular adenomas and combined adenomas and carcinomas in males at doses as low as 450 mg/kg/day (about 8 times the maximum recommended human dose [MRHD] of 12 mg twice daily on a mg/m² basis). In the same study, doses greater than 2,000 mg/kg/day (about 32 times the [MRHD]) were associated with an increased incidence of colon adenomas in both males and females. In rats, dietary administration of bosentan for two years was associated with an increased incidence of brain astrocytomas in males at doses as low as 500 mg/kg/day (about 16 times the [MRHD]; no effect dose of 125 mg/kg/day, about 4 times the MRHD) and females at doses of 3,000 mg/kg/day (no-effect dose of 2,000 mg/kg/day, about 128 times the MRHD). An increased incidence of thyroid follicular adenomas was also observed in male rats at doses as low as 2,000 mg/kg/day (about 32 times the MRHD). However, the relevance of these findings to humans is not known.

6 Pharmaceutical Particulars

6.1 List of Excipients

Maize starch, pregelatinised maize starch, sodium starch glycollate type A, povidone, glycerol dibehenate, magnesium stearate, and Opadry complete film coating system 21K520019 Yellow.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Store in original container.

6.5 Nature and Contents of Container

Supplied in PVC/PE/PVdC/Al blister packs.
Not all pack sizes and presentations are marketed in Australia and HDPE bottle containing 56 and 60 tablets.

6.6 Special Precautions for Disposal

In Australia any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

CAS number.

147536-97-8 (anhydrous substance).
Chemical name: benzenesulphonamide, 4- (1,1-dimethylethyl)-N- [6-(2hydroxyethoxy)- 5-(2-methoxyphenoxy) [2,2'- bipyrimidin] -4-yl]-, monohydrate.
Molecular formula: C₂₇H₂₉N₅O₆S (anhydrous); C₂₇H₂₉N₅O₆S.H₂O (monohydrate).
Molecular weight: 551.62 (anhydrous); 569.64 (monohydrate).
Bosentan monohydrate, a white to off-white powder, is practically insoluble at low pH (0.1 mg/100 mL at pH 1.1 and 4.0; 0.2 mg/100 mL at pH 5.0).
Solubility increases at higher pH values (43 mg/100 mL at pH 7.5). In the solid state, bosentan monohydrate is very stable, is not hygroscopic and shows no light sensitivity.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (S4) - Prescription Only Medicine.

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Bosentan RBX 125 mg Tablets

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