- Drugs List
- Therapeutic Indications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
Oral formulations of bosentan.
Pulmonary arterial hypertension - grade 3 functional status
Reduce numbers of new digital ulcers in systemic sclerosis
Treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with WHO functional class III functional status.
Reduction in number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease.
Pulmonary arterial hypertension
Initially 62.5mg twice a day, increased after four weeks to 125mg twice a day (maximum 250mg twice a day).
Regularly review treatment to ensure continued benefits outweigh any risks (in particular hepatotoxic effects).
If clinical deterioration occurs despite at least eight weeks of treatment, consider alternative therapy.
Patients who show an initial response but start to deteriorate after several months of treatment may benefit from a dose increase to 250mg twice a day. The potential risks, in particular hepatic toxicity which is dose dependent, should be considered.
Systemic sclerosis with ongoing digital ulcer disease
Initially 62.5mg twice a day, increased after four weeks to 125mg twice a day.
Re-evaluate treatment on a regular basis taking into consideration the risks of hepatic toxicity.
Pulmonary arterial hypertension:
Children aged 1 to 18 years:
2mg/kg twice a day.
The manufacturers advise that in children, increases above this dose do not result in increased plasma concentrations so are unlikely to provide any additional clinical benefit.
The following alternative dosing schedule may be suitable:
Children aged 12 to 18 years with bodyweight above 40kg:
Initially 62.5mg twice a day, increased after four weeks to 125mg twice a day (maximum 250mg twice a day).
Children aged 2 to 18 years with bodyweight 20kg to 40kg:
Initially 31.25mg twice a day, increased after four weeks to 62.5mg twice a day.
Children aged 2 to 18 years with bodyweight 10kg to 20kg:
Initially 31.25mg once a day, increased after four weeks to 31.25mg twice a day.
Additional Dosage Information
Following any interruptions to treatment, the dose should be re-titrated.
Abrupt withdrawal may lead to a rebound effect. Consider discontinuing treatment gradually for example halving the dose every three to seven days.
Children under 1 year
Serum transaminases above 3 times upper limit of normal at baseline
Systolic blood pressure < 85mmHg at initiation
Moderate hepatic impairment
Precautions and Warnings
Children aged 1 to 18 years
Females of childbearing potential
HIV patients receiving highly active anti-retroviral therapy
Left ventricular dysfunction
Advise ability to drive/operate machinery may be affected by side effects
Treatment should only be initiated if systolic blood pressure > 85mmHg
Treatment to be initiated and supervised by a specialist
Never rechallenge treatment after hepatic injury if AST/ALT > 8 x ULN
Exclude pregnancy prior to initiation of treatment
Monitor haemoglobin at baseline, monthly for first 4 months, then quarterly
Perform liver function tests before commencing therapy
Ensure negative monthly pregnancy tests throughout treatment
Monitor for signs of fluid retention
Monitor liver function tests 2 weeks after any dose increase
Monitor liver function tests monthly during treatment
Patients with fluid retention should be treated with diuretics
Advise patients to report signs of hepatic damage (malaise, jaundice etc.)
Consider veno-occlusive disease if pulmonary oedema occurs
Discontinue if jaundice or other clinical symptoms of hepatic injury
To discontinue, reduce dose gradually
Discontinue if AST or ALT level exceeds 8 x ULN
Reduce dose or discontinue if AST/ALT is 3-5 times upper limit of normal
Suspend treatment and/or reduce dose if AST/ALT is 5-8 times ULN
Not licensed for all indications in all age groups
Male: May cause infertility
Female: Barrier or non-hormonal contraception advised during treatment
Female: Effect of hormonal contraceptive may be reduced
Efficacy in patients with severe pulmonary arterial hypertension has not been established. If clinical deterioration occurs, transfer to a therapy recommended in the severe stage of the disease.
Use caution in patients with HIV infection receiving antiretroviral therapy. Experience is limited but combination of bosentan and antiretroviral therapy may increase the risk of hepatic toxicity and haematological adverse effects. When initiating bosentan in patients using ritonavir-boosted protease inhibitors, monitor patient tolerability, paying special attention during the initial phase to the risk of hypotension and changes in liver function tests. Combination may also affect the efficacy of the antiretroviral therapy, as such the control of HIV infection should also be monitored.
Decreases in haemoglobin have been reported. Effects are dose dependent and should stabilise within 4 to 12 weeks of treatment. Investigate any clinically relevant decreases in haemoglobin to determine the cause and appropriate treatment. In some cases, red blood cell transfusions have been required.
Elevations in serum transaminases have been reported. Effects are dose dependent, usually occurring within the first 26 weeks of treatment but may present at any time. Following changes in transaminases and/or symptoms of hepatic injury treatment may require interruption, dose reduction and/or discontinuation as follows:
ALT/AST greater than 3 times the upper limit of normal (ULN) and less than or equal to 5 times the upper limit of normal (ULN):
Repeat liver function test to confirm the result. If confirmed, review treatment on an individual basis. Treatment may be continued, possibly at a reduced dose or stopped. Monitor serum transaminases at least every 2 weeks until they return to pre-treatment levels. Following recovery of serum transaminases, treatment may be reintroduced at a reduced dose.
ALT/AST greater than 5 x ULN and less than or equal to 8 x ULN:
Repeat liver function test to confirm the result. If confirmed, suspend treatment and monitor serum transaminases at least every 2 weeks until they return to pre-treatment levels.
Following recovery of serum transaminases, treatment may be reintroduced at a reduced dose.
ALT/AST greater than 8 x ULN or clinical signs/symptoms of hepatic injury:
Permanently discontinue treatment.
Decision to continue or re-introduce treatment should balance potential benefits with potential risks on an individual patient basis. The advice of a hepatologist is recommended. When re-introducing treatment, check serum transaminases within 3 days of re-introduction, after a further 2 weeks and in line with standard monitoring recommendations thereafter.
Pregnancy and Lactation
Bosentan is contraindicated in pregnancy.
At the time of writing there is limited published data available regarding the use of bosentan during pregnancy. Animal data has shown reproductive toxicity however the doses administered are not comparable with human use. Reports during human pregnancy are extremely limited and as such the potential human risk is unclear. Passage across the placenta is unknown. The molecular weight and long elimination half life suggest bosentan and its active metabolite will cross the placenta however as it is highly plasma protein bound, exposure is likely to be limited.
The manufacturers state bosentan is contraindicated during pregnancy. In addition to advice on contraception, the manufacturer recommends monthly pregnancy tests to allow early detection of unplanned pregnancy. As pulmonary hypertension itself carries a high risk of maternal death, following confirmation of a pregnancy, ongoing treatment should be managed by an appropriate specialist.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Bosentan is contraindicated in breastfeeding.
At the time of writing, there is little published information regarding the use of bosentan during breastfeeding. It is unknown whether bosentan is present in human milk and no animal studies have been reported. The molecular weight and long elimination half life suggest passage of bosentan and its active metabolite is likely however as it is highly plasma protein bound, the amount of drug in the milk may be limited. Should ingestion occur, effects on the exposed infant are unknown. The manufacturers do not recommend breastfeeding during treatment with bosentan. An alternative drug may be preferred especially while nursing a newborn or preterm infant.
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Abnormal liver function tests
Decrease in haemoglobin
Increases in hepatic enzymes (reversible)
Oxygen saturation decreased
Respiratory tract infection
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Last Full Review Date: January 2018
Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 3rd edition (2015) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.
Medications and Mothers' Milk, Sixteenth Edition (2014) Hale, T and Rowe, H, Hale Publishing, Plano, Texas.
Summary of Product Characteristics: Tracleer (bosentan) 62.5 mg and 125 mg film-coated tablets. Actelion Pharmaceuticals Ltd. Revised October 2017.
Summary of Product Characteristics: Stayveer 62.5 mg and 125 mg film-coated tablets. Actelion Pharmaceuticals Ltd. Revised September 2017.
NICE - Evidence Services.
Available at: www.nice.org.uk
Last accessed: 17 January 2018.
US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Last accessed: 24 January 2018.
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Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content
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