Bosentan for Pulmonary arterial hypertension

Bosentan is an endothelin receptor antagonist. It binds to the endothelin receptors and inhibits them resulting in vasodilation. It is used to treat the following conditions [Ref]:

  • It is indicated in the treatment of pulmonary arterial hypertension WHO class 1 to improve exercise tolerance and prevent further deterioration.

  • Idiopathic or congenital pulmonary arterial hypertension in children who are 3 years of age or older to improve vascular resistance.

Off-label uses of Bosentan include:

  • Prevention of digital ulcers in patients with scleroderma.
  • Raynaud's phenomenon.

Note: In patients with Pulmonary arterial hypertension and WHO functional class IV symptoms, it may be used as second-line therapy.

WHO Functional Classification for Pulmonary Hypertension

WHO Class 1 No limitation to the activity
WHO Class 2 Slight limitations to the activity. Ordinary activity may cause some symptoms
WHO Class 3 Marked limitation of activity. Less than ordinary activity causes symptoms
WHO Class 4 Severe limitation of physical activity. Any activity causes symptoms or patients with right heart failure.

Bosentan Dose in Adults  

Bosentan dose in the treatment of Pulmonary artery hypertension:

  • Weight less than 40 kgs:
    • 62.5 mg orally twice a day.
  • Weight more than 40 kgs:
    • 62.5 mg orally twice a day for 4 weeks initially.
    • The dose may be raised to a maintenance dose of 125 mg twice a day.
    • Doses greater than 125 mg twice a day may increase the risks of hepatotoxicity without any additional benefits.
    • Treatment may be tapered off over 3 - 7 days and not discontinued abruptly.

Dose modification when co-administered with ritonavir:

  • Those who have taken ritonavir for at least ten days: 
    • Bosentan 62.5 mg should be used as a starting dose once a day or every other day, depending on tolerance. 
  • Those receiving bosentan therapy: 
    • Bosentan should be stopped 36 hours before starting ritonavir. 
    • After starting ritonavir medication for at least 10 days, bosentan 62.5 mg should be resumed once a day or every other day, depending on tolerance.

Off-label use in the therapy of Prevention of digital ulcers in systemic sclerosis:

  • 62.5 mg orally twice a day for 4 weeks followed by an increase to a maintenance dose of 125 mg twice a day for up to 12 weeks.


Off-label use in the treatment of Raynaud phenomenon in systemic sclerosis:

  • 62.5 mg orally twice a day for 4 weeks followed by an increase to a maintenance dose of 125 mg twice a day.

Bosentan Dose in Children

Dose in the treatment of Pulmonary arterial hypertension:

Infants and Children younger than 12 years:

  • 1 mg/kg/dose orally twice a day initially
  • The dose should be raised to a maximum of 125 mg/dose after starting with a target dose of 2 mg/kg/dose administered twice day.

Children older than 12 years and Adolescents:

weight > 40 kgs:

  • 62.5 mg twice daily oral
  • Aim for a goal dosage of 125 mg administered twice a day.

Weight 20-40 kgs:

  • A twice-daily oral dose of 31.25 mg
  • The dose should be raised to a target of 62.5 mg twice daily.

Alternate dosing as per manufacturer's labeling:

  • Children older than 3 years:
    • 16 - 24 kg:
      • 48 mg orally twice a day.
    • 4 - 8 kgs:
      • 16 mg orally twice a day.
    • 24 - 40 kg:
      • 64 mg orally twice a day.
    • 8 - 16 kgs:
      • 32 mg orally twice a day.
  • Adolescents:
    • more than 40 kgs:
      • 4 weeks of taking 62.5 mg twice a day orally
      • Updating the dosage to a goal level of 125 mg twice daily is possible.
    • less than 40 kgs:
      • 5 mg orally twice a day.

Pregnancy Risk Factor: X

[US Boxed Warning]

  • A pregnancy test is required before starting therapy with bosentan for female patients of reproductive potential.
  • Before starting therapy, pregnant women must be notified.
  • Therapy and for up to one month following the last dose of therapy, at least two effective contraceptives must be used (except for patients who have received intrauterine devices or tubal ligation).
  • Monthly pregnancy tests can be requested. Missed cycles must be reported.
  • It can also decrease sperm count in men.

Bosentan Use during Breastfeeding:

  • It is not advised to breastfeed during this therapy.

Bosentan Dose in Renal Disease:

  • Dose adjustment in patients with renal impairment is not required and the drug is not removed from the body by dialysis.

Bosentan Dose in Liver Disease:

Liver dysfunction at treatment initiation:

  • Mild impairment (Child-Pugh class A):
    • Adjustment in dosage is not necessary.
  • Moderate to severe impairment (Child-Pugh class B and C) and/or baseline transaminase more than 3 times the upper limits of normal:
    • Avoid its use.

Hepatotoxicity during treatment:

  • Elevation Liver enzymes accompanied by clinical symptoms of hepatotoxicity like fatigue, nausea & vomiting, abdominal pain, fever, or jaundice or serum bilirubin more than 2 times the upper limits of normal:

    • Discontinue treatment.
  • AST/ALT more than 3 times but less than 5 times the upper limits of normal in patients weighing more than 40 kgs:

    • Reduce the dose to 62.5 mg twice daily or withhold treatment and monitor at least every two weeks.
    • May reintroduce treatment if the levels return to baseline.
    • After reintroducing treatment, recheck transaminases within three days and at least every two weeks thereafter.
  • AST/ALT more than 5 times but less than 8 times the upper limits of normal in patients weighing more than 40 kg:

    • Stop treatment.
    • Monitor Liver functions every 2 weeks.
    • May reintroduce treatment if the levels return to baseline.
    • After reintroducing treatment, recheck transaminases within three days and at least every two weeks thereafter.
  • AST/ALT more than 8 times the upper limits of normal:

    • Stop therapy and do not reintroduce.

Common Side Effects of Bosentan Include:

  • Central Nervous System:
    • Headache
  • Cardiovascular:
    • Edema
  • Respiratory:
    • Respiratory Tract Infection
  • Hepatic:
    • Increased Serum ALT
    • Increased Serum AST

Less Common Side Effects of Bosentan Include:

  • Endocrine & Metabolic:
    • Fluid Retention
  • Cardiovascular:
    • Flushing
    • Chest Pain
    • Syncope
    • Hypotension
    • Palpitations
  • Respiratory:
    • Sinusitis
  • Hematologic & Oncologic:
    • Anemia
  • Neuromuscular & Skeletal:
    • Arthralgia

Contraindications to Bosentan 

  • Allergy to bosentan and any component of this formulation
  • Use of glyburide or cyclosporine simultaneously (Glibenclamide).
  • Pregnancy.
  • Moderate to severe liver impairment

Warnings and Precautions

  • Fluid retention and peripheral swelling:

    • Patients may develop peripheral edema and fluid retention may occur requiring diuretics therapy.
    • Patients with heart failure should use it with caution.
    • The AHA in its scientific statement has labeled it as an agent that may exacerbate myocardial dysfunction.
  • Hematologic effects

    • A reduction in hemoglobin or hematocrit can occur during the first weeks of therapy.
    • Before starting therapy, it is important to monitor hemoglobin and hematocrit after 1 and 3 months, and every 3 months thereafter.
  • Hepatotoxicity: [US Boxed Warning]

    • Bosentan is liver toxic and can cause elevations in transaminase and bilirubin.
    • It is important to monitor the liver functions and adjust the dosage.
    • Patients who are on long-term therapy for more than one year may develop liver fibrosis or cirrhosis.
    • Patients with hepatic injury symptoms or bilirubin levels that exceed the normal upper limit should be stopped from receiving treatment.
    • Patients with a baseline liver disease that is moderate or severe in severity and patients with transaminases greater than three times the normal upper limit should not be initiated therapy.
  • Hypersensitivity

    • DRESS (Drug Reaction With Eosinophilia Systemic Symptoms), and rash are examples of allergy responses.
  • Spermatogenesis:

    • It can adversely impact sperm count.
  • Pulmonary venoocclusive disease

    • If patients develop signs of pulmonary embolism after receiving bosentan therapy, it is important to consider the possibility that they have pulmonary vein-occlusive disease. Treatment may be stopped.

Bosentan: Drug Interaction

Risk Factor C (Monitor therapy)

Benzhydrocodone

CYP3A4 Inducers (Moderate) may lower the level of benzhydrocodone in the blood. More specifically, hydrocodone serum concentrations could be decreased.

CloZAPine

CloZAPine's serum levels may be lowered by moderate CYP3A4 inducers.

Codeine

The active metabolite(s) of codeine's serum concentrations may be lowered by CYP3A4 Inducers (Moderate).

CYP2C9 Inhibitors (Moderate)

may increase the amount of bosentan in the serum. Management: Because doing so would probably produce a considerable increase in the drug's blood concentrations, it is not recommended to use bosentan along with both a CYP2C9 inhibitor and a CYP3A inhibitor at the same time. Monograph for further details.

CYP3A4 Inhibitors (Moderate)

may increase the amount of bosentan in the serum. Management: Because doing so would probably produce a considerable increase in the drug's blood concentrations, it is not recommended to use bosentan along with both a CYP2C9 inhibitor and a CYP3A inhibitor at the same time. Monograph for further details.

CYP3A4 Inhibitors (Strong)

may increase the amount of bosentan in the serum. Management: Because doing so would probably produce a considerable increase in the drug's blood concentrations, it is not recommended to use bosentan along with both a CYP2C9 inhibitor and a CYP3A inhibitor at the same time. Monograph for further details.

CYP3A4 Substrates (High risk with Inducers)

The amount of CYP3A4 substrates in the blood may be reduced by bosentan (High risk with Inducers).

Doravirine

The serum concentration of doravirine may drop in response to CYP3A4 Inducers (Moderate).

Eltrombopag

May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates.

Estriol (Systemic)

CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Systemic).

Estriol (Topical)

CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Topical).

FentaNYL

CYP3A4 Inducers (Moderate) may decrease the serum concentration of FentaNYL.

Gemfibrozil

may increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Agents indicated as exceptions should be examined in separate drug interaction monographs.

Glecaprevir and Pibrentasvir

Glecaprevir and Pibrentasvir's serum concentrations may be affected by CYP3A4 Inducers (Moderate).

HYDROcodone

The serum levels of HYDROcodone may drop in response to CYP3A4 Inducers (Moderate).

Ibrutinib

Ibrutinib's serum levels may be decreased by CYP3A4 Inducers (Moderate).

Ifosfamide

Ifosfamide's active metabolite may be seen at lower blood concentrations while using CYP3A4 Inducers (Moderate) (s). Ifosfamide's active metabolite may be present in higher blood quantities while using CYP3A4 Inducers (Moderate) (s).

Macimorelin

Bosentan may lessen Macimorelin's ability to serve as a diagnostic aid.

Mirodenafil

The serum concentration of Mirodenafil may be decreased by CYP3A4 Inducers (Moderate).

Naldemedine

The serum concentration of naldemedine may drop in response to CYP3A4 Inducers (Moderate).

NiMODipine

NiMODipine's serum levels may be decreased by CYP3A4 Inducers (Moderate).

Phosphodiesterase 5 Inhibitors

The blood concentration of phosphodiesterase 5 inhibitors may be reduced by bosentan. Taking phosphodiesterase 5 inhibitors may cause the serum levels of Bosentan to increase. 

RifAMPin

may lower the level of bosentan in the serum. This effect is most likely to occur after the initial few weeks of concomitant rifampin use. Bosentan's serum levels may rise when RifAMPin is present. Most likely, this impact will be felt within the first several weeks of concurrent therapy (and maybe the greatest immediately following initiation of the combination). The first four weeks of concurrent therapy should include weekly monitoring of liver function tests, and thereafter, as necessary, weekly monitoring should resume.

Rolapitant

CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rolapitant.

Simvastatin

Bosentan may decrease the serum concentration of Simvastatin.

Teriflunomide

May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates.

Vitamin K Antagonists (eg, warfarin)

Bosentan may hasten the metabolism of vitamin K antagonists.

Zolpidem

CYP3A4 Inducers (Moderate) may cause zolpidem levels in the blood to drop.

Risk Factor D (Consider therapy modification)

Atazanavir

Atazanavir's serum levels might decrease if you take bosentan. The serum levels of bosentan may rise when atazanavir is used. Bosentan and atazanavir (without ritonavir) should not be used together. When taken in conjunction with atazanavir/ritonavir, modifications to the dosage of bosentan are necessary.

Brigatinib

Response to CYP3A4 Inducers may result in a reduction in the serum concentration of Brigatinib (Moderate). Management: Whenever possible, refrain from using brigatinib with weak CYP3A4 inducers. Increase the daily dose of brigatinib by 30 mg increments after seven days of therapy, up to a maximum of twice the dose.

Clarithromycin

The active metabolite(s) of clarithromycin's serum concentrations may rise when taken with bosentan. In particular, 14-hydroxyclarithromycin concentrations may rise in response to bosentan. Bosentan may decrease the level of clarithromycin in the serum. The serum levels of bosentan may rise when clarithromycin is used. Management: If at all feasible, consider using a different antibiotic. Bosentan toxicity might rise and clarithromycin's clinical activity could change.

Cobicistat

might raise the serum level of bosentan. For further information, see the entire medication interaction monograph.

Daclatasvir

The blood level of Daclatasvir may decrease when CYP3A4 Inducers (Moderate) are present. Treatment: If daclatasvir is used with a moderate CYP3A4 inducer, increase the dosage to 90 mg once day.

Darunavir

Bosentan may lower the level of Darunavir in the serum. Bosentan's serum levels may rise in response to darunavir. Bosentan 62.5 mg should be used everyday or every other day in people receiving darunavir that has been cobicistat- or ritonavir-boosted for at least 10 days. Before beginning boosted darunavir, stop taking bosentan for at least 36 hours. Then, please wait at least 10 days before starting it again.

Estrogen Derivatives (Contraceptive)

Bosentan may reduce oestrogen derivative levels in the blood (Contraceptive). Management: Use an alternative (i.e., non-hormonal) means of contraception rather than only relying on hormonal contraceptives for all women of reproductive potential who are taking bosentan. 

Fosamprenavir

When utilising bosentan, the serum concentration of fosamprenavir may decrease. The use of fosamprenavir may cause an increase in the blood levels of bosentan. Treatment: Administer bosentan 62.5 mg once day or every other day to adult patients who have been taking fosamprenavir for at least 10 days. Bosentan should be temporarily stopped before starting fosamprenavir (for at least 36 hours). After that, give it a 10-day break before beginning again.

GuanFACINE

CYP3A4 Inducers (Moderate) may decrease the serum concentration of GuanFACINE. Management: Increase the guanfacine dose by up to double when initiating concomitant therapy with moderate CYP3A4 inducers. Increase guanfacine dose gradually over 1-2 weeks if moderate CYP3A4 inducer therapy is just beginning.

Indinavir

may increase the amount of bosentan in the serum. If you use bosentan, your serum concentration of indinavir can decrease. In patients on indinavir, bosentan should be started at 62.5 mg once day or every other day, and then modified based on tolerability (see ritonavir fordosing if that agent is used). Watch out for any possible indinavir side effects as well.

Lopinavir

may increase the amount of bosentan in the serum. If you use bosentan, your serum levels of lopinavir can decrease. Treatment: Administer bosentan 62.5 mg once or every other day to adult patients who have been taking lopinavir/ritonavir for at least 10 days. Bosentan must be temporarily stopped (for at least 36 hours) and at least 10 days must pass before commencing lopinavir or ritonavir.

Lorlatinib

Lorlatinib's hepatotoxic effects might be made worse by CYP3A4 inducers (Moderate). By CYP3A4 Inducers, lorlatinib's serum levels could be reduced (Moderate). Combining lorlatinib with low-dose CYP3A4 inducers is not recommended. If such a combination is required, the levels of AST, ALT, and bilirubin should be assessed within 48 hours after starting the combination and at least three times throughout the first week of treatment.

Lurasidone

Lurasidone's serum levels may be reduced by moderate CYP3A4 inducers. Management: If provided with moderate CYP3A4 inducers for seven or more days, watch for any diminished effects of the lurasidone and consider raising the dosage.

Nelfinavir

may increase the amount of bosentan in the serum. If you use bosentan, your serum levels of nelfinavir can decrease. In patients on nelfinavir, bosentan should be begun at a dose of 62.5 mg once day or every other day, and then modified based on tolerability. Watch out for any potential changes in the clinical response to nelfinavir as well.

Palbociclib

Palbociclib's serum levels may be decreased by moderate CYP3A4 inducers. Management: The Canadian label advises against using mild CYP3A4 inducers, however the US label makes no specific advice on their usage.

Perampanel

The serum concentration of Perampanel may be decreased by CYP3A4 Inducers (Moderate). When using perampanel alongside strong and moderate CYP3A4 inducers, the beginning dosage should be increased to 4 mg/day.

Progestins (Contraceptive)

Bosentan may reduce the serum concentration of progestins (Contraceptive). Management: Use an alternative (i.e., non-hormonal) means of contraception rather than only relying on hormonal contraceptives for all women of reproductive potential who are taking bosentan.

Ritonavir

May increase the serum concentration of Bosentan. Management: Use bosentan 62.5 mg daily or every other day in adult patients who have been on ritonavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting ritonavir; wait until at least 10 days on ritonavir before restarting.

Saquinavir

Bosentan may decrease the serum concentration of Saquinavir. Saquinavir may increase the serum concentration of Bosentan. Management: Use bosentan 62.5 mg/day or every other day in adult patients taking saquinavir/ritonavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting saquinavir/ritonavir; wait at least 10 days before restarting bosentan.

Tipranavir

Tipranavir levels in the serum might be decreased by bosentan. When tipranavir is administered, the serum levels of bosentan may increase. Treatment: Administer bosentan 62.5 mg once day or every other day to adult patients who have been taking tipranavir/ritonavir for at least 10 days. Temporarily stop taking bosentan before starting tipranavir/ritonavir (for at least 36 hours). Then, before starting it again, kindly wait at least 10 days.

Tolvaptan

may raise the level of OATP1B1/1B3 (SLCO1B1/1B3) Substrates in the serum.

Risk Factor X (Avoid combination)

Antihepaciviral Combination Products

CYP3A4 Inducers (Moderate) may decrease the serum concentration of Antihepaciviral Combination Products.

Asunaprevir

CYP3A4 Inducers (Moderate) may decrease the serum concentration of Asunaprevir.

Axitinib

CYP3A4 Inducers (Moderate) may decrease the serum concentration of Axitinib.

Bedaquiline

CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bedaquiline.

Bosutinib

CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bosutinib.

Cobimetinib

CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cobimetinib.

CycloSPORINE (Systemic)

May increase the serum concentration of Bosentan. Bosentan may decrease the serum concentration of CycloSPORINE (Systemic).

Dasabuvir

CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dasabuvir.

Deflazacort

The serum concentrations of the active metabolite(s) of Deflazacort may be lowered by CYP3A4 Inducers (Moderate).

Elbasvir

Elbasvir's serum levels may be reduced by moderate CYP3A4-inducing drugs.

Encorafenib

Encorafenib's serum levels may be decreased by CYP3A4 Inducers (Moderate).

Flibanserin

Flibanserin's serum levels may drop if CYP3A4 Inducers (Moderate) are used.

GlyBURIDE

may intensify Bosentan's hepatotoxic effects. Bosentan's serum concentration might drop because to GlyBURIDE. Bosentan may lower the level of GlyBURIDE in the blood.

Grazoprevir

The serum concentration of Grazoprevir may fall in response to CYP3A4 Inducers (Moderate). 

Neratinib

Neratinib's serum levels may be reduced by CYP3A4 Inducers (Moderate). 

Nisoldipine

The serum concentration of nisoldipine may fall in response to CYP3A4 Inducers (Moderate). 

Olaparib

Olaparib's serum levels may be decreased by CYP3A4 Inducers (Moderate). 

Ranolazine

Ranolazine's serum levels may be reduced by moderate CYP3A4 inducers. 

Simeprevir

Simeprevir's serum levels may be decreased by CYP3A4 Inducers (Moderate).

Sonidegib

Sonidegib's serum levels may be decreased by CYP3A4 Inducers (Moderate). 

Ulipristal

Ulipristal's serum concentration might drop if you take bosentan. 

Velpatasvir

The serum concentration of Velpatasvir may fall in response to CYP3A4 Inducers (Moderate). 

Venetoclax

Venetoclax serum levels may be decreased by CYP3A4 Inducers (Moderate).

How to take Bosentan?

  • It may be taken with or without regard to meals.
  • Prior to ingestion, the dispersible tablets may be dissolved in a little amount of water.

Mechanism of action of Bosentan:

  • It acts as an antagonist to endothelin-receptors on the endothelium, vascular smooth muscles and other tissues.
  • Vasodilation is caused by the inhibition of endothelin receptors.

98% of the drug's ingredients are protein-bound.

 It is metabolized via CYP2C9 or 3A4. It has a bioavailability of about 50% and a half-life elimination of about 5 hours. The time to reach plasma peak concentrations takes between 3 and 5 hours and is primarily excreted via feces.

International Brands of Bosentan:

  • ACT Bosentan
  • APO-Bosentan
  • BIO-Bosentan
  • MYLAN-Bosentan
  • PMS-Bosentan
  • SANDOZ Bosentan
  • TEVA-Bosentan
  • Tracleer
  • Bosencard
  • Bosentadin
  • Bosentadine
  • Bosentas
  • Boxtel
  • Lupibose
  • Pahsentan
  • Pulmiprove
  • Pulmofirst
  • Pulmonat
  • Pulmoten
  • Stayveer
  • Tracleer
  • Trasentan
  • Usenta
  • Zuxtana

Bosentan Brands in Pakistan:

Bosentan [Tabs 125 mg]

Bosmon Hilton Pharma (Pvt) Limited

Bosentan [Tabs 62.5 mg]

Bosmon Hilton Pharma (Pvt) Limited